Minimal-Change Disease

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Background

Minimal-change disease (MCD), also known as lipoid nephrosis or nil disease, is the most common single form of nephrotic syndrome in children. It refers to a histopathologic lesion in the glomerulus that almost always is associated with nephrotic syndrome. It typically is a disease of childhood, but it also can occur in adults.

Pathophysiology

It is postulated that MCD is a disorder of T cells, which release a cytokine that injures the glomerular epithelial foot processes. This, in turn, leads to a decreased synthesis of polyanions. The polyanions constitute the normal charge barrier to the filtration of macromolecules, such as albumin. When the polyanions are damaged, leakage of albumin follows. The identity of this circulating permeability factor is uncertain, although it is postulated that it may be hemopexin.

Some of the cytokines that have been studied in MCD are interleukin-12 (IL-12) and interleukin-4 (IL-4). IL-12 levels have been found to be elevated in peripheral blood monocytes during the active phase and normalized during remission. Interleukin-18 (IL-18) can synergize with IL-12 to selectively increase the production of vascular permeability factor from T cells. In addition, levels of IL-4 and CD23 (a receptor for immunoglobulin E [IgE][1] ) have been found to be elevated in peripheral blood lymphocytes.

Synaptopodin is a proline-rich protein intimately associated with actin microfilaments present in the foot processes of podocytes. Greater synaptopodin expression in podocytes is associated with a significantly better response to steroid therapy. On the other hand, the expression of synaptopodin does not predict progression of MCD or diffuse mesangial hypercellularity to focal segmental glomerulosclerosis (FSGS). Thus, this marker could be used in the future to help determine appropriate therapy.

Interleukin-13 (IL-13) has been implicated in the pathogenesis of MCD. In a study on Chinese children in Singapore, it was shown that IL-13 genetic polymorphisms correlate with the long-term outcome of MCD. An animal study by Lai et al suggested that IL-13 overexpression can cause podocyte foot process fusion and proteinuria.[2]

In patients who develop acute renal failure, endothelin 1 expression is greater in the glomeruli, vessels, and tubules than in the nonacute renal failure group. The glomerular epithelial cells (podocytes) and the slit diaphragm connecting the podocyte foot processes play a primary role in the development of proteinuria.

Nephrin is a major component of the slit diaphragm. The slit diaphragm is often missing in MC nephrotic syndrome (MCD) kidneys. The role of nephrin and the slit diaphragm in MCD is not known. However, genetic variants of a glomerular filter protein may play a role in some patients with MCD.

Izzedine et al found a lack of glomerular dysferlin expression associated with minimal-change nephropathy in a patient with limb-girdle muscular dystrophy type 2B.[3] In the same study, 2 of 3 other patients with dysferlinopathy had microalbuminuria.

CD 80, a protein found in B cells and responsible for T-cell activation, is found to be increased in patients with MCD. However, the levels of this protein are not elevated in the urines of patients with FSGS compared with patients with MCD. Thus, this may have clinical applicability in distinguishing these two entities.[4]

Epidemiology

Frequency

United States

In preadolescents, minimal-change nephrotic syndrome (MCNS) makes up 85-95% of all cases of nephrotic syndrome. In adolescents and young adults, the prevalence is 50%, while in adults, MCNS accounts for 10-15% of primary nephrotic syndrome cases. The incidence of nephrotic syndrome is 2-7 new cases annually per 100,000 children, and the prevalence is 15 cases per 100,000 children.

Mortality/Morbidity

Very few patients progress to end-stage renal disease. These patients are those who have FSGS that has been misdiagnosed as MCD.

Race

Sex

Age

History

Physical

Causes

Almost all cases are idiopathic, but a small percentage of cases (approximately 10-20%) may have an identifiable cause. Causes may include the following:

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Light microscopy: In patients with MCD, the glomerulus is, by definition, normal or nearly so when examined with the light microscope; however, the precise limits of normal are not clearly defined. This creates difficulty in differentiating the appearance of minimal change with mild mesangial proliferation from a mesangial proliferative glomerulonephritis. Diagnosis can be even more difficult because, at the peak age of onset (approximately 3 y), the mesangial and epithelial cells are more prominent. In adult patients, diagnosis is made more challenging by superimposed arterionephrosclerosis secondary to hypertension. In children with frequently relapsing MCD, some involuted glomeruli may be present. These lesions are small and sclerotic but retain their podocyte and parietal epithelial cell constituents. The presence of these glomeruli is related to the duration of the disease.

The most common tubular lesion is protein and lipid droplets in epithelial cells due to increased reabsorption. The presence of areas of tubular atrophy and interstitial fibrosis should raise the suspicion of FSGS.

Immunohistology: These studies usually do not demonstrate significant glomerular deposition of immunoglobulins or complement components in patients with MCD. Some biopsy specimens may be positive for low-level IgM deposits not accompanied by mesangial dense deposits.

Electron microscopy: Retraction of the epithelial foot processes is observed consistently in patients with MCD. This is, at times, erroneously described as foot-process fusion and results from disordered epithelial cell structure with withdrawal of the dendritic process. This finding is not unique to MCD, and the diagnosis is one of exclusion of other diseases based on lack of other processes on light microscopy, immunohistology, or electron microscopy.

Medical Care

Corticosteroids are the treatment of choice, leading to complete remission of proteinuria in most cases. Approximately 90% of children respond within 2 weeks to prednisone at a dose of 60 mg/msq/d. The treatment is continued for another 6 weeks, at lower doses of prednisone, after the remission of proteinuria. In some children, proteinuria fails to clear by 6-8 weeks, and performing a renal biopsy may be useful to determine if another process may be present.

Adults respond more slowly than children. A response in up to 80-90% has been recorded in adolescents and adults. However, the time to remission is up to 16 weeks. If patients are steroid-resistant or they relapse frequently, a trial of immunosuppressants is given.

MCD secondary to Hodgkin lymphoma is frequently resistant to steroids and will remit with cure of the primary disease.

Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, alone or in combination should be used with a goal of reducing the proteinuria. Blood pressure and renal function should be monitored closely in patients on angiotensin converting enzyme inhibitors and angiotensin II receptor blockers.

Consultations

Diet

Activity

Medication Summary

Diuretics are used to decrease severe edema. NSAIDs also can be used to decrease proteinuria. Patients usually respond to steroids. The response of patients to steroids is used to divide patients into various groups. The following terms are used to categorize the response of patients:

Because MCNS accounts for 90% of all cases of idiopathic nephrotic syndrome in children, steroids are started empirically. A biopsy is performed only in those cases where no remission occurs. In comparison, a biopsy is performed in all adults before the initiation of treatment. Adults tend to respond more slowly, with more than 25% taking as long as 12-16 weeks to undergo complete remission. A typical initial regimen in adults consists of oral prednisone in a daily dosage of 1 mg/kg of body weight for 8-16 weeks (or for 1 wk after remission has been induced). The patient is then placed on an alternate-day single-dose (1 mg/kg) regimen to minimize the incidence of adverse effects. If proteinuria disappears or is reduced to a very low level, high-dose alternate-day therapy is continued for several weeks to 1 month and then slowly tapered over several months in an attempt to reduce the likelihood of relapse.

To prevent relapse, steroids are continued for several weeks after remission. Patients are grouped into the following:

Steroid-sensitive patients: These patients have complete remission within 8-12 weeks with infrequent relapses. Children usually respond within 4-6 weeks, whereas adults respond in up to 15 weeks. Treatment usually is continued for another 6 weeks after complete remission of proteinuria occurs.

Steroid-dependent patients or frequent relapsers: If remission is followed by recurrence, a second course of steroids is given. Those patients who need steroids repeatedly are categorized as frequent relapsers or steroid-dependent patients. Relapse in these patients can occur either during tapering of steroids or after cessation of therapy. In these patients, cytotoxic drugs, such as Cytoxan, chlorambucil, or cyclosporine, can be considered to either induce a remission or decrease the adverse effects of continuous steroid use. Cytotoxic drugs, such as 2 mg/kg/d of cyclophosphamide for 8-12 weeks, can be used in such patients. Cyclosporine (4-6 mg/kg/d) also can be used in patients who continue to relapse or who are steroid-dependent. Because cyclophosphamide is cheaper and has a better response rate, it is preferable over cyclosporine in most patients with steroid-dependent or frequently relapsing MCD.

MMF may also be beneficial to patients with frequent relapses. This was suggested by a small study where 7 patients with MCD and FSGS with multiple relapses were treated with MMF (1 g bid). After 1 year, 5 of the 7 patients were still in remission, and the steroid dose was significantly decreased. In addition, the immunomodulator levamisole also has been used in children.

Steroid-resistant patients: If no reduction in proteinuria occurs by 12-16 weeks, adults are considered steroid-resistant. The most common cause of this is misdiagnosis. Studies in adults and children have shown that both cyclophosphamide and cyclosporine added to steroid treatment may induce remission.[6] Moreover, if these patients relapse at a later time, they tend to become steroid-sensitive.

Secondary steroid-resistant: Some patients develop secondary steroid resistance after an initial response to steroids.

In children, repeat biopsy can alter the treatment plan in a significant number of patients. Long-term follow-up of patients with MCD persisting post puberty shows that they are at increased risk of osteoporosis, myopia, and hypertension.

In patients who do not respond to treatment, follow-up biopsies have been found to show either IgM nephropathy or FSGS.

A study by Swartz et al of 55 children with steroid-resistant or steroid-dependent MCD determined that 23 of these patients also had mesangial IgM that was visible through immunofluorescence (one of the characteristics of IgM nephropathy).[7] The investigators also found that the children with MCD and immunofluorescently-visible IgM responded better to treatment with cyclosporine than to therapy with cyclophosphamide.

Adults are particularly prone to the adverse effects of corticosteroids, but they do well on cyclophosphamide.

Cyclosporine may be used as an alternative to cyclophosphamide in order to avoid toxicities associated with the latter.[8] Keeping the dosage of cyclosporine at a minimum and carefully monitoring the drug’s levels have been shown to be helpful in avoiding cyclosporine-associated nephrotoxicity.

Rituximab has been shown to be effective against minimal-change disease. Relapse has been linked to the reappearance of B19 cells, which rituximab depletes. Rituximab may therefore have a role in the treatment of steroid-dependent and multirelapsing patients. In one trial with immunosuppressant-dependent young adults, a good response was seen with rituximab. It has been shown to be reasonably well tolerated.[9, 10]

Rituximab has also been shown to be very effective in small trials in adults with steroid resistance.[11]

In 20% of steroid-resistant patients, a genetic mutation may be responsible. One of these is the NPHS2 mutation; however, heterozygotes respond well to steroids.[12] The treatment of MCD with tacrolimus has produced varying results.[13, 14, 15]

The choice of immunosuppressants includes cyclophosphamide and chlorambucil. These drugs expose the patient to a wide range of serious adverse effects that include life-threatening infections, gonadal dysfunction, bone marrow dysfunction, and, in the case of chlorambucil, increased risk of leukemia. Pulse cyclophosphamide failed to adequately suppress recurrence of minimal-change nephrotic syndrome in a small group of children who were steroid-dependent. In children with steroid-resistant nephrotic syndrome, those who received tacrolimus (another calcineurin inhibitor) and steroids had a higher complete/partial remission rate and increased chances of sustained remission with fewer adverse effects compared with those who received cyclophosphamide.[16]

Cyclosporine is considered to be an acceptable drug for maintenance therapy in patients with frequent relapses and steroid dependency. However, it is less efficacious than cyclophosphamide at maintaining sustained remission.

Mycophenolate mofetil (MMF) has been shown in limited studies to be beneficial to patients who are steroid-dependent or with frequent remissions. Unfortunately, the evidence for the benefit of this drug is scant at this time, and it should be considered only when patients develop serious adverse effects to steroid treatment and refuse treatment with cyclophosphamide. Long-term remission with rituximab (an anti-CD20 antibody) in patients who have failed conventional immunosuppressive therapy has been tried with reasonable success and acceptable side effect profile. However, randomized controlled trials need to be conducted before guidelines can be issued.[9, 17]

Furosemide (Lasix)

Clinical Context:  Has potent diuretic effects by blocking the sodium reabsorption in the thick ascending limb of the loop of Henle.

Class Summary

These agents control volume overload.

Prednisone (Sterapred)

Clinical Context:  Exerts anti-inflammatory effect via the inhibition of inflammatory mediator gene transcription.

Class Summary

For remission of proteinuria.

Cyclophosphamide (Cytoxan, Neosar)

Clinical Context:  Interferes with normal function of DNA by alkylation and cross-linking strands of DNA and by possible protein modification.

Class Summary

For remission of nephrotic syndrome.

Cyclosporine A (Sandimmune, Neoral)

Clinical Context:  Inhibits production and release of IL-2, leading to inhibition of IL-2–mediated activation of T lymphocytes.

Chlorambucil (Leukeran)

Clinical Context:  To induce remission of proteinuria. Interferes with DNA replication and RNA transcription.

Class Summary

For remission of nephrotic syndrome.

Levamisole (Ergamisol)

Clinical Context:  Stimulates formation of antibodies and enhances T-cell responses. Acts as a biochemical modulator of fluorouracil.

Mycophenolate mofetil (CellCept)

Clinical Context:  Inhibitor of de novo purine pathway with preferential inhibitory effects on T and B lymphocyte proliferation, has been used to treat steroid-dependent nephrotic syndrome.

Class Summary

To induce remission of nephrotic syndrome.

Further Inpatient Care

Further Outpatient Care

Complications

Prognosis

Author

Abeera Mansur, MD, Consultant Nephrologist, Doctors Hospital and Medical Center, Pakistan

Disclosure: Nothing to disclose.

Coauthor(s)

Florin Georgescu, MD, Consulting Staff, Kidney Specialists of Savannah

Disclosure: Nothing to disclose.

Susie Lew, MD, Professor, Department of Medicine, Division of Renal Diseases and Hypertension and Nephrology, George Washington University Medical Center

Disclosure: Amgen Consulting fee Consulting; Amgen Grant/research funds investigator; Amgen Honoraria Speaking and teaching; Gambro Consulting fee Consulting; Genzyme Honoraria Speaking and teaching; Genzyme Consulting fee Consulting; Reata investigator; Boehringer Ingelheim Honoraria Speaking and teaching; Questcor Grant/research funds investigator

Specialty Editors

Anil Kumar Mandal, MD, Clinical Professor, Department of Internal Medicine, Division of Nephrology, University of Florida School of Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Eleanor Lederer, MD, Professor of Medicine, Chief, Nephrology Division, Director, Nephrology Training Program, Director, Metabolic Stone Clinic, Kidney Disease Program, University of Louisville School of Medicine; Consulting Staff, Louisville Veterans Affairs Hospital

Disclosure: Dept of Veterans Affairs Grant/research funds Research; American Society of Nephrology Salary ASN Council Position

Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine

Disclosure: Renal Ventures Ownership interest Other

Chief Editor

Vecihi Batuman, MD, FACP, FASN, Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System

Disclosure: Nothing to disclose.

References

  1. Shao YN, Chen YC, Jenq CC, et al. Serum immunoglobulin E can predict minimal change disease before renal biopsy. Am J Med Sci. Oct 2009;338(4):264-7. [View Abstract]
  2. Lai KW, Wei CL, Tan LK, et al. Overexpression of interleukin-13 induces minimal-change-like nephropathy in rats. J Am Soc Nephrol. May 2007;18(5):1476-85. [View Abstract]
  3. Izzedine H, Brocheriou I, Eymard B, et al. Loss of podocyte dysferlin expression is associated with minimal change nephropathy. Am J Kidney Dis. Jul 2006;48(1):143-50. [View Abstract]
  4. Garin EH, Mu W, Arthur JM, Rivard CJ, Araya CE, Shimada M, et al. Urinary CD80 is elevated in minimal change disease but not in focal segmental glomerulosclerosis. Kidney Int. Aug 2010;78(3):296-302.
  5. Kontchou LM, Liccioli G, Pela I. Blood pressure in children with minimal change nephrotic syndrome during oedema and after steroid therapy: the influence of familial essential hypertension. Kidney Blood Press Res. 2009;32(4):258-62. [View Abstract]
  6. Hamasaki Y, Yoshikawa N, Hattori S, et al. Cyclosporine and steroid therapy in children with steroid-resistant nephrotic syndrome. Pediatr Nephrol. Nov 2009;24(11):2177-85. [View Abstract]
  7. Swartz SJ, Eldin KW, Hicks MJ, Feig DI. Minimal change disease with IgM+ immunofluorescence: a subtype of nephrotic syndrome. Pediatr Nephrol. Jun 2009;24(6):1187-92. [View Abstract]
  8. Cattran DC, Alexopoulos E, Heering P, et al. Cyclosporin in idiopathic glomerular disease associated with the nephrotic syndrome : workshop recommendations. Kidney Int. Dec 2007;72(12):1429-47. [View Abstract]
  9. Sellier-Leclerc AL, Macher MA, Loirat C, Guerin V, Watier H, Peuchmaur M. Rituximab efficiency in children with steroid-dependent nephrotic syndrome. Pediatr Nephrol. Jun 2010;25(6):1109-15. [View Abstract]
  10. Hoxha E, Stahl RA, Harendza S. Rituximab in adult patients with immunosuppressive-dependent minimal change disease. Clin Nephrol. Aug 2011;76(2):151-8. [View Abstract]
  11. Munyentwali H, Bouachi K, Audard V, Remy P, Lang P, Mojaat R. Rituximab is an efficient and safe treatment in adults with steroid-dependent minimal change disease. Kidney Int. Jan 16 2013;[View Abstract]
  12. Caridi G, Gigante M, Ravani P, et al. Clinical features and long-term outcome of nephrotic syndrome associated with heterozygous NPHS1 and NPHS2 mutations. Clin J Am Soc Nephrol. Jun 2009;4(6):1065-72. [View Abstract]
  13. Li X, Li H, Chen J, et al. Tacrolimus as a steroid-sparing agent for adults with steroid-dependent minimal change nephrotic syndrome. Nephrol Dial Transplant. Jun 2008;23(6):1919-25. [View Abstract]
  14. Sinha MD, MacLeod R, Rigby E, Clark AG. Treatment of severe steroid-dependent nephrotic syndrome (SDNS) in children with tacrolimus. Nephrol Dial Transplant. Jul 2006;21(7):1848-54. [View Abstract]
  15. Westhoff TH, Schmidt S, Zidek W, Beige J, van der Giet M. Tacrolimus in steroid-resistant and steroid-dependent nephrotic syndrome. Clin Nephrol. Jun 2006;65(6):393-400. [View Abstract]
  16. Gulati A, Sinha A, Gupta A, Kanitkar M, Sreenivas V, Sharma J. Treatment with tacrolimus and prednisolone is preferable to intravenous cyclophosphamide as the initial therapy for children with steroid-resistant nephrotic syndrome. Kidney Int. Nov 2012;82(10):1130-5. [View Abstract]
  17. Fujinaga S, Hirano D, Nishizaki N, Kamei K, Ito S, Ohtomo Y, et al. Single infusion of rituximab for persistent steroid-dependent minimal-change nephrotic syndrome after long-term cyclosporine. Pediatr Nephrol. 2010;25(3:359.
  18. Waldman M, Crew RJ, Valeri A, et al. Adult minimal-change disease: clinical characteristics, treatment, and outcomes. Clin J Am Soc Nephrol. May 2007;2(3):445-53. [View Abstract]
  19. Ahmad H, Tejani A. Predictive value of repeat renal biopsies in children with nephrotic syndrome. Nephron. Apr 2000;84(4):342-6. [View Abstract]
  20. Araya CE, Wasserfall CH, Brusko TM, et al. A case of unfulfilled expectations. Cytokines in idiopathic minimal lesion nephrotic syndrome. Pediatr Nephrol. May 2006;21(5):603-10. [View Abstract]
  21. Audard V, Larousserie F, Grimbert P, et al. Minimal change nephrotic syndrome and classical Hodgkin's lymphoma: report of 21 cases and review of the literature. Kidney Int. Jun 2006;69(12):2251-60. [View Abstract]
  22. Bagga A, Hari P, Moudgil A, Jordan SC. Mycophenolate mofetil and prednisolone therapy in children with steroid-dependent nephrotic syndrome. Am J Kidney Dis. Dec 2003;42(6):1114-20. [View Abstract]
  23. Bonilla-Felix M, Parra C, Dajani T, et al. Changing patterns in the histopathology of idiopathic nephrotic syndrome in children. Kidney Int. May 1999;55(5):1885-90. [View Abstract]
  24. Cho BS, Yoon SR, Jang JY, Pyun KH, Lee CE. Up-regulation of interleukin-4 and CD23/FcepsilonRII in minimal change nephrotic syndrome. Pediatr Nephrol. Apr 1999;13(3):199-204. [View Abstract]
  25. Choi MJ, Eustace JA, Gimenez LF, et al. Mycophenolate mofetil treatment for primary glomerular diseases. Kidney Int. Mar 2002;61(3):1098-114. [View Abstract]
  26. Day CJ, Cockwell P, Lipkin GW, Savage CO, Howie AJ, Adu D. Mycophenolate mofetil in the treatment of resistant idiopathic nephrotic syndrome. Nephrol Dial Transplant. Nov 2002;17(11):2011-3. [View Abstract]
  27. Dijkman HB, Wetzels JF, Gemmink JH, Baede J, Levtchenko EN, Steenbergen EJ. Glomerular involution in children with frequently relapsing minimal change nephrotic syndrome: an unrecognized form of glomerulosclerosis?. Kidney Int. Jan 2007;71(1):44-52. [View Abstract]
  28. Donia AF, Gazareen SH, Ahmed HA, et al. Pulse cyclophosphamide inadequately suppresses reoccurrence of minimal change nephrotic syndrome in corticoid-dependent children. Nephrol Dial Transplant. Oct 2003;18(10):2054-8. [View Abstract]
  29. Grimbert P, Audard V, Remy P, Lang P, Sahali D. Recent approaches to the pathogenesis of minimal-change nephrotic syndrome. Nephrol Dial Transplant. Feb 2003;18(2):245-8. [View Abstract]
  30. Humphreys BD, Vanguri VK, Henderson J, Antin JH. Minimal-change nephrotic syndrome in a hematopoietic stem-cell transplant recipient. Nat Clin Pract Nephrol. Sep 2006;2(9):535-9; quiz 540. [View Abstract]
  31. Jennette JC, Falk RJ. Adult minimal change glomerulopathy with acute renal failure. Am J Kidney Dis. Nov 1990;16(5):432-7. [View Abstract]
  32. Kyrieleis HA, Lowik MM, Pronk I, et al. Long-term outcome of biopsy-proven, frequently relapsing minimal-change nephrotic syndrome in children. Clin J Am Soc Nephrol. Oct 2009;4(10):1593-600. [View Abstract]
  33. Lahdenkari AT, Kestila M, Holmberg C, Koskimies O, Jalanko H. Nephrin gene (NPHS1) in patients with minimal change nephrotic syndrome (MCNS). Kidney Int. May 2004;65(5):1856-63. [View Abstract]
  34. Matsumoto K, Kanmatsuse K. Increased IL-12 release by monocytes in nephrotic patients. Clin Exp Immunol. Aug 1999;117(2):361-7. [View Abstract]
  35. Nakayama M, Katafuchi R, Yanase T, Ikeda K, Tanaka H, Fujimi S. Steroid responsiveness and frequency of relapse in adult-onset minimal change nephrotic syndrome. Am J Kidney Dis. Mar 2002;39(3):503-12. [View Abstract]
  36. Niaudet P. Treatment of childhood steroid-resistant idiopathic nephrosis with a combination of cyclosporine and prednisone. French Society of Pediatric Nephrology. J Pediatr. Dec 1994;125(6 Pt 1):981-6. [View Abstract]
  37. Nolasco F, Cameron JS, Heywood EF, Hicks J, Ogg C, Williams DG. Adult-onset minimal change nephrotic syndrome: a long-term follow-up. Kidney Int. Jun 1986;29(6):1215-23. [View Abstract]
  38. Prasad GV, Vincent L, Hamilton R, Lim K. Minimal change disease in association with fire coral (Millepora species) exposure. Am J Kidney Dis. Jan 2006;47(1):e15-6. [View Abstract]
  39. Smith JD, Hayslett JP. Reversible renal failure in the nephrotic syndrome. Am J Kidney Dis. Mar 1992;19(3):201-13. [View Abstract]
  40. Tang HL, Chu KH, Mak YF, et al. Minimal change disease following exposure to mercury-containing skin lightening cream. Hong Kong Med J. Aug 2006;12(4):316-8. [View Abstract]
  41. Tarshish P, Tobin JN, Bernstein J, Edelmann CM Jr. Prognostic significance of the early course of minimal change nephrotic syndrome: report of the International Study of Kidney Disease in Children. J Am Soc Nephrol. May 1997;8(5):769-76. [View Abstract]
  42. The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the International Study of Kidney Disease in Children. J Pediatr. Apr 1981;98(4):561-4. [View Abstract]
  43. Wei CL, Cheung W, Heng CK, et al. Interleukin-13 genetic polymorphisms in Singapore Chinese children correlate with long-term outcome of minimal-change disease. Nephrol Dial Transplant. Apr 2005;20(4):728-34. [View Abstract]