AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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) 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 Singapore Chinese children, it was shown that IL-13 genetic polymorphisms correlate with the long-term outcome of MCD.

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.

Lack of glomerular dysferlin expression has been recently associated with minimal change nephropathy in a patient with limb-girdle muscular dystrophy type 2B. Two of the three patients with this disease had increased microalbuminuria.

Although there have been a multitude of studies recently published, the mechanism by which T cells increase glomerular permeability has remained unproven.

Frequency

United States

In preadolescents, minimal-change nephrotic syndrome (MCNS) makes up 85-95% of all causes of nephrotic syndrome. In adolescents and young adults, the prevalence is 50%. In the population older than 40 years, it is found in 20-25% of cases with nephrotic syndrome. Incidence is 2-7 new cases 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.

• Hypovolemic shock is perhaps the most serious complication of MCD. Hypovolemic shock typically occurs during the edema-forming phase of relapse and may be precipitated by diarrhea, sepsis, drainage of ascitic fluid, or the use of diuretics.
• Hypertension, somewhat paradoxically, also may occur in approximately 9-14% of children. Hypertension occurs in approximately 30% of adults, with a greater incidence in older patients (>60 y).
• Thromboembolic events are serious complications of nephrotic syndrome. Peripheral thrombosis may result in gangrene, and deep venous thrombosis in the legs or pelvic veins may be a source of pulmonary emboli. Bacterial infections, especially peritonitis, occur with greater frequency, partly because of the loss of immunoglobulin G (IgG) and complement factors B and D in the urine. In fact, the largest reduction in mortality in these patients follows the introduction of antibiotics rather than any specific therapy.

Race

• Asians may be at increased risk.

Sex

• It is found twice as frequently in boys than in girls.
• The frequency is the same between the sexes in adults.

Age

• The incidence peaks in children aged 2 years, with approximately 80% being younger than 6 years at the time of diagnosis.
• In adults, the mean age of onset is 40 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Edema may be preceded by an upper respiratory tract infection, an allergic reaction to a bee sting, or the use of certain drugs or malignancies.
• Facial edema is noted first.
• Malaise and easy fatigability can occur.
• Weight gain often is an additional feature.
• The patient also may present with the following:
• • Hypovolemia
  • Hypertension
  • Thromboembolism
  • Infection

Physical

• The blood pressure usually is normal in children but may be elevated in adults.
• Dependent edema is the most prominent sign. The retina has a wet appearance. Subungual edema with horizontal lines (called Muehrcke lines) also may occur.
• Hernias may be found, and the elasticity of the ears may be decreased.
• Heavy proteinuria over an extended period of time leads to a state of protein depletion with muscle wasting, thinning of the skin, and growth failure.
• Pleural and ascitic fluid can accumulate. Rarely, cellulitis, peritonitis, or pneumonia may be the first indication of an underlying nephrotic syndrome.
• Children may have growth failure.

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:

• Idiopathic
• Secondary
  
  
  • Drugs - Nonsteroidal anti-inflammatory drugs (NSAIDs), rifampin, interferon, ampicillin/penicillin, trimethadione, mercury-containing cosmetic skin cream
  • Toxins - Mercury, lithium, bee stings, fire coral exposure
  • Infection - Infectious mononucleosis, HIV, immunization
  • Tumor - Hodgkin lymphoma (most commonly), carcinoma, other lymphoproliferative diseases
  • Posthematopoietic stem cell transplant

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

C1q nephropathy
Focal segmental glomerulosclerosis
Immunoglobulin M (IgM) nephropathy
Membranous nephropathy
Other variables

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Urine analysis is benign, but profound proteinuria and oval fat bodies may be observed.
• • In children, the critical level for diagnosis is more than 40 mg/h/m².
  • In adults, the threshold is more than 3.5 g/d/1.73 m².


• A random albumin-to-creatinine concentration ratio is in excess of 5.
• Urine specific gravity is high because of proteinuria.
• A 24-hour urine measurement is obtained for protein and creatinine clearance.
• Hypoalbuminemia is an important marker of nephrotic syndrome. The level at which edema occurs varies, but it tends to be lower in children than in adults. Nephrotic syndrome in children is defined by a serum albumin of less than 2.5 g/dL.
• Hyperlipidemia also is a feature of a nephrotic state.
• Renal function usually is normal except in cases of undiagnosed FSGS or in those cases that progress to acute renal failure.
• Serologic workup (including antinuclear antibodies, complements, and cryoglobulins) is normal.
• Hyponatremia often is observed, which is, in part, a spurious finding secondary to the hyperlipidemic state. This condition also occurs from water retention caused by hypovolemia and antidiuretic hormone release.
• Elevated hemoglobin and hematocrit are consequences of plasma volume contraction.

Imaging Studies

• Renal sonogram is normal.

Procedures

• Because of the high prevalence of MCD in children with nephrotic syndrome, an empiric trial of corticosteroids commonly is the first step in therapy. Renal biopsy typically is performed only in resistant cases. Generally, if proteinuria remains after 2 relapses or courses of steroids, a tissue diagnosis should be made before starting cytotoxic or immunosuppressive therapy.

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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

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. 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. One case report describes long-term remission with rituximab (an anti-CD20 antibody) in a patient who had failed conventional immunosuppressive therapy.

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. 

• Hypovolemia
  
  
  • This necessitates immediate volume expansion with purified plasma protein fraction and isotonic sodium chloride solution.
  • The administration of parenteral albumin infusion is not appropriate long-term management for patients with hypoalbuminemia because it has only a transient effect. Such crises should be avoided with recognition of the earlier signs of hypovolemia, including abdominal pain, increase in hematocrit, and response to contributing factors (eg, diarrhea, septicemia, diuretic therapy).
• Edema
  
  
  • This condition should be controlled by dietary sodium restriction.
  • Small amounts of edema are not of much clinical significance.
  • The use of diuretics should be reserved for patients with severe cases of edema, particularly in the presence of respiratory or gastrointestinal symptoms, and when the condition restricts activity.
• Thrombotic episodes should be prevented by mobilization and meticulous attention to venipuncture and intravenous infusion sites. Established episodes should be managed with heparinization.
• Infections
  
  
  • These must be treated aggressively.
  • Cellulitis, peritonitis, otitis, and pneumonia are common infections.
  • Susceptibility to pneumococcal infections warrants the administration of penicillin prophylaxis to patients in relapse; corticosteroids increase the problem of infection.

Consultations

• Consultation with a nephrologist generally is needed. The nephrologist has the expertise to perform and interpret the renal biopsy.
• A renal pathologist has the expertise to interpret biopsy findings under light microscopy, immunofluorescence, and electron microscopy.

Diet

• An adequate dietary protein intake, in accordance with the recommended daily allowance (RDA) is necessary. No evidence suggests that hepatic albumin synthesis is elevated with protein intake that is higher than the RDA.
• Dietary sodium restriction helps forestall the progression of edema and also is prudent in the management of hypertension.

Activity

• Mobilization, rather than bed rest, is indicated to avoid thromboembolic complications.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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:

Complete remission: This is defined as complete resolution of proteinuria for at least 3-5 consecutive days.

Partial remission: This is defined as a reduction in the degree of proteinuria without complete clearing.

Relapse: This is defined as a reoccurrence of proteinuria for at least 3-5 consecutive days.

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

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

Drug Category: Diuretics

These agents control volume overload.

Drug Category: Corticosteroids

For remission of proteinuria.

Drug Category: Antineoplastic agents

For remission of nephrotic syndrome.

Drug Category: Immunosuppressant agents

For remission of nephrotic syndrome.

Drug Category: Immunomodulators

To induce remission of nephrotic syndrome.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients are treated in an outpatient setting. Complications of MCD may require admission.

Further Outpatient Care

• Carefully monitor medication doses and adverse effects.
• Monitor vital signs for possible onset of hypertension.
• Monitor volume status.
• Monitor for signs of infection.

Complications

• The most common complications are from the adverse effects of medications.
• Additional complications may include peritonitis, infections, and acute renal failure. Acute renal failure occurs because of either acute tubular necrosis or acute tubulointerstitial nephritis.
• Patients with nephrotic syndrome have an increased incidence of arterial and venous thromboemboli, particularly deep vein and renal vein thrombosis. Renal vein thrombosis is known to occur in patients with MCD, although the incidence is lower than in patients with membranous nephropathy.
• Hypercholesterolemia and hypertriglyceridemia can lead to accelerated atherosclerosis and perhaps cause progressive glomerular injury.

Prognosis

• Use of antibiotics and glucocorticoids and better-organized schedules of management have substantially reduced the mortality rates associated with MCD. Deaths still occur from disease complications.
• Relapses eventually cease. Only approximately 5% of children continue to have steroid-responsive relapses when older than 18 years.
• Adults have a similarly good prognosis. Survival rates of 85-90% are observed 10 years or more after disease onset.
• Chronic renal failure is extremely rare in patients who are steroid-responsive. If chronic renal failure occurs, the possibility that the pathologic lesion is different or has evolved must be considered.

Patient Education

• Family members should be observant for edematous changes in the patient.
• Refer the patient and family for psychosocial counseling.
• Impose moderate sodium restrictions and ensure adequate protein intake.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Explain to the family that children initially are treated without a tissue diagnosis.
• FSGS may be misdiagnosed as MCNS because of sampling error.
• Complications may occur due to immunosuppressive therapy.
• A secondary treatable cause may be overlooked.
• Explain the consequences of not receiving treatment for MCD. Also explain that not all patients receiving treatment respond to conventional therapies.

Special Concerns

• In addition to other adverse effects, growth retardation can occur with steroid use in children.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Ahmad H, Tejani A. Predictive value of repeat renal biopsies in children with nephrotic syndrome. Nephron. Apr 2000;84(4):342-6. [Medline].
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• Audard V, Larousserie F, Grimbert P, Abtahi M, Sotto JJ, Delmer A, 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. [Medline].
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• 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. [Medline].
• 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. [Medline].
• Sinha MD, MacLeod R, Rigby E, Clark AG Nov 25. Treatment of severe steroid-dependent nephrotic syndrome (SDNS) in children with tacrolimus. Nephrol Dial Transplant. Jul 2006;21(7):1848-54Epub. [Medline].
• Smith JD, Hayslett JP. Reversible renal failure in the nephrotic syndrome. Am J Kidney Dis. Mar 1992;19(3):201-13. [Medline].
• Tang HL, Chu KH, Mak YF, Lee W, Cheuk A, Yim KF, et al. Minimal change disease following exposure to mercury-containing skin lightening cream. Hong Kong Med J. Aug 2006;12(4):316-8. [Medline].
• Tarshish P, Tobin JN, Bernstein J. 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 1997 May; 8(5): 769-76[Medline]. J Am Soc Nephrol. 1997;8 (5):769-76. [Medline].
• Wei CL, Cheung W, Heng CK, Arty N, Chong SS, Lee BW, 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. [Medline].

Article Last Updated: Jun 11, 2007