A 56 year old man presented to his doctor with swelling of the feet, tiredness and breathlessness of three weeks duration. He had developed hypertension; BP of 160/100 mmHg about three months back and was on a beta blocker for its control. He was not diabetic, did not have arthralgia or arthritis, a rash or photosensitivity or Raynaud’s phenomenon. His optic fundi showed mild early hypertensive nephropathy with silver wiring of the vessels. He had pitting edema up to midcalf, abdominal wall edema with a suspicion of ascites and small bilateral pleural effusions. There was no cardiomegaly, AF, or hepatomegaly. He had a good appetite and had not lost weight in the past 3 months. He was on no other drugs not even aspirin or lipid lowering therapy.
He was a lawyer by profession and spent long hours standing on his feet. Meals were irregular and often consisted of fast food bought at the canteen. He did not have a family history of diabetes or hypertension in his parents or grandparents and was the first of five siblings who were all healthy. He was affluent and lived in upper class suburbia in physical comfort. His urine dipstick was +++ for protein in the doctor’s office.
The significant finding was 8gm/L of proteins in his 24 hour urine. Serum proteins were 2.4 gm/L. Serum creatinine was .9 mg/dl. The serology for autoimmune diseases was negative, blood sugar levels did not indicate diabetes, triglycerides and lipids were just above normal. So he has proteinuria, edema, ascites and pleural effusion with significant proteinuria and hypoproteinemia and lipidemia.
His doctor tells him he has a nephrotic syndrome and he asks about the prognosis. What should he be told?
- He needs to have a biopsy of the kidney to determine what kind of nephropathy he has.
- If the biopsy shows that he has membranous nephropathy which is the commonest type of glomerulopathy expected in older adults spontaneous remission occurs in approximately 30% of affected patients, and among patients who continue to have nephrotic syndrome, end-stage renal disease develops in 40 to 50% over a period of 10 years.
- What you should know: MN is seen in all ethnic and racial groups and in both sexes, but idiopathic MN is more common in white males over the age of 40 years. MN in young women should raise the suspicion of lupus. MN is less commonly seen in children, in whom it is often associated with hepatitis B or, less commonly, autoimmune or thyroid disease.
- Why does this disease occur? A total of 70 to 80% of patients with membranous nephropathy have circulating autoantibodies to the phospholipase A2 receptor (PLA2R), and 1 to 3% have circulating antibodies to thrombospondin type-1 domain-containing 7A (THSD7A). In the remaining patients, the target antigen is unknown. In patients with anti-PLA2R antibodies, there is a tight correlation between antibody levels and disease activity, which suggests a causal relationship.
- Is treatment available? Yes for 3 months a trial of diuretics, fluid restriction, lipid lowering drugs and an ACE-I like captopril or enalapril will be given, A reduction of more than 25% of the proteinuria will be considered a response.
- Immunosuppressive therapy.
- Ponticelli’s regime: Controlled trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. N Engl J Med 1984;310:946–950. (A high incidence of incidental infection specially TB in third world countries made this unpopular)
- Jha V, Ganguli A, Saha TK, et al. A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy. J Am Soc Nephrol 2007;18:1899–1904. The side effects of this are, though the regime is effective in 60 to 70% of patients, hyperglycemia, myelosuppression, infections, infertility, and cancer.
- Alfaadhel T, Cattran D. Management of membranous nephropathy in Western countries. Kidney Dis (Basel) 2015;1:126–137. Calcineurin inhibitors, including cyclosporine, are effective and are the preferred treatment for membranous nephropathy.
- More-selective B-cell depletion with rituximab, therefore, appears to be a promising approach.
- Ruggenenti P, Cravedi P, Chianca A, et al. Rituximab in idiopathic membranous nephropathy. J Am Soc Nephrol 2012;23:1416–1425.
- Ruggenenti P, Fervenza FC, Remuzzi G. Treatment of membranous nephropathy: time for a paradigm shift. Nat Rev Nephrol 2017;13:563–579.
- Fervenza FC, Abraham RS, Erickson SB, et al. Rituximab therapy in idiopathic membranous nephropathy: a 2-year study. Clin J Am Soc Nephrol 2010;5:2188–2198.
How specific is the anti-PLA2R antibody to membranous glomerulopathy?
Anti-PLA2R antibodies have been identified in up to 82 percent of patients with primary MN in six additional cohorts from Europe and China. In one study, anti-PLA2R strongly correlated with clinical status; in another study, lower anti-PLA2R titers were associated with a higher rate of spontaneous remission, and, in two other studies, a decline in anti-PLA2R predicted the clinical response to immunosuppressive therapy. A fifth study found that higher anti-PLA2R titers within two years of diagnosis predicted substantially greater progression of kidney function decline over the subsequent five years of follow-u. This indicates that these antibodies should be monitored especially when treating with calcineurin inhibitors.
What drugs are likely to cause membranous nephropathy?
Many drugs, primarily used to treat rheumatoid arthritis have been implicated in the development of MN, including nonsteroidal antiinflammatory drugs (NSAIDs), penicillamine, parenteral gold salts, bucillamine, alemtuzumab, mercurial salts, elemental mercury, and possibly anti-tumor necrosis factor (anti-TNF) agents (etanercept, infliximab, or adalimumab).
How was the MENTOR trial designed?
The Membranous Nephropathy Trial of Rituximab (MENTOR) to investigate whether rituximab would be noninferior to cyclosporine in inducing and maintaining remission of proteinuria, regardless of patients’ baseline anti-PLA2R status, for up to 24 months in patients with apparent primary membranous nephropathy. This investigator-initiated, open-label, randomized, multicenter, noninferiority trial was conducted at 22 sites in North America.
Who were the participants?
Patients with membranous nephropathy were eligible if their diagnosis was confirmed by renal biopsy, with the biopsy sample examined by light, immunofluorescence, and electron microscopy. Renal biopsy samples were centrally reviewed by the two principal investigators and two renal pathologists. Patients also had to be 18 to 80 years of age, have proteinuria of more than 5 g per 24 hours on average in two 24-hour urine samples obtained within 14 days, have a decline of less than 50% in proteinuria despite renin–angiotensin system blockade for at least 3 months before randomization, and have a stable quantified 24-hour creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area.
All patients received best-practice supportive care that included blockers of the renin–angiotensin system, blood-pressure management targeting a value of less than 130/80 mm Hg, dietary sodium restriction to less than 4 g per day, and dietary protein restriction to 0.8 to 1 g of protein per kilogram of body weight per day during at least the previous 3 months before randomization. Do remember that the restriction of proteins is not “no proteins in diet” but restriction of proteins. In underprivileged patients in the Third World .8 gm of proteins per kg per day is all the patients can afford so do take a careful dietary history and do not make further protein restrictions.
If proteinuria remained at a level of at least 5 g per 24 hours and the creatinine clearance was at least 40 ml per minute per 1.73 m2, patients were randomly assigned in a 1:1 ratio to receive rituximab or cyclosporine.
Patients who were assigned to the rituximab group received 1000 mg of intravenous medication (Rituxan, Genentech) on days 1 and 15. If proteinuria was reduced from baseline by at least 25% at 6 months but there was not complete remission, a second course of rituximab was administered regardless of the CD19+ B-cell count. If complete remission was observed at 6 months, no second course was given. If proteinuria was reduced by less than 25% by 6 months, the patient was considered to have treatment failure and no further rituximab was administered.
Patients who were assigned to the cyclosporine group received dose-adjusted cyclosporine (Neoral, Novartis), starting at an oral dose of 3.5 mg per kilogram per day, divided into two equal doses given at 12-hour intervals. Target trough blood levels of cyclosporine were 125 to 175 ng per milliliter. Blood levels were assessed every 2 weeks until the target trough level was reached. If complete remission was observed at 6 months, cyclosporine was tapered and discontinued over a 2-month period. If proteinuria was reduced from baseline by less than 25% at 6 months, the patient was considered to have treatment failure and cyclosporine was discontinued. If proteinuria was reduced by at least 25%, cyclosporine was continued for an additional 6 months. At the end of 12 months, cyclosporine was tapered by one third of the maintenance dose monthly and discontinued after 2 months. A persistent and otherwise unexplained increase in the serum creatinine level of more than 30% was managed by dose reduction as described previously. If the creatinine level did not fall to baseline values despite dose reductions, cyclosporine was discontinued and the patient was considered to have treatment failure.
Outcome and follow-up.
The primary clinical outcome was the composite of complete or partial remission at 24 months. Secondary clinical outcomes included the composite of complete or partial remission at 6, 12, and 18 months; complete remission at 6, 12, 18, and 24 months; time to treatment failure up to 24 months; end-stage renal disease; and adverse events. Continuous secondary outcomes, including anti-PLA2R levels, quality of life as assessed with the modified Kidney Disease Quality of Life Short Form (KDQOL-SF), version 1.3, proteinuria, and creatinine clearance, were systematically recorded only up to the occurrence of treatment failure.
Complete remission was defined as proteinuria of no more than 0.3 g per 24 hours and a serum albumin level of at least 3.5 g per deciliter. Partial remission was defined as a reduction in proteinuria of at least 50% from baseline plus final proteinuria between 0.3 g and 3.5 g per 24 hours regardless of creatinine clearance or the serum albumin level. We defined no response as no reduction in proteinuria of at least 25% from baseline. Relapse was defined as the development of proteinuria of more than 3.5 g per 24 hours after a complete or partial remission. End-stage renal disease was defined as a creatinine clearance of no more than 15 ml per minute, the initiation of dialysis, or renal transplantation.
The treatment effect of rituximab as compared with cyclosporine appeared to be consistent across subgroups defined according to age, proteinuria, anti-PLA2R antibody status, and history of immunosuppressive therapy at baseline. However, a test for interaction with sex indicated a more pronounced benefit of rituximab in women than in men (P<0.001 for interaction), which was probably due to baseline imbalances in anti-PLA2R levels. The interaction disappeared after adjustment for anti-PLA2R levels at baseline.
At 24 months, 23 patients (35%) in the rituximab group and none of the patients in the cyclosporine group had a complete remission (risk difference, 35 percentage points; 95% CI, 24 to 47). Of these patients, 18 were positive for anti-PLA2R antibodies at baseline and all were antibody-negative at 24 months.
A total of 26 patients (40%) in the rituximab group and 52 (80%) in the cyclosporine group had treatment failure by 24 months (hazard ratio, 0.34; 95% CI, 0.21 to 0.54).
At the end of the treatment period (12 months), 39 patients (60%) in the rituximab group and 34 (52%) in the cyclosporine group had a complete or partial remission (hazard ratio for response, 0.85; 95% CI, 0.55 to 1.32)
The decline in anti-PLA2R antibody levels was faster and of greater magnitude and duration in anti-PLA2R–positive patients in remission in the rituximab group than in those in the cyclosporine group and was accompanied by a greater decline in proteinuria.
The incidence of adverse events was similar in the rituximab group and the cyclosporine group (71% and 78% of patients, respectively). The incidence of adverse events of grade 3 or higher was 52% in the rituximab group and 68% in the cyclosporine group, and the incidence of serious adverse events was 17% and 31%, respectively.
Rituximab was noninferior to cyclosporine in inducing proteinuria remission at 12 months and was superior in maintaining long-term proteinuria remission up to 24 months in patients with membranous nephropathy who were at high risk for progressive disease. The superiority of rituximab at 24 months appeared to be driven by the significantly lower incidence of relapse in the rituximab group than in the cyclosporine group during the observation period at months 13 to 24.
In conclusion, rituximab was noninferior to cyclosporine in inducing proteinuria remission at 12 months and was superior in maintaining long-term proteinuria remission up to 24 months in patients with membranous nephropathy who were at high risk for progressive disease.
July 4, 2019
N Engl J Med 2019; 381:36-46