Background Minimal change disease (MCD) is also known as nil disease. Minimal change disease is defined by nephrotic syndrome with normal appearing light microscopy with foot process effacement on electron microscopy in the absence of cellular infiltrates or immune deposits.
Background Low levels of mesangial IgM and/or C3 without ultrastructural evidence for electron dense deposits is acceptable for a diagnosis of minimal change glomerulopathy. IgA mesangial deposition is a rare occurrence and whether or not it represents a pathological or a coincidental finding is uncertain.
Electron Microscopy A. Normal podocyte foot processes B. MCD with podocyte foot process effacement
Background Most common form of nephrotic syndrome in children. In children younger than 10 years, MCD makes up to 90% of all cases of nephrotic syndrome. In adolescents above the age of 10, MCD accounts for 50% of nephrotic cases. While in adults, MCD accounts for 10-15% of primary nephrotic syndrome cases.
Background In children, MCD is found twice as frequently in boys than in girls. The frequency is the approximately the same between the sexes in adults. The incidence peaks in children at age with approximately 80% being younger than 6 years at the time of diagnosis. In adults, the mean age of onset is 40 years. The percentage of nephrotic patients with MCD is highest in Asian and Caucasian populations. Waldman et al. CJASN 2: p445, 2007.
Pathophysiology The underlying cause of MCD is still uncertain, however, evidence points to T-cell dysfunction as a major player. First postulated by Shalhoub in 1974, this theory (also known as the Shalhoub hypothesis) is supported by the following observations: - Remissions of MCD occur in the setting of a measles infection where viral associated immunosuppression occurs. - MCD occurs more frequently in patient’s with lymphoma. - MCD is responsive to steroids and alkylating drugs. - Atopic individuals who have exaggerated Th2 responses to common allergens are at a higher risk of developing MCD.
Pathophysiology The following observations support the possibility of a circulating “permeability factor” of immune origin which alters glomerular podocyte permeability causing proteinuria: - A T-cell hybridoma made from patient with MCD released a substance that when injected into rats, induced proteinuria and foot process effacement. - Two kidneys of a young donor with presumptive MCD (never biopsied) were transplanted into two recipients without baseline proteinuria. Proteinuria diminished rapidly in both recipients and was absent by week six. Koyama A et al. KI 40: p453, 1991. Ali AA et al. Transplantation 58: p849, 1994.
Permeability Factor – IL-13 One of the leading permeability factor suspects is IL-13. IL-13 is known to be an autocrine growth factor for the Reed-Sternberg cell in Hodgkin’s lymphoma. IL-13 expression was upregulated in T cells in children with steroid sensitive nephrotic syndrome who were in relapse. Receptors of IL-13 have been demonstrated on podocytes and stimulation of cultured monolayers of podocytes with IL-13 lead to decreased transepithelial electrical resistance. Skinnider BF et al. Int Arch Allergy Immunol 126: p 267, 2001. Yap HK et al. JASN 10: p 529, 1999. Van den Berg JG et al. JASN 11: p413, 2000.
Permeability Factor – IL-13 Rats were transfected with the IL-13 gene, which resulted in the overexpression of IL-13. Transfected rats demonstrated significant albuminuria, hypoalbuminemia and hypercholesterolemia when compared to controls. Kin-Wai L et al. JASN 18: p 1476, 2007.
Permeability Factor – IL-13 At day 70, light microscopy was indistinguishable from control rats, however, the EM of transfected rats demonstrated up to 80% foot process effacement.
Permeability Factor – IL-13 Glomerular gene expression was significantly down- regulated for nephrin, podocin and dystroglycan, proteins found on the podocyte and thought to be essential in maintaining the filtration barrier. This decrease was not due to loss of podocytes as glomerular expression of WT-1 (a podocyte specific cell marker) showed no difference in IL-13 and control rats.
Pathophysiology – Role of B-cells - It was serendipitously noted in a few cases of patients with lymphoproliferative disorders and nephrotic syndrome that when treated with rituximab the nephrotic syndrome unexpectedly remitted. - Recent case reports have demonstrated complete remission in patients with steroid dependent/resistant minimal change disease when treated with rituximab. - One case report, noted that a patient remained in remission for 9 months while B-cells counts were undetectable, but relapse occurred when B-cells returned. - Could the permeability factor be produced by B-cells or by T- cells through pathways regulated or stimulated by B-cells? Gilbert R et al. Pediatric Nephrology 21: p1698, 2006. Yang T et al. NDT 23:p377, 2008.
Etiologies Idiopathic (80-90% of cases) Secondary Drugs – NSAIDs, gold, rifampin, penicillins, trimethadione Toxins - mercury, lead Atopic agents - bee stings, poison ivy, pollen Infection – Syphilis, Infectious mononucleosis, HIV Tumor - Hodgkin lymphoma (most commonly), other lymphoproliferative diseases, carcinomas Other glomerular diseases – IgA nephropathy, Lupus, PKD. Glassock R. NDT 18:p vi52, 2003.
IgA and MCD Albeit an uncommon occurrence, mesangial IgA deposition in MCD has been reported since the 1980s in a few case series. Typically the IgA deposition is mild and questions have been raised if IgA plays a pathogenic role constituting an overlapping syndrome, whether the finding is coincidental, or is this variant of MCD. All patients responded to corticoidsteroid treatment with remission of nephrotic syndrome, which is atypical for IgA nephropathy.
IgA and MCD Choi et al in published the findings of 60 patients (43 adults and 17 children) with MCD and mesangial IgA deposition. - 363 cases of MCD were seen at a single center in Seoul, Korea over a 6 year period of which mesangial IgA deposits were noted in 60 patients (16.8%) - Hematuria occurred in 69% of the adults and 88% of the children of which seven patients presented with macroscopic hematuria. Choi J et al. Yonsei Medical Journal 31:p258, 1990.
IgA and MCD Tsukada et al published a single center case series out of Tokyo, Japan. - Of the 63 patient’s diagnosed with MCD over a 6 year period, 15 had mesangial IgA deposition (23.8%). - There were no differences in creatinine clearance or amount of proteinuria. - Hematuria resolved after treatment with steroids in all 15 patients. Tsukada M et al. Nephrology 6:pA18, 2001.
IgA and MCD A case report of two patients with MCD and mesangial IgA deposition who remitted with glucocorticoid treatments was published in 1989. The two patients were rebiopsied, which demonstrated that the previous mesangial expansion and mesangial IgA deposits disappeared. As it is unusual for IgA deposits to disappear in serial renal biopsies in patients with IgA nephropathy, the authors proposed that this finding represents a distinct clinical syndrome and is not merely coincidental. Ignatius KP et al. AJKD 16:p361, 1989.
Clinical Findings Although there is an abundance of data regarding the course, response to treatment and outcomes in pediatric patients, much less is known about adults with MCD. Typically MCD is characterized by sudden onset (days to weeks) of the signs and symptoms of the nephrotic syndrome (edema, proteinuria, hypoalbuminemia and hyperlipidemia). Hypertension, hematuria and renal dysfunction are seen in a minority of cases in both children and adults with MCD.
Clinical Findings Some proposed mechanisms for acute kidney injury include ischemic tubular injury and interstitial edema or nephrosarca leading to tubular collapse. Susceptibility to bacterial infections is a considerable source of morbidity, proposed mechanisms include: hypogammaglobulinemia from urinary losses impaired production of antibodies decreased levels of alternative complement factor D
Clinical Findings on Presentation Study Korbet et al Nolasco et alMak et al Fujimoto et al Nakayama et al Waldman et alISKDC Number of Patients408951336295401 Age41423728574512wk-16yr Male48%56%70%67%52%39%66% Proteinuria (g/d)8.710.216.412.413.59.9 Serum albumin (g/dl)22.214.171.124.8 2.2 Hypertension21%30%55%9%32%42%14% Microscopic hematuria21%28%33%15%43%29%22% Renal insufficiency (SCr > 1.3mg/dl)18%61%55%15%33%18%29%
Clinical Findings – MCD Patients with AKI Waldman et al. CJASN 2: p445, 2007.
Treatment - Glucocorticoids Glucocorticoid therapy remains the mainstay of treatment with complete remission in 75-97% of adults with MCD. There is only one randomized control treatment trial in adults with MCD that compared prednisone with no therapy (n=31). - 75 % of prednisone treated patients had remission to <1g/day of proteinuria within 6 months. - In the untreated group, 50% were in remission at 18 months and approximately 70% at three years. There are no randomized control trials comparing prednisone to other agents for the initial therapy in adults with MCD. Black DA et al. BMJ 3:p421, 1970.
Treatment - Glucocorticoids StudyKorbet et alNolasco et alMak et alFujimoto et alNakayama et alWaldman et alISKDC Number of Patients408951336295401 Remission98%91%92%97%98% 92% 95% Complete91%78%76%97%93%75%95% Partial7%13%16%5% 17% Steroid Resistance2%9%8%3%2% 8% 5% Initial response to steroids (1-1.5mg/kg/day) in adult onset minimal change disease. Complete remission defined as < 0.3 g/d of proteinuria. Partial remission defined as >50% reduction of proteinuria from baseline.
Glucocorticoid Treatment Response There were no features at presentation that predicted a response (or lack thereof) to steroids. Responders tended to have a slightly lower serum creatinine at presentation compared with nonresponders but this was not statistically significant (1.3 vs 1.6mg/dl). Of note, seven steroid resistant patients underwent repeat biopsy in the Waldman study, FSGS was identified in six cases. (whether the diagnosis of FSGS was missed on initial biopsy or there was progression to FSGS is uncertain). Waldman et al. CJASN 2: p445, 2007.
Glucocorticoid Time to Remission Compared to children, time to complete remission is prolonged with 50% responding in 4 weeks and 10-25% requiring more than 4 months of therapy.
Relapses StudyKorbet et alNolasco et alMak et alFujimoto et al Nakayama et alWaldman et alISKDC Number of Patients408951336295401 Total Relapses 65%76%70%37%62% 73% 71% Frequent- relapsers 16%26% 27% 44% Steroid- dependent 40% 14%50% 10% 18% Relapse defined as resumption of nephrotic range proteinuria (>3.5 g/d). Frequent relapsers defined as >3 relapses in 1 year period. Steroid dependent defined as relapse upon tapering steroid therapy or within 4 weeks of discontinuation of steroids.
Second Line Treatment For frequent relapsers and steroid-dependent patients. No prospective treatment trials, all retrospective observational reports. Both cyclophosphamide and cyclosporine reported to induce and maintain remission in up to 60% of MCD patients, less so in steroid resistant cases (10%). Cyclosporine tends to achieve a more rapid remission, but between 60-90% of patients relapse after discontinuation making cyclosporine dependence a major issue. Meyrier A et al. NDT 18:p vi79, 2003. Ponticelli et al. KI 43:p1377, 1993.
Second Line Treatment Although small retrospective case series have used azathioprine, mycophenolate mofetil, and tacrolimus, the data is very limited. Lemivasole - An immunomodulator which enhances antibody production and phagocytic activity of PMNs and monocytes, has been used in children with frequent relapses and steroid-dependence with increasing rates of steroid free remissions. - A few case reports in adults suggesting possible role in the treatment of MCD. Rituximab
Prognosis Study Korbet et al Nolasco et alMak et al Fujimoto et al Number of Patients40895133 Follow up (mo) 549116946 Nephrotic20%6%2%3% ESRD5%1%2% Death8%17%2%3% Complications of nephrotic syndrome have been reported in 21% of adults in long term follow up including: - Thrombotic events 13% - Life threatening infections 11% - Myocardial infarction 9% Mortality rate is higher in adults as compared to children which is approximately 3%.