Minimal change disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Minimal change disease was first described by F. Munk in 1913, when he coined the term “lipoid nephrosis” following the observation of lipid-laden macrophages in the proximal tubular epithelial cells and oval fat bodies in urine. In 1925, Fahr and colleagues noted the resemblance of minimal change disease to focal segmental glomerulosclerosis (FSGS). Ever since its early description, the term “lipoid nephrosis” has been criticized due to the clinical irrelevance of the lipid-laden cells seen on microscopy.

• The term “lipoid nephrosis,” introduced in the early 1900s in which microscopic lipid droplets in urine and tubular cells were noticed in minimal change disease.^[1][2]

• Minimal change disease was discovered, in 1950s during ultra-structural analyses and extensive fusion of podocyte foot processes was observed.^[3][4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, Serge Korjian; Vamsikrishna Gunnam M.B.B.S [2]

Minimal change disease can be classified based on the underlying clinical etiology of disease into primary and secondary. Minimal change disease currently has no pathological classification system. Based on the proposed Columbia classification, minimal change disease was considered an entity within the spectrum of focal segmental glomerulonephritis (FSGS).

• Minimal change disease may be classified into the following variants with only minor changes on light microscopy and these variants may represent MCD or focal segmental glomerulosclerosis (FSGS)
  • Idiopathic mesangial proliferative glomerulonephritis.
  • Immunoglobulin M (IgM) nephropathy.
  • C1q nephropathy.

• Focal(<50% of glomeruli are involved) or diffuse(>50% of glomeruli are involved) is an non specific sign for glomerular injury.
• IDIOPATHIC MESANGIAL PROLIFERATIVE GLOMERULONEPHRITIS is seen in ^[1]
  • lupus nephritis
  • IgA nephropathy
  • Postinfectious glomerulonephritis

• No immune deposits are found in idiopathic mesangial proliferative glomerulonephritis.

• In IGM nephropathy patients present with deposits of IgM and complement with electron dense deposits in the mesangium.^[2]
• Patients who are presenting with IgM nephropathy are less much likely to respond to immunosuppressive agents than those with MCD.

• Mesangial deposits on electron microscopy and C1q deposits on immunofluorescence microscopy are noed in patients with C1Q nephropathy.^[3][4]
• C1Q nephropathy is a subgroup of primary focal segmental glomerulosclerosis.^[5]

• The clinical classification of minimal change disease is based on the underlying etiology of the disease.

• In primary (idiopathic) cases, the underlying cause is not known.

• Secondary forms of minimal change disease are associated with certain environmental exposures, such as allergies (bee sting), malignancies (lymphomas and leukemias), medications (NSAID, penicillamine, ampicillin), and other toxins (gold, mercury).^[6]

• Minimal change disease currently has no classification system.
• Early observations noted that a small number of patients with minimal change disease have focal tip lesions.^[7]
• Based on the proposed Columbia classification by D’Agati and colleagues in 2004, minimal change disease was considered an entity within the spectrum of focal segmental glomerulonephritis (FSGS) and may have a clinical course similar to those with “tip lesion” subtype of FSGS.^[8]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, Serge Korjian ; Vamsikrishna Gunnam M.B.B.S [2]

Minimal change disease (MCD) is one of the major cause of idiopathic nephrotic syndrome (NS).Minimal-change disease (MCD), also known as lipoid nephrosis or nil disease.The exact pathogenesis of minimal change disease is not well-understood. T-cell dysfunction may mediate the pathogenesis of minimal change disease.Due to the remarkable observation of disease recurrence after transplantation and the resolution of renal disease in recipients of kidneys from donors with MCD, it has been suggested that the presence of circulatory compounds may be attributable to the disease. Factors associated with the pathophysiology of minimal change disease include glomerular permeability factor (GPF) from T cells, hemopexin, interleukin (IL)13, cardiotrophin-like cytokine (CLC)-1, and vascular endothelial growth factor (VEGF).

• The exact pathogenesis of minimal change disease is not well-understood.^{[1] [2][3][4]}
• T-cell dysfunction plays an important role in the pathogenesis of minimal change disease.^[5]
• Increased levels of several cytokines are also implemented in the pathogenesis of minimal change disease.^[6]
• It is understood that minimal change disease is the result caused by either “two-hit” theory which include the induction of CD80 (B7-1) and regulatory T-cell (Treg) dysfunction.^[7][8]
• T cells release pro-inflammatory cytokines that ultimately damage the polyanion barrier of the renal glomerulus and subsequently heavy proteinuria.^[9]
• When measured, CD8 lymphocytes increased and CD4 lymphocytes decreased in relapses of disease, emphasizing the role of an abnormal T cell response in MCD.^[10]
• Due to the remarkable observation of disease recurrence after transplantation and the resolution of renal disease in recipients of kidneys from donors with MCD, it has been suggested that the presence of circulatory compounds may be attributable to the disease.^[1][3][4]
• In guinea pigs , glomerular permeability factor (GPF), a possible lymphokine that has an activity similar to tumor necrosis factor (TNF), is produced by T cells.^[11]
• Products secreted from T cell hybridomas from patients with MCD were contributory to the induction of significant proteinuria in rats.^[12]
• Hemopexin, a plasma glycoprotein and an acute phase reactant in humans, seems to enhance the role of GPF and further promote proteinuria through the glomerular basement membrane.^[13]

• The following is a list that shows factors that have been shown to be associated with the pathogenesis of MCD
  • GPF from T cells^[12][11]
  • Hemopexin^[13][14]
  • Interleukin-(IL)13^[15]
  •  IL-12^[16][17]
  •  Tumor necrosis factor-alpha (TNF-α)
  • Cardiotrophin-like cytokine (CLC)-1^[18]
  • Angiopoietin-like 4 (Angpl4)^[18]
  • Soluble urokinase plasminogen activator receptor (suPAR)^[19]
  • Vascular endothelial growth factor (VEGF)^[20]
  • Heparinase^[20]
  • Sialidase^[20]
  • C-mip intracellular protein^[20]
  • CD80^[20]
  • Beta-3 integrin 1^[20]

• In MCD, albumin excretion is significantly elevated with consequential hypoalbuminemia, increased protein catabolism, and hyperlipidemia that may be so extensive that cannot be compensated.^[21][22]
• However, Carrie and colleagues showed that the fractional excretion of dextran was decreased in MCD patients, suggesting a probable decrease in the size of the glomerular pores.^[21]
• A decrease in nephrin and dystroglycan, two important podocyte proteins, and consequential slit-pore membrane obliteration between podocyte foot processes occur with effacement or fusion of the foot processes.^[23]
• However, recent data in 2004 showed that the degree of podocyte effacement does not seem to correlate with the degree of proteinuria.^[24][25]

• The loss of important proteins also includes immunoglobulin and complement proteins, such as factor B. Concomitantly, serum concentrations of IgA and IgG were found to be low in patients with MCD.^[26][27]
• In contrast, an elevation in serum concentration of IgM and occasional glomerular IgM deposition further underscore the hypothesis.^[26][28]
• This finding suggested that patients with MCD may have abnormal immunological capacity of immunoglobulin switching.
• The most likely etiology for switching defect may be a deficiency of thymic cell function.^[26][9]
• In conclusion, patients with MCD are more susceptible to infections. Other significant components lost in urine include and thyroid-binding globulin,and iron and copper-binding transferrin.^{[29][30][31][32][33]}

• Loss of protein S and antithrombin III lead to excessive production of factors V and VIII, making minimal change disease a hypercoagulable state.^[9]

• The development of Minimal change disease (MCD) is the result of genetic mutations in protein tyrosine phosphatase receptor type O also known as glomerular epithelial protein 1 (GLEPP1).^[34][35]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

The cause of minimal change disease occur sporadically with no clear cause has not been identified. Few cases occur due to genetic mutations.

Minimal change disease may be caused by:

• MCD is preceded by the following environmental conditions^[1][2]:
  • Upper respiratory tract infection
  • Allergy to bee sting
  • NSAID
  • Gold
  • Penicillamine
  • Ampicillin
  • Mercury

Less common causes of disease minimal change disease include:^[2][1]

• Hodgkin’s lymphoma
• Non-Hodgkin’s lymphoma
• Leukemia

The role of genetics in the development of minimal change disease and focal segmental glomerulosclerosis has been widely investigated. Several genetic mutations at the level of the podocyte are currently believed to be involved in minimal change disease. However, most congenital diseases cause a severe form of disease, ie. steroid-resistant nephric syndrome. In fact, they are more likely to result in FSGS rather than only minimal change disease:^{[3][4][5][6][7]}

• NPHS1 – nephrin
• NPHS2 – podocin
• ACTN4 – Alpha-actinin 4
• TRPC6 – Canonical transient receptor potential 6
• INF2 – Inverted formin 2
• CD2AP
• R22Q9

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2], Syed Hassan A. Kazmi BSc, MD [3]

The differential diagnosis of minimal change disease must always include other renal etiologies of nephrotic syndrome, such as focal segmental glomerulosclerosis (FSGS) and IgM nephropathy, and causes of peripheral edema and hypoalbuminemia, such as congestive heart failure, liver cirrhosis, and protein-losing enteropathy.

Minimal change disease should be differentiated from other glomerular diseases. The various types of glomerular diseases may be differentiated from each other based on associations, presence of pitting edema, hemeturia, hypertension, hemoptysis, oliguria, peri-orbital edema, hyperlipidemia, type of antibodies, light and electron microscopic features. The following table differentiates between various types of glumerular diseases:

Some infectious diseases such as HIV, HBV, HCV, syphilis, leprosy, malaria, and schistosomiasis may cause glomerular diseases.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  ; Vamsikrishna Gunnam M.B.B.S [2]

Minimal change disease (MCD) is considered a disease of childhood. It is responsible for up to 70-90% of nephrotic syndrome in patients less than 10 years of age, and up to 50% of older children. Among children, several studies have shown a male predominance with approximately 2:1 male to female ratio.

• The incidence of Minimal change disease (MCD) is approximately 2-7 per 100,000 individuals worldwide.^[1][2]

• The prevalence of Minimal change disease (MCD) is not known.^[3]
• The prevalence of Minimal change disease (MCD) is approximately 10–50 cases per 100,000 individuals worldwide.^[4]

• Minimal change disease (MCD) is considered a disease of childhood.
• It is responsible for up to 70-90% of nephrotic syndrome in patients less than 10 years of age, and up to 50% of older children.^[5][6][7]

• MCD is much less common in the adult population. Nonetheless, it still accounts for 10-15% of nephrotic syndromes in adults.^[8][7]

• Among children, several studies have shown a male predominance with approximately 2:1 male to female ratio.^{[9] [10]}
• However, gender differences in pediatric and adult MCD have not been consistent throughout the literature.
• In one study that recruited 95 adult patients with MCD over a 15-year period, results showed that 80% of subjects are white with a slight female predominance (60%).^[9]
• Among adults, the median age for presentation is approximately 30-40 years.^[11]

• MCD is more common in Asia (approximately 2:1) than it is in North America or Europe.^{[12] [13]}
• It has been reported to be as rare as 1 case per million in USA.^[14][15]
• The reason behind such discrepancy is unknown; but it is believed to be due to variations in routine work-up procedures and diagnostic clinical practices.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

The cause of minimal change disease has not been identified or idiopathic. Nephrotic syndrome is most commonly as a result of damage to the clusters of tiny blood vessels (glomeruli).But secondary causes may be due to Drugs, Toxins, Infection, and Tumor.

Common risk factors in the development of minimal change disease include:^[1]

• Children within the Age >1 year and <8 years
• Hodgkin lymphoma
• leukemia
• Recent viral illness
• Toxins such as Mercury, bee stings, fire coral exposure are one of the causes for minimal change disease.
• Medications such as:^[2]
  • Salazopyrin
  • Mercury
  • Tiopronin
  • Lithium
  • D-penicillamine
  • Gold
  • Tyrosine-kinase inhibitor

Less common causes of minimal change disease include:^[3][4]

• Hepatitis B or HCV infection
• Low birth weight (LBW)
• Hematopoietic stem cell transplantation

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, Serge Korjian ; Vamsikrishna Gunnam M.B.B.S [2]

Complications associated with the pathogenesis of the disease as a nephrotic syndrome include thromboembolic events and disorders of hemostasis, hyperlipidemia, vulnerability to infections, and hypertension. Before the steroid era, patients died of renal failure and from infections. Nowadays, patients have excellent renal outcomes when they are still steroid-responsive and virtually all patients survive with a normal creatinine clearance. Although renal outcomes are considered excellent with appropriate therapy, the risk of chronic renal disease cannot be completely ruled out, especially among patients receiving nephrotoxic medications for prolonged periods of time.

• The hallmark of minimal change disease in children is acute-onset proteinuria that progresses into nephrotic syndrome.^[1][2]
• Fatigue and subsequent edema develops with symptoms of periorbital edema and weight gain.^[3]
• Children are less likely to present with other clinical features, such as hypertension, renal failure, or hematuria.^[3][4]

• In contrast, adults are more likely to present with hypertension in approximately 40% of cases, and hematuria in approximately 30% of cases.
• A reduced estimated glomerular filtration rate (eGFR) at presentation is also not uncommon.
• Finally, infections, such as pneumonia in an otherwise healthy individual, may be the first sign of nephrotic syndrome in minimal change disease.^[3]

• Complications associated with the pathogenesis of the disease as a nephrotic syndrome include thromboembolic events and disorders of hemostasis, hyperlipidemia, vulnerability to infections, and hypertension.^[5][6][7]
• The frequency of acute kidney injury (AKI) associated with minimal change disease is also higher.
• According to Waldman and colleagues, who studied 95 patients with adult-onset minimal change disease, the rate of acute kidney injury was approximately 25%.^[5]
• Whereas early reports showed that AKI is a reversible complication, larger trials suggested that creatinine was still significantly higher in these patients at 15-year follow-up.^[5]
• Accordingly, the true renal outcome following AKI in minimal change disease is still controversial and requires further investigation.
• The presence of chronic kidney disease raises the suspicion of focal segmental glomerulosclerosis (FSGS).
• Waldman and colleagues described the following risk factors for acute kidney injury^[5]:
  • Male gender
  • Older age > 54.5 years
  • Hypertension
  • Hypoalbuminemia
• Steroid resistance, defined as steroid therapy for more than 4 months, is not uncommon in adults.^[5]
• A subset of patients becomes steroid-resistant and is thus associated with the progression of disease into focal segmental glomerulosclerosis (FSGS).
• Cyclosporine may induce remission in approximately 60% of patients,^[8][9][10]
• Whereas cyclophosphamide may induce remission in approximately 25-60% of patients for five years.
• Resistance to cyclosporine and cyclophosphamide has also been described.^[5]
• Similarly, the diagnosis of FSGS in patients who fail to respond to alternative therapy should also be highly considered.^[5]
• Common complications of minimal change disease may be due in fact complications of medications, such as
  • weight gain,
  • osteoporosis,
  • cataract,
  • diabetes, and cardiovascular events associated with corticosteroids.^{[11][12][13][14]}
• The rate of these complications has become much less frequent with the use of steroid-sparing agents and the use of “alternate-day” steroid therapy.^[11][15]
• Similarly, the use of alkylating agents, such as cyclophosphamide, is also associated with reversible and irreversible azoospermia and oligospermia at higher doses of 150-250 mg/kg;^[16][17][18] also, higher than 168 mg/kg, according to one meta-analysis.^[19]
• Comparison between control subjects and children with idiopathic nephrotic syndrome receiving a cumulative dose of 23,000 mg of alternate-day steroid therapy for a mean duration of 53 months showed no increased risk in osteoporosis.^[15]
• Renal outcomes are generally excellent in patients receiving steroid therapy.
• Nonetheless, cyclosporine-induced nephrotoxicity, even without a decrease in GFR, is observed in patients receiving cyclosporine therapy for more than 18-24 months.^[20][8]

• Outcomes in minimal change disease have been mostly studied in the pediatric population, with very little knowledge in in adults.^[21][22]
• Before the steroid era, patients died of renal failure and from infections.^[23]
• Nowadays, patients have excellent renal outcomes when they are still steroid-responsive and virtually all patients survive with a normal creatinine clearance.^[23][24]
• Up to 80% of children with nephrotic syndrome respond to corticosteroids and become in full remission within 1 month of steroid therapy. Of those, 30% require only 1 course of steroids, 20% require several courses, and 30-50% suffer from frequently relapsing nephrotic syndrome (FRNS) when steroids are discontinued.^[25][24]
• Age at disease onset is strongly associated with the frequency of relapses in children.

• It was once believed that only 10% of children with minimal change disease persist into adulthood. More recent data shows that the rate is in fact higher, reaching approximately 25-42%. Risk factors for persistence of minimal change disease into adulthood are as follows:^{[24][26][23][27][28]}

• Young age at diagnosis
• Increased number of relapses
• Use of alkylating agents and cyclosporine

• Although renal outcomes are considered excellent with appropriate therapy, the risk of chronic renal disease cannot be completely ruled out, especially among patients receiving nephrotoxic medications for prolonged periods of time.^[24]

• There are much less knowledge of outcomes and prognosis of adult-onset minimal change disease.
• In adults, 90% achieve remission with corticosteroids, but the rate of relapse of the first episode of nephrotic syndrome is as high as 70%, where approximately 30% have frequent relapses.^[3]
• Young patients < 40 years at onset of disease are found in some studies to experience recurrence of disease than their older peers; these findings, however, have not been consistent in the literature.^{[29][30][31][3]}
• The number of relapses is ultimately associated with long-term renal outcomes and steroid dependence.^[3]

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