Immunosuppression with drugs in renal transplant.

Let us see what we are up against once a solid organ like the kidney is transplanted into a patient after their original one has failed. Here kidney transplant will be dealt with according to a review article in the NEJM 2004.

What happens in an acute rejection reaction? Inflammatory processes are set in motion spear headed by the T lymphocytes instigated by the Antigen Presenting Cells (APCs) mainly the dendritic cells. Lets add a few details. Lymphocytes are either naive i.e. they have not encountered the antigen or be memory cells and it appears that viral antigens may resemble MHC antigens and sensitize the lymphocytes which will then react more quickly and vigorously.

What happens next is the 3 signal activation of the inflammatory reaction which primes the system to produce active T cells and alloantibody.

  1. Signal 1. These are the antigens on the dendritic cells which through the CD3 complex transduce the T cell.
  2. Signal 2. Dendritic cells provide costimulation, delivered when CD80 and CD86 on the surface of dendritic cells engage CD28 on T cells. Signals 1 and 2 activate three signal transduction pathways: the calcium–calcineurin pathway, the RAS–mitogen-activated protein (MAP) kinase pathway, and the nuclear factor-κB pathway.9 These pathways activate transcription factors that trigger the expression of many new molecules, including interleukin-2, CD154, and CD25. Interleukin-2 and other cytokines (e.g., interleukin-15)
  3. Signal 3. “Target of rapamycin” (mTOR) pathway is activated.,” This is the trigger for cell proliferation. Lymphocyte proliferation also requires nucleotide synthesis.

Proliferation and differentiation lead to the production of a large number of effector T cells.

B cells are activated when antigen engages their antigen receptors, usually in lymphoid follicles or in extrafollicular sites, such as red pulp of spleen, or possibly in the transplant, producing alloantibody against donor HLA antigens. Thus, within days the immune response generates the agents of allograft rejection, effector T cells and alloantibody.

Effector T cells that emerge from lymphoid organs infiltrate the graft and orchestrate an inflammatory response. In T-cell–mediated rejection, the graft is infiltrated by effector T cells, activated macrophages, B cells, and plasma cells and displays interferon-γ effects, increased chemokine expression, altered capillary permeability and extracellular matrix, and deterioration of parenchymal function. The diagnostic lesions of T-cell–mediated rejection reflect mononuclear cells invading the kidney tubules (tubulitis) and the intima of small arteries (arteritis). Macrophages that are activated by T cells participate through delayed-type hypersensitivity, but the injury remains antigen-specific.

Alloantibody against donor antigens that is produced systemically or locally in the graft targets capillary endothelium. Antibody-mediated rejection is diagnosed by clinical, immunologic, and histologic criteria, including a demonstration of complement factor C4d in capillaries. A failure of the graft to produce urine, a rise or failure to fall in the serum creatinine should raise a suspicion of acute rejection either immediate post -operatively or within a week of the transplant or maybe later. Ultrasound of the graft, renal scan, renal biopsy will all be required as well as a fluid and frusemide challenge and a careful follow up of the volume status and urine output.

So to sum it up the T-cell mediated response is a cellular response characterized by mononuclear cell infiltration and the antibody rejection is a vascular response damaging the endothelium of the capillaries. Both cellular and antibody responses can occur together.

How does the graft survive with immunosuppression?

Some adaptive responses take place.  Changes in the organ — a loss of donor dendritic cells and a resolution of injury — contribute to the adaptation. Regulatory T cells may also be able to control alloimmune responses, by analogy with their ability to suppress autoimmunity, although this hypothesis is unproven. The crucial element is that host T cells become less responsive to donor antigens when antigen persists and immunosuppression is maintained. 

This may be a general characteristic of T-cell responses in vivo, in which antigen persistence with inadequate costimulation triggers adaptations that limit T-cell responsiveness. The resulting partial T-cell anergy (known as “adaptive tolerance” or “in vivo anergy”) is characterized by decreased tyrosine kinase activation and calcium mobilization (signal 1) and decreased response to interleukin-2 (signal 3). Adaptation in clinical transplantation resembles in vivo anergy — for example, both can occur in the presence of calcineurin inhibitors.

What is the aim of immunosuppression?

Immunosuppressive drugs appear to restrict/ reduce antigen presentation and make T cell activation less likely.

Immunosuppressive Drugs. Site of action.

Some of the sites where drugs act. As the sites are different a combination of drugs is more effective than one drug alone.

Immunosuppression can be achieved by depleting lymphocytes, diverting lymphocyte traffic, or blocking lymphocyte response pathways.

Immunosuppressive drugs have three effects:

  1. the therapeutic effect (suppressing rejection),
  2. undesired consequences of immunodeficiency (infection or cancer),
  3. nonimmune toxicity to other tissues.

Immunodeficiency leads to characteristic infections and cancers, such as post-transplantation lymphoproliferative disease, which are related more to the intensity of immunosuppression than to the specific agent used.

Immunosuppressive drugs include small-molecule drugs, depleting and nondepleting protein drugs (polyclonal and monoclonal antibodies), fusion proteins, intravenous immune globulin, and glucocorticoids


Immunosuppressive Therapies in Organ Transplantation

Natural and synthetic glucocorticoids remain at the forefront of anti-inflammatory and immunosuppressive therapies.  However, long-term use of oral glucocorticoids is associated with serious side effects, including osteoporosis, metabolic disease and increased risk of cardiovascular disease. The glucocorticoid receptor (GR) is a DNA binding protein that regulates transcription initiation and the discovery that many of the immunosuppressive actions of glucocorticoids are mediated by interference with signalling by the key inflammatory transcriptional regulators. Although categorically distinct, the innate (the relatively non-specific immediate host defence system that provides a rapid reaction to infection and tissue damage) and adaptive (the more slowly acquired, highly antigen-specific response) immune systems interact and often overlap during an inflammatory response. Foreign antigens are taken up by antigen presenting cells; particularly dendritic cells, but also macrophages, that then migrate to draining lymph nodes where they instruct the adaptive immune system (T and B lymphocytes), shaping the subsequent immune response. Glucocorticoids inhibit many of the initial events in an inflammatory response. They also promote the resolution of inflammation although the mechanisms by which they do so have received less attention than those associated with suppression of the initial response. Acutely, glucocorticoids inhibit the vasodilation and increased vascular permeability that occurs following inflammatory insult and they decrease leukocyte emigration into inflamed sites, effects that require new protein synthesis. Glucocorticoids act as agonists of glucocorticoid receptors, but at higher doses they have receptor-independent effects.

There is no consensus on the optimal dose or maintenance schedule of glucocorticoids following kidney transplantation. As part of a triple-agent immunosuppressive regimen, it is administered as methylprednisolone at 7 mg/kg (maximum of 500 mg) intravenously in the operating room, then initiate oral prednisone at a dose of 1 mg/kg per day (maximum dose of 80 mg) for the first three days posttransplant, which is then lowered to 20 mg/day for the first week. The daily dose is then tapered every week by 5 mg, resulting in 15 mg/day for one week, 10 mg/day for one week, and then 5 mg/day. In the absence of acute rejection, it is generally usual to reduce glucocorticoids to a dose of 5 mg per day by one month following kidney transplantation.

The use of long-term glucocorticoids may vary from center to center and patient to patient. In an attempt to minimize toxicity and to decrease overall immunosuppression, slow tapering and ultimate withdrawal of glucocorticoids has also been attempted.

Small molecule immunosuppressive drugs.

Most small-molecule immunosuppressive agents are derived from microbial products and target proteins that have been highly conserved in evolution. Small-molecule immunosuppressive drugs at clinically tolerated concentrations probably do not saturate their targets. For example, cyclosporine acts by inhibiting calcineurin but only partially inhibits calcineurin as used clinically. Without target saturation, the drug’s effects are proportional to the concentration of the drug, which makes dosing and monitoring critical. Cyclosporine acts by inhibiting calcineurin but only partially inhibits calcineurin as used clinically. Without target saturation, the drug’s effects are proportional to the concentration of the drug, which makes dosing and monitoring critical.

Depleting protein immunosuppressive agents

Depleting protein immunosuppressive agents are antibodies that destroy T cells, B cells, or both. T-cell depletion is often accompanied by the release of cytokines, which produces severe systemic symptoms, especially after the first dose. The use of depleting antibodies reduces early rejection but increases the risks of infection and post-transplantation lymphoproliferative disease and can be followed by late rejection as the immune system recovers. Recovery from immune depletion takes months to years and may never be complete in older adults. 

Nondepleting protein drugs

These are monoclonal antibodies or fusion proteins that reduce responsiveness without compromising lymphocyte populations. They typically target a semi redundant mechanism such as CD25, which explains their limited efficacy but the absence of immunodeficiency complications. These drugs have low nonimmune toxicity because they target proteins that are expressed only in immune cells and trigger little release of cytokines.

Small Molecule Drugs.

Characteristics of Small-Molecule Immunosuppressive Drugs Used in Organ Transplantation or in Phase 2–3 Trials.

Azathioprine, is derived from 6-mercaptopurine, was the first immunosuppressive agent to achieve widespread use in organ transplantation. The developers of azathioprine, Gertrude Elion and George Hitchings, were acknowledged by a share of the 1988 Nobel Prize. Azathioprine is thought to act by releasing 6-mercaptopurine, which interferes with DNA synthesis. Other possible mechanisms include converting costimulation into an apoptotic signal. After cyclosporine was introduced, azathioprine became a second-line drug and largely replaced by mycophenolate mophetil.

Initial therapy following transplant: IV, Oral: 2 to 5 mg/kg once (Cristelli 2013; manufacturer labeling).

Maintenance: Oral: 1 to 3 mg/kg (usual dose: 50 to 150 mg/day) once daily or 100 mg once daily (for patients <75 kg) or 150 mg (for patients ≥75 kg) once daily (Remuzzi 2007) or 2 mg/kg/day with dose adjusted based on safety/tolerability (Cristelli 2013).

Pregnant patients: ≤2 mg/kg/day.

Most transplant centers administer mycophenolate (MMF or EC-MPS) as an antimetabolic agent to kidney transplant recipients rather than azathioprine. This practice is based upon multiple large trials and meta-analyses showing lower acute rejection rates, and possibly improved graft survival, with MMF as compared with azathioprine.

Calcineurin Inhibitors.

Cyclosporine and tacrolimus selectively inhibit calcineurin, thereby impairing the transcription of interleukin (IL)-2 and several other cytokines in T lymphocytes. Calcineurin inhibitors have been mainstays of immunosuppression in solid organ transplantation for over three decades.

Cyclosporine and tacrolimus are occasionally used in the treatment of various immune-mediated diseases. However, concerns about their long-term toxicity (especially kidney dysfunction and hypertension) and the availability of newer biologic agents have restricted the use of cyclosporine and tacrolimus to patients who have not responded to conventional treatment.

Cyclosporine, a cornerstone of immunosuppression in transplantation, is in effect a prodrug that engages cyclophilin, an intracellular protein of the immunophilin family, forming a complex that then engages calcineurin. Cyclosporine is a lipophilic cyclic peptide of 11 amino acids derived from a fungus.

Cyclosporine and tacrolimus act primarily on T helper cells, although some inhibition of T suppressor and T cytotoxic cells may also occur. Cyclosporine also increases the expression of transforming growth factor (TGF)-beta, which may be an important mechanism by which it causes renal fibrosis. Unlike some other immunosuppressive agents, such as azathioprine and the alkylating agents, cyclosporine and tacrolimus lack clinically significant myelosuppressive activity.

The adverse effects of cyclosporine, which are related to the concentration of the drug, include nephrotoxicity, hypertension, hyperlipidemia, gingival hyperplasia, hirsutism, and tremor. Cyclosporine can also induce the hemolytic–uremic syndrome and post-transplantation diabetes mellitus. Recent developments include monitoring of the peak cyclosporine levels two hours after administration to better reflect exposure to the drug. A chemically modified cyclosporine, ISA(TX)247, is under development.

Most centers start calcineurin inhibitor therapy just before transplantation or within the first 24 hours of transplantation. Some centers delay the introduction of a calcineurin inhibitor until the serum creatinine has decreased by 50 percent from the pretransplant value or the patient has significant urine output. However, there is little evidence that delayed, rather than immediate, initiation of a calcineurin inhibitor results in lower rates of delayed graft function.

Liquid cyclosporine is available in capsules, oral solution, and concentrate for injection:

●Liquid-filled capsules of 25 mg and 100 mg are stored at less than 86°F (30°C) but not frozen.

●The oral solution of 100 mg/mL in 50 mL bottles remains stable for two months after opening if stored in the original container at less than 86°F (30°C) but does not require refrigeration and should not be frozen.

●Concentrate for injection of 50 mg/mL in 5 mL ampules should be stored at less than 86°F (30°C) and protected from light and freezing. Dilutions in 5 percent glucose or normal saline are stable for 24 hours. Substantial amounts of cyclosporine may be lost during intravenous administration through plastic tubing. Polyoxyethylated castor oil that is contained in the concentration for intravenous cyclosporine infusion can cause phthalate stripping from polyvinyl chloride (PVC)-containing intravenous tubing. Thus, when intravenous nonmodified cyclosporine is administered, PVC-free intravenous fluid containers and tubing should be used.

Modified — Capsules and solution are for oral use; no parenteral formulation is available. Patients who need an intravenous formulation should be prescribed cyclosporine nonmodified concentrate for injection. Cyclosporine modified capsules or the equivalent generic product are preferred due to superior pharmacokinetic profile compared with the nonmodified formulation:

●Capsules of 25 mg and 100 mg should be stored at 68 to 77°F (20 to 25°C); some generic formulations are available in a 50 mg capsule.

●The oral solution of 100 mg/mL is available in 50 mL bottles, which remains stable for two months after opening if stored in the original container at 68 to 77°F (20 to 25°C).

Cyclosporine modified – For nonautoimmune disease, cyclosporine modified is initially dosed at 4 to 10 mg/kg/day orally in two divided doses. Most clinicians start at the lower end of the dosing range and make adjustments based upon drug concentrations. The first dose may be administered within 24 hours of transplantation. In newly transplanted patients, the initial dose of cyclosporine modified is the same as the initial dose of cyclosporine nonmodified, although cyclosporine modified is preferred.

Tacrolimus engages another immunophilin, FK506-binding protein 12 (FKBP12), to create a complex that inhibits calcineurin with greater molar potency than does cyclosporine and is a macrolide antibiotic. Initial trials indicated that there was less rejection with tacrolimus than with cyclosporine, but recent analyses suggest that in the current dosing strategies, the efficacy of cyclosporine is similar to that of tacrolimus. Tacrolimus resembles cyclosporine in that it can result in nephrotoxicity and the hemolytic–uremic syndrome, but it is less likely to cause hyperlipidemia, hypertension, and cosmetic problems and more likely to induce post-transplantation diabetes. Tacrolimus has been suspected of inducing more BK-related polyomavirus nephropathy than has cyclosporine in patients who have undergone kidney transplantation, especially when used with mycophenolate mofetil, but renal function may be better with tacrolimus. New developments include a preparation of modified-release tacrolimus to permit once-daily dosing.

The use of tacrolimus has increased steadily, and the drug is now the dominant calcineurin inhibitor, but most transplantation programs exploit the strengths of both tacrolimus and cyclosporine, depending on the risks in individual patients. Hypertension, hyperlipidemia, and the risk of rejection argue for tacrolimus, whereas a high risk of diabetes (e.g., older age or obesity) argues for cyclosporine.

Tacrolimus– Tacrolimus is typically dosed at 0.1 to 0.2 mg/kg/day orally in two divided doses. Most clinicians start at the lower end of the dosing range and make adjustments based upon drug concentrations. The product information recommends the following for tacrolimus initiation [16]:

•At 0.1 mg/kg/day in kidney transplant recipients who also receive mycophenolate mofetil plus an interleukin (IL)-2 receptor antagonist

•At 0.2 mg/kg/day in kidney transplant recipients treated with azathioprine rather than mycophenolate mofetil

•At 0.1 to 0.15 mg/kg/day in adult liver transplant recipients

•At 0.075 mg/kg/day in adult heart transplant recipients

Extended-release tacrolimus products – In patients receiving mycophenolate mofetil, glucocorticoids, and basiliximab induction, extended-release tacrolimus capsules (Astagraf XL) should be given at a dose of 0.15 to 0.2 mg/kg/day prior to reperfusion or within 48 hours of the completion of the transplant procedure. In patients treated with mycophenolate mofetil and glucocorticoids without basiliximab induction, extended-release tacrolimus capsules should be given as a single dose of 0.1 mg/kg within 12 hours prior to reperfusion, then 0.2 mg/kg at least 4 hours after the preoperative dose, and within 12 hours after reperfusion, then 0.2 mg/kg daily [13]. The recommended starting dose of extended-release tacrolimus tablets (Envarsus) in de novo kidney transplant patients is 0.14 mg/kg/day with antibody induction [20].

Drug monitoring — Therapeutic monitoring of cyclosporine and tacrolimus is complicated by the narrow margin between adequate immunosuppression and toxicity. Whole blood should be used as a sample for both drugs. A variety of assays are available, and clinicians should become familiar with the one used in their local laboratory.

Cyclosporine should be monitored using 12-hour trough (C0), two-hour post-dose (C2), or abbreviated area under the time concentration curve (AUC) . Although monitoring of C0 is common practice, there is a poor correlation with safety, efficacy, and drug exposure using this strategy. Some centers use C2 monitoring among kidney transplant recipients since these concentrations may correlate more closely with exposure, and higher C2 concentrations have been associated with decreased acute rejection rates in the first year. In one study of liver transplant patients, C2 was more closely associated with the first four-hour post-dose cyclosporine exposure (AUC0-4) than C0. C2 monitoring may be more accurate but is often more difficult and less convenient for the patient. Most centers monitor either C0 or C2 concentrations but not both. In rare circumstances, assessing both may be beneficial in a patient with absorption issues.

Tacrolimus should be monitored using 12- and 24-hour trough (C0) concentrations for the immediate-release and extended-release preparations, respectively.

Blood concentrations should be checked two to three days after starting cyclosporine or tacrolimus and after any dose change. Typically, after transplant, concentrations are measured every one or two days while hospitalized. After discharge, levels should be measured once or twice weekly for the first month, then weekly until three months posttransplantation, then every two weeks until six months posttransplant, and then monthly. Some stable, low-risk patients may have concentrations monitored every two to three months. However, if drugs that affect cyclosporine or tacrolimus metabolism are added or withdrawn, more frequent measurement of trough concentrations will be required. Tacrolimus and cyclosporine reach steady-state concentrations after four to six doses.

Inosine Monophosphate Dehydrogenase Inhibitors: mycophenolate mofetil.

 Mycophenolic acid inhibits inosine monophosphate dehydrogenase, a key enzyme in purine synthesis. Mycophenolate mofetil is a prodrug that releases mycophenolic acid, and in large-scale trials with cyclosporine, it was superior to azathioprine in preventing rejection of kidney transplants.  Protocols using mycophenolate mofetil and calcineurin inhibitors improved patient survival and graft survival and reduced early and late allograft rejection.

Renal transplantation:


CellCept: Initial: 1 g twice daily. Maintenance dose may vary based on concomitant immunosuppression. Doses >2 g/day have been associated with an increased incidence of adverse effects but may be necessary in some patients (EMMC study group 1999; TMMRT study group 1996).

Myfortic: Oral: Initial: 720 mg twice daily. Maintenance doses may vary based on concomitant immunosuppression.

IV: CellCept: See oral dosing for CellCept; IV and oral doses (of mycophenolate mofetil) are equivalent. If converting from Myfortic to IV CellCept, convert Myfortic to equivalent CellCept oral dose first. Transition to oral therapy as soon as tolerated.

Target-of-Rapamycin Inhibitors (mTOR)

Sirolimus, everolimus and temsirolimus engage FKBP12 to create complexes that engage and inhibit the target of rapamycin but cannot inhibit calcineurin. Inhibition of the target of rapamycin blocks signal 3 by preventing cytokine receptors from activating the cell cycle.

Sirolimus (rapamycin) is a macrocyclic triene antibiotic that is produced by fermentation of Streptomyces hygroscopicus. Sirolimus was discovered from a soil sample collected in Rapa Nui, which is also known as Easter Island [1]. Although it was originally developed as an antifungal agent, it was later found to have immunosuppressive (US FDA approval in 2003 for prevention of acute rejection in kidney transplantation) and antiproliferative properties that may be useful to treat or prevent proliferative diseases such as tuberous sclerosis, psoriasis, and malignancy. Temsirolimus and everolimus are both analogs of sirolimus approved for the treatment of renal cell carcinoma. In April 2010, everolimus was approved by the US FDA for prevention of acute rejection in kidney transplantation.

Sirolimus is available in a 1 mg/mL oral solution (60 mL) and a 0.5, 1, and 2 mg triangular-shaped tablet. Although the oral solution and tablet are not bioequivalent, clinical equivalence has been demonstrated [3].

Everolimus is available as a 0.25, 0.5, and 0.75 mg round, flat tablet.



Sirolimus – Sirolimus is typically administered as a tablet, although a solution is available for those who are not able to swallow.

Sirolimus oral solution should be taken in the following manner:

•Empty the medication from the amber syringe into a glass or plastic container.

•Then, it should be vigorously stirred with 2 ounces of water or orange juice.

•After immediately drinking the mixture, the container should again be filled with an equal amount of fluid and consumed immediately.

Sirolimus should not be mixed with grapefruit juice.

•The oral solution should be protected from light and stored under refrigeration at all times to prevent degradation.

Everolimus – Everolimus is administered as a tablet.

Dose — Clinical trials of initial immunosuppressive regimens after kidney transplant have included sirolimus as a component of a regimen that includes cyclosporine and glucocorticoids. In these trials, a one-time loading dose of 6 or 15 mg (three times the maintenance dose), followed by a maintenance dose of either 2 or 5 mg/day, was utilized.

An initial everolimus dose of 0.75 mg given orally twice daily is recommended for adult kidney transplant patients in combination with reduced-dose cyclosporine.

Sirolimus and everolimus were developed for use with cyclosporine, but the combination increased nephrotoxicity, the hemolytic–uremic syndrome, and hypertension. Sirolimus has been combined with tacrolimus (e.g., the Edmonton protocol for pancreatic islet transplantation) to avoid the toxicity of sirolimus–cyclosporine combinations. However, a controlled trial in renal transplantation showed that sirolimus plus tacrolimus produced more renal dysfunction and hypertension than did mycophenolate mofetil plus tacrolimus, which indicates that sirolimus potentiates tacrolimus nephrotoxicity.

The principal nonimmune toxic effects of sirolimus and everolimus include hyperlipidemia, thrombocytopenia, and impaired wound healing. Other reported effects include delayed recovery from acute tubular necrosis in kidney transplants, reduced testosterone concentrations, aggravation of proteinuria, mouth ulcers, skin lesions, and pneumonitis. However, sirolimus and everolimus may reduce cytomegalovirus disease. 

Practitioners can reduce the toxicity of the combination of a target-of-rapamycin inhibitor and a calcineurin inhibitor by withdrawing one of the drugs. For example, withdrawing cyclosporine in patients in stable condition who are receiving the sirolimus–cyclosporine combination reduces renal dysfunction and hypertension, with a small increase in rejection episodes, which suggests a strategy for avoiding the toxic effects of calcineurin inhibitors.

Dihydroorotate Dehydrogenase Inhibitors

Leflunomide is a dihydroorotate dehydrogenase inhibitor that is approved for rheumatoid arthritis. Dihydroorotate dehydrogenase is a key enzyme in pyrimidine synthesis. Its active metabolite, A77 1726, was modified to create FK778. Leflunomide is not in widespread use as an immunosuppressant in renal transplant but may be substituted for mycophenolate in the presence of BK viremia or nephropathy. FK778 may have activity against BK-related polyomavirus and have a lower incidence of gastrointestinal effects than does mycophenolate mofetil, but its nonimmune toxic effects such as anemia must be evaluated.

Non depleting and fusion antibodies

Daxiliximab and Basiliximab

The anti-CD25 monoclonal antibodies daclizumab and basiliximab are widely used in transplantation for induction in patients who have a low-to-moderate risk of rejection.

Depleting antibodies.

Polyclonal antithymocyte globulin is produced by immunizing horses or rabbits with human lymphoid cells, harvesting the IgG, and absorbing out toxic antibodies (e.g., those against platelets and erythrocytes). As an induction agent, polyclonal antithymocyte globulin is usually used for 3 to 10 days to produce “profound and durable” lymphopenia that lasts beyond one year. 

In addition to immunodeficiency complications, toxic effects of polyclonal antithymocyte globulin include thrombocytopenia, the cytokine-release syndrome, and occasional serum sickness or allergic reactions. Rabbit preparations of polyclonal antithymocyte globulin (such as Thymoglobulin and ATG-Fresenius) are favored over horse polyclonal antithymocyte globulin because of greater potency.

Muromonab-CD3, a mouse monoclonal antibody against CD3, has been used for 20 years to treat rejection and for induction. Muromonab-CD3 binds to T-cell-receptor–associated CD3 complex and triggers a massive cytokine-release syndrome before both depleting and functionally altering T cells. Humans can make neutralizing antibodies against muromonab-CD3 that terminate its effect and limit its reuse. Prolonged courses of muromonab-CD3 increase the risk of post-transplantation lymphoproliferative disease. The use of muromonab-CD3 declined when newer small-molecule immunosuppressive drugs reduced rejection episodes. A trial of a humanized anti-CD3 monoclonal antibody in kidney transplantation was stopped.

Alemtuzumab, a humanized monoclonal antibody against CD52, massively depletes lymphocyte populations. It is approved for treating refractory B-cell chronic lymphocytic leukemia but is not approved for immunosuppression in transplantation.

Rituximab (anti-CD20 monoclonal antibody) eliminates most B cells and is approved for treating refractory non-Hodgkin’s B-cell lymphomas, including some post-transplantation lymphoproliferative disease in organ-transplant recipients. Rituximab is used off-label in combination with maintenance immunosuppressive drugs, plasmapheresis, and intravenous immune globulin to suppress deleterious alloantibody responses in transplant recipients.

Renal transplant is a complex problem to deal with. New drugs are developing. Non-glucocorticoid therapies are being used. results have got better. Most patients survive at least 5 years and more if their doctor gets it right. I hope you learnt something useful.

Why and how of renal allograft rejection and why the different types of rejection need to be treated differently.

Since renal transplants took off in the 1960s the bugbear of allograft rejection hit nephrologists and their patients. It became the problem that had to be dealt with immediately and for the duration of the patient’s life.

The introduction of immunosuppression by means of powerful calcineurin inhibitors in the 1980s and better immunologic matching of recipients with donors changed the character of acute rejection. The overall risk of acute rejection within 1 year after transplantation is now less than 15%. Although the management of acute rejection has been much improved, chronic rejection and survival beyond 5 years remain problems that need attention. That attention is being given to this problem a series of conferences known as the Banff Conference, the 10th one held in Canada which I mention here.

The 10th Banff Conference on Allograft Pathology was held in Banff, Canada from August 9 to 14, 2009. A total of 263 transplant clinicians, pathologists, surgeons, immunologists and researchers discussed several aspects of solid organ transplants with a special focus on antibody mediated graft injury. The willingness of the Banff process to adapt continuously in response to new research and improve potential weaknesses, led to the implementation of six working groups on the following areas: isolated v‐lesion, fibrosis scoring, glomerular lesions, molecular pathology, polyomavirus nephropathy and quality assurance. Banff working groups will conduct multicenter trials to evaluate the clinical relevance, practical feasibility and reproducibility of potential changes to the Banff classification. There were also sessions on quality improvement in biopsy reading and utilization of virtual microscopy for maintaining competence in transplant biopsy interpretation. In addition, compelling molecular research data led to the discussion of incorporation of omics‐technologies and discovery of new tissue markers with the goal of combining histopathology and molecular parameters within the Banff working classification in the near future.

The 2017 Banff Conference was held in Barcelona, Spain. The 2019 Banff Conference was held in Pittsburgh, Pennsylvania, and the 2021 Banff Conference will be in Banff, Alberta, Canada. These are held by the Banff Foundation for Allograft Pathology – BANFF

Rejection can be:

  1. Hyperacute (occurring within minutes),
  2. Acute (occurring within days to weeks),
  3. Late acute (occurring after 3 months),
  4. Chronic (occurring months to years after transplantation).

Rejection can also be classified according to pathophysiological changes:

  1. cellular-interstitial
  2. vascular, antibody-endothelial)
  3. severity (extent of histologic inflammation and injury, as scored and graded by means of the Banff schema)
  4. response to treatment (presence or absence of glucocorticoid resistance)
  5. presence or absence of renal dysfunction (indicating acute or subclinical rejection, respectively)
  6. immunologic mechanisms (adaptive or innate immune system response).

The Innate Immune System.

Who are the culprits?

The T cells. Whenever there is innate injury pathways of inflammation are upregulated, and aggravate the rejection process either directly or indirectly through the activation and recruitment of T lymphocytes. Injured tissues express ligands of the toll-like receptor system — damage-associated molecular-pattern (DAMP) molecules — and other innate danger molecules. Toll-like receptors normally detect pathogens, but they can also sense the presence of foreign-tissue molecules and can produce factors that cause the maturation and activation of dendritic cells. Dendritic cells (DCs), named for their probing, ‘tree-like’ or dendritic shapes, are responsible for the initiation of adaptive immune responses and hence function as the ‘sentinels’ of the immune system and were initially mistaken for cutaneous nerve cells.

The complement system.

Another element of innate immunity, the complement system, produces C3a and C5a, which directly activate intragraft T cells and antigen-presenting cells. Antigenpresenting cells (APCs) are a heterogeneous group of immune cells that mediate the cellular immune response by processing and presenting antigens for recognition by certain lymphocytes such as T cells. Classical APCs include dendritic cells, macrophages, Langerhans cells and B cells.

An increase in major-histocompatibility-complex (MHC) class I peptide–related sequence A (MICA) antigens on endothelial surfaces can activate natural killer cells and CD8 T cells. Moreover, there is an association between poor graft outcomes and sensitization to the highly polymorphic MICA antigens in HLA-matched transplants.

Who are you going to chose as a donor?

Transplants obtained from a spouse, friend, or altruistic donor under optimal physiological conditions and with shorter ischemia times lead to excellent results, even when genetic and HLA differences are greater than from deceased donors, who are of older age, with the presence of hypotension or hypertension, diabetes, renal impairment, donation after cardiac death, and prolonged ischemia of the graft due to a delay in shipping.

Who has preformed antibodies?

Antibodies that can mediate rejection include those against HLA molecules, endothelial-cell antigens, and ABO blood-group antigens on endothelial cells and red cells. Most recipients do not have antibodies against HLA molecules before transplantation unless they were sensitized by exposure to alloantigens through pregnancy, blood transfusion, or previous transplantation.

Antibodies against ABO antigens. Will you use a kidney donor who is ABO incompatible?

Kidneys selected for transplantation are routinely assigned to recipients with a compatible blood group; however, ABO-incompatible kidneys have been successfully transplanted with the use of an experimental protocol that entails perioperative removal of antibodies from the recipient by means of plasmapheresis or immunoadsorption. After they have been removed, anti–blood-group antibodies can rise to pretreatment levels after transplantation, adhere to the microvasculature, and activate complement, yet they generally do not injure the endothelium. This anomaly has been attributed to “accommodation” within the kidney, but the mechanism responsible for this benign response is unknown. In contrast, injury to the graft by anti-HLA antibodies is frequently insidious, and accommodation is uncommon.

Hyper acute rejection/ activation of complement cascade in the graft.

Rejection of the renal graft that occurs almost immediately after release of the vascular cross-clamps is classified as hyperacute. Instead of “pinking up” as a result of normal reperfusion, the kidney appears flaccid and mottled, reflecting the deposition of antibodies against HLA antigens expressed on the endothelium of the glomeruli and microvasculature. Activation of the classic complement cascade within the graft is followed by endothelial necrosis, platelet deposition, and local coagulation. In these cases, the initial transplant ends with removal of the kidney.

Acute Antibody-Mediated Rejection.

Can this be delayed for weeks? Why is it necessary to recognize that it is antibody mediated?

Antibody-mediated rejection often begins within days after transplantation (or within weeks, if antilymphocyte antibody therapy was given). The main feature is rapid graft dysfunction due to inflammation. An anamnestic response engendered by previous exposure to the relevant antigen rapidly generates high titers of complement-fixing antibodies. The main targets of these “recall” antibodies are MHC antigens displayed by the endothelium of the donor peritubular and glomerular capillaries.

Is the rejection likely to be steroid resistant?

 Agonistic angiotensin II type 1 (AT1)–receptor antibodies have been associated with corticosteroid-resistant vascular rejection accompanied by malignant hypertension, but their pathogenic role remains unclear. Microthrombi, with hemorrhage and arterial-wall necrosis and infarction, occur in severe cases. Detection of potentially harmful antibodies before transplantation should prompt a search for an alternative donor or an aggressive approach to post-transplantation management.

Early diagnosis and treatment are essential for salvaging grafts undergoing acute antibody-mediated rejection. Treatments include removal of antibodies by plasmapheresis or immunoadsorption, high-dose pulses of glucocorticoids, intravenous immune globulin, and antiproliferative agents. Supplementary therapies include rituximab or antilymphocyte antibody, if there is concurrent T-cell–mediated rejection. These treatments can be useful when given as prophylaxis to highly sensitized or ABO-mismatched recipients.  Eculizumab (a monoclonal antibody that inhibits the cleavage of C5) and bortezomib (a proteasome inhibitor that can inhibit plasma cells) are new, investigational agents that have shown promise in preliminary studies of antibody-mediated acute rejection, but the results require confirmation.

T cell mediated acute rejection.

This is the most common form of acute allograft rejection. It is initiated when donor alloantigens are presented to the T lymphocytes of the recipient by antigen-presenting cells (APCs). Immature dendritic cells within the graft carry donor antigens from the transplanted organ to the recipient’s draining lymph nodes and spleen; during their journey, these antigens mature into APCs. The recipient’s antigen-presenting dendritic cells also participate and circulate through the graft. The APCs then home to lymphoid organs, where they activate the recipient’s T cells. These T cells differentiate into various subgroups and return to the graft, where they take part in destroying the transplanted organ.

Endogenous antigens are digested into peptides by proteosomes and are loaded into class I MHC. Exogenous antigens are degraded in or within endosomes and are loaded into class II MHC. Assembly of the MHC within the cell’s endoplasmic reticulum precedes its transport through the Golgi apparatus and its ultimate expression on the cell surface along with peptide, where the MHC–peptide complex interacts with CD8+ or CD4+ T lymphocytes. β2m denotes β2-microglobulin, CLIP class II-associated invariant-chain peptide, and TAP transporter associated with antigen processing.

Role of the T cells in recognizing antigens.

The T cells in graft rejection seem to be more experienced in recognizing allograft antigen (up to 10% will recognize antigens versus 1% in normal people). They pick up the antigen displayed by the APCs from the donor (direct pathway) and the recipient (indirect pathway). They have a low threshold for reacting to MHC antigens. The recipient’s APCs can also take up membrane fragments of other cells; these fragments contain MHC molecules bearing “predigested” peptides derived from the donor’s MHC glycoproteins (the semidirect pathway). APCs can present such MHC–peptide complexes to CD4 T cells, which in turn activate CD8 T cells.

This picture may help you understand the differentiated T cells and their products.

After presentation of antigen by the antigen-presenting cell (APC), naive T lymphocytes become activated, proliferate, and differentiate into subtypes with characteristic cytokine profiles. Type 1 helper T (Th1) cells drive the cellular immune response, and type 2 helper T (Th2) cells produce the humoral immune response. Regulatory T (Treg) cells can limit the rejection response, and type 17 helper T (Th17) cells can mediate glucocorticoid-resistant rejection. APC denotes antigen-presenting cell, DC donor cell, IFN-γ interferon-γ, MHC major histocompatibility complex, TCR T-cell receptor, and TGF-β transforming growth factor β.

T-cell activation requires signals other than those engendered by the MHC–peptide complex, termed costimulatory signals. T cells become anergic when presented with an antigen in the absence of these signals, and agents that block these signals are under development. Early clinical trials of agents that block costimulation were disappointing; Belatacept, a fusion protein containing CTLA-4 and the Fc fragment of IgG1, blocks T-cell stimulation engendered by the CD80–CD28 and CD86–CD28 pathways. Clinical trials are assessing this more potent inhibitor as a potential replacement for nephrotoxic calcineurin inhibitors.

How do CD8 cells physically damage the graft itself?

 Invading CD8 T lymphocytes, which have immunologic specificity for the allograft, cross the basement membrane of the tubule, where they proliferate and induce apoptosis of tubular cells. Sublethally injured tubular cells can also transform from their native epithelial phenotype into primitive mesenchymal myofibroblasts, promoting interstitial fibrosis. Necrosis of tubular epithelial cells and basement-membrane rupture cause urinary leakage, graft dysfunction, and progressive tubular atrophy.

Acute vascular rejection.

Vascular rejection is a severe condition that does not respond to glucocorticoid therapy and instead requires potent antilymphocyte-antibody therapy (muromonab-CD3 [Orthoclone OKT3, Ortho Biotech] or antithymocyte globulin).

Late acute allograft rejection

Late acute allograft rejection is often severe and difficult to reverse, with a high risk of subsequent graft loss. Its main features are active immune inflammation and chronic tubulointerstitial damage, which frequently involves graft-directed antibody. It can develop in graft recipients with high-grade immunity against the transplant or in those who receive reduced amounts of immunosuppressive therapy because of cancer, prior severe infection, or noncompliance.

Chronic allograft rejection — ongoing immune injury to the graft — is due to a failure to maintain sufficient immunosuppression to control residual antigraft lymphocytes or antibodies. Its features include a progressive decline in renal function, invasion of the renal parenchyma by T cells, and persistent infiltration of the interstitium by T cells and macrophages. Occasionally, one also sees smooth-muscle proliferation and hyperplasia in vessels, forming a neointima; focal destruction of internal elastic lamina; and finally, vascular occlusion.

What does the future hold?

Despite technical advances and improvements in management, the alloimmune response remains the primary obstacle to successful kidney transplantation. Rejection of the graft entails much more than T-cell responses. Other elements include the innate immune system of natural killer cells, macrophages, and complement; the adaptive immune system of antigen-specific T lymphocytes and B cells; and cells intrinsic to the graft, such as endothelium. Antibody-mediated rejection is increasingly recognized as a contributor to late graft injury.

Current therapies are focused on the initial stages of T-cell activation, and this strategy has minimized early acute rejection. However, we need to improve our understanding of the mechanisms underlying chronic graft dysfunction and develop better treatments to prevent loss of the graft. Protocols that are designed to induce immunologic tolerance and the transplantation of organs in highly sensitized patients (those previously exposed to alloantigens) are also likely to alter the nature and presentation of rejection.


  1. Brian J. Nankivell, M.D., Ph.D., 
  2. and Stephen I. Alexander, M.B., B.S., M.P.H.

October 7, 2010
N Engl J Med 2010; 363:1451-1462
DOI: 10.1056/NEJMra0902927

CNS complications in renal transplant long term.

If you are caring for patients with renal transplants expect complications requiring hospitalisation within the first year in the majority of patients. In this post I am going to be dealing with the most common etiologies of neurological complication after kidney transplant: infection, malignancy, medication, surgical complications, seizure, and stroke. Some of the problems with the drugs used for induction and maintenance and other neurological complications may be seen.

Neurological infections are fairly common post-operatively, and are associated with increased morbidity and mortality in this population.

Infection is of specific concern in the post-operative patient as immunosuppressive regimens alter both the typical presentation and types of organisms observed. In general, classification of post-operative infections can be divided into the first month after transplant, one to six months after transplant, and beyond 6 months. CNS infection which include meningitis, encephalitis, and abscess) have significant morbidity and mortality in renal transplant patients, and symptoms can range from non-specific (such as headache, fever, and altered mental status) to focal neurologic deficits and coma. Work-up will include CSF culture and analysis including PCR, blood cultures, and brain imaging. Other complications include malignancy, medication related, acute neuropathy, and other neurological pathology


CNS infection accounts for a significant percentage of neurological complications after solid organ transplant, including in kidney recipients. Infection is of specific concern in the post-operative patient as immunosuppressive regimens alter both the typical presentation and types of organisms observed. CNS infection (including meningitis, encephalitis, and abscess) has significant morbidity and mortality in renal transplant patients, and symptoms can range from non-specific (such as headache, fever, and altered mental status) to focal neurologic deficits and coma. When attempting to identify a causative organism, the post-surgical timeline is important as there is a correlation between time post-transplant and likely organisms (3). In general, classification of post-operative infections can be divided into the first month after transplant, one to six months after transplant, and beyond 6 months (Table 1). Management of infection in post-transplant patients typical involves initiation of empiric anti-microbial therapy (antibiotics, antivirals or anti-fungal therapy) with narrowing of agents after the causative organism is determined and decreasing or stopping entirely the immunosuppression regimen. As many symptoms of CNS infection in this population are nonspecific, determining whether these symptoms are caused by infection or a non-infectious etiology may be challenging. In general, work-up will include CSF culture and analysis including PCR, blood cultures, and brain imaging.

Table 1

Typical organisms after renal transplant by time period (36)

Time after transplantLikely organismsTypical presentationDiagnosisTreatment
First monthStreptococcus pneumoniae, Neisseria meningitidis, Listeria monocytogenes, Haemophilus influenzaNonspecific; ranging from headache, fever, meningismus, altered mental statusCSF with neutrophilic predominance, decreased glucose, elevated proteinEmpiric treatment including ceftriaxone, vancomycin, ampicillin, narrowing therapy after culture results
Aspergillus fumigatusNonspecific; seen with comorbid respiratory diseaseAntigen or antibody present in CSF, branching hyphae visualized in CSFAntifungals including voriconazole, amphotericin
Candida speciesDisseminated fungemia with CNS symptomsPseudohyphae visualized in CSF, PCR, positive cultureFluconazole
Amphotericin can be considered in severely ill or neutropenic patients
1–6 monthsMycobacterium tuberculosisNon-specific; consider in patients from endemic areas, travel or exposure history, or history of latent infectionCSF Acid Fast Bacteria stain may miss the diagnosis. Interferon-Gamma Release Assay as screen. Decreased glucose, leukocytosis with lymphocytic predominance, increased protein, and increased adenosine deaminaseMultiple drug therapy including isoniazid, rifampin, ethambutol, pyrazinamide
CytomegalovirusNon-specific, but may include symptoms of retinitis, GI manifestationsCSF PCRGanciclovir, foscarnet
Varicella Zoster VirusEncephalitis, headache, altered mental status, seizure. May or may not have skin manifestationsPCR of CSF, may require multiple samples to rule out as it can initially be negativeIntravenous acyclovir with appropriate hydration. Can consider valacyclovir prophylaxis after infection fully treated to prevent reactivation
6 months and beyondCryptococcus neoformansNonspecific; fever, headacheCSF PCR, antigen, cultureAmphotericin, flucytosine. Will need continued treatment with fluconazole for life even after CSF culture negative. Poor prognosis
Toxoplasma gondiiAltered mental status, seizure, focal neuro signsSerum toxoplasma IgG, supportive imaging findings include ring-enhancing lesionsPyrimethamine with leucovorin
Prophylaxis can include Trimethoprim-Sulfamethoxazole or pyrimethamine with leucovorin if cannot tolerate TMP-SMX
JC virusAMS, seizure, focal neuro signsCSF PCRNo treatment. Consider reducing immunosuppression. Poor prognosis

In the immediate post-operative period, CNS infection is most often caused by typical bacterial organisms although opportunistic infections from environmental organisms and reactivation of latent tuberculosis infection can occur. Typical bacteria causing neurological infection include Streptococcus pneumoniaeNeisseria meningitidisListeria monocytogenesand Haemophilus influenza. Common presentation of these patients includes headache, fever, malaise, altered mental status, and meningismus. Opportunistic infections including Mycobacterium tuberculosisAspergillus fumigatus, and Candida species can also occur. Tuberculosis is rare as a primary infection post-operatively, but immunosuppression can cause reactivation of latent infection. These patients will have similar presentation to typical bacterial meningitis but may have radiographic evidence of lesions and CSF analysis will reveal very low glucose with a lymphocytic pleocytosis (compared to neutrophilic predominance in typical bacterial infection) with positive acid fast staining and culture. 

Aspergillus fumigatus is a fungus present in the environment, and infections are associated with pre-existing respiratory disease with asthma like symptoms. CNS infection with Aspergillus is associated with multiple lesions on CT or MRI and diagnosis may be made via antigen, serology, or fungal culture. Finally, CNS infection with Candida species can be seen in patients with disseminated fungemia due to immunosuppression.

Risk of infection is highest from one to six months after transplantation as immunosuppression becomes maximally effective and dominant organisms shift to more atypical pathogens. Cytomegalovirus (CMV) is the most common opportunistic infection in kidney transplant recipients, present in up to 8% of patients. This prevalence has decreased due to improved recognition of donor and recipient seropositivity and prophylactic treatment (7). Risk is highest with donor seropositivity and recipient seronegativity, induction immunosuppression, and older donors (8). Infection may occur as a primary infection, reinfection of latent recipient infection, or most commonly donor-derived. Symptoms are generally nonspecific in CNS infection, but more characteristic systemic features include leukopenia, thrombocytopenia, and evidence of infection of other tissues with CMV such as retinitis, pneumonitis, or GI disease.

Finally, CMV infection has been implicated in case reports of post-operative Guillain Barrè syndrome. Guillain-Barre Syndrome (GBS) is an auto-immune disease affecting the peripheral nervous system. The exact mechanisms of GBS is unknown but is posited to involve humoral and cell-mediated autoimmunity in response to some antigenic trigger, infectious or otherwise. GBS typically presents as an ascending paralysis and sensory loss with areflexia and can progress to respiratory failure as symptoms spread proximally. Treatment includes respiratory support, rehabilitation, and immunotherapy with plasmapheresis and/or intravenous immunoglobulins.

Primary infection with Epstein Barr Virus (EBV) is a rare complication after renal transplant, but reactivation can occur and EBV is a significant cause of morbidity and mortality due to its association with post-transplant lymphoproliferative disorder (PTLD) discussed later in this review.

Other viruses affecting the nervous system that can sometimes be seen in this post-operative period include human herpes virus 6 (HHV6), varicella zoster (VZV), and BK Polyoma Virus.

Human polyomavirus infection may result in different disease manifestations, which depend on whether or not there is sustained viral replication although in the immunocompetent they do not cause significant disease.

  1. Progressive multifocal leukoencephalopathy (PML) is caused by high-level replication of JCPyV, mostly in oligodendrocytes, without significant inflammation is typically seen in patients with advanced AIDS who have PML and who have been treated with immunosuppressive drugs used for transplantation or the treatment of autoimmune diseases (eg, multiple sclerosis).
  2. BKPyV-associated nephropathy in kidney transplant recipients is characterized by high-level virus replication and a significant inflammatory response due to necrosis, denudation of the basement membrane, and infiltration of granulocytes and lymphocytes.
  3. Immune reconstitution inflammatory syndrome is characterized by an exaggerated inflammatory response to abundant PyV antigen upon brisk recovery of immunity. The prototypes are BKPyV-associated hemorrhagic cystitis after allogenic hematopoietic cell transplantation and the unmasking of PML after the start of antiretroviral therapy for HIV infection or following the removal of natalizumab through plasmapheresis in multiple sclerosis patients.
  4. Oncogenic effects of PyVs are characterized by viral early gene expression activating host cells, but without subsequent late gene expression and cytopathic release of progeny virus. Uncoupling from capsid protein expression, assembly, and cell lysis may also underlie BKPyV-associated urothelial cancers.

After 6 months, immunosuppressive regimens tend to decrease in intensity and overall risk of infection decreases. However, infection with rare atypical organisms can still occur with chronic immunosuppression, and organisms such as Cryptococcus neoformansToxoplasma gondii, tuberculosis, and JC virus (causing progressive multifocal leukoencephalopathy) may be seen.


Recipients of kidney transplant require immunosuppressive therapy in order to prevent rejection of the transplanted organ. Immunosuppression can be divided into induction and maintenance therapy with additional potential treatment of acute rejection. Induction therapy is given around the time of transplantation, is generally more potent with greater immunosuppression than maintenance therapy, and is done in order to prevent acute rejection. In contrast, maintenance immunosuppression is typically initiated at the time of transplant but continued long-term for the duration of the graft. Typical agents may include glucocorticoids, calcineurin inhibitors (CNIs), anti-metabolic agents, and mTOR inhibitors. Choice of agents will vary based on patients’ individual factors including risk for rejection and balancing potential side effects.

Induction therapy agents work via depletion of T-cells resulting in blunted immune response.

Medications used for induction include anti-thymocyte globulins, alemtuzumab (a humanized recombinant monoclonal antibody against CD25), and basiliximab (an IL-2R antagonist). None of these agents have specific neurotoxicities as common adverse effects so it is very unlikely that neurological complications will be seen early in the transplant scenario.

The cytokine release syndrome may give non-specific neurological symptoms. Antilymphocyte antibodies (ATG, Atgam, and alemtuzumab) may cause cytokine release syndrome, a systemic inflammatory response caused by initial immune cell activation. This is mentioned here as common symptoms (including fever, nausea, vomiting, diarrhea, tachycardia, hypotension, and seizures) are nonspecific and can mimic those of CNS infection after transplant. Basiliximab has not been associated with cytokine release syndrome and is overall well tolerated for kidney transplant induction therapy.

How are glucocorticoids used in renal transplant?

Glucocorticoids are used in both induction and maintenance therapy for their immunosuppression, as well as for the treatment of acute rejection.

How do glucocorticoids work?

These drugs function via multiple pathways, with inhibition of various cytokines including Il-1, Il-2, IL-6, TNF-A, and IFN-gamma.

Which are the commonly corticoids used?

The most commonly used glucocorticoids used for renal transplant patients are oral prednisolone, prednisone, and intravenous methylprednisolone.

Why are these agents not ideal for maintenance of immunosuppression?

These agents are not ideal for maintenance therapy because of the well characterized side effects of chronic steroid use, including multiple adverse neurological symptoms. Thankfully, most if not all neurological complications of corticosteroids are reversible with reduction or withdrawal of the offending agent. One of the most common neurological side effects of glucocorticoid use is steroid-induced myopathy.

How does steroid myopathy present?

Patients with steroid myopathy typically present with gradual onset of proximal muscle weakness with atrophy. Lower extremities are usually affected first and more severely than the upper extremities. It is usually not associated with myalgia or tenderness and there is no rise in muscle enzymes.

Glucocorticoids have a direct catabolic effect on skeletal muscle. Symptoms of the condition can begin any time from days to months after therapy begins and its incidence and severity are related to steroid dose. The diagnosis is clinical, and muscle enzymes are typically normal. The condition is surprisingly common, with previous studies showing approximately 50% of patients on steroids after solid organ transplant developing symptoms. Treatment is supportive for pain control of the myalgia and removal of steroid with full resolution taking months after discontinuation.

What are the other effects of corticosteroids on the brain?

The neuropsychiatric side effects of corticosteroid therapy are well known. Initially, steroid use is associated with elevation in mood, a potential hypomanic state, and disruption of sleep.

What will happen when the dose of steroids is increased?

Symptoms associated with higher doses for longer duration include sleep disruption, restlessness and akathesia, depression (including increased risk of suicidality), cognitive impairment, and most rarely psychosis. The majority of these symptoms are reversible with withdrawal of the agent. Risk of neuropsychiatric side effects is increased with dose, duration of therapy, age of patient, and pre-morbid psychiatric disorder.

Can steroids cause a rise in the intracranial pressure?

Finally, there have been cases of Idiopathic Intracranial Hypertension associated with long term administration of corticosteroid therapy, but these are rare and reversed with cessation of the agents.

Calcineurin inhibitors (CNIs)

The most commonly used CNIs for immunosuppression are cyclosporine and tacrolimus. The precise mechanism of CNI neurotoxicity is still unknown.

A 34 year old patient had a renal transplant donated by sibling a year ago. He now has tremor, headache, and fatigue. the tremor is a fine tremor at rest and on exertion in both hands preventing him from using his cell phone and computer. He has taken 3 days leave of absence from his work as an accountant and needs 4-8 tablets of paracetamol to keep his headache under control. His blood pressure is no longer controlled by his dose of beta blockers.

What could this be caused by?

Tacrolimus and cyclosporine can both cause it. Since he is on tacrolimus reducing or witholding the dose may help to control the symptoms.

He may have Posterior Reversible Encephalopathy Syndrome (PRES) in renal transplant recipients.

Severe neurotoxicity with tacrolimus or cyclosporine is rare in renal transplant, but seizure, polyneuropathy, encephalopathy, visual disturbances, and coma have all been reported.

Neurotoxicity associated with cyclosporine and tacrolimus can present in multiple ways ranging from more common mild symptoms to rare, but life-threatening, manifestations. Approximately half of patients will report at least one neurological symptom, with tremor, headache, and fatigue being among the most frequently observed. These symptoms are frequently associated with higher drug levels and typically resolve either with time, decrease in dose, or in some cases substitution of cyclosporine with tacrolimus or vice versa. Severe neurotoxicity with tacrolimus or cyclosporine is rare in renal transplant, but seizure, polyneuropathy, encephalopathy, visual disturbances, and coma have all been reported.

Both tacrolimus and cyclosporine are associated with development of Posterior Reversible Encephalopathy Syndrome (PRES) in renal transplant recipients. The exact mechanism of PRES is poorly understood but believed to be reversible subcortical brain edema caused by endothelial injury. Brain imaging studies reveal vasogenic edema typically (but not exclusively) of the bilateral parietal and occipital regions. Patients present initially with hypertension, headache, altered mental status, and visual disturbances, and may progress to seizures, stupor, and eventually coma. As the name of the condition suggests, most cases are reversible with supportive care including blood pressure control and discontinuation of responsible agents, but delay in diagnosis may lead to permanent deficits and death. Most cases of CNI-associated PRES presented within the first year after transplant, a majority of patients had CNI levels either elevated or high-normal, and a majority had hypertension. However, there have been cases of CNI-associated PRES with normotension, therapeutic levels of CNI, and after years of treatment.

A distinct pain syndrome has been reported with both tacrolimus and cyclosporine use. Termed Calcineurin Inhibitor Induced Pain Syndrome (CIPS), the entity is associated with bilateral, symmetric distal leg pain sparing hip areas and usually involving the feet, ankles, and knees. CIPS will affect some 2–15% of renal transplant patients on CNIs, and usually presents within the first year after kidney transplant (44). The pain is worsened with activity and improved with rest. Labs will show increased alkaline phosphatase and calcium, and imaging studies (MRI) reveal marrow edema in the regions of pain (45). CIPS is usually self-limited but can recur. . Treatment can be supportive for pain-management, removal of the CNI and replacement with non-CNI immunosuppression, or treatment with calcium channel blocking agents. There is one case report of rapid improvement in symptoms with one-time infusion of iloprost.

Other agents

Bortezomib is a small molecule proteasome inhibitor approved by the FDA for the treatment of multiple myeloma that is now finding increased usage as immunosuppressive therapy for renal transplant patients. Side effects in the renal transplant population are similar to multiple myeloma patients. The significant neurological side effect of bortezomib is a distal peripheral neuropathy and it is fairly common, affecting 20–40% of renal patients. Symptoms initially begin in a “stocking glove” distribution before spreading more proximally. The neuropathy is typically a painful, sensory polyneuropathy; motor neuropathy is rare (51). While reversible, neuropathy symptoms take a median of three months to resolve and may persist for longer. The most significant risk factor for development of neuropathy associated with bortezomib is pre-existing peripheral neuropathy. Some evidence exists suggesting reduction of incidence with concomitant dexamethasone dosing.

Acute neuropathy

Peripheral neuropathy after kidney transplant can present secondary to medications used for immunosuppression and antibiotic prophylaxis, acute neuropathy can also occur as a complication of surgery. The pathophysiology is believed to involve direct compression and ischemia of the nerve, possibly caused by steal phenomenon following anastomosis of the graft renal artery to the iliac artery.Acute femoral neuropathy (AFN) is a relatively uncommon complication, with incidence ranging 2% to 4%. Presentation of AFN can vary depending on where along the nerve’s course the damage occurs. Motor complications are more common, with the majority of patients presenting with weakness of hip flexion and knee extension either immediately after surgery or in the days following. Atrophy of these muscles can occur in severe or prolonged cases. Sensory impairment occurs less frequently and presents as numbness and/or paresthesia of the anterior-medial thigh. EMG studies confirm a femoral neuropathy. Overall prognosis of AFN is good, and recovery of neurologic function is the most frequent outcome, but symptoms may last weeks to months. Treatment includes physical therapy and medications for neuropathic pain in cases of painful sensory neuropathy.


Causes of seizure after renal transplant include drug toxicity, metabolic disorders (electrolyte disturbances), organ dysfunction, CNS infection, ischemic and hemorrhagic stroke, and PRES. Thankfully, the majority of seizures after renal transplant are isolated events and patients will not go on to develop a seizure disorder. Therapy is therefore focused on treating the underlying etiology. There is no role for primary seizure prophylaxis for all post-transplant patients, but patients who do have a seizure should be started on an anti-epileptic regimen. Levetiracetam is the drug of choice for seizure prevention, with lorazepam and fosphenytoin being used for status epilepticus. Levetiracetam is ideal due to its lack of interactions between it and the common immunosuppressive. As it is excreted renally, levetiracetam dosage must be adjusted according to renal function.Go to:


Cerebrovascular disease is seen frequently in patients who have undergone kidney transplantation, with an incidence of stroke or TIA of 5% in the first year and 9.4% in the second year. A large proportion of the incidence can be explained by frequent comorbidities of renal transplant patients; diabetes, age, post-transplant kidney function, and previous stroke are all risk factors for ischemic stroke after transplant while diabetes, PKD, and hypertension are associated with hemorrhagic stroke.

Renal patients also may develop post-transplant polycythemia and hypercoagulability which increase the risk of stroke. Prevention is aimed at control of risk factors (cholesterol, hyperglycemia, and hypertension) as well as prevention via antiplatelet agents such as aspirin. Control of cholesterol is especially important as some of the immunosuppressive regimens may cause hypercholesterolemia. Prophylactic anticoagulation is not a mainstay of therapy for all patients post-transplant.


Solid organ transplant recipients have a four-fold increased incidence of malignancy compared to the general population, and this is believed to be due to decreased immune surveillance and an increased susceptibility to oncogenic viruses due to immunosuppression. Post transplant lymphoma disorder (PTLD) is the most common malignancy seen after renal transplant. Post-operative primary CNS tumor is uncommon. While renal transplant is associated with lower rates of PTLD compared to most organ systems, a small percentage (1–2%) of kidney recipients will develop this complication. The two largest risk factors for development of PTLD after renal transplant are immunosuppression and Epstein Bar Virus serostatus. There is an increased risk (up to twenty-four fold) of PTLD among EBV-negative recipients of EBV-positive donor organs. The majority of PTLD tumors in transplant patients contain the EBV genome, suggesting a pathogenic role for the virus. However, EBV negative PTLD has been documented a minority (30%) of PTLD patients and the EBV genome can also be found in patients with this tumor who are not immunosuppressed.

Kidney transplantation is the most common solid organ transplant in the United States, with over 17,000 transplants performed annually while over 100,000 patients remain on the waiting list. This number has continued to rise over the past years as kidney transplantation offers improved survival and quality of life compared to hemodialysis for the majority of patients with end-stage renal disease, and is ultimately more cost-effective over the course of patients’ lives. However, during the first year after transplant, patients frequently encounter complications requiring hospitalization, typically due to immunosuppressive medications or infection due to chronic immunosuppression. Neurological complications are a common issue after kidney transplant, with between 30–60% of patients experiencing some neurological complication. Neurological complications are associated with increased morbidity and mortality and should be kept on the differential for all post-transplant patients. Discussed here are the most common etiologies of neurological complication after kidney transplant: infection, malignancy, medication, surgical complications, seizure, and stroke.


As immunosuppression has improved, organ transplant has become more common and safer overall. As more patients experience improved survival, the total number of patients at risk for chronic complications increases as well. Neurological symptoms are a significant contributor to morbidity and mortality after kidney transplant. Serious neurological complications result in hospitalization, and therefore physicians must be aware of the conditions unique to this population.

Aaron Shoskes and Robert W

Transl Androl Urol. 2019 Apr; 8(2): 164–172.doi: 10.21037/tau.2018.08.11

Progressive Dyspnoea: Pulmonary fibrosis.

Revising a little physiology of the lungs.

The lungs are very soft spongy organs whose purpose is to allow air from the atmosphere (by volume, dry air contains 78.09% nitrogen, 20.95% oxygen, 0.93% argon, 0.04% carbon dioxide, and small amounts of other gases. Air also contains a variable amount of water vapor, on average around 1% at sea level, and 0.4% over the entire atmosphere). The pressure in the pulmonary capillaries is always kept below the plasma protein oncotic pressure to prevent the transudation of interstitial fluid so the inside of the pulmonary capillary wall is kept dry. The input pressure into the capillary bed represents the mean pulmonary arterial pressure (15 mmHg). The output pressure represents the pulmonary venous pressure, which is also equivalent to the pulmonary capillary wedge pressure or left atrial pressure (5 to 6 mmHg). Total blood flow represents the cardiac output (5 to 6 L/min).

Pulmonary blood pressure is normally a lot lower than systemic blood pressure. Normal pulmonary artery pressure is 8-20 mm Hg at rest. If the pressure in the pulmonary artery is greater than 25 mm Hg at rest or 30 mmHg during physical activity, it is abnormally high and is called pulmonary hypertension.

The pressure drop from the pulmonary arteries to the left atrium is approximately 10 mmHg compared against a 100 mmHg pressure gradient in the systemic circulation. Therefore, PVR (pulmonary vascular resistance) is one-tenth of the resistance of systemic circulation. Low PVR maximizes the distribution of blood to the peripheral alveoli and ultimately allows for proper gas exchange. Multiple mechanisms regulate and contribute to pulmonary vascular resistance. Broad categories include pulmonary vascular pressure, lung volume, gravity, smooth muscle tonicity, and alveolar hypoxia. All these can be can play a role in interstitial lung diseases.

Complete pulmonary function testing (PFT; spirometry, lung volumes, diffusing capacity for carbon monoxide [DLCO]) and resting and ambulatory pulse oximetry are obtained in virtually all patients with suspected ILD. These tests are helpful in establishing the pattern of lung involvement (eg, restrictive, obstructive, or mixed) and assessing the severity of impairment. In patients with IPF, PFTs typically demonstrate a restrictive pattern (eg, reduced forced vital capacity [FVC], but normal ratio of forced expiratory volume in one second [FEV1]/FVC), a reduced DLCO, and, as the disease progresses, a decrease in the six-minute walk distance.

What does the pulmonary capillary wedge pressure represent?

It measures the left atrial pressure and is normally 5-6 mmHg,

A 65 year old man sees his doctor because he is feeling very tired and gets breathless within 50 feet of walking on flat ground. Two months ago he could walk for 2 kilometre daily at a brisk pace as part of his physical fitness regime. He has an irritating cough but does not bring up any sputum. He is afebrile, has no chest pain or muscle aches and pains in his limbs or trunk. His appetite is as usual. What other information would you ask him for?

Is he a smoker? Ask for details.

Has he been exposed to silica or dust? He could have visited a mine or inspected a stone crusher or gone on a desert safari?

Has he been treated with radiation or any drugs for cancer therapy?

Has he been started on new drugs for joint diseases like rheumatoid arthritis?

Does he feel that his eyes are dry? Does he have a dry mouth? (Sjogren’s syndrome, scleroderma).

Do his fingers and toes become cold and blue in cold water? Look for other manifestations of SLE, rheumatoid arthritis.

Does he think his muscles are getting weak i.e. he cannot climb stairs, get out of a low or soft chair or carry heavy grocery bags etc? Is he Cushingoid? May have been on corticosteroids causing proximal myopathy.

Is there a family history of lung disease or any of these diseases: ILD, premature graying, cryptogenic cirrhosis, aplastic anemia, other bone marrow diseases

You suspect fibrosis in the lungs. When you take a history and examine this patient what will you look for?

First exclude heart failure as it is much more common than ILD. Does he have hypertension or heart failure or an arrhythmia? Any ECG changes of IHD?

In ILD other than disease-specific symptoms, cough, progressive exertional dyspnea, and exercise limitation are the main presenting symptoms. The diagnosis is often delayed by several months or even years. A thorough history, including environmental exposures, medication use, and extrapulmonary signs, should be taken as given above. On chest auscultation, fine crackles (also called Velcro rales or crepitations) are indicative of fibrosis, although squeaks may be heard in patients with hypersensitivity pneumonitis. Premature graying of hair and hematologic abnormalities may be a sign of telomeropathy-related fibrosis. In CTDs, pulmonary fibrosis may develop either after the underlying condition is diagnosed or before the extrapulmonary manifestations are observed. Hands, joints, and skin should be thoroughly examined.  

What tests will you do to confirm your diagnosis?

 There is no laboratory test specific for a diagnosis of IPF, so the role of laboratory testing in patients with newly identified ILD is to identify or exclude processes in the differential diagnosis.

Chest imaging.

  1. Chest Xray.
  2. HRCT. A diagnosis of IPF cannot be made based on HRCT appearance alone. The characteristic HRCT features of IPF include peripheral, basilar predominant opacities associated with honeycombing and traction bronchiectasis-bronchiolectasis. Honeycombing refers to clusters of cystic airspaces approximately 3 to 10 mm in diameter, usually in a subpleural location. While honeycombing is essential to making a definite HRCT diagnosis of usual interstitial pneumonia (UIP), it is absent in probable and indeterminate UIP

Serological tests.

  1. Rule out connective tissue disorders: SLE, rheumatoid arthritis: antinuclear antibodies, anti-cyclic citrullinated peptide antibodies, and rheumatoid factor.
  2. Determine degree of inflammation currently: C-reactive protein (CRP) and erythrocyte sedimentation rate are nonspecific measures.
  3. If suggestive symptoms or signs are present: antisynthetase and other myositis panel antibodies (eg, anti-Jo-1, anti-PL7, anti-melanoma differentiation associated gene [MDA]-5), creatine kinase, aldolase, Sjögren’s antibodies (anti-SS-A, anti-SS-B), and scleroderma antibodies (anti-topoisomerase [scl-70], anti-PM-1).

Complete lung function

The CLP are done to establish the pattern of lung involvement (eg, restrictive, obstructive, or mixed). The major types of pulmonary function tests (PFTs) are spirometry, spirometry before and after a bronchodilator, lung volumes, and quantitation of diffusing capacity for carbon monoxide. Additional PFTs, such as measurement of maximal respiratory pressures, flow-volume loops, submaximal exercise testing, and bronchoprovocation challenge, are useful in specific clinical circumstances. Before doing lung function tests withhold bronchodilators i.e. short-acting inhaled bronchodilators (eg, albuterol, salbutamol, ipratropium) should not be used for four hours prior to testing. Long-acting beta-agonist bronchodilators (eg, salmeterolformoterol) are typically held for 12 hours prior to testing. The ultra long-acting beta agonists (eg, indacaterololodaterol, vilanterol) and the long-acting anticholinergic agents glycopyrrolate (glycopyrronium), tiotropium, and umeclidinium are held for 24 hours. Aclidinium would be held for 12 hours, based on twice daily dosing. 

Spirometry, the most readily available and useful pulmonary function test, measures the volume of air exhaled at specific time points during a forceful and complete exhalation after a maximal inhalation. The total exhaled volume, known as the forced vital capacity (FVC), the volume exhaled in the first second, known as the forced expiratory volume in one second (FEV1), and their ratio (FEV1/FVC) are the most important variables reported.

When to use spirometry? Spirometry is a key diagnostic test for asthma and chronic obstructive pulmonary disease (COPD) (when performed before and after bronchodilator) and is useful to assess for asthma or other causes of airflow obstruction in the evaluation of chronic cough. It is also used to monitor a broad spectrum of respiratory diseases, including asthma, COPD, interstitial lung disease, and neuromuscular diseases affecting respiratory muscles.

The slow vital capacity (SVC) can also be measured with spirometers which collect data for at least 30 seconds. The SVC may be a useful measurement when the FVC is reduced and airway obstruction is present. Slow exhalation results in a lesser degree of airway narrowing, and the patient may produce a larger, even normal vital capacity. In contrast, the vital capacity with restrictive disease is reduced during both slow and fast maneuvers. 

Performance of spirometry before and after bronchodilator is used to determine the degree of reversibility of airflow limitation. Administration of albuterol by metered-dose inhaler (MDI) is indicated if baseline spirometry demonstrates airway obstruction or if one suspects asthma or COPD. Albuterol (4 inhalations of 90 to 100 mcg) or an equivalent short-acting beta agonist is administered by metered dose inhaler with a spacer or chamber device.

In a patient with airway obstruction, an increase in the FEV1 of more than 12 percent and greater than 0.2 L suggests acute bronchodilator responsiveness . In patients with asthma, bronchodilator administration often results in improvement, and in some patients with asthma, post-bronchodilator testing may improve to normal spirometry values. Among patients with COPD, administration of bronchodilator sometimes leads to a significant change in FEV1, but reversal to normal spirometry rules out a diagnosis of COPD.

 Airway obstruction located in the pharynx, larynx, or trachea (upper airways) is usually impossible to detect from standard FVC maneuvers. Whenever stridor is heard over the neck and for evaluation of unexplained dyspnea flow-volume loops, which include forced inspiratory and expiratory maneuvers, are performed. Reproducible forced inspiratory vital capacity (FIVC) maneuvers may detect variable extrathoracic upper airway obstruction, as can be seen with vocal fold paralysis or dysfunction, which causes a characteristic limitation of flow (plateau) during forced inhalation but little if any obstruction during exhalation.

Bronchoprovocation challenge.  Spirometry is used to assess the airway hyperresponsiveness to a variety of bronchoprovocation challenges, such as methacholine, histamine, mannitol, and isocapnic hyperpnea. 

When is supine and sitting spirometry used? How can you assess diaphragmatic weakness? To evaluate respiratory muscle weakness, spirometry can be obtained with the patient supine and sitting. Diaphragmatic weakness is suggested by a decrease in the supine VC >10 percent. Unilateral diaphragmatic paralysis is usually associated with a decrease in VC of 15 to 25 percent; bilateral diaphragmatic paralysis can be associated with a decrease in supine VC approaching 50 percent.

Imaging with the patient in the prone position should be performed only if there are subtle dependent opacities of unclear clinical significance.

When should lung volumes be determined and how? Measurement of lung volumes is important when spirometry shows a decreased forced vital capacity. Body plethysmography is the gold standard for measurement of lung volumes, particularly in the setting of significant airflow obstruction. Alternative methods include helium dilution, nitrogen washout, and measurements based on chest imaging.

Maximal inspiratory pressure (MIP), measured at RV, is the maximal pressure that can be produced by the patient trying to inhale through a blocked mouthpiece after a full exhalation. Maximal expiratory pressure (MEP) is the maximal pressure measured during forced expiration (with cheeks bulging) through a blocked mouthpiece after a full inhalation (TLC). Measurement of maximal inspiratory and expiratory pressures is indicated whenever there is an unexplained decrease in vital capacity or respiratory muscle weakness is suspected clinically.

Measurement of the single-breath diffusing capacity for carbon monoxide (DLCO, also known as transfer factor or TLCO) is quick, safe, and useful in the evaluation of restrictive and obstructive lung disease, as well as pulmonary vascular disease.

In the setting of restrictive disease, the diffusing capacity helps distinguish between intrinsic lung disease, in which DLCO is usually reduced, and other causes of restriction, in which DLCO is usually normal. In the setting of obstructive disease, the DLCO helps distinguish between emphysema and other causes of chronic airway obstruction.

Six-minute walk test — The six-minute walk test (6MWT) is a good index of physical function and therapeutic response in patients with chronic lung disease, such as COPD, pulmonary fibrosis, or pulmonary arterial hypertension. During a 6MWT, healthy subjects can typically walk 400 to 700 m. In addition to total distance walked, the magnitude of desaturation and timing of heart rate recovery have been associated with clinical outcomes.

The incremental shuttle walk test (ISWT) is a 12 level test in which the subject walks at a progressively increasing speed for 12 minutes over a 10 meter course, where each 10 m trip between cones is a “shuttle”. Heart rate can be monitored by pulse oximetry or telemetry. The walking speed increases every minute from an initial 0.5 m/sec to 2.37 m/sec at level 12. The test is stopped when the subject is limited by dyspnea or heart rate (>85 percent predicted maximum), is unable to maintain the required speed, or completes the 12 levels. The primary outcome is the distance covered, which is calculated from the number of completed shuttles.

Pulse oxygen saturation 

A clear consensus has not been reached about what value for resting oximetry differentiates normal and abnormal. At sea level, values for pulse oxygen saturation (SpO2) ≤95 percent are considered abnormal, although a decrease to 96 percent in a patient who has previous values of 99 percent could be abnormal. Exertional decreases in SpO2 ≥5 percentage points are also considered abnormal. A value of SpO2 ≤88 percent is generally an indication for supplemental oxygen, although the benefits of supplemental oxygen in patients with normal resting saturations and exertional decreases to ≤88 percent are unclear. Confirm by checking ABGs.

Arterial blood gases  are a helpful adjunct to pulmonary function testing in selected patients. The primary role of measuring ABGs in stable outpatients is to confirm hypercapnia when it is suspected on the basis of clinical history (eg, respiratory muscle weakness, advanced COPD), an elevated serum bicarbonate level, and/or chronic hypoxemia. ABGs also provide a more accurate assessment of the severity of gas exchange impairment in patients who have low normal pulse oxygen saturation (eg, <92 percent).

When do you need to do pulmonary function tests?

  1. Evaluation of symptoms such as chronic persistent cough, wheezing, dyspnea, and exertional cough or chest pain
  2. Objective assessment of bronchodilator therapy
  3. Evaluation of effects of exposure to dusts or chemicals at work
  4. Risk evaluation of patients prior to thoracic or upper abdominal surgery
  5. Objective assessment of respiratory impairment
  6. Monitoring disease course and response to therapy

Why does pulmonary fibrosis develop?

The brief answer is we don’t know. Keep exposure to birds and molds in mind as well as pulmonary sarcoidosis, an underlying autoimmune disease, or if no cause is identified, an idiopathic interstitial pneumonia

The formation of fibrosis is an essential response against pathogens and in normal wound healing. Much is still unknown about the pathophysiology of specific disease entities and the factors that differentiate normal wound repair from progression to fibrosis. What factors are needed to cause persistent pulmonary fibrosis? Triggers, susceptibility, and initial inflammatory responses are required to initiate and maintain fibrosis and and the degree of each varies among diseases. The current assumption is that in later phases, common mechanisms play a role. At this stage clinical intervention is unlikely to help the patient.

At present the most favored hypothesis for the formation of pulmonary fibrosis is the early aging of alveolar epithelial cells and subclinical pathogenic stimulus. Senescence of alveolar epithelial cells and fibroblasts appears to be a central phenotype that promotes lung fibrosis.

What role do bacteria play in the development of fibrosis?

Innate immune cells, such as monocyte-derived alveolar macrophages, appear to be critical for the development of lung fibrosis. In one study, bacterial DNA could not be detected in lung tissue from patients with IPF, but other work has identified an abundance of prevotella, veillonella, and escherichia in bronchoalveolar-lavage fluid from such patients. In addition, both an increased overall bacterial burden and an abundance of streptococcal and staphylococcal organisms have been associated with an increased risk of disease progression in patients with IPF.

Diffuse parenchymal lung diseases encompass a large number of conditions, which are fortunately rare. They have an intrinsic heterogeneity. In most of them, the pulmonary alveolar walls are infiltrated by various combinations of inflammatory cells, fibrosis, and proliferation of certain cells that make up the normal alveolar wall. Since these pathologic abnormalities predominate in the lung interstitium, the disorders are termed interstitial lung diseases (ILDs). The commonest of these lung diseases is idiopathic pulmonary fibrosis (IPF). Among all patients with fibrotic ILDs other than IPF, 13 to 40% have a progressive fibrosing phenotype i.e. are genetic in susceptibility.

ILDs can be divided into five broad clinical categories, however clinicians most often see patients with CTD–ILD, IPF, CHP, sarcoidosis, or unclassifiable fibrotic ILD.

  1. ILDs related to distinct primary diseases (e.g., sarcoidosis, Langerhans-cell granulomatosis, eosinophilic pneumonia, lymphangioleiomyomatosis, and pulmonary alveolar proteinosis);
  2. ILDs related to environmental exposures, including pneumoconiosis due to inhalation of inorganic substances (asbestos, silica, other fumes, vapors, dusts) and hypersensitivity pneumonitis mostly related to inhalation of organic particles (e.g., domestic or occupational exposure to mold or birds or other exposures);
  3. ILDs induced by drugs, illicit drugs, or irradiation; amiodaronebleomycin, long-term nitrofurantoin, biologic therapies)
  4. ILDs associated with connective tissue disorders (CTDs), including RA–ILD and SSc–ILD, idiopathic inflammatory myopathy, and primary Sjögren’s disease.
  5. Idiopathic interstitial pneumonias, which include IPF, idiopathic nonspecific interstitial pneumonia.

Currently, there is a specific interest in the potential development of fibrosis after coronavirus disease 2019 (Covid-19). Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of pulmonary symptoms, male sex, older age, obesity, and coexisting conditions appear to be risk factors for the development of SARS. Pulmonary fibrosis is a known complication of acute respiratory distress syndrome (ARDS), and there are similarities in the fibroproliferative response and risk factors between lung fibrosis in the context of ARDS and lung fibrosis in the context of other diseases. Nevertheless, analysis of long-term follow-up data after ARDS or infection with another strain of SARS-CoV in 2003 showed fibrotic changes that remained mostly stable over time and had little clinical relevance.

Having made a diagnosis of IPF it is necessary to distinguish it from other forms of ILD.

Shown below are some patterns of imaging in ILD.

Some atypical features of IPf include including upper-lung or midlung predominance, peribronchovascular predominance, subpleural sparing, predominant consolidation, extensive ground-glass opacities, extensive mosaic attenuation , and diffuse nodules or cysts, should raise suspicion of an interstitial lung disease other than IPF.

Lung biopsy.

When the combination of clinical and imaging data is not diagnostic, a thoracoscopic lung biopsy can be considered if the results are expected to influence therapy. Biopsy samples should be taken from multiple lobes, and surgeons should avoid sampling the most severely affected areas, since samples from these areas typically show advanced, nondiagnostic fibrosis. The procedure should not be performed in high-risk patients, including those with high oxygen requirements (e.g., >2 liters per minute), pulmonary hypertension, rapid disease progression, severely reduced FVC or DLco, multiple coexisting conditions, or frailty. Transbronchial lung cryobiopsy has been increasingly advocated as a replacement for thoracoscopic biopsy.

Nonpharmacologic management strategies help patients with IPF live healthier, more normal lives, and the importance of these approaches cannot be overemphasized. Smoking cessation should be a priority for patients who are actively using tobacco products. Influenza, pneumococcal, and other age-appropriate vaccines should be administered. Oxygen administration reduces exertional dyspnea and improves exercise tolerance.57 An oxyhemoglobin saturation of 88% or less at rest, during exertion, or during sleep should prompt initiation of home oxygen therapy. The oxygen prescription should be informed by 6-minute walk tests or treadmill testing of oxygen saturation, as well as by nocturnal oximetry or polysomnography when indicated 

Pulmonary rehabilitation, a structured exercise program designed for adults with advanced lung disease, has been shown to improve exercise capacity and health-related quality of life for patients with IPF.

Only a minority of patients with IPF receive a transplant. Lung transplantation can prolong survival and improve quality of life for highly selected candidates however, only 66% of transplant recipients with IPF survive for more than 3 years after transplantation and only 53% survive for more than 5 years. Common complications include primary graft dysfunction, acute and chronic forms of allograft rejection, cytomegaloviral and other infections, and cancer. IPF has not been shown to recur in the allograft. 

Pharmacological therapy is available but is prohibitively expensive.

Two medications, nintedanib and pirfenidone, have been shown to be safe and effective in the treatment of IPF; both are recommended for use in patients with IPF In placebo-controlled, randomized trials, each drug has been shown to slow the rate of FVC decline by approximately 50% over the course of 1 year. Both have shown some efficacy in reducing severe respiratory events, such as acute exacerbations, and hospitalization for respiratory events. Pooled data and meta-analyses suggest that these agents may reduce mortality. The cost of each medication is estimated to exceed $100,000 annually. Patients should initially be prescribed 150 mg of nintedanib, to be taken by mouth twice daily. The medication should be taken with food and can be continued indefinitely. Patients taking nintedanib commonly have diarrhea, which can often be managed with antidiarrheal agents. The dose can be decreased to 100 mg twice daily if unmanageable side effects occur. Monitor liver function tests ans avoid if patient is on anticoagulants. Caution should be used when treating patients with cardiovascular risk factors, including those who have coronary artery disease.

Treatment guidelines for IPF include a strong recommendation against the use of prednisone in combination with azathioprine and oral N-acetylcysteine, a regimen associated with an increase in mortality by a factor of 9, as compared with placebo. A clinical trial showed no effect of N-acetylcysteine monotherapy on lung function. Interferon-γ, endothelin antagonists, and warfarin are ineffective or harmful in patients with IPF.

There are no data from clinical trials to support the use of antacids to slow the progression of IPF or ILD.

A phase 2 trial of pamrevlumab, an intravenously administered antibody targeting connective-tissue growth factor, slowed the decline in FVC, as compared with placebo, over a period of 48 weeks. PBI-4050, which targets multiple profibrotic cytokines and alters fibroblast function, may improve FVC when administered in combination with nintedanib. 

TD139, an inhaled galectin-3 inhibitor, has been shown to lower galectin-3 expression on alveolar macrophages in IPF.

Trials of BMS-986020 ( number, NCT01766817. opens in new tab), an oral LPA antagonist, and BG00011 (NCT01371305. opens in new tab), a monoclonal antibody targeting the αVβ6 integrin, have been completed, and the results are pending. A phase 1 study has shown that PRM-151 (recombinant pentraxin-2) is safe in patients with IPF; a phase 2 study (NCT02550873. opens in new tab) has been completed.

Two clinical trials of antimicrobial therapy potentially targeting the lung microbiome in IPF are ongoing (NCT02759120. opens in new tab; and EudraCT number, 2014-004058-32. opens in new tab).

Controlling cough.

There are several possible approaches for the management of cough in IPF, though none are universally effective.

  1. A trial of thalidomide confirmed that it could be used to ameliorate cough in patients with IPF.
  2. pirfenidone may attenuate cough.
  3. The P2X3 antagonist AF-219/MK-7264 (gefapixant) suppresses idiopathic cough; a trial of this agent in patients with IPF has been completed.
  4. Inhaled cromolyn preparation was shown to ameliorate cough in patients with IPF.

Watch out for complications.

Patients with IPF are at increased risk for venous thromboembolism, lung cancer, and pulmonary hypertension.

Incidental pulmonary nodules should be managed according to established guidelines for high-risk patients.

Pulmonary hypertension occurs in some patients with IPF, management in the outpatient setting should consist solely of supplemental oxygen, without pulmonary vasodilator therapy.

Once believed to be a single disease caused by smoking and characterized by a progressive loss of lung function with age, COPD should currently be considered a clinical syndrome with many causes in addition to smoking. This does not mean that health care professionals should refrain from encouraging all their patients who smoke to quit, but it does mean that the pathogenic mechanisms in mild-to-moderate COPD may differ from those in severe-to-very-severe cases of airflow limitation.

Idiopathic Pulmonary Fibrosis

List of authors.

  • David J. Lederer, M.D., 
  • and Fernando J. Martinez, M.D.

May 10, 2018
N Engl J Med 2018; 378:1811-1823
DOI: 10.1056/NEJMra1705751.

Heart Failure: Types: Management.

What exactly is heart failure?

The clinical syndrome of heart failure arises when impairment of ventricular filling or ejection of blood results in the inability of the heart to provide adequate perfusion to the tissues while maintaining normal cardiac filling pressures. The ejection fraction is measured or clinical signs of a failing heart are assessed. Clinical signs which should worry the clinician are worsening dyspnoea specially the inability to perform personal functions like walking for personal tasks, changing clothes or bathing without help, loss of appetite with loss of muscle mass and cachexia, refractory fluid retention like edema, ascites, pulmonary edema. Patients with low cardiac output may have signs of poor perfusion, including narrowed pulse pressure, cool extremities, hypotension, and mental status changes.

What is the end result of heart failure?

The patient dies earlier than if they did not have heart failure, they need hospitalisation more frequently, renal dialysis may need to be initiated earlier and the general quality of life deteriorates.

How will you determine the severity and etiology of heart failure or cardiomyopathy?

There is no diagnostic test for HF, since it is largely a clinical diagnosis that is based upon a careful history and physical examination. Clinician should take note of impaired renal function tests, hypoalbuminemia, hyponatremia, a falling hemoglobin and in the case of right heart failure impaired liver function tests. Elevated serum natriuretic peptide levels  are present in advanced heart failure but no specific level indicates the degree of heart failure. An ECG and an x ray chest are useful and essential tests. Patients presenting with fluid retention may complain of leg or abdominal swelling. If new episodes of ischemic heart disease are suspected check Troponin T or I.

What should you concentrate on in the history? Ask about the level of exercise that the patient can manage. Take a history according to the New York Heart Association. This is based on the ability of the patient to do physical exercise or work as given below:

  • Class I – Patients with heart disease without resulting limitation of physical activity. Ordinary physical activity does not cause HF symptoms such as fatigue or dyspnea.
  • Class II – Patients with heart disease resulting in slight limitation of physical activity. Symptoms of HF develop with ordinary activity but there are no symptoms at rest.
  • Class III – Patients with heart disease resulting in marked limitation of physical activity. Symptoms of HF develop with less than ordinary physical activity but there are no symptoms at rest.
  • Class IV – Patients with heart disease resulting in inability to carry on any physical activity without discomfort. Symptoms of HF may occur even at rest. This constitutes refractory HF requiring specialized interventions. This stage includes patients in NYHA functional class IV with refractory HF.

To follow up your patient you must maintain accurate records.

What else will the history tell you?

  • New symptoms; angina getting worse, either more frequent or prolonged or unprovoked; patient has changed his routine and is doing more exercise or carrying unaccustomed load;
  • Palpitations; dizziness; syncope; disorientation.
  • New medication has been prescribed like a calcium channel blocker, beta blocker or diuretic or NSAID.
  • Stroke.
  • Embolic event.
  • Recent infection like a cold, flue, pneumonia, UTI.
  • BP has gone out of control.
  • Emotional event or depression.

All these can change the stage of heart failure that the patient is in. Heart failure is classified into stages which affect the management of heart failure? Heart failure is a progressive syndrome which evolves through different stages. Staging helps to determine whether there is worsening of the failure, the need for special intervention or drugs or the need to deal with structural changes surgically. Given below are the stages.

Stages in the development of HF — There are several stages in the evolution of HF, as outlined by the American College of Cardiology Foundation/American Heart Association guidelines:

  1. Stage A – At high risk for HF but without structural heart disease or symptoms of HF.
  2. Stage B – Structural heart disease but without signs or symptoms of HF. This stage includes patients in NYHA functional class I with no prior or current symptoms or signs of HF.
  3. Stage C – Structural heart disease with prior or current symptoms of HF. This stage includes patients in any NYHA functional class (including class I with prior symptoms).
  4. Stage D – Refractory HF requiring specialized interventions. This stage includes patients in NYHA functional class IV with refractory HF.

Which diagnoses can be missed clinically? In two series, in which explanted hearts were assessed each spanning two decades, 17 and 13 percent of patients were misdiagnosed prior to transplantation, particularly patients with nonischemic cardiomyopathy (30 and 22 percent with clinical misdiagnosis).Conditions that can be missed clinically include cardiac sarcoidosis, myocarditis, arrhythmogenic right ventricular cardiomyopathy (in both series), and hypertrophic cardiomyopathy and noncompaction (in one series).

There are two basic pathophysiologic myocardial mechanisms that cause reduced cardiac output and HF: systolic and diastolic dysfunction. Systolic and diastolic dysfunction each may be due to a variety of etiologies.

What is systolic heart failure?

Heart failure with reduced ejection fraction — HF with reduced EF ([HFrEF] is also known as systolic HF or HF due to systolic dysfunction. Most randomized controlled trials for HF have enrolled patients with HFrEF, and therapy with established efficacy is available for HFrEF but not HF with preserved EF (HFpEF)

What is the etiology of heart failure with reduced ejection fraction?

Coronary artery disease accounts for 62%; hypertension was a major cause is now less frequent as the blood pressure can now be better controlled, accounts for 10%. Idiopathic dilated cardiomyopathy (DCM), and valvular disease are other likely causes.

In dilated cardiomyopathy 50% are still labelled idiopathic indicating how little we know. In diagnoses that are missed myocarditis accounts for 9% and IHD for 7%, infiltrative diseases like amyloid account for 5%, peripartum cardiomyopathy for 4% as does hypertension and HIV. Connective tissue disorders account for 3%, substance abuse also for 3%, doxorubicin and other unknown causes for 10%.

The history will help you diagnose IHD, hypertension, drug and substance abuse and, combined with a clinical examination, valvular heart disease.

Heart failure with preserved ejection fraction — HFpEF is also known as diastolic HF. This refers to HF in patients with a left ventricular EF ≥50 percent or >50 percent. Patients with left ventricular EFs between 41 and 49 may be categorized as having “HFpEF, borderline” with characteristics similar to patients with HFpEF. Previously thought to occur in the aging population is now often found in patients below the age of 60 years. The most significant symptom is chest pain with no epicardial changes in the ECG. Increasing dyspnoea and orthopnoea are other common problems as well as fatigue.

The most common stresses encountered by patients with HFpEF are exercise, AF, hypertension, intravenous fluid load, and ischemia:

When will you assess for systolic function?

  1. When there are signs and symptoms of heart failure or when these signs are worsening.
  2. Signs or symptoms suggestive of heart disease such as unexplained electrocardiographic abnormality, palpitations, stroke, or peripheral embolic event.
  3. When information on LV systolic function as well as diastolic function, chamber geometry, regional wall motion, and valve function is needed for diagnosis and management.
  4. When there are signs or symptoms of coronary artery disease assessment of regional and global LV systolic function is commonly combined with stress testing.
  5. The presence of ventricular arrhythmias is a common indication for evaluation of LV function and structure as part of an evaluation to determine whether there is a structural cause for the arrhythmia.
  6. Planned or prior exposure to potentially cardiotoxic therapy. Patients undergoing treatment with potentially cardiotoxic therapy require serial evaluation of LV systolic function for early detection of cardiotoxicity, which may affect continued treatment.
  7. Evaluation of cardiac risk prior to a procedure for which LV systolic dysfunction may be a risk factor or contraindication such renal transplant.

Definition — LVEF is a measure of the percentage of blood ejected during systole in relation to the total end-diastolic volume. The stroke volume (SV) is the difference between end-diastolic and end-systolic LV volumes. LVEF is calculated by dividing the SV by the end-diastolic volume as follows:

SV = (LV end-diastolic volume) – (LV end-systolic volume)

LVEF (%) = SV/ (LV end-diastolic volume) x 100

A larger ventricle requires a lower EF to achieve the same SV (as compared with a smaller ventricle).

In addition to quantitative calculation of LVEF, semi-quantitative (eg, visual estimates) and qualitative (normal, hyperdynamic, depressed) assessments of LV systolic function have also been described and used clinically 

How robust or reliable is EF in clinical practice?

  1. LVEF does not give the cause of reduction of LV function hence is not based upon etiology or pathophysiology. It has been included in as a criterion in many clinical trials (including HF trials).
  2. LVEF does not indicate whether the dysfunction in the ventricle is global or regional.
  3. LVEF does not give the size of the ventricle.
  4. It commonly changes over time, may be impacted by blood pressure and valvular function, and slightly varies by the method used.

What are the methods used for measuring EF?

Echocardiography, cardiovascular magnetic resonance (CMR), cardiac computed tomography, and radionuclide angiography can all be used to measure EF.

When to suspect advanced heart failure.

Advanced HF should be suspected when a patient with HF experiences persistent severe symptoms despite optimal evidence-based therapy (pharmacologic therapy plus cardiac resynchronization therapy, as indicated and tolerated). The patient may already have diagnosed heart disease or may develop advanced failure at the first instant.

To evaluate advanced heart failure do an echocardiography which can be useful for assessment of biventricular function, estimating hemodynamics, and evaluation other cardiac conditions such as valve disease, congenital abnormalities, and pericardial disease.

Objective assessment of exercise capacity with a six-minute walk test and/or a cardiopulmonary exercise test can confirm the presence of severely limited exercise capacity, quantified it by measuring oxygen uptake (Vo2).

What is the refractory volume overload

Patients with advanced HF often present with refractory volume overload despite escalating doses of diuretics.

  1. Volume overload: look for pulmonary congestion, peripheral edema, ascites, and elevated jugular venous pressure.
  2. A requirement of very high doses of loop diuretics, such as furosemide ≥160 mg/day or equivalent, or frequent use of metolazone is common in advanced HF.
  3. Look for worsening renal function.
  4. Inadequate diuresis despite escalating doses of diuretics.

What else could the symptoms be caused by?

  1. Differential diagnosis of fatigue include deconditioning, sleep apnea, and depression.
  2. Chronic obstructive pulmonary disease and HF may be difficult to distinguish.
  3. Patients presenting with fluid retention may complain of leg or abdominal swelling.
  4. HF should be distinguished from other causes of edema including venous thrombosis or insufficiency, renal sodium retention, drug side effect (eg, calcium channel blocker), and cirrhosis.

What abnormality do patients with diastolic heart failure display?

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome in which patients have symptoms and signs of HF with normal or near normal left ventricular ejection fraction (LVEF ≥50 percent). Patients with HFpEF display normal LV volumes and evidence of diastolic dysfunction eg, abnormal pattern of LV filling and elevated filling pressures. HFpEF can be caused by all the conditions that cause HFrEF and specially valvular heart disease, pericardial disease, and high output HF.

How to treat HFpEF.

Pharmacological treatment of HFrEF.

The goals of pharmacologic therapy of HFrEF are to improve symptoms, reduce risk of hospitalization, slow or reverse deterioration in myocardial function, and reduce mortality.

 The heart contains mineralocorticoid receptors and aldosterone is produced locally in the diseased heart in proportion to the severity of HF. The latter effect is mediated by the induction of aldosterone synthase (CYP11B2) by angiotensin II in the failing ventricle. Locally produced aldosterone may create a vicious cycle by stimulating angiotensin converting enzymes in the local renin-angiotensin system, an effect blocked by mineralocorticoid receptor antagonism. Direct effects of aldosterone on the heart may include promoting the development of cardiac hypertrophy and fibrosis, proarrhythmia, and, with chronic pressure overload, promoting the transition from hypertrophy to HF.

Activatable mineralocorticoid receptors are also present in coronary artery and aortic vascular smooth muscle cells. These receptors can be activated by aldosterone as well as by angiotensin II; thus, inhibition of this system may contribute to the beneficial effects of angiotensin inhibition in patients with HF.

Activation of these receptors may contribute to the increased incidence of stroke and coronary events in patients with primary aldosteronism compared with matched patients with primary (essential) hypertension. Ref: RALES trial.

Clinical trials in HFpEF do not show good results with treatment.

Treatment is aimed at the causative conditions.

In patients with current or recent (eg, within 60 days) elevated natriuretic peptide (either brain natriuretic peptide [BNP] ≥100 pg per mL or N-terminal pro-BNP [NT-proBNP] ≥360 pg per mL) who can be carefully monitored for changes in serum potassium and renal function, use suggest treatment with a mineralocorticoid receptor antagonist 

Mineralocorticoids receptor antagonist.

  1. Spironolactone; the initial dose is 12.5 mg once daily, which is titrated as tolerated every four weeks to the maximum tolerated dose. The goal dose is 25 to 50 mg, provided that there is no dose-limiting hyperkalemia, worsening renal function, or hypotension.
  2. Eplerenone; the initial dose is 25 mg once daily, which is titrated in four weeks to 50 mg, as tolerated.
  3. Triamterene.
  4. Amiloride.

How to management hyperkalemia:

  1. Keep the serum potassium level >4.5; advise a low potassium diet,
  2. Avoid potassium containing salt substitutes,
  3. Avoid NSAIDs,
  4. Avoid ACE-I and ARBs and if it is essential to prescribe them measure potassium weekly and if it goes >5.0 mEq/L reduce MRA.
  5. Discontinue MRA if the serum potassium level is >5.5 mEq/L.
  6. If MRA usage is limited by hyperkalemia, down-titrate or discontinue ARB or ACE inhibitor to allow for treatment with MRA.

Diuretics — Diuretic therapy (loop and thiazide) are used in patients with HFpEF to treat volume overload. Use with caution to avoid excessive preload reduction and hypotension.

Calcium channel blockers — Calcium channel blockers may also be useful in the treatment of hypertension in patients with HFpEF, though the evidence is very limited

Avoid beta blockers.

Angiotensin II receptor blockers — There is no evidence from randomized clinical studies that ARB therapy directly improves overall morbidity or mortality in patients with HFpEF.

Angiotensin receptor-neprilysin inhibitor — The role of angiotensin receptor-neprilysin inhibitor in patients with HFpEF is uncertain and may evolve as further data are available.

The PARAGON-HF trial compared clinical outcomes with sacubitril-valsartan versus valsartan in 4796 patients with NYHA class II to IV HF, LVEF of ≥45 percent, and elevated natriuretic peptide levels. NYHA class improvement was slightly more frequent in the sacubitril-valsartan group.

Ineffective drugs: use of organic nitrates, phosphodiesterase-5-inhibitors or digoxin (except for ventricular rate control in atrial fibrillation) to treat patients with HFpEF does not help.

Asymptomatic diastolic dysfunction — Diastolic dysfunction with normal systolic function without HF (also known as preclinical diastolic dysfunction) is a common finding in older adults and a predictor of mortality.

Start initially with diuretic therapy (as need to treat volume overload), an renin-angiotensin system inhibitor (ARNI, ACE inhibitor, or single agent ARB), and a beta blocker.

The combination of hydralazine plus nitrate is an alternative to an angiotensin system blocker only if neither ACE inhibitor, ARNI, nor single agent ARB is tolerated.

What to do next?

Use a mineralocorticoid receptor antagonist, ivabradine,  dapagliflozin, empagliflozin, hydralazine plus nitrate (in addition to initial therapy with an angiotensin system blocker or hydralazine plus nitrate), and digoxin.

Ivabradine ( a hydrochloride) is used in inappropriate sinus tachycardia, stable angina and heart failure and cardiomyopathy. It is used orally with a calibrated syringe. Begin with a dose of 2.5 mg twice a day to a maximum of 7.5 mg twice a day. Adjust to maintain a heart rate of 50-60/min.

Dapaglifozin is a antidiabetic agent, sodium-glucose cotransporter 2 (SGLT2) inhibitor used in Type 2 diabetes. Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. (Funded by AstraZeneca; DAPA-HF number, NCT03036124. opens in new tab.) In addition to diuretic and related hemodynamic actions of SGLT2 inhibitors, effects on myocardial metabolism, ion transporters, fibrosis, adipokines, and vascular function have also been proposed.

Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Reduced number, NCT03057977.)

In patients with type 2 diabetes, sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and the risk of serious adverse renal events, benefits that are not seen with other antihyperglycemic drugs. In large-scale, randomized, placebo-controlled trials, the risk of hospitalization for heart failure was 30 to 35% lower among patients who received SGLT2 inhibitors than among those who received placebo; this benefit was most striking in patients who had a left ventricular ejection fraction of 30% or less before treatment. In addition, the risk of progression of renal disease (including the occurrence of renal death or the need for dialysis or renal transplantation) was 35 to 50% lower among patients who received SGLT2 inhibitors than among those who received placebo. These cardiorenal benefits cannot be explained by an action of SGLT2 inhibitors to lower blood glucose, since similar effects have not been seen with other antidiabetic drugs that have greater antihyperglycemic actions.

A clinician should be prepared to treat HFpEF and HFrEF with different drugs. Hence it is very important to check the ejection fraction in each patient and do it repeatedly

Native Valve Endocarditis. Questions that will be asked.

I am starting this post with a vignette from an article by Henry F. Chambers, M.D., and Arnold S. Bayer, M.D. August 6, 2020
N Engl J Med 2020; 383:567-576.

A 72-year-old man with type 2 diabetes mellitus, stage 2 chronic kidney disease, and a history of mild aortic stenosis is admitted to the hospital with fever, dysuria, and urinary frequency. His temperature is 38.9°C, the pulse is regular at 110 beats per minute, and the blood pressure is 145/95 mm Hg. His lungs are clear; a grade 3/6 systolic ejection murmur is heard at the right upper sternal border. Laboratory tests are notable for a hemoglobin level of 12 g per deciliter, a white-cell count of 13,500 per cubic millimeter (with 80% polymorphonuclear cells), a serum glucose level of 340 mg per deciliter (18.7 mmol per liter), a serum creatinine level of 1.7 mg per deciliter (150 μmol per liter), and a urinalysis with 3+ protein, 20 to 50 white cells per high-power field, and 4+ glucose. Two blood cultures and a urine culture are positive for ampicillin-susceptible Enterococcus faecalis. How would you further evaluate and treat this patient?

Clinically Dukes criteria are used to determine whether the patient is likely to have bacterial endocarditis.

Major clinical criteria

  • Positive blood culture
    • Typical microorganisms (Staphylococcus aureus, viridans streptococci, Streptococcus gallolyticus, HACEK [haemophilus species, aggregatibacter (formerly actinobacillus) species, cardiobacterium species, Eikenella corrodens, and kingella species], and community-acquired enterococci in the absence of a primary focus) consistent with infective endocarditis from two separate blood cultures
    • Microorganisms consistent with infective endocarditis from persistently positive blood cultures, defined as ≥2 positive cultures from blood samples drawn >12 hr apart or all of 3 or a majority of ≥4 separate cultures of blood (with first and last sample drawn at least 1 hr apart)
      Single positive blood culture for Coxiella burnetii or phase I IgG antibody titer >1:800
  • Positive echocardiography
    • Vegetation (defined as an oscillating intracardiac mass on a valve or supporting structure), abscess, or new partial dehiscence of a prosthetic valve
    • New valvular regurgitation (an increase or change in preexisting murmur is not sufficient
  • Minor clinical criteria
  • Presence of predisposing cardiac condition or intravenous drug use
  • Temperature ≥38.0°C (100.4°F)
  • Vascular phenomena such as systemic arterial emboli, septic pulmonary emboli, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, or Janeway lesions
    Immunologic phenomena such as glomerulonephritis, Osler nodes, Roth spots, or rheumatoid factor
  • Positive blood cultures that do not meet major criteria, or serologic evidence of active infection with organism consistent with infective endocarditis
    * Adapted from Li et al.

A definite diagnosis is based on two major criteria, five minor criteria, or one major criterion plus three minor criteria. Possible endocarditis is based on three minor criteria or one major criterion plus one minor criterion. If criteria for either definite or possible endocarditis are not met, the diagnosis of infective endocarditis is rejected.

What is a vegetation?

A presumed injury to the valvular endothelium or endocardium leads to the exposure of collagen tissue to which platelets adhere and a network of fibrin forms. This forms a micro-thrombus or sterile vegetation. In other words a vegetation is a micro-thrombus at the site of exposed collagen tissue where the endothelium has been denuded.

Why do the vegetations form an excellent culture medium for bacteria to grow on?

There is usually a poor immune response to the presence of bacteria in the host: neutrophils do not penetrate the vegetation well nor do antibodies and other host defence mechanisms which activate the alternative pathway of the complement cascade: bind the acute-phase reactant C-reactive protein: activate procoagulant activity on the surface of endothelial cells: upon binding to epithelial and endothelial cells and macrophages, induce production of cytokines, nitric oxide, and chemokines: initiate the influx of neutrophils. Hence bacteria can grow unhindered inside the vegetation.

What is the usual source of the bacteria? 

The mouth is where most of the bacteria reside in the body. They lie under the dental plaque and in infected gums and gum abscesses. Dental procedures lead to the invasion of blood with oral bacteria. Infected skin lesions can also be the source. Invasive procedures like injections (specially when drug addicts do not adhere to sterile techniques), biopsies can be the source, indwelling transcutaneous devices such as IV lines, CV lines can all serve as conduits for the entry of bacteria into the blood.

What are the characteristics of vegetations that lead to most of the clinical features of bacterial endocarditis?

High bacterial densities, rapid growth of the vegetation, and friability and fragmentation of the growing vegetation, drive the four mechanisms that are responsible for most of the clinical features of infective endocarditis and its complications.

What are the clinical features driven by the vegetations?

The clinical features of infective endocarditis and its complications driven by the vegetations are:

  1. valvular destruction,
  2. paravalvular extension of infection, and
  3. heart failure;
  4. microvascular and large-vessel embolization; metastatic infection of target organs (e.g., the brain, kidneys, spleen, and lungs);
  5. immunologic phenomena such as hypocomplementemic glomerulonephritis and
  6. false positive serologic findings of rheumatoid factor,
  7. antineutrophil antibodies, or syphilis.

What are the cardiac conditions that predispose to infective endocarditis?

These include congenital disease (e.g., ventricular septal defect and bicuspid aortic valve) and acquired valvular disease (e.g., degenerative valvular disease, aortic stenosis, and rheumatic heart disease).

Rheumatic heart disease, the most common predisposing condition for infective endocarditis in developing countries, is uncommon in developed countries, where the most frequent predisposing cardiac conditions are degenerative valvular diseases, congenital valvular abnormalities, and intracardiac devices.

What are the non-cardiac risk factors predisposing to endocarditis?

These include poor dentition, intravenous drug use, hemodialysis, chronic liver disease, diabetes, compromised immunity, neoplastic disease, and indwelling intravascular devices.

What is the clinical presentation of endocarditis?

If you see long term fever without an obvious cause and heart murmur, these are the two signature features of infective endocarditis, and are present in approximately 90% and 75% of patients, respectively.

Infective endocarditis may present acutely with a rapidly progressive course complicated by congestive heart failure, stroke, systemic or pulmonary embolization, severe sepsis or septic shock,


subacutely with nonspecific symptoms such as low-grade fever, malaise, chills, sweats, dyspnea, back pain, arthralgias, and weight loss over a period of weeks or sometimes months.

Microembolic or immunologic phenomena such as splinter hemorrhage, conjunctival hemorrhage, Osler nodes (distal vasculitic lesions of the fingers and toes), Janeway lesions (vasculitic lesions of the palms and soles), and Roth spots (hemorrhagic retinal lesions) are present in 5 to 10% of patients only.

What bacteria are likely to be isolated from the blood?

Worldwide, gram-positive bacteria account for approximately 80% of cases of native-valve infective endocarditis.

These bacteria include Staphylococcus aureus in 35 to 40% of cases of native-valve infective endocarditis, streptococci in 30 to 40% (viridans streptococci in approximately 20% and Streptococcus gallolyticus [formerly S. bovis] and other streptococci in approximately 15%), and enterococci in 10%.

Coagulase-negative staphylococci, a common cause of prosthetic-valve infective endocarditis, are uncommon in native-valve infective endocarditis, except for S. lugdunensis, which resembles S. aureus clinically.

HACEK species (haemophilus species, aggregatibacter [formerly actinobacillus] species, cardiobacterium species, Eikenella corrodens, and kingella species), fungi, polymicrobial infection, and, rarely, aerobic gram-negative bacilli are isolated in 5% of cases.

When can a definite pathological diagnosis be made of endocarditis?

A definite pathological diagnosis can be made if organisms are identified on histologic analysis or culture of the vegetation, intracardiac abscess, or peripheral embolus, or if evidence of a vegetation or intracardiac abscess is confirmed by histologic analysis showing active endocarditis.

A definite or possible clinical diagnosis of infective endocarditis is based on a combination of major and minor criteria that are rooted in microbiologic, echocardiographic, and clinical metrics.

How sensitive are the Dukes criteria?

The sensitivity of the modified Duke criteria for infective endocarditis is approximately 80% for definite cases and higher if possible cases are included.

These criteria have lower sensitivity in infections related to a prosthetic valve or cardiac device, endocarditis on the right side of the heart, and culture-negative infective endocarditis.

The negative predictive value is approximately 90% when criteria are not met for either definite or possible infective endocarditis.

How useful are blood cultures in bacterial endocarditis?

  • Blood cultures are the most important microbiological tests for the diagnosis and treatment of infective endocarditis, and they fulfill a major Duke criterion.
  • Antimicrobial therapy largely depends on the blood-culture isolate and its antimicrobial susceptibility.
  • Approximately 90 to 95% of cases of native-valve infective endocarditis are blood culture–positive. To maximize recovery of a pathogen, three separate sets of blood cultures drawn 30 minutes apart are recommended before the initiation of antibiotics. 
  • Blood culture–negative cases are most commonly caused by recent administration of antimicrobial agents or by organisms that grow poorly or not at all in standard blood culture media (e.g., bartonella species, Coxiella burnetiiTropheryma whipplei, and legionella). Serologic and molecular testing for likely pathogens should be performed if blood cultures are negative; this testing is guided by epidemiologic clues (e.g., C. burnetii infection may be associated with exposure to farm animals, and Bartonella quintana infection may be associated with homelessness).

On what is molecular diagnosis based on?

  • Molecular diagnosis is based on nucleic acid amplification by polymerase chain reaction (PCR),
  • For PCR diagnostic tests, the reported sensitivities are 33 to 90% and the reported specificities are 77 to 100%. The preferred specimen for molecular assays is an excised valve or vegetation.
  • Plasma DNA amplification assays may assist in microbiologic diagnosis in cases in which the pathogen is difficult to determine.

What is the role of the echocardiogram in the management of bacterial endocarditis?

Echocardiography is an essential tool in the diagnosis and management of infective endocarditis. The sensitivity for detection of vegetations in native-valve infective endocarditis is 50 to 60% with transthoracic echocardiography (TTE) and 90% or more with transesophageal echocardiography (TEE). The specificities of both are approximately 95%. Because TTE is also less sensitive than TEE for detecting intracardiac complications (e.g., paravalvular abscess), TEE is preferred to rule out infective endocarditis in patients in whom this condition is suspected and to assess intracardiac complications.

Among newer forms of imaging, the most widely studied is 18F-fluorodeoxyglucose cardiac positron-emission tomography (PET) plus computed tomography (CT). PET-CT is most applicable to the diagnosis and evaluation of prosthetic-valve infective endocarditis; its role in native-valve infective endocarditis is poorly studied and unclear.

What antibiotic therapy will you choose and why?

Always use combination therapy.  In general, vancomycin plus ceftriaxone is a reasonable choice for empirical therapy to cover likely pathogens while cultures are pending in patients with native-valve infective endocarditis.

Infective endocarditis that is caused by penicillin-non susceptible strains of viridans streptococci, S. gallolyticus, abiotrophia species, or granulicatella species can be treated with a combination of penicillin or ceftriaxone plus gentamicin; vancomycin monotherapy is an option, although there is less overall experience with this agent.

An antistaphylococcal penicillin (e.g., oxacillin) is the drug of choice for infective endocarditis that is caused by methicillin-susceptible strains of S. aureus (MSSA). Randomized, controlled trials have shown that combination therapy with an antistaphylococcal penicillin and either gentamicin or rifampin does not improve outcomes and is associated with adverse events; therefore, this combination is not recommended. Cefazolin is a reasonable alternative for patients with MSSA who cannot receive penicillin without adverse effects. One concern with cefazolin is that some strains have an “inoculum effect,” which is defined as an increase in the broth dilution minimum inhibitory concentration (MIC) to 16 μg per milliliter or greater at an inoculum of 5×107 CFU per milliliter (100 times the standard inoculum of approximately 5×105 CFU per milliliter). This inoculum effect, which is due at least in part to hydrolysis of cefazolin by staphylococcal penicillinase, may be associated with clinical failure.

Daptomycin or vancomycin monotherapy is recommended for treatment of native-valve infective endocarditis caused by methicillin-resistant S. aureus (MRSA)

Combination therapy is recommended for the treatment of enterococcal infective endocarditis. Penicillin or ampicillin in combination with low-dose, synergistic gentamicin has been the standard treatment for decades. The usefulness of this regimen is limited by gentamicin toxicity and an increasing incidence of high-level resistance to gentamicin that indicates a lack of synergy. Observational data suggest that a 6-week course of ampicillin plus ceftriaxone is an acceptable alternative for treatment of infective endocarditis caused by ampicillin-susceptible strains of E. faecalis. If the ampicillin–gentamicin combination is used, the efficacy of combination therapy for 2 weeks followed by ampicillin alone for 4 to 6 weeks may be similar to that of the standard combination regimen for 4 to 6 weeks and is less toxic.

What are the the three main indications for surgery in bacterial endocarditis?

The three main indications for surgery in patients with native-valve infective endocarditis are heart failure due to valvular dysfunction or perforation, uncontrolled endocardial infection (e.g., paravalvular extension or persistent bacteremia), and prevention of systemic embolization, especially to the brain.

One small randomized, controlled trial compared early surgery during the initial hospitalization and within 48 hours after randomization (in 37 patients) with conventional treatment (in 39 patients) in patients with endocarditis on the left side of the heart, severe valvular regurgitation (without heart failure), and large vegetations (>10 mm in diameter). Early surgery significantly reduced the risk of the combined end point of in-hospital death or embolic events within 6 weeks after randomization, but this decreased risk was driven entirely by decreases in the risk of systemic embolism.

Modified Duke criteria for the clinical diagnosis of infective endocarditis are not based on the results of molecular diagnostic testing. As these methods improve in accuracy and become routinely available, their role in diagnosis will need to be taken into account.

Whether routine brain magnetic resonance imaging (MRI) and other advanced imaging techniques such as PET-CT improve the diagnosis, treatment, and outcomes in patients with native-valve infective endocarditis is unclear. MRI is more sensitive than CT for detecting central nervous system (CNS) lesions, and the presence of asymptomatic embolic lesions in patients with suspected infective endocarditis is a minor criterion in support of the diagnosis. Routine brain MRI has been recommended to detect silent CNS emboli in patients who are candidates for valvular surgery, although whether this improves outcomes is unknown.







Male Infertility.

Recently there was a news item that male fertility is reducing globally because of reducing sperm count? Is that how the human race is going to disappear with a small sizzle? Not a meteor or some natural disaster bringing our species to extermination in a dramatic event as happened to the dinosaurs? Just not having babies anymore? Potential grandparents tragically fading away?

The Nottingham study is just one in a mounting pile of research indicating that the quality and quantity of men’s sperm is on the decline and suggests that sperm counts have dropped by half in the last 50 years or so and that a higher percentage are poor swimmers – slow, ungainly or beset by genetic flaws. The exact cause of that decline is not well understood. … But many researchers suspect chemical residues in the environment may be partly to blame.May 24, 2019 › us-news › may › toxic-americ…

Being stressed out and sedentary is no good for sperm and it’s even worse if you smoke, drink alcohol or use recreational drugs. For example, a large review of studies from 26 regions across the world found that smoking decreased sperm by 13-17%. Another study found that smoking marijuana regularly (more than once weekly) lowers sperm count in young men and that the effect is exacerbated when they also use other recreational drugs.

There’s also a growing consensus that some chemicals found in everyday products such as plastic bottles, metal food cans, detergents, flame retardants, food, toys, cosmetics and pesticides can affect a man’s reproductive health. Those chemicals, referred to as “endocrine disruptors” interfere with the body’s natural hormone systems – by blocking production or effects of the male hormone testosterone, for instance.

Those effects may begin while babies are still developing in their mother’s womb says Niels Skakkebæk, professor at the University of Copenhagen and senior researcher at the Department of Growth and Reproduction at Rigshospitalet in Denmark. He points out that poor sperm quality is associated with an increased risk of testicular cancer and also a history of congenital reproductive defects, including undescended testes. One theory is that all those conditions are linked to the mother’s exposure to environmental contaminants at critical moments during pregnancy when the baby’s sex organs develop.

Endocrine disruptors may also affect sperm in adult men. A 2014 study of the effects of 96 of those chemicals on human sperm found that they affected sperm’s ability to swim, navigate and fertilize an egg.

How many sperm should there be? How many of them should be able to swim and what other characteristics make them healthy?

A study ” Sperm Morphology, Motility, and Concentration in Fertile and Infertile Men” was carried out by David S. Guzick, M.D., Ph.D., James W. Overstreet and their team and published in NEJM in November 8, 2001 (N Engl J Med 2001; 345:1388-1393). I am putting down some salient points.

Two semen specimens from each of the male partners in 765 infertile couples and 696 fertile couples were taken at nine sites. The female partners were all determined to be normal. The sperm concentration and motility were determined at the sites; semen smears were stained at the sites and shipped to a central laboratory for an assessment of morphologic features of sperm with the use of strict criteria.

The subfertile ranges were a sperm concentration of less than 13.5×106 per milliliter, less than 32 percent of sperm with motility, and less than 9 percent with normal morphologic features.

The fertile ranges were a concentration of more than 48.0×106 per milliliter, greater than 63 percent motility, and greater than 12 percent normal morphologic features. Values between these ranges indicated indeterminate fertility.

There was extensive overlap between the fertile and the infertile men within both the subfertile and the fertile ranges for all three measurements. Although each of the sperm measurements helped to distinguish between fertile and infertile men, none was a powerful discriminator. The percentage of sperm with normal morphologic features had the greatest discriminatory power.

The results of this study confirm that measurements of sperm concentration, motility, and morphology all provide useful information for diagnosing male infertility. Sperm morphology, as measured according to strict criteria, appears to be the most informative semen measurement for discriminating between fertile and infertile men. However, none of the measures, alone or in combination, can be considered diagnostic of infertility.

What is likely to be the cause of male infertility?

  • Idiopathic male infertility describes an infertile man with a normal semen analysis and no apparent cause for infertility,
  • Whereas infertile men with idiopathic dysspermatogenesis have abnormal semen analyses.
  • Secondary [hypogonadotropic] hypogonadism) – 2 to 5 percent.
  • Primary testicular defects in spermatogenesis – 65 to 80 percent (of which the majority have idiopathic dysspermatogenesis, an isolated defect in spermatogenesis without an identifiable cause).
  • Sperm transport disorders – 5 percent.


The disorders in many infertile men are characterized primarily by descriptions of observed abnormalities, such as decreased sperm number, movement, or egg-penetrating and fusion capabilities. Even testicular biopsies rarely shed insight on the underlying etiology; they simply indicate the extent of spermatogenic impairment.
How do you start the evaluation of an infertile man? The history should include details of recreational drugs, alcohol intake, any diseases like diabetes, cystic fibrosis, spermatocele or obvious signs of hypogonadism or use of medical drugs which could affect the endocrine system. The frequency and timing of intercourse should be discussed.
A thorough physical examination should follow and then a semen analysis should be done after 2-7 days abstinence from intercourse with any partner. Repeat a semen analysis one week later.
More details of the history should include:
  • Sexual developmental history, including testicular descent, pubertal development, loss of body hair, or decrease in shaving frequency

  • Chronic severe systemic illness and history of major head or pelvic trauma

  • Infections, such as mumps orchitis, sinopulmonary symptoms, sexually transmitted infections, and genitourinary tract infections (including prostatitis)

  • Surgical procedures involving the inguinal and scrotal areas, such as vasectomy or orchiectomy

  • Drugs and environmental exposures, including alcohol, tobacco, marijuana, opioids, radiation therapy, anabolic steroids, corticosteroids, cytotoxic chemotherapy (current or past), drugs that cause hyperprolactinemia, and exposure to toxic chemicals (eg, pesticides)

  • Sexual history, including libido, frequency of intercourse, and previous fertility assessments of the man and his partner

    The physical examination should include a general medical examination to determine overall health, obesity, and overt signs of endocrinopathies that are uncommon causes of male infertility (eg, thyroid dysfunction or Cushing’s syndrome).

    Because some infertile men have combined defects in testosterone and sperm production, the examination should also focus on findings suggestive of androgen deficiency. The clinical manifestations of androgen deficiency depend upon the age of onset. Androgen deficiency during early gestation presents as atypical genitalia; in late gestation as micropenis; in childhood as delayed pubertal development; and in adulthood as decreased sexual function, infertility, and, eventually, loss of secondary sex characteristics. The examination of the man should include the following components.

    Skin – Men with iron overload syndromes as the cause of infertility may have diffuse or patchy hyperpigmentation. Men with Cushing’s syndrome may have thin skin, ecchymoses, and/or broad purple striae. Loss of pubic, axillary, and facial hair, decreased oiliness of the skin, and fine facial wrinkling suggest long standing testosterone deficiency.

    External genitalia – Several abnormalities that affect fertility can be recognized by examination of the external genitalia:

    • Incomplete sexual development can be recognized by examining the phallus and testes and finding small testes and other findings of incomplete pubertal development.

    • Diseases that affect sperm maturation and transport can be detected by examination of the scrotum for absence of the vasa, epididymal thickening, and large varicoceles.

    • Decreased volume of the seminiferous tubules can be detected by measuring testicular size by Prader orchidometer or calipers. The Prader orchidometer consists of a series of plastic ellipsoids with a volume from 1 to 35 mL. In an adult man, a testicular volume below 15 mL or a testicular length (measured on the longest axis) less than 3.6 cm are considered small.

Look for
  • Semen volume and pH
  • Microscopy for:
    • Sperm concentration, count, motility, and morphology
    • Debris and agglutination
    • Leukocyte count
    • Immature germ cells

What are the reference norms that WHO has set?

The WHO has published lower reference limits for semen analyses  The following parameters represent the generally accepted 5th percentile (lower reference limits and 95% CIs in parentheses), derived from a study of over 1900 men whose partners had a time to pregnancy of ≤12 months:

  • Volume – 1.5 mL (95% CI 1.4-1.7)
  • Sperm concentration – 15 million spermatozoa/mL (95% CI 12-16)
  • Total sperm number – 39 million spermatozoa per ejaculate (95% CI 33-46)
  • Morphology – 4 percent normal forms (95% CI 3-4), using “strict” Tygerberg method
  • Vitality – 58 percent live (95% CI 55-63)
  • Progressive motility – 32 percent (95% CI 31-34)
  • Total (progressive and nonprogressive) motility – 40 percent (95% CI 38-42)

After the initial evaluation (history, physical exam, and two semen analyses), men with infertility should undergo the following evaluation: look for a couples infertility factor if there is idiopathic male infertility i.e. normal semen, recommend ART (assisted reproductive technology) such as IVF (in vitro fertilisation). Intracytoplasmic sperm injection (ICSI) refers to a technique in which a single sperm is injected directly into the cytoplasm of a mature oocyte. This procedure is performed as part of an in vitro fertilization (IVF) cycle, and provides an effective method for assisting fertilization in men with suboptimal semen parameters or who experienced no or low fertilization rates after conventional IVF.

Sperm concentration <10 million/mL — Because Klinefelter syndrome is common in men presenting with infertility and sperm concentrations <10 million/mL, serum total testosterone (on a blood sample obtained between 8 and 10 AM), serum follicle-stimulating hormone (FSH), and luteinizing hormone (LH).

Severe oligozoospermia or azoospermia: genetic testing is required. Karyotyping is recommended for infertile men with elevated serum FSH and LH concentrations and a sperm concentration less than 10 million/mL

Evaluation of obstructive azoospermia (those who have normal endocrine testing, normal testicular volume, palpable vasa deferentia on examination, and azoospermia: ejaculatory duct obstruction can be diagnosed by a scrotal or transrectal ultrasound showing dilated seminal vesicles. Transrectal ultrasound might be modestly more sensitive in detecting obstructive azoospermia. Patients with obstructive azoospermia should be referred to a urologist who specializes in infertility for further evaluation and treatment.

Genetic testing.

The common genetic abnormality found is Klinefelter’s syndrome. This syndrome is the clinical manifestation of a male who has an extra X chromosome. The most common genotype is 47,XXY but greater and lesser numbers of X chromosomes have also been reported, resulting in karyotypes such as 48,XXXY and 46,XY/47,XXY mosaicism. Only the most severe phenotypes of Klinefelter syndrome are recognized before puberty. Neonates with Klinefelter syndrome may present with micropenis (<1.9 cm for neonate) or clinodactyly, hypospadias, or cryptorchidism. Prepubertal boys with Klinefelter syndrome may present with behavioral abnormalities, language delay, learning disabilities, or hypertelorism. Boys of pubertal age with Klinefelter syndrome tend to be taller than expected based on mid-parental height and have legs that grow out of proportion to arm length. Their leg length is, on average, 4 to 8 cm greater than men without Klinefelter syndrome. Adult men with Klinefelter syndrome may present with infertility due to azoospermia or symptoms and signs of androgen deficiency (gynecomastia, sexual dysfunction, or osteoporosis). Men with classic Klinefelter syndrome have very small, firm testes (≤4 cc each). The small testicular volume is due to progressive fibrosis and destruction of both functional (steroidogenic and spermatogenic) compartments of the testes. Sperm may be harvested and preserved at attaining puberty. The use of gonadotropins, aromatase inhibitors, or selective estrogen receptor modulators to increase spermatogenesis are ineffective. ART may be tried.

Genetic testing is also done to look for Y chromosome microdeletion or testing for cystic fibrosis transmembrane conductance regulator (CFTR) mutations. Other chromosomal abnormalities that result in testicular hypofunction have been reported.

  • The 46,XY/XO karyotype leads to a syndrome characterized by short stature and features typical of Turner syndrome. The gonads vary from streak to dysgenetic to normal testes; as a result, the sexual phenotype varies from complete female to complete male. If the patient has both a streak gonad and a dysgenetic testis (“mixed gonadal dysgenesis”), the risk of gonadoblastoma is approximately 20 percent. Gonadectomy should therefore be performed in these patients.
  • The 47,XYY karyotype was initially thought to be associated with hypogonadism, but subsequent reports have not confirmed this relationship.

  • Microdeletions in specific regions of the long arm of the Y chromosome occur in up to 20 percent of men with azoospermia or severe oligospermia.

Mutation in the FSH and LH receptor genes

  • Another rare cause of primary hypogonadism is a mutation in the follicle-stimulating hormone (FSH) receptor gene. One report described five men found to be homozygous for an inactivating mutation of the FSH receptor. These subjects had variably low sperm counts and inhibin B concentrations and high serum FSH concentrations.
  • Luteinizing hormone (LH) receptor mutations result in Leydig cell hypoplasia and testosterone deficiency in the first trimester in utero, resulting in varying degrees of male pseudohermaphroditism.

Cryptorchidism may affect one or both testes.

  • If only one testis is undescended, the sperm count will be subnormal in 25 to 33 percent and the serum FSH concentration will be slightly elevated. The presence of these abnormalities suggests that both testes are abnormal, perhaps congenitally, even though only one fails to descend.
  • If both testes are undescended, the sperm count will usually be severely subnormal and the serum testosterone may also be reduced.

Disorders of androgen biosynthesis. This is associated with incomplete virilisation.

Myotonic dystrophy, an autosomal dominant disorder that leads to muscle atrophy, is accompanied by hypogonadism that is usually not recognized until adulthood. Small testes and decreased sperm production are more common than decreased serum testosterone levels.

Congenital anorchia. This form of testicular regression occurs after 20 weeks of gestation, so that at birth, male sexual differentiation is normal but testes are absent and hypogonadism is severe.


Varicosity of the venous plexus within the scrotum, called a varicocele, has long been considered a possible cause of damage to the seminiferous tubules and thereby of infertility. As a result, ligation of varicoceles has long been practiced as a treatment for infertile men, although available data do not support this practice.

Acquired causes of male infertility.

Infections such as mumps and HIV affect the seminiferous tubules and the Leydig cells.

Alkylating agents, such as cyclophosphamide, chlorambucil, cisplatin, and busulfan, can damage the seminiferous tubules to a degree sufficient to cause azoospermia and markedly elevated serum follicle-stimulating hormone (FSH) concentrations. Cisplatin or carboplatin also can decrease the sperm count, but the count typically recovers, at least partially. Ketoconazole can also cause oligospermia. Chronic glucocorticoid use can also lower testosterone levels by approximately one-third; the mechanism is not clear, but inhibition may occur at both the testis and pituitary.

Radiation either directly to the testes or even through shielding for leukemia, lymphoma also damages the seminiferous tubules.

Environmental toxins such as the nematocide dibromochloropropane is known to decrease spermatogenesis in men in vivo.

Trauma and testicular torsion is one of the most common reasons for the loss of a testicle before puberty. Orchiectomy is standard treatment for testicular cancer, which is often bilateral.

Autoimmune damage — Many men with idiopathic infertility have antisperm antibodies. It is not known, however, if these antibodies are the result of an autoimmune process or a response to damage by some other mechanism.

The hypogonadism that accompanies autoimmune polyglandular disease is also characterized by hypothyroidism and hypoadrenalism.

Cirrhosis is occasionally associated with hypogonadism, as manifested by a reduction in the serum testosterone concentration. More than one mechanism appears to be involved. In some cases, primary gonadal injury appears to be more prominent, as suggested by increased serum FSH and LH concentrations. In others, suppression of hypothalamic or pituitary function appears to play a primary role, as suggested by serum LH concentrations that are not elevated. Hypogonadism due to cirrhosis is rapidly corrected following liver transplantation.

Acute alcohol ingestion also may cause secondary hypogonadism, as manifested by subnormal serum testosterone concentration levels without increases in either LH or FSH.

Severe chronic kidney disease may also be associated with hypogonadism.

As you can see that the health of the sperm is a delicate matter depending on genes, hormones, infections, alkylating agents and other agents used in chemotherapy and radiation, systemic illnesses. Restoring the sperm to health is not an easy task and there is a heavy reliance on RTA and IVF to help out the infertile man.


Headaches. Is this a migraine?

A 23-year-old woman who has recently graduated from university, has been applying for a job for 5 months but has not succeeded. She is depressed and according to her family has lost her self esteem. She presents to you with five episodes of headache during the past 2 months. Each episode begins with yawning, sensitivity to light, and a depressed mood that is followed by the gradual onset of neck pain that spreads to the occipital region and eventually to the retro-orbital region on the right side. The pain becomes incapacitating over a period of 1 to 2 hours and is associated with nausea and sensitivity to light and sound. With two of the episodes, she had jagged lines in her vision for 15 minutes as the neck pain was beginning; with all the episodes, she had severe fatigue and difficulty concentrating and finding words. The headache last approximately 24 hours, and, after resolution, she has several hours of residual neck soreness, fatigue, and depressed mood. How will you evaluate and treat this patient?

Sounds like migraine. She is the right age, gender and has depression and anxiety about getting a job. What else can this be associated with? Migraine may be associated with increased risks of several other disorders, including asthma, stroke, anxiety and depression, and other pain disorders. When she was 10 years old she suffered from nightmares, headaches with vomiting and her work at school suffered. She was withdrawn from school for 2 months, her paediatrician diagnosed anxiety, she was sent to visit her grandmother in the village. There, a faith healer prayed over her, her father encouraged her to ride horses at the farm and she gradually became better and returned home and joined school again. The headaches did not recur until now.

Plan of management.

Management should include establishing an accurate diagnosis, identifying and modifying potential exacerbating factors (including medications), developing a plan for the treatment of acute attacks, and determining whether preventive therapy is warranted.

A complete physical examination is warranted including a careful neurological examination. Since this is her initial presentation as an adult, examine the optic fundi and even though there are no indications that it anything but migraine do imaging studies for an intracranial  lesion. It is not necessary to do cranial imaging every time she has a headache unless a new neurological symptom or sign develops. Keep an eye on her blood pressure. Lab tests should include a complete blood picture, tests for renal and liver functions and blood sugars at least. These do not need to be repeated for every episode of headache.

Why isn’t migraine just a bad headache? A migraine may be associated with a stroke especially in the older patients and those with diabetes and hypertension hence needs to be distinguished as a migraine from a sentinel headache preceding a subarachnoid hemorrhage or a hemorrhagic stroke.

A variety of premonitory symptoms  may occur hours before the headache begins and postdromal symptoms  may last for hours after the headache ends. Yawning, mood change, light sensitivity, neck pain, and fatigue are common premonitory symptoms that may persist during and after the headache.

There may be an aura.

Aura symptoms may include visual disturbances (e.g., wavy lines or bright or dark spots), other sensory changes (e.g., numbness or tingling), language dysfunction, and vertigo.

Cutaneous allodynia (the experience of normal touch as uncomfortable) is also a common component of a migraine attack. Patients may not recognize or spontaneously report these symptoms, but when asked to record them, they can often identify the onset of an attack several hours before a headache occurs and realize that the disabling features of an attack often outlast the headache.

Some presumed triggers of migraine may be manifestations of the premonitory phase of a migraine attack; food, light, sound, and odor triggers that are identified by patients may in some cases be early symptoms of gastrointestinal and sensory sensitivity that are part of the attack.

What happens to the brain during a migraine attack?

The diverse and highly variable symptoms of migraine reflect complex alterations in the functioning of the nervous system. Changes in the activity of multiple brain regions during migraine attacks have been visualized with functional imaging techniques and quantified with the use of clinical electrophysiological techniques. These studies reveal activation of the hypothalamus, thalamus, brain stem, and cortex corresponding with various symptoms of a migraine attack, including those occurring before and after headache.

Although migraine is associated with intracranial vasodilation a cross sectional study was done and magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura was carried out. (The Lancet Neurology. Volume 12, Issue 5, May 2013, Pages 454-461) Migraine pain was not accompanied by extracranial arterial dilatation, and by only slight intracranial dilatation. It is now clear that constriction of blood vessels is not a required mechanism of therapies for migraine.12 Although migraine is associated with an increased relative risk of stroke and cardiovascular disease,14,15 the mechanisms underlying this association remain uncertain, and it is exceedingly rare for cerebral ischemia or infarction to occur during a migraine attack. Future migraine research should focus on the peripheral and central pain pathways rather than simple arterial dilatation.

Diagnosis of migraine. Don’t mistake a migraine for cervical pain or sinus infection.

 Migraine headache is characteristically severe, unilateral, and throbbing, it may also be moderate, bilateral, and constant in quality. The features of migraine other than headache, particularly sensitivity to light and sound, nausea, and interference with the ability to function, may be more useful in diagnosis than the character of the headache. Other common migraine symptoms, including aura, cognitive dysfunction, dizziness, and fatigue, may lead physicians to order brain imaging, yet this is generally unnecessary if symptoms have a gradual onset and are transient. Neck pain is another common symptom of migraine, but it is frequently misinterpreted as a manifestation of a disorder in the cervical spine, often leading to unnecessary scans of this region. Patients or physicians frequently believe that migraine is related to sinus disease, whereas the majority of patients who receive a diagnosis of “sinus headache” in fact have migraine.

Lifestyle changes which may help.

  • Don’t skip a meal.
  • Get regular sleep at your usual time.
  • Don’t drink too much caffeine.
  • Do regular exercises.
  • You may need extra medicines before, during and after menstrual periods.

Medicines which make a migraine worse.

Many medicines make migraines worse or trigger them. They include oral contraceptives, postmenopausal hormone therapy, nasal decongestants, selective serotonin-reuptake inhibitor antidepressants, and proton-pump inhibitors. In some patients, the frequency and severity of attacks can be dramatically reduced by adjusting or discontinuing these medications. In addition, regular use of analgesic medications, particularly opioids and barbiturate–caffeine–analgesic combinations, can increase migraine frequency and severity, even when taken only once or twice a week. This exacerbation cannot be explained simply by tolerance, dependence, or addiction but rather is a direct adverse effect on migraine. Withdrawing the frequently used medication can result in marked improvement, but this may require substantial time and effort, and in some patients, inpatient treatment is needed.

How will you abort an acute migraine attack?

  • Triptans such as almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan will provide relief by 2 hours and the patient is usually free of the headache in 24 hours. Nasal or subcutaneous delivery is more effective than oral. Don’t prescribe to any one with coronary artery disease.
  • Ergots also provide pain relief in 2 hours and can be used as a nasal spray or subcutaneous injection and is often used for refractory migraine.
  • Acetaminophen (paracetamol) will provide pain relief in 19% of patients. Use with an antiemetic like prochlorperazine (Stemetil) or chlorpromazine (Phenergan), metoclopramide (maxolon).
  • NSAIDs like aspirin, diclofenac, ibuprofen, ketorolac and naproxen will also provide relief in 2 hours in 20-40% of patients. Use with triptans.
  • Combinations of acetaminophen-aspirin and caffeine or naproxen and sumatriptan may also provide pain relief in 2 hours in 20% of patients.
  • Single pulse TMS (transcranial magnetic stimulation) through a handheld device will also work in about 20% of patients.
  • CGRP (calcitonin gene-related peptide) receptor antagonists are under investigation. These are remigepant, ubrogepant,
  • A review of three trials evaluating valproate products (divalproex sodium, sodium valproate, and valproic acid) at doses ranging from 500 to 1500 mg daily for migraine prevention found that valproate was significantly more effective than placebo as measured by the number of patients experiencing a ≥50 percent reduction in migraine frequency in adults.
  • Intravenous valproate. The utility of IV valproate for the treatment of acute migraine in children is not established, and the existing evidence is limited and retrospective
  • Anti-inflammatory drugs, and antiemetic agents individually or in combination) should be taken as early as possible after the onset of a migraine attack.
  • Preventive therapies (e.g., beta-blockers, candesartan, tricyclic antidepressants, and anticonvulsant agents as well as botulinum toxin for chronic migraine) should be considered on the basis of the frequency and severity of attacks, response to medications for acute migraine, and coexisting conditions.
  • Recent clinical trials support the efficacy of new therapies targeting calcitonin gene–related peptide (CGRP) for the treatment of acute migraine and for migraine prevention. The  CGRP is a therapeutic target in migraine because of its hypothesized role in mediating trigeminovascular pain transmission and the vasodilatory component of neurogenic inflammation. The US Food and Drug Administration (FDA) approved the CGRP  antagonists erenumab, fremanezumab, and galcanezumab in 2018 and eptinezumab in 2020 for migraine prevention.

In clinical practice, a substantial percentage of patients report dissatisfaction with triptans because of a slow or incomplete response. For some, the addition of a nonsteroidal antiinflammatory drug (NSAID) (including nonprescription preparations), or taking one of these medications independently, can be effective.

Multiple ergotamine preparations are available, and intravenous dihydroergotamine in particular is a mainstay of treatment for refractory migraine in urgent care or inpatient settings. Intranasal, subcutaneous injectable, rectal suppository, or other non-oral preparations of therapies for acute migraine may be able to achieve therapeutic levels more quickly than oral preparations and are indicated if nausea and vomiting are a feature of migraine attacks.

Be careful with triptans. The primary concern with frequent triptan use is not safety but rather the potential development of medication-overuse headache, which the ICHD, third edition, defines as more than 10 days per month of triptan use in a person who has 15 or more days of headache per month.

When are you going to initiate preventive therapy in a patient?

There is no evidence supporting a specific “threshold” migraine frequency for which preventive therapy is clearly warranted, although it is generally agreed that preventive therapy should be considered if migraine occurs at least once per week or on 4 or more days per month. Preventive therapy may also be tried in the following situations:

  • Frequent or long lasting migraine headaches
  • Migraine attacks that cause significant disability or diminished quality of life despite appropriate acute treatment
  • Contraindication to acute therapies
  • Failure of acute therapy
  • Serious adverse effects of acute therapies
  • Risk of medication overuse headache
  • Menstrual migraine

All currently available preventive medication therapies for migraine were initially developed for other indications and have been secondarily adopted as treatments for migraine. Antihypertensive agents (e.g., beta-adrenergic blockers and candesartan), anticonvulsant agents (e.g., topiramate and divalproex sodium), and tricyclic antidepressants (e.g., amitriptyline and nortriptyline) are standard preventive therapies for migraine. For some patients, these agents can be highly effective, although the average difference in headache days per month between preventive therapies and placebo has been small in clinical trials. Adverse effects are common for most of the preventive therapies, and patients often report an initial response that “wears off” despite increasing doses. Adherence to treatment is generally poor.

OnabotulinumtoxinA is a Food and Drug Administration (FDA)–approved therapy for the prevention of chronic migraine, defined as headache occurring on more than 15 days per month, with migraine features on at least 8 of those days. There is limited evidence to support the use of nonprescription agents — including coenzyme Q10, riboflavin, magnesium, melatonin, and petasites (Petasites are a genus of flowering plants in the sunflower family, Asteraceae) — but these agents are nonetheless widely used because of their acceptable side-effect profile.

Preventive migraine therapy also is indicated to reduce the risk of neurologic damage and/or impairment in the presence of uncommon migraine conditions including:

  • Hemiplegic migraine
  • Migraine with brainstem aura
  • Persistent aura without infarction
  • Migrainous infarction

Which preventive therapy to choose? For patients with hypertension, a beta-blocker or candesartan may be warranted; for those with insomnia, a tricyclic antidepressant may be considered; and for patients who are obese, topiramate may be appropriate.

How to use beta blockers.

  • Propranolol in two divided doses starting at 40 mg daily; dose range 40 to 160 mg daily
  • Metoprolol in two divided doses starting at 50 mg daily; dose range 50 to 200 mg daily
  • Nadolol starting at 20 mg once a day; dose range 20 to 240 mg daily
  • Atenolol starting at 25 mg daily; dose range 25 to 100 mg once daily

For calcium channel blockers verapamil appears to be popular, flunarizine, nimodipine and nifedipine are also used. Tolerance tends to develop.

Of the ACEi/ARBs lisinopril appears to be more effective.

The tricyclic antidepressants most commonly used for migraine prevention include amitriptyline, nortriptyline, doxepin, and protriptyline. Amitriptyline is the only tricyclic that has proven efficacy for migraine; there are insufficient data regarding the other tricyclics The tricyclic antidepressant amitriptyline (starting dose 10 mg at bedtime, dosage range 20 to 50 mg at bedtime) was effective for migraine prevention in four trials. In other trials, the serotonin-norepinephrine reuptake inhibitor venlafaxine (starting at 37.5 mg once a day, dosage range 75 to 150 mg once a day) was also effective as prevention for migraine.

A 2012 guideline from the AAN concluded that topiramate and sodium valproate are established as effective for migraine prevention, while evidence is insufficient to determine the effectiveness of gabapentin.

Topiramate — Several placebo-controlled studies, a systematic review, and a meta-analysis have found that topiramate is effective preventive therapy for migraine. Significant reductions in migraine frequency occurred within the first month at topiramate doses of 100 and 200 mg/day.

The young woman described in the vignette has migraine with and without aura. If her neurologic examination is normal, there is no indication for an imaging study, given that she has had multiple episodes of typical duration with complete resolution of symptoms between episodes and no “red flags,” such as an abrupt onset of symptoms, fever, concurrent clinically significant illness, or persistent headache between attacks. Many practitioners reflexively order an imaging study when attacks include neurologic symptoms in addition to headache, but such symptoms are characteristic of migraine. Current medications should be reviewed as possible exacerbating factors. Consistency of lifestyle factors (diet, caffeine intake, sleep, and exercise) should be encouraged, and a strategy for the treatment of acute attacks with triptans, NSAIDs, antiemetics, or a combination of these agents should be developed, with an emphasis on treating as early as possible after migraine onset. The frequency and severity of migraine attacks should be monitored to assess whether preventive therapy may be indicated; options include a beta-blocker, candesartan, a tricyclic antidepressant, an anticonvulsant (topiramate or divalproex sodium), or onabotulinumtoxinA (if headache occurs ≥15 days per month). This choice should be informed by coexisting conditions and potential adverse effects. Paper or electronic symptom diaries can be very helpful in assessing the clinical course of migraine and the response to therapies. If pharmacologic therapies are ineffective or have unacceptable side effects, neuromodulation approaches should be considered.

I had not detailed menstrual headaches, nor given the details of neuromodulation therapy. I am adding an excellent comment by Dr Ayesha Arif, which I am sure will add to every one’s knowledge.

Emerging treatments for migraine include:

  1. Lasmiditan,a highly selective 5 HT receptor agonist.
  2. Monoclonal antibody therapy directed against Calcitonin gene related peptide
  3. Neuromodulation devices
  4. External Trigeminal nerve stimulation
  5. Non invasive vagus nerve stimulation with the help of GammaCore device(FDA approved device)It is placed at a point on the neck. By stimulating the vagus nerve this device can stimulate the parasympathetic nervous system which will inhibit vagal afferents to the trigeminal nucleus caudalis and results in reduction of acute pain of migraine.


Two thirds of pre menopausal female migraine sufferers actually have menstrual migraine

1) All patients with menstrual migraine should be given acute abortive therapies to abort the acute attack of migraine in the form of triptans and ergots. Migraine non specific analgesics like NSAIDs, acetaminophen and narcotics can also be given.

2)Short term prophylactic therapies include NSAIDS and triptans for 4 to 5 days during perimenstrual period and estrogen transdermal patches/gel.Naproxen sodium 550 mg 6 days before to 7 days after menses can also be given.

(3) Continuous prophylactic therapies include hormonal and non hormonal therapies. Hormonal therapies include long duration combined oral contraceptive pills (after ruling out contraindications) without the placebo week for the first three months. It helps to minimize the decline in serum estradiol level which is actually the cause of migraine. GnRH analogues should be reserved for cases refractory to treatment with continuous COC pills but are associated with serious menopausal symptoms. Non hormonal therapies include B blockers,calcium channel blockers, tricyclic antidepressants,and anticonvulsants but are reserved for patients with irregular and unpredictable menses




Rheumatoid arthritis and Psoriatic arthritis

Rheumatoid arthritis is a common autoimmune disease that is associated with progressive disability, systemic complications, early death, and socioeconomic costs. The cause of rheumatoid arthritis is unknown, and the prognosis is guarded. However, advances in understanding the pathogenesis of the disease have fostered the development of new therapeutics, with improved outcomes. The current treatment strategy, which reflects this progress, is to initiate aggressive therapy soon after diagnosis and to escalate the therapy, guided by an assessment of disease activity, in pursuit of clinical remission. The mortality rate is higher among patients with rheumatoid arthritis than among healthy persons, and cardiovascular (myocardial infarction, heart failure and stroke) and other systemic complications remain a major challenge. These increased rates are not explained by traditional risk factors, use of glucocorticoids or nonsteroidal antiinflammatory drugs, or shared genetic features. Inflammation in rheumatoid arthritis also affects the brain (fatigue and reduced cognitive function), liver (elevated acute-phase response and anemia of chronic disease), lungs (inflammatory and fibrotic disease), exocrine glands (secondary Sjögren’s syndrome), muscles (sarcopenia), and bones (osteoporosis).

Rheumatoid arthritis is characterized by synovial inflammation and hyperplasia (“swelling”), autoantibody production (rheumatoid factor and anti–citrullinated protein antibody [ACPA]), cartilage and bone destruction (“deformity”), and systemic features, including cardiovascular, pulmonary, psychological, and skeletal disorders.

Infectious agents (e.g., Epstein–Barr virus, cytomegalovirus, proteus species, and Escherichia coli) and their products (e.g., heat-shock proteins) have long been linked with rheumatoid arthritis, and although unifying mechanisms remain elusive, some form of molecular mimicry is postulated has been postulated in rheumatoid arthritis. Increased T cell senescence may contribute to molecular mimicry.

Smoking and other forms of bronchial stress (e.g., exposure to silica) increase the risk of rheumatoid arthritis among persons with susceptibility HLA–DR4 alleles.

Why are women more susceptible to rheumatoid arthritis? Molecular explanations for such phenomena are emerging from animal models of inflammation, which show a link between the hypothalamic–pituitary–adrenal axis and cytokine production.

Why the systemic loss of tolerance is linked to a localized onset of inflammation in the joint is still unclear (transitional phase of rheumatoid arthritis).  Autoantibodies, such as rheumatoid factor and ACPA, are often (but not always) detected in patients before the development of arthritis (pre-articular phase of rheumatoid arthritis); in some series, autoantibody levels have increased and there has been evidence of epitope spreading as the onset of disease approaches.

Psoriasis begins as a relatively benign skin diseases but progresses to complicated skin disease and arthritis. Psoriatic arthritis is  chronic and inflammatory and involves the joints, entheses, bone, axial skeleton, and skin, with heterogeneous clinical features associated with substantial disability and reduced life expectancy. There is accumulating evidence that interleukin-17 is central to the pathogenesis of psoriatic arthritis and other spondyloarthritides, such as ankylosing spondylitis. In the management of psoriatic arthritis inhibition of interleukin-17 signaling by brodalumab induces significant clinical responses in patients with psoriasis. By contrast, efficacy has not been observed for brodalumab in clinical trials involving patients with rheumatoid arthritis or Crohn’s disease.

Five subtypes of  psoriatic arthritis have been described.

  • The oligoarticular subtype affects four or fewer joints and typically occurs in an asymmetric distribution.
  • The polyarticular subtype affects five or more joints; the involvement may be symmetric and resemble rheumatoid arthritis.
  • The distal subtype, which affects distal interphalangeal joints of the hands, feet, or both, usually occurs with other subtypes, occurring alone in only 5% of patients.
  • Arthritis mutilans, a deforming and destructive subtype of arthritis that involves marked bone resorption or osteolysis, is characterized by telescoping and flail digits.
  • The axial or spondyloarthritis subtype primarily involves the spine and sacroiliac joints.

These patterns may change over time. Given below is the CASPAR classification for psoriatic arthritis.

The diagnosis of psoriatic arthritis is based on the recognition of clinical and imaging features, since there are no specific biomarkers. Involvement of at least five domains is possible; these include psoriasis, peripheral joint disease, axial disease, enthesitis, and dactylitis. Patients should be carefully assessed for these domains, with the understanding that various domain combinations may be present in an individual patient. The personal history and family history of psoriasis are often positive. Inflammatory arthritis, enthesitis, dactylitis, and joint distribution provide important clues, as do extraarticular features such as inflammatory bowel disease and uveitis. It is important to look for psoriatic skin lesions, particularly in the groin, umbilical area, hairline, ears, and natal (i.e., intergluteal) cleft. Nail lesions, including pits and onycholysis, as well as the presence of spinal disease, support the diagnosis.

Risk factors.

There are several environmental risk factors for psoriatic arthritis. These include obesity; severe psoriasis; scalp, genital, and inverse (or intertriginous) psoriasis; nail disease; and trauma or deep lesions at sites of trauma (Koebner’s phenomenon)

Differential diagnosis.

It is necessary to differentiate psoriatic arthritis from rheumatoid arthritis, osteoarthritis, gout, pseudogout, systemic lupus erythematosus, and other forms of spondyloarthritis.

Rheumatoid arthritis is characterized by proximal, symmetric involvement of the joints of the hands and feet, with sparing of the distal interphalangeal joints, whereas in more than 50% of patients with psoriatic arthritis, the distal joints are affected; the involvement tends to be characterized by a “ray” distribution, with all the joints of the same digit involved and other digits spared. This is noticeable both clinically and radiographically. At its onset, psoriatic arthritis tends to be oligoarticular and less symmetric than rheumatoid arthritis, although with time, psoriatic arthritis may become polyarticular and symmetric. The affected joints are less tender in psoriatic arthritis than in rheumatoid arthritis and may have a purplish discolorationSpinal involvement (sacroiliac joints or the lumbar, thoracic, or cervical spine) occurs in more than 40% of patients with psoriatic arthritis but is uncommon in patients with rheumatoid arthritis.

Psoriatic monoarthritis, particularly involving the toes, or dactylitis may be misdiagnosed as gout or pseudogout. The uric acid level may be elevated in patients with psoriatic arthritis, as well as in those with gout, making the differential diagnosis difficult, particularly if crystal analysis of joint fluid is negative or cannot be performed.

The distal-joint involvement that is characteristic of psoriatic arthritis is also observed in osteoarthritis. In psoriatic arthritis, palpation of distal joints reveals soft swelling due to inflammation, whereas in osteoarthritis, swelling arises from a bony osteophyte and is solid.

Ankylosing spondylitis typically begins late in the second decade of life or early in the third decade, whereas psoriatic spondyloarthritis is more likely to develop in the fourth decade of life. Psoriatic spondyloarthritis may be less severe than ankylosing spondylitis, with less pain and infrequent sacroiliac-joint ankylosis; an asymmetric distribution of syndesmophytes (bony growths originating inside a ligament of the spine) is more common in cases of psoriatic arthritis.

Bone erosions are observed in 47% of patients within the first 2 years, despite the use of traditional disease-modifying medications in more than half the patients. In an observational trial involving patients with psoriatic arthritis treated with anti–tumor necrosis factor (TNF) agents such as  adalimumab, etanercept, or infliximab, the rate of partial remission was 23%. However, relapse rates are high when biologic agents are discontinued.

Differential responses in patients with rheumatoid arthritis versus those with psoriatic arthritis provide further evidence that these diseases have different causal mechanisms. The observed clinical response to brodalumab among patients with psoriatic arthritis in this study (March 9, 2017 N Engl J Med 2017; 376:957-970
DOI: 10.1056/NEJMra1505557) supports the concept that interleukin-17 pathways are critical in the pathogenesis of psoriatic skin and joint disease. The clinical response of psoriatic skin disease to brodalumab has been established in previous studies among patients with psoriasis, including approximately 20% who also had psoriatic arthritis.

Genetic differences between rheumatoid arthritis and psoriatic arthritis.

Rheumatoid arthritis, is associated with class II major histocompatibility complex (MHC) alleles, psoriasis and psoriatic arthritis are associated with class I MHC alleles.

Psoriatic arthritis is a highly heritable polygenic disease. The recurrence risk ratio (defined as the risk of disease manifestation in siblings vs. the risk in the general population) is greater than 27, which is substantially higher than the recurrence risk ratio for psoriasis or rheumatoid arthritis. Most notably, HLA-C*06 is a major risk factor for psoriasis but not for psoriatic arthritis. In psoriatic arthritis, frequencies of HLA-B*08, B*27, B*38, and B*39 have been observed, with specific subtypes of those alleles linked to subphenotypes, including symmetric or asymmetric axial disease, enthesitis, dactylitis, and synovitis. It has been shown consistently that T cells are important in psoriasis and psoriatic arthritis.

A central role for CD8+ T cells in disease pathogenesis is supported by the association with HLA class I alleles, oligoclonal CD8+ T-cell expansion, and the association of psoriatic arthritis with human immunodeficiency virus disease.

When should a diagnosis of rheumatoid arthritis be made?

  • Inflammation of three or more joints.
    • Arthritis is typically present in the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the hands. The wrists are also commonly involved, as are the metatarsophalangeal (MTP) joints in the feet, but any upper or lower extremity joint may be affected. Symmetric polyarthritis, particularly of the MCP, MTP, and/or PIP joints, strongly suggests RA.
    • Although distal interphalangeal (DIP) joint disease can occur in patients with RA, DIP involvement strongly suggests a diagnosis of osteoarthritis or psoriatic arthritis
  • Positive rheumatoid factor (RF) and/or anti-citrullinated peptide/protein antibody (such as anti-cyclic citrullinated peptide [CCP])) testing.
  • Elevated levels of C-reactive protein (CRP) or the erythrocyte sedimentation rate (ESR).
  • Diseases with similar clinical features have been excluded, particularly psoriatic arthritis, acute viral polyarthritis, polyarticular gout or calcium pyrophosphate deposition disease, and systemic lupus erythematosus (SLE).
  • The duration of symptoms is more than six weeks.
  • Serology: RFs occur in 70 to 80 percent of patients with RA. Their diagnostic utility is limited by their relatively poor specificity, since they are found in 5 to 10 percent of healthy individuals, 20 to 30 percent of people with SLE, virtually all patients with mixed cryoglobulinemia (usually caused by hepatitis C virus [HCV] infections).
  • Anti-citrullinated peptide antibodies.  The specificity of ACPA for RA is relatively high, usually over 90 percent. ACPA can occur in other diseases, including several autoimmune rheumatic diseases, tuberculosis, and sometimes chronic lung disease.
  • Other factors such as genetic factors, tissue factors, epitopes and acute phase reactants such as IL-6 have not found to correlate with disease activity or prevention of bone destruction.

2013 Update of the EULAR recommendations (the table of 2010 recommendations can be seen in the online supplement or the original publication). The 2020 EULAR has been cancelled because of COVID-19 pandemic.




Diabetes in pregnancy.

Why is there insulin resistance in pregnancy? The placenta secretes  diabetogenic hormones which include growth hormone, corticotropin-releasing hormone, placental lactogen (chorionic somatomammotropin), prolactin, and progesterone. These and other metabolic changes ensure that the fetus has an ample supply of nutrients.

Why does gestational diabetes develop?

Gestational diabetes mellitus develops during pregnancy in women whose pancreatic function is insufficient to overcome the insulin resistance associated with the pregnant state. Among the main consequences are increased risks of preeclampsia, macrosomia, and cesarean delivery, and their associated morbidities.

What is the likelihood if a pregnant woman has an abnormally high blood sugar?

  • A woman may have type 1 or type 2 pre-existing diabetes at the time of conception.
  • Develop transient hyperglycemia caused by placental hormones and transient pancreatic insufficiency: gestational diabetes.
  • Undiagnosed type 2 diabetes in reproductive-age women related to the ongoing epidemic of obesity. There has been an attempt to distinguish women with probable preexisting diabetes that is first recognized during early pregnancy. These women will need to be followed up and treated for Type 2 diabetes after the pregnancy is over. This is different from those whose disease is a transient manifestation of pregnancy-related insulin resistance and diagnosed in the late second or the third trimester.
  • The oral glucose tolerance test is no longer recommended for the diagnosis of diabetes except in gestational diabetes.
  • One-step and two-step approaches to OGTT for gestational diabetes.

    • Two-step approach – The two-step approach is the most widely used approach for identifying pregnant women with gestational diabetes mellitus in the United States. The first step is a 50 gram one-hour glucose challenge test (GCT) without regard to time of day/previous meals. Screen-positive patients go on to the second step, a 100 gram, three-hour oral glucose tolerance test (GTT), which is the diagnostic test for gestational diabetes mellitus.

    • One-step approach – The one-step approach omits the screening test and simplifies diagnostic testing by performing only a 75 gram, two-hour oral GTT but requires an overnight fast. The following thresholds have been proposed to define a positive screen: ≥130 mg/dL, ≥135 mg/dL, or ≥140 mg/dL (7.2 mmol/L, 7.5 mmol/L, or 7.8 mmol/L).

    • The positive predictive value (PPV) of this test varies depending on the prevalence of gestational diabetes mellitus in the population tested and the GTT criteria used for diagnosis of gestational diabetes mellitus. A 50 gram one-hour plasma glucose >182 mg/dL (10.1 mmol/L) had >95 percent probability of gestational diabetes mellitus. At glucose levels ≥200 mg/dL (11.1 mmol/L), others have reported PPVs of 47 to 80 percent for an abnormal GTT.
Range of diagnostic criteria for gestational diabetes mellitus
Approach Criteria Fasting mg/dL One-hour mg/dL Two-hour mg/dL Three-hour mg/dL
Two step (100-gram load) Carpenter and Coustan 95 (5.3 mmol/L) 180 (10.0 mmol/L) 155 (8.6 mmol/L) 140 (7.8 mmol/L)
Two step (75-gram load) CDA 95 (5.3 mmol/L) 191 (10.6 mmol/L) 160 (8.9 mmol/L)
One step (75-gram load) WHO 92 to 125 (5.1 to 6.9 mmol/L) 180 (10.0 mmol/L) 153 to 199 (8.5 to 11 mmol/L)
IADPSG 92 to 125 (5.1 to 6.9 mmol/L) 180 (10.0 mmol/L) 153 (8.5 mmol/L)

Why worry about gestational diabetes or hyperglycemia in a pregnant woman? Here is a list of complications likely to arise.

  • Preeclampsia, gestational hypertension
  • Polyhydramnios
  • Macrosomia and large for gestational age infant
  • Maternal and infant birth trauma
  • Operative delivery (cesarean, instrumental)
  • Perinatal mortality
  • Fetal/neonatal hypertrophic cardiomyopathy
  • Neonatal respiratory problems and metabolic complications (hypoglycemia, hyperbilirubinemia, hypocalcemia, polycythemia)

Diagnosis of Diabetes in non-pregnant patients.

  • Early screening and diagnosis allow for the identification of at-risk persons (so that preventive measures, primarily lifestyle changes, may be undertaken) and those with early disease (so that treatment can be initiated).
  • The diagnostic cutoff point for diabetes is a fasting plasma glucose level of 126 mg per deciliter (7.0 mmol per liter) or more or a glycated hemoglobin level of 6.5% or more; the diagnosis requires confirmation by the same or the other test.
  • A fasting glucose level of 100 to 125 mg per deciliter (5.6 to 6.9 mmol per liter) is consistent with prediabetes; the range of glycated hemoglobin levels that are diagnostic of prediabetes is controversial, but the American Diabetes Association recommends a range of 5.7 to 6.4%.
  • Hemoglobinopathies and conditions of altered red-cell turnover can give spurious results for glycated hemoglobin; racial and ethnic differences in glycated hemoglobin levels have been reported for given ambient glucose levels.
  • Testing of glycated hemoglobin or fasting plasma glucose appears to identify different groups of patients with diabetes and prediabetes, yet both tests identify patients at similar risk for adverse sequelae.
  • Approximately one-quarter of women with A1C 5.7 to 6.4 percent ([39 to 46 mmol/mol] suggestive of impaired glucose intolerance) in early pregnancy develop gestational diabetes mellitus when screened and tested later in pregnancy compared with <10 percent of those with A1C <5.7 percent (39 mmol/mol).
  • A two-step testing approach at 24 to 28 weeks of gestation, is recommended by the American College of Obstetrician and Gynecologists (ACOG) guidelines (50 gram oral glucose challenge test followed by the 100 gram three-hour oral glucose tolerance test [GTT] in screen-positive women)

When is glycated Hb unreliable?

Depending on the assay, spuriously low values may occur in patients with certain hemoglobinopathies (e.g., sickle cell disease and thalassemia) or who have increased red-cell turnover (e.g., hemolytic anemia and spherocytosis) or stage 4 or 5 chronic kidney disease, especially if the patient is receiving erythropoietin. In contrast, falsely high glycated hemoglobin levels have been reported in association with iron deficiency and other states of decreased red-cell turnover.

Obesity is associated with an increased risk of adverse pregnancy outcomes. Lifestyle-intervention studies have not shown improved outcomes. Metformin improves insulin sensitivity and in pregnant patients with gestational diabetes it leads to less weight gain than occurs in those who do not take metformin.