Diagnosis and causes of minimalchange disease
Burton D Rose, MD
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INTRODUCTION — Minimalchange disease (MCD; also called nil disease or lipoidnephropathy) is the most commoncause of the nephrotic syndrome in children, accounting for 90 percent of cases under the age of 10 and more than 50 percent in older children [1]. It also accounts for 10 to 15 percent of cases in adults of all ages [2]. The plasmacreatinineconcentration is usually normal, but in adults is often slightly elevated at presentation; in addition, acute renal failure can occur [2]. (See "Acute renal failure in minimalchange disease and other forms of nephrotic syndrome").
The terms minimalchange and nil disease reflect the observation that lightmicroscopy in this disorder is either normal or reveals onlymildmesangial cell proliferation (showhistology 1A-1B). Immunofluorescence and lightmicroscopytypically show no evidence of immunecomplexdeposition. The characteristic histologicfinding in minimalchange disease is diffuse effacement of the epithelial cellfootprocesses on electronmicroscopy, a finding also observed with focal glomerular sclerosis (see below).
PATHOGENESIS — It has been proposed that minimalchange disease reflects a disorder of T lymphocytes. These T cells, which are presumably sensitive to corticosteroids and cyclosporine, are thought to release a cytokine that injures the glomerular epithelial cells [3-6]. (See "Mechanisms of immuneinjury of the glomerulus"). In one report, for example, a T cellhybridomamadefrom a patient with minimalchange disease released a substance that caused both proteinuria and footprocessfusion when injected into rats [4].
Further evidence in support of a circulating glomerular toxin has come from a report of a cadaver transplantdonor with active and relatively refractoryminimalchange disease [7]. In this setting, the diseased kidney was placed in a normalenvironment. Proteinuriarapidly fell in the recipients within a few days and was persistently within the normalrange within six weeks.
The identity of this permeabilityfactor is stilluncertain. Datafrom one group of investigators suggest that hemopexin, an acutephasereactant, may be the activefactor as determined by some experimentalmodels of minimalchange disease [8,9]. Whether this finding is applicable to patients with minimalchange disease is unknown. Additional possiblefactors includeinterleukin-4, vascular endothelial growthfactors, and low molecular weightsubstances [10].
It is also unclear if the factor(s) responsible for minimalchange disease is the same circulatingfactor that has been found in patients with recurrentprimaryfocalglomerulosclerosisafter renal transplantation. The latter disorder has been thought to be etiologically similar to but moresevere than minimalchange disease. (See "Focalglomerulosclerosis: Recurrenceaftertransplantation").
Epithelial celldamage may lead to proteinuria in minimalchange disease by decreasing the synthesis of polyanions such as heparan sulfate; thesepolyanions constitute most of the normalchargebarrier to the glomerular filtration of macromolecules such as albumin, which is anionic in the physiologic pH range. The albuminuria in minimalchange disease is in part due to loss of charge-selectivity in the glomerular wall [11,12]. In comparison, there is only a slight increase in the filtration of larger neutralmacromolecules, suggesting that the size-selective barrier in the glomerular capillarywall is relatively intact; this is in contrast to most other glomerular diseases in which the proteinuria is primarily due to an increased number of largepores in the glomerular capillarywall, leading to an impairment in size-selectivity [11]. (See "Evaluation of isolated proteinuria in adults" for a briefreview of the mechanisms by whichprotein excretion is increased in glomerular diseases).
The characteristic histologicfinding, diffuse effacement or flattening of the epithelial cellfootprocesses, may result in part because of altered interactions between extracellular matrixproteins and podocytes. Indirect and verylimitedevidencesuggests that podocytes are normally anchored to the glomerular basementmembrane via adhesionmolecules, such as alpha3-beta1 integrin and the dystroglycans. In patients with MCD but not in those with focalsegmentalglomerulosclerosis or in normalcontrols, levels of beta-dystroglycan are significantly reduced, suggesting that the mechanism of footprocessfusion may differ in the two disorders [13]. Corticosteroidtherapy appears to normalize beta-dystroglycan levels in those with MCD.
DIAGNOSIS — The diagnosis of minimalchange disease is made by renal biopsy in adults. In comparison, the high prevalence of MCD in children commonlyleads to an empiric trial of corticosteroids, with a renal biopsybeingperformed only in resistant patients. The incidence of MCD in the latter group is approximately 50 percent for children under the age of six but onlyfourpercent in older children [1]. (Also see "Minimalchangevariants: Mesangial proliferation; IgM nephropathy; C1q nephropathy"). Other causes of the nephrotic syndrome that might be treated differently, such as membranousnephropathy, focal glomerular sclerosis, and primaryamyloidosis, are morecommonly seen in adults.
Minimalchangeversusfocalglomerulosclerosis — The biopsydiagnosis of primaryfocalglomerulosclerosis (FGS) requires the finding of segmentalsclerosis in some glomeruli. Thus, samplingerror could easily lead to misclassification of a patient with FGS as MCD.
ETIOLOGY — Almost all cases of MCD are idiopathic, although infrequent patients have an identifiable cause.
Nonsteroidal antiinflammatorydrugs — Nonsteroidal antiinflammatorydrugs (NSAID), particularly fenoprofen, are one of the most commoncauses of secondary MCD [14]. Most, but not all, patients with this disorderhave a concurrent acuteinterstitialnephritis, manifested by renal insufficiency, hematuria, and pyuria as well as heavyproteinuria. (See "NSAIDs: Acute renal failure and nephrotic syndrome"). A similar combined disorder has been reported with ampicillin, rifampin, and interferon [15]. Discontinuation of drugtherapyleads to spontaneous resolution of the nephrotic syndrome. To date, selective COX-2 inhibitors have not been associated with this pattern of injury. (See "Overview of selective COX-2 inhibitors").
Malignancy — MCD may be associated with hematologicmalignancies, particularly Hodgkin's disease and less often other lymphomas or leukemias [16,17]. In contrast, solidtumors usually produce an immunecomplex-mediated disease such as membranousnephropathy; MCD has been reported but the relation to the tumor has not been proven [18]. The activity of the renal disease in this settingtypically parallels that of the malignancy, with the proteinuria disappearing when remission is induced by radiation or chemotherapy. It is presumed that the tumorcells secrete a cytokine that is toxic to the glomerular epithelial cells. In some cases, however, the course of the nephrotic syndrome does not follow that of the malignancy; how this occurs is not clear [19].
In almost all cases, the underlying malignancy is either already diagnosed or clinically apparent (as with lymphadenopathy in Hodgkin's disease) at the time of onset of the nephrotic syndrome. Thus, an extensive evaluation for an occultunderlying malignancy is not indicated in patients with minimalchange disease in the absence of suggestive symptoms or findings (such as unexplained weightloss, fever, lymphadenopathy, anemia, or guaiac-positivestools). A tumorwork-up is also not indicated solely for an elevated erythrocytesedimentationrate; the latter is a commonfinding in the nephrotic syndrome, occasionally exceeding 100 mm/h. (See "Erythrocytesedimentationrate in renal disease").
Chronic graft-versus-host-disease afterperipheral bloodstemcelltransplant has also been associated with MCD [20]. This has been postulated to be the result of the interplay between hostsusceptibility and circulatingcytokines.
Others — Other lesscommoncauses of MCD include: Lithium (see "Renal toxicity of lithium") Tiopronin, used in the treatment of cystinuria, which can also cause other types of glomerular disease [21,22] (see "Cystinestones") Pamidronate, which is most commonlyassociated with collapsingfocal glomerular sclerosis [23]. (See "Collapsing FGS not associated with HIV infection"). Unusual associations with systemiclupuserythematosus and IgA nephropathy [24-26]. (See "Types of renal disease in systemiclupuserythematosus").
Heavyproteinuria in the last disorder is generally a bad prognostic sign with advanced glomerular injury on renal biopsy. However, there is a subgroup of patients who present with the nephrotic syndrome and, on renal biopsy, havediffusefootprocessfusion and IgA deposition but onlyminimal glomerular changes on lightmicroscopy. These patients typically behave as if they have MCD, sincesteroidtherapyinduces completeremission of proteinuria and, in some cases, partial or completeresolution of the glomerular IgA deposits [25,26]. The mechanismunderlying this relationship is not understood. (See "Treatment and prognosis of IgA nephropathy").
Lastly, minimalchange disease may be associated with foodallergy, as manifested by symptoms or by skintesting of asymptomatic cases [27]. Some of these patients respond with a decline in proteinuria to the institution of oligoantigenic diets; however, the efficacy of this regimen has not been rigorously tested.
Use of UpToDate is subject to the Subscription and LicenseAgreement. REFERENCES 1.The primary nephrotic syndrome in children. Identification of patients with minimalchange nephrotic syndromefrominitialresponse to prednisone. A report of the InternationalStudy of Kidney Disease in Children. J Pediatr 1981; 98:561.
2.Nolasco, F, Cameron, JS, Heywood, EF, et al. Adult-onset minimalchange nephrotic syndrome: A long-termfollow-up. Kidney Int 1986; 29:1215.
3.Sewell, RF, Short, CD. Minimal-changenephropathy: How does the immunesystemaffect that glomerulus? Nephrol DialTransplant 1993; 8:108.
4.Koyama, A, Fujisaki, M, Kobayashi, M, et al. A glomerular permeabilityfactorproduced by human T cellhybridomas. Kidney Int 1991; 40:453.
5. Cunard, R, Kelly, CJ. T cells and minimalchange disease. J Am Soc Nephrol 2002; 13:1409.
6. Sahli, D, Pawlak, A, Valanciute, A, et al. A novelapproach to investigation of the pathogeneis of activeminimal-change nephrotic syndrome using substracted cDNA livrary screening. J Am Soc Nephrol 2002; 13:1238.
7.Ali, AA, Wilson, E, Moorhead, JF, et al. Minimal-change glomerular nephritis. Normalkidneys in an abnormalenvironment. Transplantation 1994; 58:849.
8.Cheung, PK, Klok, PA, Baller, JF, Bakker, WW. Induction of experimentalproteinuria in vivo followinginfusion of humanplasmahemopexin. Kidney Int 2000; 57:1512.
9.Cheung, PK, Stulp, B, Immenschuh, S, et al. Is 100KF an isoform of hemopexin? Immunochemicalcharacterization of the vasoactiveplasmafactor 100KF. J Am Soc Nephrol 1999; 10:1700.
10. Short, CD, Brenchley, PE, Webb, NA. Minimalchange disease, focalsegmentalglomerulosclerosis and proteinuria. Nephrol DialTransplant2003; 18:1.
11.Guasch, A, Deen, WM, Myers, BD. Chargeselectivity of the glomerular filtrationbarrier in healthy and nephrotic humans. J Clin Invest 1993; 92:2274.
12.Guasch, A, Hashimoto, H, Sibley, RK, et al. Glomerular dysfunction in nephrotic humans with minimalchanges or focalglomerulosclerosis. Am J Physiol 1991; 260:F728.
13.Regele, HM, Fillipovic, E, Langer, B, et al. Glomerular expression of dystroglycans is reduced in minimalchangenephrosis but not in focalsegmentalglomerulosclerosis. J Am Soc Nephrol 2000; 11:403.
14.Warren, GV, Korbet, SM, Schwartz, MM, Lewis, EJ. Minimalchangeglomerulopathyassociated with nonsteroidal antiinflammatorydrugs. Am J Kidney Dis 1989; 13:127.
15. Averbuch, SD, Austin, HA, III, Sherwin, SA, et al. Acuteinterstitialnephritis with the nephrotic syndromefollowing recombinantleukocyte A interferontherapy for mycosis fungoides. N Engl J Med 1984; 310:32.
16.Dabbs, DJ, Morel-MarogerStriker, L, Mignon, F, Striker, G. Glomerular lesions in lymphomas and leukemias. Am J Med 1986; 80:63.
17. Alpers, CE, Cotran, RS. Neoplasia and glomerular injury. Kidney Int 1986; 30:465.
18.Meyrier, A, Delahousse, M, Callard, P, Rainfray, M. Minimalchange nephrotic syndromerevealing solidtumors. Nephron 1992; 61:220.
19.Korzets, Z, Golan, E, Manor, Y, et al. Spontaneously remittingminimalchangenephropathy preceding a relapse of Hodgkin's disease by 19 months. Clin Nephrol 1992; 38:125.
20.Rao, PS. Nephrotic syndrome in patients with peripheral bloodstemcelltransplant. Am J Kidney Dis 2005; 45:780.
21.Lecoules, S, Duvic, C, Herody, M, Nedelec, G. [Tiopronin-induced nephrotic syndrome with minimal glomerular lesions]. Presse Med 1999; 28:273.
22.Ferraccioli, GF, Peri, F, Nervetti, A, et al. Tiopronin-nephropathy: clinical, pathological, immunological and immunogeneticcharacteristics. Clin Exp Rheumatol 1986; 4:9.
23.Barri, YM, Munshi, NC, Sukumalchantra, S, et al. Podocyte injuryassociated glomerulopathies induced by pamidronate. Kidney Int 2004; 65:634.
24.Dube, GK, Markowitz, GS, Radhakrishnan, J, et al. Minimalchange disease in systemiclupuserythematosus. Clin Nephrol 2002; 57:120.
25.Mustonen, J, Pasternack, A, Rantala, A. The nephrotic syndrome in IgA glomerulonephritis: Response to corticosteroidtherapy. Clin Nephrol 1983; 20:172.
26.Cheng, IK, Chan, KW, Chan, MK. Mesangial IgA nephropathy with steroid-responsive nephrotic syndrome: Disappearance of mesangial IgA deposits followingsteroid-induced remission. Am J Kidney Dis 1989; 14:361.
27.Lagrue, G, Laurent, J, Rostoker, G. Foodallergy and idiopathic nephrotic syndrome. Kidney Int Suppl 1989; 27:S147.
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