Minimal Change Disease

Chia-shi Wang

Patrick H. Nachman

INTRODUCTION/GENERAL CONSIDERATIONS

Minimal change disease (MCD) is characterized by nephrotic syndrome and normal glomerular histology by light microscopy, with podocyte effacement on electron microscopy.¹ In most cases of MCD, the underlying etiology is unknown. Disruptions in the glomerular filtration barrier lead to massive proteinuria.² MCD accounts for nearly 80% of primary nephrotic syndrome in children and approximately 15% in adults.¹,³ Laboratory testing and kidney biopsy are important to establish the diagnosis and rule out secondary causes of nephrotic syndrome and other histologic conditions. Whereas a diagnosis of MCD is presumed in children with nephrotic syndrome, a kidney biopsy is required for diagnosis in adults.¹ The mainstay of treatment is corticosteroids, followed by other immunosuppressive agents for those intolerant of corticosteroids or those with poorly controlled disease. The response to treatment differs between children and adults, although both groups face a high risk of relapse and relapse-associated morbidity.⁴

PATHOGENESIS

Box 5.1 lists selected secondary conditions associated with MCD.⁵,⁶,⁷,⁸,⁹,¹⁰,¹¹ In general, secondary MCD is rare, and reports are limited to single cases or case series.⁵ The vast majority of MCD cases do not have identifiable causes and are termed “primary” MCD. Though rare, secondary MCD provides insights into the pathogenesis of primary MCD in that they result in the same morphologic and functional disturbances. The well-described association with Hodgkin and non-Hodgkin lymphoma suggests an immunologic basis for MCD pathogenesis, possibly related to the release of inflammatory cytokines by lymphocytes that alter the glomerular filtration barrier.¹²,¹³ In MCD secondary to medications, there is an association with hypersensitivity to the agents with concomitant acute interstitial nephritis. The release of factors from activated inflammatory or immune cells may similarly be the basis of MCD due to medications.⁵,¹⁴

Several observations support an immunologic basis for primary MCD. Spontaneous nephrotic syndrome remission has been linked to measles infection in reports going back to the 1940s, presumably because of the suppression of cell-mediated immunity by the virus.¹⁵,¹⁶ Primary MCD is highly sensitive to immunosuppressive therapies, including corticosteroids and alkylating agents.¹⁶,¹⁷ MCD has also been linked with various atopic conditions such as eczema, hives, contact dermatitis, and hay fever and rhinitis.⁵ More recently, advances in genomic research allowed examination into genetic predispositions toward altered immune response in MCD. Coding variants in the major histocompatibility complex II genes and the PLCG2 gene, involved in adaptive and innate immune systems, respectively, have been found to be associated with steroid-sensitive nephrotic syndrome in children.¹⁸

Box 5.1 Selected Secondary Causes of Minimal Change Disease

Oncologic
	Hodgkin disease Non-Hodgkin lymphoma Leukemia Thymoma Lung and bronchus carcinoma Colorectal carcinoma Renal cell carcinoma
Drugs
	NSAIDs Lithium Antimicrobials TNF-α antagonists Mesalamine Penicillamine
Infections
	Syphilis Malaria Hepatitis B Tuberculosis Mycoplasma pneumonia HIV
HIV, human immunodeficiency virus; NSAIDs, nonsteroidal anti-inflammatory drugs; TNF, tumor necrosis factor.
Data from Glassock RJ. Secondary minimal change disease. Nephrol Dial Transplant. 2003;18(suppl 6):vi52-vi58; Bacchetta J, Juillard L, Cochat P, Droz JP. Paraneoplastic glomerular diseases and malignancies. Crit Rev Oncol Hematol. 2009;70(1):39-58; Koya M, Pichler R, Jefferson JA. Minimal-change disease secondary to etanercept. Clin Kidney J. 2012;5(5):420-423; Adiga A, Goldfarb DS. The association of mesalamine with kidney disease. Adv Chronic Kidney Dis. 2020;27(1):72-76; Amoura A, Moktefi A, Halfon M, et al. Malaria, collapsing glomerulopathy, and focal and segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2020;15(7):964-972; Asinobi AO, Ademola AD, Okolo CA, Adepoju AA, Samuel SM, Hoy WE. Kidney disease in hepatitis B surface antigen-positive children: experience from a centre in south-west Nigeria and a review of the Nigerian literature. Paediatr Int Child Health. 2018;38(1):16-22; Akano N, Yoshioka K, Matsui K, Takemura T, Matsubara K, Maki S. Transient massive proteinuria associated with Mycoplasma pneumoniae infection. Am J Kidney Dis. 1991;18(1):123-125.

Both T cells and B cells have been implicated in MCD pathogenesis. An imbalance of T-cell subpopulations and cytokine profiles has been found, including a prevalence of circulating CD8⁺ T suppressor cells, increased type 2 T helper cell cytokine profile, and reduced function of regulatory T cells.¹ Favorable clinical response of patients to B-cell depletion through anti-CD20 monoclonal antibodies suggests the importance of B cells in MCD pathogenesis.¹⁹ Delayed reconstitution of isotype-switched memory B cells after rituximab treatment was found to be protective against disease relapse, though the exact mechanism is not known.²⁰ It is still unclear how immune dysregulation potentiates disruption in the glomerular filtration barrier and podocyte injury. A current hypothesis is that the altered immune system releases circulating factors that injure the podocytes, resulting in the loss of proteins through the glomeruli and resulting in nephrotic syndrome. Podocytes may additionally have alterations that predisposes them to injury.²¹ A recent study identified circulating nephrin autoantibodies in the sera of 18 of 62 (29%) children
and adult patients with active biopsy-proven MCD from the Nephrotic Syndrome Study Network (NEPTUNE), as well as the deposition of IgG colocalized with nephrin in the kidney biopsy tissue in a subset of patients. The levels of antinephrin antibodies were significantly reduced or absent in remission of proteinuria. The baseline clinical characteristics and the median time from enrollment to complete remission were similar between the antinephrin positive and negative patients.²²

CLINICAL FINDINGS

Signs and Symptoms

Nephrotic syndrome is the chief presentation of MCD (Box 5.2). On presentation, it is not possible to differentiate MCD from other histologic subtypes of nephrotic syndrome, such as membranous nephropathy (MN) or focal segmental glomerulosclerosis (FSGS).

Patients with MCD tend to present earlier in life than other primary nephrotic syndrome histologic subtypes.²³ Children typically present in early childhood, with a median age of onset of 3 years.²⁴ Nephrotic syndrome presenting in the neonatal period or infancy would suggest genetic causes of nephrotic syndrome and not primary MCD. In older children and adolescents, FSGS and secondary causes of nephrotic syndrome increase in likelihood and are important to rule out (see section “Differential Diagnosis”).²⁵ The estimated incidence of primary nephrotic syndrome in children, suspected to be majority MCD, is around 2 per 100,000 children. Incidence is highest among Asian children, around 7 per 100,000.²⁶ In adults, MCD can present at any age, although the majority of patients are <40 years. Mean age at diagnosis has been reported to be 31 to 48 years.²⁷,²⁸,²⁹,³⁰,³¹ Estimated annual incidence is 0.6 per 100,000.³²

Edema is usually the dominant complaint leading to medical attention and workup. It may be overlooked initially, as patients attribute the edema to allergies (in case of periorbital edema) and/or weight gain. The fluid accumulation is gravity dependent and may shift throughout the day. Periorbital edema is usually more prominent in the morning, and lower extremity edema is more obvious later in the day. Scrotal, penile, and labial edema can be particularly distressing and can cause local area skin breakdown.²⁵ Ascites can cause abdominal pain and decreased appetite. Pleural effusions are common, although generally they are not associated with dyspnea.

Patients typically have fatigue and malaise on presentation. Low blood pressure may also occur because of intravascular volume depletion.³³ In adults, hypertension (˜20%-40%) and microscopic hematuria (˜15%-30%) are more common on initial presentation compared to children.¹,²⁷,²⁸,²⁹,³⁰,³¹,³³ Acute kidney injury (AKI) is also present in one-fifth to one-third of adult cases and can also be found in children.³³,³⁴ Less commonly, severe disease complications prompt patients to seek medical attention and may be present on initial presentation (see section “Complications”). These include fevers and severe abdominal pain because of spontaneous bacterial peritonitis, other serious infections, gross hematuria as a result of renal vein thrombosis, and dyspnea owing to pulmonary embolism.³³,³⁵

Laboratory Findings

Urine testing is the first step in diagnosis. Urine testing can be accomplished by obtaining a spot sample to measure the urine protein to creatinine ratio or collecting 24-hour urine to quantify the proteinuria. The 24-hour urine collection may be difficult to accomplish in young children. Nephrotic-range proteinuria is defined as greater than or equal to 300 mg/dL or greater than or equal to 3+ on urinalysis, spot urine protein to creatinine ratio greater than or equal to 2,000 mg/g, or >3.5 g per 24 hours (>40 mg/m²/h in children).⁴ On urine microscopy, microscopic hematuria may be seen in about 20% of cases. Fat bodies may be seen in the urine sediments. Hyaline and granular casts may be seen in patients who are presenting with significant edema and intravascular depletion.³⁶

Other defining laboratory findings of nephrotic syndrome are hypoalbuminemia with serum albumin <2.5 g/dL. Hyperlipidemia is characteristically seen, with increased plasma cholesterol, triglycerides, and apolipoprotein B containing lipoproteins—very-low-density lipoprotein, intermediate-density lipoprotein, low-density lipoprotein, and lipoprotein(a). The lipid derangements may be due to impaired clearance and altered biosynthesis.³⁷

Compared with other histologic subtypes such as FSGS and MN, serum creatinine is typically normal on presentation for MCD, although a significant proportion of patients may present with AKI. Of note, some patients (22.3% in one report) may in fact present with low serum creatinine and an estimated glomerular filtration rate (eGFR) above 120 mL/min/1.73 m².²³ The low serum creatinine is an inaccurate assessment of glomerular filtration in the nephrotic state, possibly because of altered renal tubular handling of plasma creatinine or hyperfiltration.³⁸,³⁹,⁴⁰

Other commonly observed laboratory findings include mild hyponatremia likely secondary to intravascular depletion and water retention from antidiuretic hormone secretion.³³ Increase in serum sodium occurs after albumin infusion.⁴¹ Elevated hemoglobin and hematocrit levels and thrombocytosis can be seen with active nephrotic syndrome because of intravascular depletion. These factors contribute to increased thrombosis risk.⁴² Total serum calcium levels are low because of decreased protein-bound calcium; ionized calcium is usually normal. Vitamin D levels are low because of loss of vitamin D-binding proteins.¹

Special Tests

Once the diagnosis of nephrotic syndrome has been made, specific tests are performed to screen for secondary causes of nephrotic syndrome and MCD and other histologic subtypes of nephrotic syndrome. Common initial tests are listed in Table 5.1.³³,⁴³ Additional tests are performed based on index of suspicion for secondary conditions or other histologic subtypes of nephrotic syndrome and the results of the initial testing (see section “Differential Diagnosis”).

Imaging Studies

Chest x-ray is frequently obtained on presentation, particularly if dyspnea is present. Pleural effusions are common when patients have nephrotic syndrome. Based on the symptoms, chest x-rays are used to screen for pneumonia, mediastinal masses where there is concern for lymphoma, and pulmonary involvement in systemic diseases that can also produce nephrotic syndrome such as systemic lupus erythematosus (SLE).⁴³,⁴⁴

Ultrasound of the kidneys is important to consider, particularly if serum creatinine is elevated on presentation or if there is hematuria. Kidney ultrasound can
assess kidney size and morphology and rule out obstructive processes as part of diagnostic workup for elevated serum creatinine. With Doppler examination, the study can be used to screen for renal vein thrombosis, particularly if the patient has hematuria, flank pain, or decreased glomerular filtration rate (GFR).⁴⁵

TABLE 5.1 Common Laboratory Tests Performed in Adult and Pediatric Patients With Nephrotic Syndrome and the Screened Conditions

Tests	Condition	Target Testing Group
Serum C3 and C4 complement	SLE, C3G, PIGN	Adult and pediatric
ANA and anti-dsDNA antibodies	SLE	Adult and pediatric
Hepatitis B surface antigen and antibodies and hepatitis C antibodies	Hepatitis B and C infection	Adult and pediatric
HIV testing	HIVAN	Adult and pediatric patients with risk factors
Glucose, HbA1c	Diabetic nephropathy	Adult
Anti-PLA2R autoantibody	Membranous nephropathy	Adult
Serum protein electrophoresis and immunofixation, urine protein electrophoresis and immunofixation, and serum free κ and λ light chains	Dysproteinemias	Adults >50 yr
ANA, antinuclear antibodies; anti-dsDNA, anti-double-stranded DNA antibody; C3G, C3 glomerulopathy; HbA1c, hemoglobin A1c; HIV, human immunodeficiency virus; HIVAN, HIV-associated nephropathy; PIGN, postinfectious glomerulonephritis; PLA2R, phospholipase A2 receptor; SLE, systemic lupus erythematosus.

Kidney Biopsy

It is not possible to differentiate MCD from other primary kidney conditions that also present with nephrotic syndrome based on signs and symptoms alone. The diagnosis of MCD is thus established by kidney biopsy. MCD is characterized by normal glomeruli or only mild mesangial prominence on light microscopy. It is important to ensure adequate tissue sample with at least 8 to 10 glomeruli, as FSGS lesions may be missed.⁴ Immunofluorescence is usually negative, but low-intensity mesangial staining of immunoglobulin (Ig)M, C3, C1q, or IgA may be seen and are considered variants of MCD. Another characteristic of MCD is near complete foot process effacement on electron microscopy (Figure 5.1).¹ In children, the majority of patients with primary nephrotic syndrome have MCD that responds favorably to treatment (see section “Prognosis”). Thus, a kidney biopsy is generally not performed unless there is concern for an alternative diagnosis (Visual Abstract 5.1).⁴⁶ Considerations for kidney biopsy in a pediatric patient with nephrotic syndrome include: 12 years of age or older, steroid-resistant nephrotic syndrome (lack of complete remission at 4 weeks of therapy with daily prednisone or prednisolone at standard dose), macroscopic hematuria, systemic symptoms of vasculitis, low complement levels, AKI not related to hypovolemia, or progressive loss of kidney function.¹,⁴

FIGURE 5.1: Electron microscopy image of minimal change disease. Arrows show extensive foot process effacement. Stars show microvillus transformation of the podocytes. (Courtesy: Hong Yin, MD.)

Nephrotic syndrome in adult patients is caused by more varied underlying histologic conditions. A kidney biopsy is generally obtained at presentation for definitive diagnosis, unless a clear diagnosis is ascertained by serologic (eg, positive anti-PLA2R test in the setting of a normal eGFR) or genetic testing (eg, Alport disease established by genetic testing) or if there is a contraindication to the procedure.⁴

DIFFERENTIAL DIAGNOSIS

The diagnostic evaluation of patients who present with nephrotic syndrome and signs and symptoms suggestive of MCD includes screening for secondary causes of nephrotic syndrome and MCD (Table 5.2 and Box 5.1) and establishing the
histologic diagnosis via kidney biopsy except in children and select situations described earlier.

TABLE 5.2 Select Differential Diagnoses of Nephrotic Syndrome Including Both Primary and Secondary Conditions

Conditions
Primary glomerular diseases (by histologic classification)
	Minimal change disease Focal segmental glomerulosclerosis Membranous nephropathy Membranoproliferative glomerulonephritis IgA nephropathy
Secondary causes
	Systemic diseases
		Diabetes mellitus Systemic lupus erythematosus Sickle cell disease
	Malignancies
		Lymphoma Leukemia Solid adenocarcinomas
	Infections
		HIV Hepatitis B, C Malaria Syphilis Toxoplasmosis Mycoplasma Schistosomiasis Other viral infections: CMV, EBV, parvovirus B19, dengue, hantaviruses
	Drugs
		Nonsteroidal anti-inflammatory drugs Penicillamine Probenecid Captopril Tamoxifen Lithium Bisphosphonates
	Dysproteinemias
		Multiple myeloma Amyloidosis
	Genetic disorders (select associated genes)
		Congenital nephrotic syndrome (NPHS1) Diffuse mesangial sclerosis (PLCE1, WT1) Other genetic causes of steroid-resistant nephrotic syndrome (NPHS2, ACTN4, TRPC6) Denys-Drash, Frasier, and WAGR syndromes (WT1) Pierson syndrome (LAMB2)
CMV, cytomegalovirus; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; WAGR, Wilms tumor, aniridia, genitourinary abnormalities, and intellectual disability.
Data from Eddy AA, Symons JM. Nephrotic syndrome in childhood. Lancet. 2003;362(9384):629-639; Nephrotic syndrome in children: prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. A report of the International Study of Kidney Disease in Children. Kidney Int. 1978;13(2):159-165; Kerlin BA, Ayoob R, Smoyer WE. Epidemiology and pathophysiology of nephrotic syndrome-associated thromboembolic disease. Clin J Am Soc Nephrol. 2012;7(3):513-520; Madaio MP, Harrington JT. The diagnosis of glomerular diseases: acute glomerulonephritis and the nephrotic syndrome. Arch Intern Med. 2001;161(1):25-34; 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. 1981;98(4):561-564; Kiriakidou M, Ching CL. Systemic lupus erythematosus. Ann Intern Med. 2020;172(11):ITC81-ITC96; Kupin WL. Viral-associated GN: hepatitis B and other viral infections. Clin J Am Soc Nephrol. 2017;12(9):1529-1533; Abdurrahman MB. The role of infectious agents in the aetiology and pathogenesis of childhood nephrotic syndrome in Africa. J Infect. 1984;8(2):100-109; Perazella MA, Markowitz GS. Bisphosphonate nephrotoxicity. Kidney Int. 2008;74(11):1385-1393; Trautmann A, Vivarelli M, Samuel S, et al. IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome. Pediatr Nephrol. 2020;35(8):1529-1561.