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Minimal change disease: Etiology, clinical features, and diagnosis in adults

Minimal change disease: Etiology, clinical features, and diagnosis in adults
Literature review current through: Jan 2024.
This topic last updated: Feb 01, 2024.

INTRODUCTION — Minimal change disease (MCD) is a major cause of the nephrotic syndrome in children (approximately 90 percent) and in a minority of adults (approximately 10 percent). MCD and primary focal segmental glomerulosclerosis (FSGS) are both examples of pathogenic mechanisms that predominantly affect the podocyte ("podocytopathies").

The epidemiology, pathogenesis, etiology, clinical features, and diagnosis of MCD in adults will be reviewed here. Other aspects of MCD, including the treatment of MCD in adults, the diagnosis and treatment of MCD in children, and acute kidney injury (AKI) in MCD are presented separately:

(See "Minimal change disease: Treatment in adults".)

(See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children".)

(See "Treatment of idiopathic nephrotic syndrome in children".)

(See "Acute kidney injury (AKI) in minimal change disease and other forms of nephrotic syndrome".)

EPIDEMIOLOGY — Although minimal change disease (MCD) is the most common cause of the nephrotic syndrome in children, MCD also accounts for a smaller proportion of cases of the nephrotic syndrome in adults. In a study published in 1987, MCD was present in 10 to 15 percent of cases of adult nephrotic syndrome [1]. The percentage of nephrotic adults with MCD has since decreased [2]. (See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children", section on 'Primary nephrotic syndrome'.)

In addition to age, ethnicity is an important predictor of the percentage of nephrotic patients with MCD, although epidemiologic studies may be confounded by prevailing ethnic differences in the studied populations. The percentage of nephrotic patients with MCD is highest in Asian populations and White populations, while the percentage of nephrotic patients with underlying focal segmental glomerulosclerosis (FSGS) lesions (mostly genetic and related to APOL1 high-risk alleles) is highest in African American populations [3,4].

PATHOGENESIS — The underlying cause of minimal change disease (MCD) is unclear. Accumulating evidence suggests that systemic T cell dysfunction results in the production of a glomerular permeability factor. This circulating factor directly affects the glomerular capillary wall, resulting in marked proteinuria and foot process effacement. In a subset of patients with MCD, autoantibodies targeting the slit diaphragm component nephrin may contribute to the pathogenesis of disease.

T cell dysfunction — The following observations are consistent with the hypothesis that cell-mediated immunity is a major pathogenic factor in MCD [5]:

Remission can be induced by measles, an infection known to modify cell-mediated immunity.

In children with glucocorticoid-sensitive nephrotic syndrome, relapses were associated with a decrease in T regulatory cells [6].

The lesion of MCD occurs more frequently in patients with Hodgkin lymphoma than in the general population. (See 'Malignancies' below.)

Atopic individuals are at higher risk for the development of MCD. (See 'Allergy' below.)

Glucocorticoids and cyclophosphamide, which modify cell-mediated responses, have proven benefit in the treatment of MCD. (See "Minimal change disease: Treatment in adults".)

Immature and relatively undifferentiated T cells (CD34+) rather than mature T cells (CD34-) have been implicated in the pathogenesis of MCD. In an animal study, for example, proteinuria and foot process effacement were observed in non-obese diabetic severe combined immunodeficient (NOD/SCID) mice after the engraftment of CD34+ but not CD34- cells harvested from patients with either glucocorticoid-sensitive MCD or focal segmental glomerulosclerosis (FSGS) [7].

Regulatory T cells may also play a role in the pathogenesis of MCD. In animal models of the nephrotic syndrome, depletion of peripheral regulatory T cells has been observed, and these cells repopulate in the setting of disease remission [8]. Furthermore, the administration of L15-0195 (a deoxyspergualin [a synthetic analogue of the immunosuppressive antitumor antibiotic spergualin] derivative) induces regulatory T cells that can induce regression of nephropathy in rats [6].

Glomerular permeability factor — A variety of observations support the possibility that a circulating factor of immune origin alters glomerular permeability in MCD, thereby resulting in proteinuria [9]:

A T cell hybridoma made from a patient with MCD released a substance that, when injected into rats, induced proteinuria and foot process effacement [10]. (See "Mechanisms of immune injury of the glomerulus".)

In an in vitro assay using isolated rat glomeruli, increased permeability to albumin was noted after incubation with sera collected from a patient with MCD and Hodgkin lymphoma [11]. Serum permeability activity did not change in response to prednisone or cyclosporine but was markedly decreased by induction of remission of Hodgkin lymphoma by chemotherapy.

Two kidneys from a patient with MCD were inadvertently transplanted into two recipients without significant baseline proteinuria [12]. In both recipients, proteinuria was present at the time of grafting but diminished rapidly and was within the normal range within six weeks.

The identity of the glomerular permeability factor in MCD has not been determined in humans. However, accruing data have implicated T helper type 2 (Th2)-derived cytokines, particularly interleukin (IL) 13 [13-19]. In rats, for example, systemic overexpression of IL-13 results in albuminuria, hypoalbuminemia, and on kidney biopsy, up to 80 percent podocyte foot process fusion by electron microscopy and no significant histologic changes by light microscopy (pathologic findings similar to those in MCD) [19]. Another candidate protein for a permeability factor is the circulating heme scavenger hemopexin. Usually inactive, hemopexin may become activated as a serine protease, leading to nephrin-dependent cytoskeletal rearrangement in podocytes and changes in permeability of the glomerular filtration barrier by a reduction in glycocalyx [20].

Role of B cells — The role of B cells in the pathophysiology of MCD was, for many years, considered negligible. However, studies on the favorable effect on MCD of rituximab, a chimeric monoclonal antibody that depletes the CD20+ B cell population, suggest that a glomerular permeability factor could be produced by B cells or T cells through pathways regulated or stimulated by B cells [21]. These results of MCD treatment with rituximab suggest a role for B cells in addition to T cells in the pathogenesis of MCD in some patients. Because rituximab appears to be effective in glucocorticoid-responsive but not glucocorticoid-resistant MCD, glucocorticoid sensitivity and resistance might reflect different pathogenic pathways. (See "Minimal change disease: Treatment in adults", section on 'Rituximab'.)

Antibodies targeting nephrin, an essential component of the slit diaphragm, have been shown to cause massive proteinuria when administered in animal models [22,23] and may contribute to the pathogenesis of MCD in a subset of human patients [24,25]. In a study of 62 adults and children with biopsy-proven MCD and no known genetic basis, circulating anti-nephrin antibodies were identified in 18 (29 percent) who had active disease at the time of sampling [24]. Antibody titers were reduced or absent during clinical response to treatment. Immunofluorescence microscopy revealed punctuate immunoglobulin G (IgG) deposits colocalized with nephrin in the kidney biopsies of nine patients, all of whom were serologically positive for anti-nephrin antibodies; no punctate deposits were seen in the biopsies of patients who were serologically negative. One female patient with childhood-onset, glucocorticoid-dependent MCD progressed to FSGS and end-stage kidney disease (ESKD); following kidney transplantation, she rapidly developed recurrent nephrotic syndrome that was associated with high titers of pretransplant circulating anti-nephrin antibodies. With plasmapheresis, she experienced remission accompanied by the disappearance of anti-nephrin antibodies. Collectively, these findings suggest that an autoimmune etiology may be responsible in a subset of patients with MCD.

Role of the glomerular basement membrane — The mechanism by which a putative circulating factor leads to a compromise of the glomerular capillary wall is incompletely understood. The glomerular capillary wall comprises three structures that separate the capillary lumen from Bowman's space: the fenestrated endothelium, the glomerular basement membrane (GBM), and the epithelium with a slit diaphragm between podocyte foot processes (figure 1). The endothelium and the GBM are strongly anionic with the electronegative charges being provided by sialic acid and heparan sulfate [26,27]. Under normal circumstances, the negative charge of the GBM repulses circulating albumin molecules since albumin is negatively charged at neutral pH.

In patients with MCD, a hypothesis to explain proteinuria was that the glomerular permeability factor diminishes the anionic properties of the GBM. Supporting data were derived from some studies in which the sieving components (Bowman's space fluid-to-plasma ratio) of dextrans of various Stokes-Einstein radii and isoelectric points were determined in healthy and nephrotic humans with MCD or membranous nephropathy [27]. The sieving coefficients of anionic dextrans were less than that of neutral dextrans in healthy subjects; by contrast, there was no difference in sieving coefficients of anionic and neutral dextrans in patients with the nephrotic syndrome.

ETIOLOGY — Most cases of minimal change disease (MCD) are idiopathic (or primary) and are not clearly associated with an underlying disease or event.

With secondary MCD, the onset of nephrotic syndrome occurs concurrently or following an extraglomerular or glomerular disease process.

Primary MCD — MCD that is not clearly associated with an underlying disease or event is considered primary (or idiopathic) MCD. The underlying cause of primary MCD is unclear but is thought to be related to the production of a circulating glomerular permeability factor that directly affects the glomerular capillary wall, resulting in marked proteinuria and foot process effacement. In a subset of patients with primary MCD, autoantibodies targeting the slit diaphragm component nephrin may contribute to the pathogenesis of disease. (See 'Glomerular permeability factor' above and 'Role of B cells' above.)

Secondary causes — MCD is associated with a variety of secondary causes, including drugs, neoplasms, infections, and allergy. Although MCD is not associated with monogenic variants, familial clustering has been occasionally reported [28].

Drugs — Many drugs can induce a nephrotic syndrome with the histopathologic appearance of MCD. Cessation of the offending drug is usually associated with improvement in the nephrotic syndrome. Drugs associated with MCD include the following [29-32]:

Nonsteroidal antiinflammatory drugs (NSAIDs) and selective cyclooxygenase (COX) 2 inhibitors. NSAIDs are the most common cause of secondary MCD. (See "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'NSAID-induced AIN and nephrotic syndrome'.)

Antimicrobial drugs (ampicillin, rifampicin, cephalosporins).

Lithium. (See "Renal toxicity of lithium", section on 'Nephrotic syndrome'.)

D-penicillamine and tiopronin. (See "Wilson disease: Management", section on 'Adverse effects' and "Cystinuria and cystine stones", section on 'Thiol-containing drugs for resistant disease'.)

Pamidronate and other bisphosphonates [33]. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Proteinuria and kidney injury'.)

Sulfasalazine and 5-aminosalicylic acid derivatives.

Trimethadione.

Gamma interferon.

Mercury exposure in skin-lightening creams [34].

Immune checkpoint inhibitors (pembrolizumab, ipilimumab, nivolumab, durvalumab) [35,36]

Malignancies — MCD has been associated with malignancies, particularly hematologic malignancies, such as Hodgkin lymphoma (previously called Hodgkin disease), non-Hodgkin lymphoma, and leukemia [37-40]. In a review of two large series of patients with Hodgkin lymphoma, 0.4 percent had MCD [37].

In many cases, the underlying hematologic disease is already apparent at the time of onset of the nephrotic syndrome. The degree of proteinuria usually parallels that of the malignancy, with the proteinuria disappearing when remission of the malignancy is obtained with radiotherapy and chemotherapy [37,38,40]. However, there are patients in whom the course of MCD does not correlate with the course of the lymphoma [39].

In some patients, MCD precedes the discovery of the lymphoma by several months or even years [37-39]. In a review of 21 patients who had both MCD and Hodgkin lymphoma, eight (38 percent) were diagnosed with MCD a median of two years prior to the diagnosis of malignancy [38]. Among these eight patients, one was glucocorticoid dependent and four were glucocorticoid resistant, but all entered remission when the lymphoma was successfully treated.

Solid tumors are more commonly associated with an immune complex-mediated disease such as membranous nephropathy [40]. However, rare cases of MCD associated with solid tumors have been reported. These include thymoma; renal cell carcinoma; mesothelioma; and bronchogenic, colon, bladder, lung, breast, pancreatic, duodenal, and prostate cancer [30,41,42]. In some, but not all, reported cases, ablation of the tumor was followed by remission of the nephrotic syndrome [42].

Infections — MCD has been associated with infections including syphilis, tuberculosis, Mycoplasma, ehrlichiosis, hepatitis C virus, Echinococcus, and borreliosis (Lyme disease) [30,32,43]. HIV infection is most often associated with a collapsing focal segmental glomerulosclerosis (FSGS), but MCD has been described [44]. (See "Overview of kidney disease in patients with HIV".)

Allergy — A history of allergy has been described in up to 30 percent of cases of MCD [45,46]. Multiple allergens have been reported in association with MCD, including fungi, poison ivy, ragweed and timothy grass pollen, house dust, medusa stings, bee stings, and cat fur. The onset or occurrence of relapses of nephrotic syndrome can be triggered by an allergic reaction or bee sting.

Limited evidence suggests that relapsing MCD may be due to food allergy in some patients. In a small series, an oligoantigenic (hypoallergenic) diet-induced remission in some patients with glucocorticoid-resistant MCD [47]. However, this finding has not been replicated in other studies.

Association with other glomerular diseases — MCD may be associated with mesangial immunoglobulin A (IgA) deposits and mild mesangial proliferation suggesting the concurrence of IgA nephropathy and MCD [44,48-50]. The mechanism underlying this relationship is not understood and may reflect concurrent disease, especially in Asian individuals [48,49]. These patients respond to glucocorticoid therapy with remission of the nephrotic syndrome, but relapses can occur [44,48-50]. (See "IgA nephropathy: Clinical features and diagnosis", section on 'Associated conditions' and "IgA nephropathy: Treatment and prognosis", section on 'IgA nephropathy with apparent minimal change disease'.)

Although the relationship is unclear, there are reports of MCD occurring in association with other glomerular or kidney diseases, including systemic lupus erythematosus ("lupus podocytopathy"), new-onset type 1 diabetes, and HIV nephropathy [30,51,52]. (See "Lupus nephritis: Diagnosis and classification", section on 'Lupus podocytopathy'.)

Other causes — Numerous other, mostly autoimmune, conditions have been described in association with MCD [30]. The mechanisms underlying this association are not identified, and the association may be coincidental rather than causal. These include chronic graft-versus-host disease after hematopoietic cell transplantation, sclerosing cholangitis, sarcoidosis, Graves' disease, thyroiditis, vasculitis, myasthenia gravis, Guillain-Barré syndrome, dermatitis herpetiformis, primary biliary cholangitis, antiphospholipid syndrome, and stiff-person syndrome [30,53-56].

Cases of MCD following immunizations, including after administration of an mRNA SARS-CoV-2 vaccine [57], have been described. (See "COVID-19: Issues related to acute kidney injury, glomerular disease, and hypertension", section on 'COVID-19 vaccine-associated glomerular disease'.)

CLINICAL FEATURES

Typical presentation — In most patients, minimal change disease (MCD) is characterized by the sudden onset over days to a week or two of the signs and symptoms of the nephrotic syndrome, often following an upper respiratory or systemic infection. The nephrotic syndrome is characterized by the constellation of proteinuria, mostly albuminuria (almost always greater than 3.5 to 4.0 g/day and occasionally more than 15 to 20 g/day); weight gain and then edema; and on laboratory testing, hypoalbuminemia (serum albumin that may be less than 1.5 to 2.0 g/dL) and, in most cases, hyperlipidemia. (See "Overview of heavy proteinuria and the nephrotic syndrome".)

The typically sudden onset of nephrotic syndrome in MCD is in contrast to the gradual increase in proteinuria over weeks to months in most other causes of nephrotic syndrome such as membranous nephropathy and most variants of focal segmental glomerulosclerosis (FSGS), with the exception of the glomerular tip variant. The sudden onset of nephrotic syndrome is reasonably specific but not very sensitive for MCD in adults and should not be used to avoid performing a kidney biopsy to confirm the diagnosis. (See 'Diagnosis' below.)

Other kidney manifestations that may be seen in patients with MCD include:

Microscopic hematuria is common in adults with MCD and occurs in 20 to 25 percent of children but is not associated with a difference in clinical course [45,58,59]. (See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children", section on 'Additional laboratory evaluation'.)

The serum creatinine concentration may be modestly (30 to 40 percent) elevated at presentation in both adults and children. Acute kidney injury (AKI) is an infrequent complication that has been primarily described in adults. (See "Acute kidney injury (AKI) in minimal change disease and other forms of nephrotic syndrome" and "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children", section on 'Additional laboratory evaluation'.)

The clinical findings at presentation in adults with MCD were illustrated in a retrospective analysis of 95 patients [58]. The following findings were noted; the age and laboratory results represent mean values:

Age – 45 years

Serum creatinine – 1.4 mg/dL (124 micromol/L)

Estimated glomerular filtration rate (eGFR) – 72 mL/min per 1.73 m2

Proteinuria – 9.9 g/day

Hematuria – 29 percent

Serum albumin – 2.2 g/dL

Serum cholesterol – 421 mg/dL (10.9 mmol/L)

Hypertension – 43 percent

AKI – 18 percent

In addition to the above findings, the nephrotic syndrome can be associated with the following complications, the pathogenesis and manifestations of which are discussed in detail elsewhere:

Increased risk of thromboembolism (see "Hypercoagulability in nephrotic syndrome" and "Complications of nephrotic syndrome in children", section on 'Thromboembolism')

Increased susceptibility to infection, particularly with encapsulated organisms, which is best described in children (see "Complications of nephrotic syndrome in children", section on 'Bacterial infection' and "Overview of heavy proteinuria and the nephrotic syndrome", section on 'Infection')

Pathologic findings — On kidney biopsy, the glomeruli appear normal by light microscopy, and there are no complement or immunoglobulin deposits on immunofluorescence microscopy. Glomerular size is usually normal by standard methods of light microscopy, although enlarged glomeruli may be observed [60].

The characteristic histologic lesion in MCD is diffuse effacement (>80 percent; also called "fusion") of the epithelial foot processes on electron microscopy (picture 1). More specifically, there is retraction, widening, and shortening of the foot processes [61,62]. The spaces between flattened podocyte foot processes are reduced in number, which may play a role in the excess albumin load into the urinary space [63]. The degree of effacement does not correlate with the degree of proteinuria [64]. Foot processes regain a normal appearance with remission of proteinuria.

DIAGNOSIS

When to suspect MCD — The diagnosis of minimal change disease (MCD) should be suspected in any adult patient presenting with symptoms and signs of the nephrotic syndrome, especially if the onset is relatively acute (over days to a week or two).

All patients presenting with the nephrotic syndrome should undergo a thorough evaluation for glomerular disease and other disorders, which generally involves laboratory testing and, in most patients, a kidney biopsy to obtain a definitive diagnosis (algorithm 1). The general evaluation of proteinuria and nephrotic syndrome in adults is discussed in more detail elsewhere. (See "Glomerular disease: Evaluation and differential diagnosis in adults", section on 'Nephrotic syndrome (heavy proteinuria and hypoalbuminemia)'.)

Establishing the diagnosis — A kidney biopsy is required to establish the diagnosis of MCD in adults and to exclude other causes of the nephrotic syndrome. There are no specific laboratory findings that can be used to distinguish MCD from other forms of nephrotic syndrome. (See 'Pathologic findings' above.)

In children, a presumptive diagnosis of MCD is usually made based upon the clinical findings at presentation and the high prevalence of MCD as a cause of the nephrotic syndrome, particularly in children under the age of 10 years. Pediatricians usually restrict kidney biopsy to individuals with glucocorticoid-resistant nephrotic syndrome. (See "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children", section on 'Decision to biopsy' and "Clinical manifestations, diagnosis, and evaluation of nephrotic syndrome in children", section on 'Confirming the diagnosis'.)

Adult patients who are found to have MCD on kidney biopsy should be evaluated for potential underlying secondary causes, particularly malignancy (eg, Hodgkin lymphoma and thymoma) and drug exposures (eg, nonsteroidal antiinflammatory drugs [NSAIDs], pamidronate).

DIFFERENTIAL DIAGNOSIS — As mentioned above, minimal change disease (MCD) is characterized pathologically by normal-appearing glomeruli on light microscopy and the absence of complement or immunoglobulin deposits on immunofluorescence microscopy. The characteristic histologic lesion is diffuse effacement of the epithelial foot processes on electron microscopy (picture 1). Although diffuse foot process effacement is also seen in other causes of the nephrotic syndrome (eg, primary focal segmental glomerulosclerosis [FSGS], membranous nephropathy, diabetic kidney disease, and amyloidosis), these disorders have characteristic findings on light and immunofluorescence microscopy and, in some disorders, blood test abnormalities that are not seen in MCD. (See 'Pathologic findings' above and "Glomerular disease: Evaluation and differential diagnosis in adults".)

Distinguishing MCD from primary FSGS — There continues to be debate as to whether MCD and focal segmental glomerulosclerosis (FSGS) fall within the spectrum of the same disease or whether they represent separate pathogenic entities [65]. Other than the descriptive changes on light microscopy, the two entities can be separated based on clinical and pathological features:

On one hand, primary MCD is characterized by the full nephrotic syndrome, complete foot process effacement on electron microscopy, and a complete response to immunosuppression (albeit with a significant chance of recurrence). Although patients may present with acute kidney injury (AKI), they usually recover, and end-stage kidney disease (ESKD) is distinctly rare.

FSGS, on the other hand, is now a descriptive term for sclerotic glomerular lesions. There are several pathogenic mechanisms associated with the FSGS lesion (eg, permeability factor related, genetic, hyperfiltration, maladaption for nephron loss, drug or viral injury). In the absence of these associations ("secondary forms of FSGS"), the patients are labeled as having "primary" FSGS, some of which has been ascribed to circulating factor(s) owing to the recurrence of the disease in kidney transplants. Importantly in primary FSGS, response to immunosuppression is seen only in approximately one-half of patients, typically partial remissions (with the exception of the tip lesion [66]), and progressive kidney failure is common in patients with persistent, high-grade proteinuria. (See "Focal segmental glomerulosclerosis: Clinical features and diagnosis" and "Focal segmental glomerulosclerosis: Treatment and prognosis".)

With primary FSGS, the biopsy diagnosis requires the finding of segmental glomerulosclerosis in at least one glomerulus in addition to diffuse foot process effacement. However, sclerotic lesions are focal, and affected glomeruli may be missed, leading to an incorrect diagnosis of MCD. As an example, sclerotic changes occur first in the juxtamedullary glomeruli, which may not be present in superficial biopsies that contain only the outer cortex or in biopsies that contain fewer than eight glomeruli, where sampling error may be important.

Specific biomarkers have been proposed separating MCD from FSGS, including podocyte B7-1, dystroglycan, angiopoietin-like 4 (Angptl4), urinary CD80, and anti-CD44. Similarly, circulating factors including cardiotrophin-like cytokine factor-1 (CLCF1), soluble urokinase receptor (suPAR), and hemopexin have also been suggested as being specific. Finally, differential gene expression in the glomeruli has been reported. However, these reports have not shown consistent results or have not been validated by other investigators [65].

Lastly, there are clear examples of patients who begin with a classic, clinical presentation of MCD but over time become increasingly refractory to immunosuppression and, on repeat kidney biopsy, show sclerotic lesions [67,68]. (See "Minimal change disease: Treatment in adults", section on 'Role of repeat kidney biopsy'.)

It has been postulated that MCD may follow mild injury to the podocyte, which is then followed by complete recovery in the majority of patients. If the injury is severe or if repair mechanisms are defective (eg, in the presence of genetic predisposing factors such as the presence of two high-risk APOL1 alleles), podocyte loss occurs, leading to sclerosis and the appearance of FSGS lesions. The latter is associated with less glucocorticoid sensitivity and progressive kidney function impairment [65]. However, it is likely that MCD and FSGS are two separate entities, and the observation that MCD lesions "progress" to FSGS may merely reflect the fact that a biopsy performed early may not reveal sclerosis since the latter phenomenon takes time to occur [65].

Minimal change variants — In addition to MCD, there are three other disorders that usually present with the nephrotic syndrome and that may show only minor changes on light microscopy: idiopathic mesangial proliferative glomerulonephritis, immunoglobulin M (IgM) nephropathy, and C1q nephropathy. These disorders may represent variants of MCD or FSGS lesions, but some clinicians believe that they may be separate conditions. Regardless of nomenclature, the finding of these variants on a kidney biopsy of an adult with nephrotic syndrome is often associated with a poorer prognosis than that of patients with classic MCD.

Idiopathic mesangial proliferative glomerulonephritis – Idiopathic mesangial proliferative glomerulonephritis is characterized by mesangial proliferation and the absence of IgG or IgA immune deposits (though IgM deposits may be present). Patients may have isolated hematuria or nephrotic range proteinuria [69,70]. Whereas the kidney prognosis is favorable for patients with isolated hematuria [69,71], it is not as good for those with nephrotic syndrome, as 10 to 30 percent may develop progressive kidney function impairment [72-75].

IgM nephropathy – IgM deposits may be found in patients with MCD, FSGS, and mesangial proliferative glomerulonephritis. Some experts, however, believe that IgM nephropathy is a distinct entity characterized by mesangial proliferation and prominent mesangial deposits of IgM and complement [70,71,76]. Others require the presence of electron dense deposits by electron microscopy as well as the finding of IgM deposition by immunofluorescence microscopy to define IgM nephropathy. The presence of IgM deposits in a patient with MCD signifies a poorer prognosis compared with MCD without deposits, as fewer than 50 percent of such patients respond to glucocorticoids [71].

C1q nephropathy – C1q nephropathy is characterized by mesangial proliferation, mesangial deposits on electron microscopy, and prominent C1q deposits on immunofluorescence microscopy in a patient with no clinical or laboratory evidence of systemic lupus erythematosus [77-82]. C1q nephropathy may be associated with MCD, FSGS, or proliferative glomerulonephritis. The treatment of C1q nephropathy is the same as it is for MCD or FSGS with no C1q deposits.

SUMMARY AND RECOMMENDATIONS

General principles – Minimal change disease (MCD) is a major cause of the nephrotic syndrome in children (approximately 90 percent) and in a minority of adults (approximately 10 percent). MCD and focal segmental glomerulosclerosis (FSGS) are both examples of pathogenic mechanisms that primarily affect the podocyte ("podocytopathies"). (See 'Introduction' above and 'Epidemiology' above.)

Pathogenesis – The underlying cause of MCD is unclear. Accumulating evidence suggests that systemic T cell dysfunction results in the production of a glomerular permeability factor. This circulating factor directly affects the glomerular capillary wall, resulting in marked proteinuria and foot process effacement. There is emerging evidence for the role of B cells and anti-nephrin antibodies in the pathogenesis of MCD. (See 'Pathogenesis' above.)

Etiology – Most cases of MCD are idiopathic (or primary) and are not clearly associated with an underlying disease or event. With secondary MCD, the onset of nephrotic syndrome occurs concurrently or following an extraglomerular or glomerular disease process. MCD is associated with a variety of secondary causes, including drugs, neoplasms, infections, and allergy. (See 'Etiology' above.)

Clinical features – In most patients, MCD is characterized by the sudden onset over days to a week or two of the signs and symptoms of the nephrotic syndrome, often following an upper respiratory or systemic infection. The typically sudden onset of nephrotic syndrome in MCD is in contrast to the gradual increase in proteinuria over weeks to months in most other causes of nephrotic syndrome. Microscopic hematuria and acute kidney injury (AKI) may also be seen in adults with MCD. Histologically, MCD is characterized by normal-appearing glomeruli by light microscopy and the absence of complement or immunoglobulin deposits by immunofluorescence microscopy. The characteristic histologic lesion in MCD is diffuse effacement of the podocyte foot processes on electron microscopy. (See 'Typical presentation' above and 'Pathologic findings' above.)

Diagnosis – The diagnosis of MCD should be suspected in any adult patient presenting with symptoms and signs of the nephrotic syndrome, especially if the onset is relatively acute (over days to a week or two). A kidney biopsy is required to establish the diagnosis of MCD in adults and to exclude other causes of the nephrotic syndrome. There are no specific laboratory findings that can be used to distinguish MCD from other forms of nephrotic syndrome. (See 'Diagnosis' above.)

Differential diagnosis – The differential diagnosis of MCD in adults includes disorders that also may present with the acute onset of the nephrotic syndrome, such as the glomerular tip lesion variant of FSGS; that are characterized by the combination of the nephrotic syndrome and AKI; or that have foot process effacement on kidney biopsy. (See 'Differential diagnosis' above.)

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Topic 3046 Version 33.0

References

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