Practice Essentials
Minimal-change disease (MCD), also known as lipoid nephrosis or nil disease, arises from a histopathologic lesion in the glomerulus and is characterized by intense proteinuria leading to edema and intravascular volume depletion. [1] It is the most common single form of nephrotic syndrome in children, but it can also occur in adults. [2]
On laboratory testing, profound proteinuria and oval fat bodies may be observed. In children, the critical level for diagnosis is proteinuria of more than 40 mg/h/m2. In adults, the threshold is more than 3.5 g/d/1.73 m2. (See Workup.)
Treatment includes measures to clear proteinuria, reverse hypovolemia, and reduce edema. Corticosteroids are the treatment of choice, leading to complete remission of proteinuria in most cases. Recurrence is common, however. Options for steroid-sparing therapy and steroid-resistant cases include cyclophosphamide, chlorambucil, mycophenolate, rituximab, and tacrolimus. See Treatment and Medication.
For patient education information, see the Nephrotic Syndrome Overview.
Pathophysiology
It is postulated that MCD is a disorder of T cells, which release a cytokine that injures the glomerular epithelial foot processes. This, in turn, leads to a decreased synthesis of polyanions. The polyanions constitute the normal charge barrier to the filtration of macromolecules, such as albumin. When the polyanions are damaged, leakage of albumin follows. The identity of this circulating permeability factor is uncertain, although it is postulated that it may be hemopexin.
Some of the cytokines that have been studied in MCD are interleukin-12 (IL-12) and interleukin-4 (IL-4). IL-12 levels have been found to be elevated in peripheral blood monocytes during the active phase and normalized during remission. Interleukin-18 (IL-18) can synergize with IL-12 to selectively increase the production of vascular permeability factor from T cells. In addition, levels of IL-4 and CD23 (a receptor for immunoglobulin E [IgE] [3] ) have been found to be elevated in peripheral blood lymphocytes.
Synaptopodin is a proline-rich protein intimately associated with actin microfilaments present in the foot processes of podocytes. Greater synaptopodin expression in podocytes is associated with a significantly better response to steroid therapy. On the other hand, the expression of synaptopodin does not predict progression of MCD or diffuse mesangial hypercellularity to focal segmental glomerulosclerosis (FSGS). Thus, this marker could be used in the future to help determine appropriate therapy.
Interleukin-13 (IL-13) has been implicated in the pathogenesis of MCD. In a study on Chinese children in Singapore, it was shown that IL-13 genetic polymorphisms correlate with the long-term outcome of MCD. [4] An animal study by Lai et al suggested that IL-13 overexpression can cause podocyte foot process fusion and proteinuria. [5]
In patients who develop acute kidney injury (AKI), endothelin 1 expression is greater in the glomeruli, vessels, and tubules than in the non-AKI 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 and is critical for preserving the glomerular capillary barrier to protein. [6] The slit diaphragm is often missing in MC nephrotic syndrome (MCD) kidneys.
CD80 is a protein expressed on the surface of several antigen-presenting cells. It is also expressed on podocytes, and increased expression of CD80 has resulted in a reduced expression of nephrin. Urinary levels of CD80 are increased in patients with MCD but not in patients with FSGS. Thus, this may have clinical applicability in distinguishing these two entities. [7]
In a study of 37 patients with MCD, 27 patients with FSGS, 30 patients with other glomerulopathies, and 71 healthy controls, Ling and colleagues found that urinary CD80 concentrations were significantly higher in patients with active MCD compared with patients with FSGS or other glomerulopathies and controls. At a cutoff value of 328.98 ng/g creatinine, urinary CD80 had a sensitivity of 81.1% and a specificity of 94.4% for diagnosing MCD. [8]
A study by Ahmed et al in 36 children with nephrotic syndrome and normal glomerular filtration rate, which included 21 chlidren with MCD, found that urinary CD80 levels were significantly higher in patients with MCD than in those with FSGS (3.5 ± 2.1 versus 1.2 ± 0.5 ng/mg creatinine; P < 0.001). CD80 levels were also higher in patients with MCD than in those with other glomerulopathies or normal controls (n=40). A urinary CD80 cutoff value of 1.5 ng/gm creatinine showed a sensitivity of 100% and a specificity of 86% for diagnosis of MCD. [9]
Izzedine et al found a lack of glomerular dysferlin expression associated with minimal-change nephropathy in a patient with limb-girdle muscular dystrophy type 2B. [10] In the same study, 2 of 3 other patients with dysferlinopathy had microalbuminuria.
B-cell–depleting agents have shown efficacy in the treatment of MCD, which suggests that B-cells may have a role in the pathogenesis of MCD. [11] Additionally, anti-nephrin antibodies may also play a role in the pathogenesis of MCD. [12]
Etiology
Almost all cases of MCD are idiopathic, but a small percentage of cases (approximately 10-20%) may have an identifiable cause. Secondary cases may be due to any of the following:
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Drugs - Nonsteroidal anti-inflammatory drugs (NSAIDs), rifampin, interferon, ampicillin/penicillin, trimethadione, mercury-containing cosmetic skin cream, immune checkpoint inhibitors [13]
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Infection - Infectious mononucleosis, HIV, immunization
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Tumor - Hodgkin lymphoma [16] (most commonly), carcinoma, other lymphoproliferative diseases
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Hematopoietic stem cell transplantation [17]
Cases of both new-onset and relapsing MCD have been reported following COVID-19 immunization with the Pfizer-BioNTech COVID-19 vaccine. [18, 19, 20]
Epidemiology
Frequency
United States
In preadolescents, minimal-change nephrotic syndrome (MCNS) makes up 85-95% of all cases of nephrotic syndrome. In adolescents and young adults, the prevalence is 50%, while in adults, MCNS accounts for 10-15% of primary nephrotic syndrome cases. The incidence of nephrotic syndrome is 2-7 new cases annually per 100,000 children, and the prevalence is 15 cases per 100,000 children.
Race-, sex-, and age-related demographics
Rates of MCD vary as follows:
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Asians may be at increased risk for MCD
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In children, MCD is found twice as frequently in boys than in girls; in adults, however, the frequency is the same between the sexes
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The incidence of MCD peaks in children aged 2 years, with approximately 80% being younger than 6 years at the time of diagnosis
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In adults, the mean age of onset is 40 years
Morbidity
Very few patients progress to end-stage renal disease. These are patients 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.
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.
The most common complications of MCD are the adverse effects of medications. Additional complications may include peritonitis, infections, and acute kidney injury (AKI). AKI occurs because of either acute tubular necrosis or acute tubulointerstitial nephritis. In a retrospective review of 95 adult patients with MCD, Waldman et al reported that 24 patients had AKI, with these individuals tending to be older and hypertensive, and to have lower serum albumin and more proteinuria than did patients who did not suffer AKI. [21]
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.
Relapses eventually cease. Only approximately 5% of children continue to have steroid-responsive relapses when older than 18 years.
Ling et al reported that urinary levels of CD80 have prognostic value in chlidren with MCD. In their study of 64 children with nephrotic syndrome, progression to chronic kidney disease occurred in 2.9% of those with CD80 levels above 328.98 ng/g creatinine, compared with 41.4% of those with levels below that threshold (P < 0.001). The predicted response to immunosuppressive therapy was 100% in patients with high urinary CD80 levels, versus 34.5% in those with low levels (P < 0.001). [22]
Adults have a similarly good prognosis. Survival rates of 85-90% are observed 10 years or more after disease onset. An observational study of 78 adult patients found that although 10% were steroid-resistant, 98% achieved remission by a median of 5 weeks; 61% relapsed, at a median of 11 months, and patients had a median of 2 relapses during follow-up. Risk of relapse was increased in patients with a higher estimated glomerular filtration rate, and early relapse occurred significantly more often in women. Five patients subsequently developed focal segmental glomerulosclerosis; those patients had a lower baseline creatinine, a higher serum albumin, and a longer time to remission and were more likely to have steroid-resistant disease. [23]
Chronic kidney disease is extremely rare in patients whose MCD is steroid responsive. If chronic kidney disease occurs, the possibility that the pathologic lesion is different or has evolved must be considered.
Patient Education
Patient education in MCD includes the following:
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Explain the consequences of not receiving treatment for MCD
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Explain to the family that children with MCD initially are treated without a tissue diagnosis
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Explain the possible adverse effects of therapy, including growth retardation in children receiving long-term corticosteroids
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Explain that not all patients receiving treatment respond to conventional therapies
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Advise family members to be observant for edematous changes in the patient
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Refer the patient and family for psychosocial counseling
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Impose moderate sodium restrictions and ensure adequate protein intake
For patient education information, see the Nephrotic Syndrome Overview.
