As we all know diabetes is on the increase; approximately 1 in five people in the third world will develop diabetes. In the future the largest number of patients with chronic renal failure seen in a dialysis unit will have diabetes either as the cause of the kidney disease or accompanying chronic renal failure. What are the problems we are faced with?
- What is the likelihood that a diabetic patient will develop nephropathy?
- How can we differentiate between diabetic glomerular damage and primary renal disease in a diabetic patient?
- Can diabetic nephropathy be prevented or its progression delayed or perhaps reversed?
- Will tight glycemic control help?
- Will the control of blood pressure and other adverse factors help to delay the onset of diabetic nephropathy?
- Why do the RAAS inhibitors work only within a certain limit and then we see a progression of the renal glomerular damage?
- Which trials are considered reliable to serve as guide lines?
- Once the reduction in GFR has occurred can we do anything to improve renal function temporarily or in a sustained manner?
- What is the role of pancreatic transplant along with renal transplant if the patient has diabetes?
Let us see how many of these queries we can answer.
Let us capitulate why diabetic nephropathy develops in the first place. Three factors seem to be foremost; hyperfiltration because of the hyperglycemia, damage to the basement membrane leading to proteinuria which increases the hyperfiltration; glomerular hypertension caused by a failure of autoregulation of renal blood flow. Vasoconstriction of the afferent arteriole in response to systemic hypertension protects the glomerular capillaries from a high filtration pressure. Persistent vasodilatation leads to hyperfiltration. Glomerular hyperfiltration (GH) is thought to play an important role in the initiation of glomerular damage, especially in the diabetic patient. However the GH is not simply a function of pressure mechanics. It is thought that GH is caused first by alteration in tubuloglomerular feedback and the activation of vasoactive mediators, such as the nitric oxide, cyclooxygenase-2–derived prostanoids, the renin-angiotensin system, protein kinase C, and endothelins, which increase glomerular capillary pressure and lead to secondary increases in GFR (detected as GH). At present clinically we can only reduce the intraglomerular pressure by the use of AAAS modulators like angiogenesis converting enzyme inhibitors (ACE-I) and angiotensin receptor blocking (ARBs) drugs. The limitation is that this slows the renal damage but when the GFR goes below a critical level the progressive damage from the chemical mediators leads to glomerulosclerosis and CKD.
Macro-albuminuria is now called severe albuminuria and microalbuminuria is called moderate albuminuria.
How can we detect hyperfiltration? A patient who has a GFR above normal has hyperfiltration. In an original report (Vora JP, Dolben J, Dean JD, et al. Renal hemodynamic in newly presenting non-insulin dependent diabetes mellitus. Kidney Int 1992; 41:829) of 110 newly diagnosed patients with type 2 diabetes mellitus, for example, the GFR was above 140 mL/min in 16 percent and more than two standard deviations above the mean of a control population in 45 percent.
In a study of 194 Pima Indians who had GFR measured using iothalamate clearance ( Nelson RG, Bennett PH, Beck GJ, et al. Development and progression of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus. Diabetic Renal Disease Study Group. N Engl J Med 1996; 335:1636.) The following results were noted:
- In 31 patients with a normal glucose tolerance test, the mean GFR was 123 mL/min.
- In 29 patients with impaired glucose tolerance, the mean GFR was 135 mL/min.
- In 30 patients with newly diagnosed type 2 disease, the mean GFR was 143 mL/min.
- In 70 patients with overt diabetes for more than five years and either normal albumin excretion or moderately increased albuminuria (formerly called “microalbuminuria”), the mean GFR was 153 mL/min;
- in 34 similar patients with overt proteinuria, the mean GFR was 124 mL/min.
The prevalence of hyperfiltration may be lower in the era of more aggressive glucose control. Hyperfiltration is linked to dilatation of the afferent arteriole of the glomerulus. Experimentally this can be reduced by infusing octreotide and appears to be linked to reduction in the concentration in blood of insulin like growth factor 2 (IGF 2). In clinical practice the use of ACE-I and ARBs reduces intraglomerular hypertension when compared to the triple regime of hydrochlorothiazide, hydrallazine and reserpine to reduce systemic blood pressure. Other anti-hypertensives can reduce intraglomerular blood pressure but only by reducing systemic blood pressure and not by their action on the RAAS system.
All newly diagnosed diabetics specially type 2 diabetes, should have their GFR checked (creatinine clearance in the clinical set-up) at the start of their treatment and this should be repeated at least once a year. All those whose GFR is 2 standard deviations above normal should have their urinary proteins checked (radio-immunoassay for microalbuminuria and a 24 hour protein assay for macroalbuminuria). This should be repeated every 6-12 months.
Can we predict if a patient is going to develop diabetic nephropathy? We can wait and see or we can categorise patients at greater risk and pay them more attention. So who should we pick up for early and frequent screening?
- Heredity: a patient who has one or both parents or a sibling with diabetic nephropathy is at an increased risk of diabetic nephropathy. This holds good for Type 1 and Type 2 diabetes. In Pima indians the incidence of diabetic nephropathy is 14% if neither parent is affected by nephropathy, 23% if one parent is affected and 46% if both parents are affected. The familial increase in risk cannot be explained by the duration of diabetes, hypertension, or the degree of glycemic control, and the genetic basis underlying the heritability of diabetic nephropathy is largely unknown.
- Age: increasing age and longer duration influence the development of nephropathy.
- Obesity is another factor which influences the development of nephropathy.
- Systemic hypertension influences the development of diabetic nephropathy.
- Raised GFR.
- Oral contraceptives may influence the onset of diabetic nephropathy.
- Glycemic control.
None of these factors have a high predictability hence it is best to do the test for proteinuria in all patients at the onset of the disease and then 6-12 monthly depending on the presence of several of the above factors.
What are the major clinical clues suggesting the presence of nondiabetic glomerular disease are:
- The onset of proteinuria within five years of the documented onset of type 1 diabetes. The latent period for overt diabetic nephropathy is usually at least 10 to 15 years . The latent period is probably similar in patients with type 2 diabetes, but the time of onset is often difficult to ascertain so nephropathy appears to develop earlier in Type 2 diabetes.
- The acute onset of renal disease. Diabetic nephropathy is a slowly progressive disorder characterized by increases in protein excretion and the serum creatinine concentration over a period of years.
- The presence of an active urine sediment containing red cells (particularly acanthocytes) and cellular casts. However, hematuria and red cell casts can also be seen with diabetic nephropathy alone.
- In type 1 diabetes, the absence of diabetic retinopathy or neuropathy. By contrast, lack of retinopathy in type 2 diabetes does not preclude diabetic nephropathy, which was absent in 12 of 27 patients with biopsy confirmed diabetic nephropathy in one study.
- Signs and/or symptoms of another systemic disease.
- Significant reduction in the glomerular filtration rate (>30 percent) within two to three months of the administration of ACE inhibitors or angiotensin II receptor blockers.
Please remember to check the creatinine clearance monthly in all patients that you have put on an ACE-I or an ARB until it becomes steady. A fall of more than 20% is unacceptable. Stop the drugs. This degree of decline can be caused either by renal artery stenosis or arteriosclerotic vascular disease in older patients.
Why does renal damage progress despite reduction in intraglomerular pressure by ACE-I and ARBs?
The drugs that act by inhibiting the RAAS (renal angiotensin aldosterone system) are the angiotensin converting enzyme inhibitors (ACE-I) and the angiotensin receptor blockers (ARB). In the presence of chronic kidney disease such as diabetic nephropathy, there is failure of the autoregulation of renal blood pressure. The result is that the afferent arteriole to the glomerulus, which should undergo vasoconstriction when the BP rises so that the glomerular capillaries can be protected, fails to do so and indeed, vasodilatation occurs. The ACE-I and ARBs reduce this vasodilatation and reduce hyperfiltration and proteinuria. They do not however “cure” the disease. There are other mechanisms of kidney tissue damage at work. The mitochondria are the power houses of the cell and extremely sensitive to oxidative stress caused by the byproducts of oxidation, such as superoxide anion (O2-) and hydrogen peroxide, which are produced in the body as a consequence of normal aerobic metabolism. These molecules are highly reactive with other biologic molecules, and are referred to as reactive oxygen species (ROS). Under normal physiologic conditions, the production of oxygen free radicals and peroxides is balanced by an efficient system of antioxidants, which are molecules capable of “scavenging” ROS, thereby preventing oxidative damage. Normally this process is tightly controlled to minimize damage, but in the case of CKD, excess production of ROS can lead to kidney cell damage and death. Oxidative stress can also increase production of pro-inflammatory proteins, which contribute to oxidative damage that leads to scarring. The ARBs and ACE-I cannot stop this process.
Once the reduction in GFR has occurred can we do anything to improve renal function temporarily or in a sustained manner?
Reducing oxidative stress. Bardoxolone methyl is a small molecule drug aimed at reducing oxidative stress and inflammation, which may improve kidney function in diabetic nephropathy and Alport nephropathy. An Nrf2 activator, it acts by stimulating the Nrf2 pathway, thereby promoting normal mitochondrial function in the body.
A Phase 3 clinical trial called BEACON investigated bardoxolone methyl to prevent or reverse CKD in patients with type 2 diabetes. However, this trial was prematurely terminated due to safety concerns over increased heart failure events. Further investigations showed that this mainly occurred in patients with high baseline levels of brain natriuretic peptide (BNP), a protein associated with heart failure. Patients are now being screened for high BNP levels and have been excluded from future bardoxolone methyl trials for safety reasons, and increased monitoring for all patients will take place within the first month of the next trial.
(Beacon trial. https://www.nejm.org/doi/pdf/10.1056/NEJMoa1306033)
Further studies on bardoxalone have been done in the BEAM trial which predicted an increase in eGFR in diabetic nephropathy.
(Beam trial. https://clinicaltrials.gov/ct2/show/NCT00811889)
Bardoxolone methyl has been studied in several human clinical trials to date , in a variety of conditions including cancer and different types of kidney disease. It appears to give good results in Alport’s syndrome, the GFR continuing to improve over a 12 month period and lasting for 24 months.
Hopefully when this drug comes into the market after FDA approval we may be able to offer a longer dialysis free life to patients with diabetic nephropathy and Alport’s disease. Clinicians will then be able to offer treatment for hyperfiltration and progressive inflammatory damage to prevent loss of kidney function in diabetic nephropathy and other renal diseases.
Tight control of diabetes; does it help to prevent nephropathy?
In both type 1 and type 2 diabetes nephropathy is less likely to develop in patients with better control of glycemia as are other microvascular complications. Since 1994 a declining incidence of diabetic nephropathy has been noted in Type 1 diabetes presumably linked to better control of hyperglycemia. In the Swedish study (Bojestig M, Arnqvist HJ, Hermansson G, et al. Declining incidence of nephropathy in insulin-dependent diabetes mellitus. N Engl J Med 1994; 330:15) the HbA1c was 7%. The reduction in risk of end-stage renal disease did not reach statistical significance (RR 0.69, 95% CI 0.46-1.05). There was no reduction in the risk of doubling of the serum creatinine level or death from renal disease (RRs 1.06 and 0.99, respectively) . Of note, the majority of the trials in the meta-analyses were not of long enough duration to show a beneficial effect of glycemic control on end-stage renal disease, which typically manifests after 10 to 20 years of diabetes duration. With increasing longevity we may be able to observe the effect of tight glycemic control more significantly.
I am putting in some trials on diabetes that have become “the classics” and all young doctors should have at least a passing familiarity with these.
United Kingdom Prospective Diabetes Study — The UKPDS was designed to compare the efficacy of different treatment regimens (diet, sulfonylurea, metformin, and insulin) on glycemic control and the complications of diabetes in approximately 4000 newly diagnosed patients with type 2 diabetes [10,11]. The target fasting blood glucose concentration was 108 mg/dL (6 mmol/L) or less. Patients in the intensive-therapy group received a sulfonylurea (chlorpropamide, glibenclamide, or glipizide) or insulin; metformin was added to the sulfonylurea if the fasting blood glucose concentration was greater than 270 mg/dL (15 mmol/L) with the latter alone, and insulin was initiated if the combination of oral agents remained ineffective. The conventional-therapy group was treated with diet alone; drugs were added if there were hyperglycemic symptoms or if the fasting blood glucose concentration was greater than 270 mg/dL (15 mmol/L). The following findings were noted:
- Over 10 years, the average glycated hemoglobin (A1C) value was 7.0 percent in the intensive-therapy group compared with 7.9 percent in the conventional-therapy group (an 11 percent reduction).
- The risk for any diabetes-related endpoint (see abstract for definition of endpoints was 12 percent lower in the intensive-therapy group (p = 0.029) and 10 percent lower for any diabetes-related death (p = 0.34). It was estimated that 19.6 patients would have to be treated to prevent any single endpoint in one patient in 10 years.
- Most of the risk reduction in the intensive-therapy group was due to a 25 percent risk reduction in microvascular disease (p = 0.001); there was a borderline statistically significant (p = 0.052) reduction in macrovascular disease.
- The benefits of intensive therapy appeared to be independent of the type of treatment administered.
- Patients in the intensive-therapy group had more hypoglycemic episodes and weight gain; weight gain was greater in those receiving insulin (4.0 kg) than in those receiving chlorpropamide (2.6 kg) or glibenclamide (1.7 kg).
The reduction in microvascular complications in patients receiving intensive therapy was of a smaller magnitude than in patients with type 1 diabetes in the Diabetes Control and Complications Trial (DCCT). In the DCCT, for example, the incidence of new retinopathy was 12 percent with intensive therapy versus 54 percent with conventional therapy. One possible explanation for this difference is that the difference in A1C values was smaller between the intensive and conventional therapy groups in the UKPDS (7.0 versus 7.9 percent) compared with the DCCT (7.2 versus 9.1 percent).
ADVANCE trial — In the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial, 5571 type 2 diabetes patients receiving intensive therapy to lower A1C (mean A1C 6.5 percent) had a reduction in the incidence of nephropathy, defined as development of macroalbuminuria, doubling of the serum creatinine to at least 2.26 mg/dL (200 micromol/L), the need for renal replacement therapy, or death due to renal disease (4.1 versus 5.2 percent, hazard ratio [HR] 0.79, 95% CI 0.66-0.93) compared with 5569 patients receiving standard therapy (A1C 7.3 percent). There was no significant effect of glycemic control on the incidence of retinopathy.
ACCORD. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, a multicenter study of type 2 diabetes, was designed primarily to examine the effects of glycemic control, lower than had previously been achieved, on CVD in subjects with longstanding diabetes. The study cohort of 10,250 adults (mean age 62 years) with a median diabetes duration of 10 years and at high risk for CVD (diagnosed with CVD or two risk factors in addition to diabetes) was randomly assigned to an intensive-treatment group with the aim of achieving A1C of less than 6 percent or a standard treatment group with a A1C goal of 7.0 to 7.9 percent. The diabetes treatment strategies took advantage of an algorithmic approach using numerous diabetes medications. The ACCORD trial also had a wing to study simultaneously the effect of control of hypertension and a wing to study the effect of lipid lowering drug fenofibrate. The glycemic control wing was terminated early due to a higher number of cardiac and other deaths which appeared to be caused by arrhythmias and other cardiac events caused by hypoglycemia leading to increased secretion of adrenaline.
GLYCEMIC TARGETS. Target A1C levels in patients with type 2 diabetes should be tailored to the individual, balancing the improvement in microvascular complications with the risk of hypoglycemia. A reasonable goal of therapy might be an A1C value of ≤7.0 percent for most patients (using a Diabetes Control and Complications Trial [DCCT]/United Kingdom Prospective Diabetes Study [UKPDS]-aligned assay in which the upper limit of normal is 6.0 percent). In order to achieve the A1C goal, a fasting glucose of 80 to 130 mg/dL (4.4 to 7.2 mmol/L) and a postprandial glucose (90 to 120 minutes after a meal) less than 180 mg/dL (10 mmol/L) are usually necessary. The A1C goal should be set somewhat higher (eg, <8 percent) for older patients and those with a limited life expectancy. The American Geriatrics Society suggests an A1C target of 8 percent for frail older adults and individuals with life expectancy of less than five years. These recommendations are supported by a decision analysis integrating multiple prediction models
How does a pancreatic transplant help when a diabetic patient undergoes a kidney transplant?
When a new kidney is grafted into a patient with diabetes it is exposed to a “diabetic” environment despite tight or not so tight control of diabetes. Remember that the patient will be on steroids hence diabetes will be difficult to control. If the pancreas is transplanted at the same time there is no need for exogenous insulin and the grafted kidney is protected from developing diabetic nephropathy.
I have taken most of my information from the database Uptodate.