Minimal-Change Disease
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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.
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.
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] [2] ) 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. An animal study by Lai et al suggested that IL-13 overexpression can cause podocyte foot process fusion and proteinuria. [3]
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 is critical for preserving the glomerular capillary barrier to protein. 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. [4]
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. [5]
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. [6]
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. [7] In the same study, 2 of 3 other patients with dysferlinopathy had microalbuminuria.
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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.
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.
Rates of MCD vary as follows:
Asians may be at increased risk for MCD
In children, MCD is found twice as frequently in boys than in girls; in adults, however, the frequency is the same between the sexes
The incidence of MCD 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
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Abeera Mansur, MD Consultant Nephrologist, Doctors Hospital and Medical Center, Pakistan
Abeera Mansur, MD is a member of the following medical societies: American College of Physicians, American Society of Nephrology
Disclosure: Nothing to disclose.
Florin Georgescu, MD Consulting Staff, Kidney Specialists of Savannah
Florin Georgescu, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Nephrology
Disclosure: Nothing to disclose.
Susie Lew, MD Professor of Medicine, Department of Medicine, Division of Renal Diseases and Hypertension, George Washington Unversity School of Medicine and Health Sciences; Medical Director, Peritoneal Dialysis Unit, George Washington University Medical Center, Gambro Healthcare/DaVita
Susie Lew, MD is a member of the following medical societies: American College of Physicians, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation
Disclosure: Received grant/research funds from Amgen for investigator; Received consulting fee from Gambro for consulting; Received grant/research funds from Questcor for investigator; Received grant/research funds from Bristol Meyers Squibb for investigator; Received grant/research funds from CMS for investigator.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Eleanor Lederer, MD, FASN Professor of Medicine, Chief, Nephrology Division, Director, Nephrology Training Program, Director, Metabolic Stone Clinic, Kidney Disease Program, University of Louisville School of Medicine; Consulting Staff, Louisville Veterans Affairs Hospital
Eleanor Lederer, MD, FASN is a member of the following medical societies: American Association for the Advancement of Science, American Federation for Medical Research, American Society for Biochemistry and Molecular Biology, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Transplantation, International Society of Nephrology, Kentucky Medical Association, National Kidney Foundation, Phi Beta Kappa
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Society of Nephrology<br/>Received income in an amount equal to or greater than $250 from: Healthcare Quality Strategies, Inc<br/>Received grant/research funds from Dept of Veterans Affairs for research; Received salary from American Society of Nephrology for asn council position; Received salary from University of Louisville for employment; Received salary from University of Louisville Physicians for employment; Received contract payment from American Physician Institute for Advanced Professional Studies, LLC for independent contractor; Received contract payment from Healthcare Quality Strategies, Inc for independent cont.
Vecihi Batuman, MD, FASN Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System
Vecihi Batuman, MD, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, International Society of Nephrology, Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.
Anil Kumar Mandal, MD Clinical Professor, Department of Internal Medicine, Division of Nephrology, University of Florida College of Medicine
Anil Kumar Mandal, MD is a member of the following medical societies: American College of Clinical Pharmacology, American College of Physicians, American Society of Nephrology, Central Society for Clinical and Translational Research
Disclosure: Nothing to disclose.
Minimal-Change Disease
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