De novo minimal change disease

De Novo Minimal Change Disease Glen S. Markowitz, MD, Craig L. Stemmer, MD, Byron P. Croker, MD, PhD, and Vivette D. D’Agati, MD ● Beyond the acute posttransplantation period, glomerular causes of proteinuria in the renal allograft include recurrent glomerulopathy, transplant-associated entities, and de novo disease. We present a case of de novo minimal change disease with reversible acute renal failure occurring 2.5 years posttransplantation in a 56-year-old man. The cause of end-stage renal disease in the native kidney was membranous glomerulopathy. De novo minimal change disease in the renal allograft is an extremely rare entity requiring stringent clinical-pathological criteria for diagnosis. Many of the cases previously reported as de novo minimal change disease fail to meet these criteria. We review the eight reported cases that appear to fulfill a strict definition of minimal change disease in the context of the current report. r 1998 by the National Kidney Foundation, Inc. INDEX WORDS: De novo minimal change disease; renal allograft; nephrotic syndrome; renal transplantation.

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ROTEINURIA in the acute posttransplantation period is not uncommon. Probable explanations for this phenomenon include acute rejection, acute tubular necrosis due to prolonged warm or cold ischemic time, lesser degrees of tubular damage due to preservation injury and leading to compromised protein resorptive capacity, or a combination of the above.1 This early-onset proteinuria usually resolves with time and has no prognostic significance.2,3 Pathological evaluation may show normal glomeruli, with ‘‘minimal changes.’’ Beyond the immediate posttransplantation period, nephrotic-range proteinuria may develop in association with chronic rejection.4 More commonly, new-onset nephrotic-range proteinuria occurs in the setting of a variety of glomerular diseases.5 Glomerular causes of nephrotic-range proteinuria in the renal allograft are divided into three main categories: transplant glomerulopathy, recurrent glomerular disease, and de novo glomerulopathy. Transplant glomerulopathy is the most common cause of nephrotic-range proteinuria in the renal allograft and typically disFrom the Department of Pathology, Renal Pathology Laboratory, Columbia Presbyterian Medical Center, New York, NY; Division of Nephrology, Delray Community Hospital, Delray, FL; and the Department of Veterans Affairs, Medical Center, Gainesville, FL. Received October 9, 1997; accepted in revised form March 17, 1998. Address reprint requests to Vivette D. D’Agati, MD, Department of Pathology, Renal Pathology Laboratory, Columbia Presbyterian Medical Center, 630 West 168th St, Rm VC 14-224, New York, NY 10032. E-mail: vdd1@columbia. edu

r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3203-0023$3.00/0 508

plays a membranoproliferative pattern without immune complex deposits.6,7 Recurrent glomerulopathy has been described for many forms of glomerular disease.8,9 Characteristic of focal segmental glomerulosclerosis is its ability to recur in the early posttransplantation period,10,11 a phenomenon that often correlates with the presence of a serum permeability factor.12 Multiple reports have highlighted the occurrence of de novo glomerulopathy in the renal allograft.5,13,14 Although membranous glomerulopathy is the most common form of de novo disease,7,15,16 most large studies have not included a single case of de novo minimal change disease.5,13,14 In fact, only scattered brief reports of de novo minimal change disease exist in the literature. We report the case of a 56-year-old man who presented with rapid-onset, severe proteinuria and subsequent acute renal failure due to de novo minimal change disease. A review of the literature on this topic follows. CASE REPORT A 56-year-old white man status post cadaveric renal transplantation 2.5 years earlier presented with mild lowerextremity edema. The patient had a history of biopsy-proven membranous glomerulonephropathy leading to end-stage renal disease and requiring hemodialysis since December of 1989. The patient had been on hemodialysis until the time of his cadaveric renal transplantation in November 1994. His serum creatinine had been stable at 1.3 mg/dL since that time. His medical history also was significant for hypertension, coronary artery disease requiring percutaneous transluminal coronary angioplasty in 1992, coronary artery bypass graft in 1993, with a current ejection fraction of 40%, peptic ulcer disease in 1994, and bilateral pneumonia in 1991. His medications included prazosin, amlodipine, prednisone (10 mg once daily), atenolol, ketaconazole, cyclosporine (75 mg

American Journal of Kidney Diseases, Vol 32, No 3 (September), 1998: pp 508-513

DE NOVO MINIMAL CHANGE DISEASE

daily in divided doses), famotidine, and magnesium. The mild lower-extremity edema was thought to be of cardiogenic origin, and he was started on Lasix 40 mg by mouth (PO) once daily. A multi-gated acquisition (MUGA) scan performed at that time indicated no interval change in cardiac output. The patient returned 2 weeks later with shortness of breath, marked lower-extremity edema, a 1-week history of ‘‘foamy urine,’’ and an interval weight gain of 26 pounds. He denied use of nonsteroidal antiinflammatory drugs. Physical examination showed an obese man with gross anasarca, a blood pressure of 120/70 mm Hg, and a heart rate of 70 beats/min. Laboratory evaluation showed a 24-hour urine protein of 7.3 g (greater than 99% albumin), a serum albumin of 3.0 g/dL (baseline 4.3), a serum cholesterol of 270 mg/dL (baseline, 170), a stable serum creatinine at 1.3 mg/dL, and a cyclosporine level of 159 ng/mL. Urinalysis showed 3⫹ protein and 5 red blood cells (RBCs) per high-power field. The patient was admitted to the hospital for management and investigation of his severe peripheral edema. On admission, a renal allograft biopsy was performed (biopsy 1). The patient subsequently developed acute renal failure with rapid rise in serum creatinine to 5.9 mg/dL within 1 week of admission, necessitating transfer to a large transplant center, where a second renal biopsy was performed (biopsy 2). The patient restarted hemodialysis therapy and was discharged 3 days later with a decline in his serum creatinine to 3.6 mg/dL, and a urinary output of 1,500 mL/day, on Lasix 120 mg PO twice daily and KCl. Because of the development of hypertension, fever, and gastrointestinal symptoms due to diverticulosis, a decision was made to withhold steroid therapy. After discharge, the patient received 1 month of hemodialysis and a slight upward adjustment of his maintenance cyclosporine level to 100 mg daily. On follow-up 6 months postbiopsy, the proteinuria had spontaneously declined to 702 mg/day, albumin rose to 3.8 g/dL, and creatinine had returned to its baseline level of 1.3 mg/dL.

Fig 1. A representative glomerulus with patent capillaries and minimal mesangial prominence. Visceral epithelial cell swelling is present (Hematoxylin and eosin; original magnification; ⴛ500.).

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PATHOLOGICAL EVALUATION

Light Microscopy Both biopsy specimens were reviewed simultaneously and showed similar findings. Biopsy 1 included two cores of renal cortex containing 12 glomeruli, and biopsy 2 consisted of a single core of renal cortex containing six glomeruli. None of the 18 glomeruli was segmentally or globally sclerotic. Glomeruli were normal in size with a mild diffuse increase in mesangial cell number and matrix (Fig 1). Glomerular capillary lumens were patent and peripheral glomerular basement membranes appeared normal in thickness, texture, and contour. There was mild visceral epithelial cell swelling. No fuchsinophilic deposits were identified with trichrome staining. The tubulointerstitial compartment displayed minimal patchy fibrosis and a sparse mononuclear infiltrate. No tubulitis, vasculitis, or other signs of rejection were identified. Proximal tubules displayed foci of dilatation, cytoplasmic shedding, regenerative nuclear atypia, epithelial simplification, and irregular tubular cytoplasmic vacuolation (Fig 2). There was mild arteriolosclerosis.

Immunofluoresence Segmental weak glomerular positivity for immunoglobulin (Ig) M and C3 was identified. Glomeruli were negative for IgG, IgA, and C1q. C3 was present focally within arterial and arteriolar walls.

Electron Microscopy Mesangial areas were mildly expanded by increased mesangial cell number and matrix. No immune-type electrondense deposits were seen. The peripheral glomerular basement membranes were normal in thickness, texture, and contour. The major ultrastructural findings were marked hypertrophy of the visceral epithelial cells with increased organellar content, intracytoplasmic transport vesicles, and

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Fig 2. Proximal tubules display mild ectasia, epithelial simplification, cytoplasmic shedding, and focal regenerative nuclear atypia (Hematoxylin and eosin; original magnification; ⴛ200.).

extensive foot process fusion involving over 95% of the total glomerular capillary surface area (Fig 3).

DISCUSSION

Stringent criteria are necessary for an accurate diagnosis of de novo glomerular disease in the renal allograft. First, the patient should meet all of the criteria for the diagnosis in the native kidney. This includes an appropriate clinical presentation as well as defining morphological criteria by light microscopic, immunofluorescence, and ultrastructural evaluation. Second, the renal

Fig 3. Electron micrograph showing marked hypertrophy of visceral epithelial cells with increased organellar content. There is complete foot process effacement (original magnification ⴛ24,000.).

findings should not be attributable to transplant rejection or drug toxicity. Knowledge of the cause of renal failure in the native kidney is required to rule out the possibility of recurrent disease. Particularly stringent criteria must be met for the diagnosis of de novo minimal change disease, an entity that at times may be considered a diagnosis of exclusion. First, the diagnosis should not be made in the immediate posttransplantation period (variably defined as 7 days) without great caution because acute rejection, preservation in-

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jury, and acute tubular necrosis commonly occur at this time,1 produce nephrotic-range proteinuria, and generally spare the glomeruli (hence ‘‘minimal changes’’). In addition, focal segmental glomerulosclerosis (FSGS) has a high rate of recurrence in the renal allograft, may recur within hours of transplantation, and may appear morphologically as minimal change disease in biopsy specimens taken early in the course of clinical recurrence, before the development of segmentally sclerotic lesions.17 Hence, the diagnosis of de novo minimal change disease is best made at least 7 days posttransplantation in a patient whose original disease was not FSGS and in the absence of subsequent evolution to FSGS. In rare cases in which de novo minimal change disease does indeed occur during the first 7 days posttransplantation, a history of persistent proteinuria beyond this period and a repeat biopsy at a later date would be required to confirm this diagnosis. Clinically, patients should manifest full nephrotic syndrome. Demonstration of the highly selective nature of the proteinuria and a clinical course characterized by either spontaneous remission or response to increase in steroid or other immunosuppressive therapy would provide strong

supportive evidence. Lastly, transplant biopsy specimens should be studied by the three modalities of light microscopy, immunofluorescence, and electron microscopy. In 1988, Gephardt et al18 reported four cases of de novo minimal change disease and reviewed the cases of purported de novo minimal change disease in the literature. Many of these cases, as well as other more recent cases in the literature, do not meet strict criteria for the diagnosis of de novo minimal change disease. The reasons for this are varied and include a case occurring on the first day posttransplantation and possibly related to ligation of a large renal vein,19 cases without well-established pretransplantation diagnoses,20,21 cases with either a pretransplantation diagnosis of focal segmental glomerulosclerosis or posttransplantation subsequent biopsy specimens showing FSGS,10,22-24 and a case in which the original renal failure in a child was thought to be attributable to minimal change disease.25 Using the more restrictive clinicopathologic definition of de novo minimal change disease just outlined, the literature is re-reviewed, and acceptable cases are depicted in Table 1.18,20,26-29 Including the case reported herein, a total of nine

Table 1. Published Reports of De Novo Minimal Change Disease Meeting Stringent Criteria Trans- 24-Hour plant Urine No. of Number Age to Biopsy Protein sAlb sChol sCreat Gloms Author of Study of Cases (yr) Sex Original Renal Disease (mo) (g) (g/dL) (mg/dL) (mg/dL) Sampled Gephardt et al18

3

NS

M

NS

M

NS

M

Membranous glomerulopathy Membranous glomerulopathy ? Goodpasture’s syndrome (not biopsied) Membranous glomerulopathy

2

17

3

245

3.9

20

10

10.8

3.6

350

3.8

70

12

10.8

3.2

390

2

50

4 & 23 days

8-90

NS

NS

Cr Cl 35 mL/min

NS (2 bx’s)

Shapiro et al26

1

38

M

Cheigh et al27

1

28

F

Unclassified GN (not MCD)

2

NR

NS

NS

NS

NS (2 bx’s)

McLeish et al20

1

22

F

4

3

NS

NS

1.6

NS

Lane et al28

1

2

M

Chronic glomerulonephritis Finnish-type congenital nephrotic syndrome

3

NR

4

NS

0.4

NS

Flynn et al29

1

3

M

Finnish-type congenital nephrotic syndrome

2

NR

NS

NS

2.3

NS

Markowitz

1

56

M

Membranous glomerulopathy

30

7.3

3

270

5.9

18

Abbreviations: NS, not stated; NR, nephrotic range; mo, months. *These three cases went on to renal failure, likely because of acute and chronic rejection.

Treatment/Follow-Up Returned to dialysis at 4 mo* Returned to dialysis at 46 mo* Returned to dialysis at 53 mo* Dialysis, Predn/Azath/ Cyclophos resolution at 24 mo Resolution of proteinuria graft still functioning at 15 yr Resolution of proteinuria after 4 mo Prednisone/resolution on day 9 steroid-responsive recurrences Prednisone not effective cyclophosphamide/ resolution Increase in cyclosporine A resolution at 6 mo

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cases are identified, two of which occurred in young male children with a previous diagnosis of Finnish-type congenital nephrotic syndrome. The remaining seven cases include five males and two females, four of whom had membranous glomerulopathy as the original cause of endstage renal disease. This high incidence of primary membranous glomerulopathy (four of nine cases) is intriguing and difficult to explain. The time course from transplant to biopsy varied between 4 days and 30 months, with most of the cases occurring before 4 months. In all cases, there was nephrotic-range proteinuria and, in most cases, hypoalbuminemia and hypercholesterolemia were described. Renal function varied from relatively normal to various degrees of renal insufficiency. The only case with overt acute renal failure is the subject of this report. Only limited follow-up data are available, but five cases apparently were responsive to therapy, and one had a spontaneous resolution. The remaining three cases went on to require hemodialysis as a result of acute and chronic rejection. Follow-up of their de novo minimal change disease is not available. Although primarily a disease of children, idiopathic minimal change disease may be seen in adults.30-32 In contrast to children with this condition, adults present with acute renal failure more often, require longer periods to respond to steroids, and have a lower frequency of relapse.30 These features tend to be more common in adults older than 40 years of age.31,32 The frequency of acute renal failure in adult minimal change disease may be as high as 20% and appears to occur more often in the setting of preexisting hypertension and arteriosclerosis.32 This same study found that most cases with acute renal failure showed changes in the proximal tubules such as epithelial simplification with flattened epithelium, absent brush borders, and dilated lumina. Because these features overlap with those seen in ischemic acute tubular necrosis, it has been proposed that the renal failure relates to hemodynamic alterations of the nephrotic syndrome occurring in the setting of preexisting arteriosclerosis, as a possible impediment to compensatory mechanisms.32 The patient that is the subject of this report presented with an explosive onset of the nephrotic syndrome, as is often seen in idiopathic

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minimal change disease. His age, 56 years, increased his risk of presenting with acute renal failure. Furthermore, the renal biopsy specimen showed features of proximal tubular damage that are often present in adult patients with minimal change disease and acute renal failure. By history, light and electron microscopy, and immunofluorescence, he showed all of the features that are typical of minimal change disease in the native kidney. Also characteristic of minimal change disease is that fact that his condition underwent a virtually complete remission. This may represent a spontaneous occurrence or may relate to the upward adjustment of his cyclosporine level, a drug that has been used with success to treat adult minimal change disease.33 Based on this favorable course, it is unlikely that this case will later evolve into focal segmental glomerulosclerosis. It is interesting to speculate why de novo minimal change disease is so rare in the renal transplant population. Anti-rejection immunosuppressive therapy may be prophylactic against the development of minimal change disease. In some patients, this process may go undiagnosed as a result of lack of ultrastructural analysis or incorrectly attributing the nephrotic-range proteinuria to rejection, drug toxicity, or the transplantation process. Among the few reported cases of de novo minimal change disease, our case is unique for the increased age of the patient (56 years), the presentation with acute renal failure, and the increased time from transplantation to biopsy (30 months). REFERENCES 1. Sethi K, First MR, Pesce AJ, Fidler JP, Pollak VE: Proteinuria following renal transplantation. Nephron 18:4959, 1977 2. Laterre EC, Van Ypersele C, Alexandre GPJ: Proteinuria in human renal allograft with special reference to glomerular permeability in acute rejection crisis, in Manuel Y, Revillard JP, Betuel H (eds): Proteins in Normal and Pathological Urine. Baltimore, MD, University Park Press, 1970, pp 300-308 3. Revillard JP, Manuel Y, Betuel H, Fries D, Traeger J: Proteinuria in human renal allografts: Sequential studies, in Manuel Y, Revillard JP, Betuel H (eds): Proteins in Normal and Pathological Urine. Baltimore, MD, University Park Press, 1970, pp 309-318 4. Harlan WR Jr, Holden KR, Williams GM, Hume DM: Proteinuria and nephrotic syndrome associated with chronic rejection of kidney transplants. N Engl J Med 277:769-776, 1967

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5. First MR, Vaidya PN, Maryniak RK, Weiss MA, Munda R, Fidler JP, Penn I, Alexander JW: Proteinuria following transplantation. Transplant 38:607-612, 1984 6. Maryniak RK, First MR, Weiss MA: Transplant glomerulopathy: Evolution of morphologically distinct changes. Kidney Int 27:799-806, 1985 7. Habib R, Broyer M: Clinical significance of allograft glomerulopathy. Kidney Int 44:S95-S98, 1993 (suppl 43) 8. Mathew TH: Recurrence of disease following renal transplantation. Am J Kidney Dis 12:85-96, 1988 9. Ramos EL: Recurrent diseases in the renal allograft. J Am Soc Nephrol 2:109-121, 1991 10. Dantal J, Baatard R, Hourmant M, Cantarovich D, Buzelin F, Soulilou JP: Recurrent nephrotic syndrome following renal transplantation in patients with focal glomerulosclerosis. Transplant 52:827-831, 1991 11. Artero M, Biava C, Amend W, Tomlanovich S, Vincenti F: Recurrent focal glomerulosclerosis: Natural history and response to therapy. Am J Med 92:375-383, 1992 12. Savin VJ, Sharma R, Sharma M, McCarthy ET, Swan SK, Ellis E, Lovell H, Warady B, Gunwar S, Chonko AM, Artero M, Vincenti F: Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N Engl J Med 334:914915, 1996 13. Schwarz A, Krause PH, Offermann G, Keller F: Recurrent and de novo renal disease after kidney transplantation with or without cyclosporine A. Am J Kidney Dis 17:524-531, 1991 14. Guttmann RD: Recurrent and de novo glomerulonephritis postrenal transplantation. Transplant Proc 28:11681170, 1996 15. Truong L, Gelfand J, D’Agati VD, Tomaszewski J, Appel G, Hardy M, Pirani CL: De novo membranous glomerulopathy in renal allografts: A report of ten cases and review of the literature. Am J Kidney Dis 14:131-144, 1989 16. Schwarz A, Krause PH, Offermann G, Keller F: Impact of de novo membranous glomerulonephritis on the clinical course after kidney transplantation. Transplant 58: 650-654, 1994 17. Silva FG: Overview of pediatric nephropathology. Kidney Int 33:1016-1032, 1988 18. Gephardt GN, Tubbs RR, Braun WE, Novick AC, McMahon JT, Steinmuller DR: Nephrotic range proteinuria with ‘‘minimal change glomerulopathy’’ in human renal allografts: Report of four cases. Am J Kidney Dis 12:51-61, 1988 19. Abouna GM, Kogure H, Porter KA, Andres GA, Lutcher CL, Sobel RE: Massive early proteinuria following renal homotransplantation. JAMA 226:631-635, 1973

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20. McLeish KR, Gohara AF, Shapiro RS: Massive posttransplant proteinuria with minimal histological changes. Transplant 29:392-396, 1980 21. Busch GJ, Galvanek EG, Reynolds ES Jr: Human renal allografts: Analysis of lesions in long-term survivors. Hum Pathol 2:253-298, 1971 22. Hoyer JR, Vernier RL, Najarian JS, Raij L, Simmons RL, Michael AF: Recurrence of idiopathic nephrotic syndrome after renal transplantation. Lancet 2:343-348, 1972 23. Hamburger J, Berger J, Hinglais N, Descamps B: New insights into the pathogenesis of glomerulonephritis afforded by the study of renal allografts. Clin Nephrol 1:3-7, 1973 24. Habib R, Hebert D, Gagnadoux MF, Broyer M: Transplantation in idiopathic nephrosis. Transplant Proc 14:489-495, 1982 25. Mauer SM, Hellerstein S, Cohn RA, Sibley RK, Vernier RL: Recurrence of steroid-responsive nephrotic syndrome after renal transplantation. J Pediat 95:261-264, 1979 26. Shapiro RS, Deshmukh A, Kropp K: Massive posttransplant proteinuria. Transplant 22:489-492, 1976 27. Cheigh JS, Mouradian J, Susin M, Studenbord WT, Tapia L, Riggio RR, Stenzel KH, Rubin AL: Kidney transplant nephrotic syndrome: Relationship between allograft histopathology and natural course. Kidney Int 18:358-365, 1980 28. Lane PH, Schnaper HW, Vernier RL, Bunchman TE: Steroid-dependent nephrotic syndrome following renal transplantation for congenital nephrotic syndrome. Pediatr Nephrol 5:300-303, 1991 29. Flynn JT, Schulman SL, deChadarevian JP, Dunn SP, Kaiser BA, Polinsky MS, Baluarte HJ: Treatment of steroidresistant post-transplant nephrotic syndrome with cyclophosphamide in a child with congenital nephrotic syndrome. Pediatr Nephrol 6:553-555, 1992 30. Nolasco F, Cameron JS, Heywood EF, Hicks J, Ogg C, Williams DG: Adult-onset minimal change nephrotic syndrome: A long-term follow-up. Kidney Int 29:12151223, 1988 31. Korbet SM, Schwartz MM, Lewis EJ: Minimalchange glomerulopathy of adulthood. Am J Nephrol 8:291297, 1988 32. Jennette JC, Falk RJ: Adult minimal change glomerulopathy with acute renal failure. Am J Kidney Dis 16:432437, 1990 33. Ittel TH, Clasen W, Fuhs M, Kindler J, Mihatsch MJ, Sieberth HG: Long-term ciclosporine A treatment in adults with minimal change nephrotic syndrome or focal segmental glomerulosclerosis. Clin Nephrol 44:156-162, 1995