Acute nonoliguric renal failure after renal transplantation

Acute nonoliguric renal failure after renal transplantation

RENAL BIOPSY TEACHING CASE Acute Nonoliguric Renal Failure After Renal Transplantation Johan W. de Fijter, MD, PhD, and Jan A. Bruijn, MD, PhD W E ...

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Acute Nonoliguric Renal Failure After Renal Transplantation Johan W. de Fijter, MD, PhD, and Jan A. Bruijn, MD, PhD


E DESCRIBE a patient who presented with acute nonoliguric renal failure and macroscopic hematuria 20 months after renal transplantation. Renal biopsy indicated an unexpected diagnosis that rightfully predicted recovery of renal function without treatment. This case shows the value of complete workup of the renal transplant biopsy when the clinical situation suggests it is not merely a case of ruling rejection in or out. CLINICAL SUMMARY

A 63-year-old man was referred to Leiden University Medical Center for management of acute renal insufficiency 8 months after cadaveric renal transplantation. His medical history included hypertension 21 years previously, end-stage renal disease, attributed to hypertensive nephropathy 5 years previously, and cadaveric renal transplantation 20 months previously. His clinical course after transplantation had been uneventful. Immunosuppression consisted of prednisone and cyclosporin. Five months after transplantation, anticoagulant therapy was started after percutaneous transluminal coronary angioplasty because of ischemic heart disease. Several medical examinations had shown normal urinary sediment and renal function (creatinine clearance, 49 mL/ min) until 6 weeks before admission. One week before presentation to the outpatient department of a local hospital, he had voided reddish-brown and cloudy urine. His temperature had been in the normal range. Neither dysuria nor oliguria was present. He did not feel any pain or discomfort in his lumbar region. Urinary cultures remained sterile. On admission to our hospital, the patient did not appear ill, his temperature was 36.8°C; blood pressure, 160/90 mm Hg; and the pulse rate was 64 beats/min. No abnormalities were found on physical examination. His prostate was not enlarged or painful. Gross hematuria was still present without oliguria. Laboratory investigation showed a urinary sediment with many red cell casts and some leukocytes. Urinary excretion of creatinine was 13.2 mmol/24h; and protein, 2 g/24h. The serum creatinine concentration was 554 µmol/L; serum urea, 31.4 mmol/L; sodium, 140 mmol/L; potassium, 5.1 mmol/L; calcium, 1.99 mmol/L; phosphate,

From the Departments of Nephrology and Pathology, Leiden University Medical Center, Leiden, The Netherlands. Received and accepted as submitted September 29, 1998. Address reprint requests to Jan A. Bruijn, MD, PhD, University of Leiden, Laboratory of Pathology, PO Box 9600, Building 1, C1Q, Leiden, The Netherlands. E-mail: [email protected]

娀 1999 by the National Kidney Foundation, Inc. 0272-6386/99/3301-0027$3.00/0 166

2.32 mmol/L; total serum protein 62 g/L; and serum albumin, 33 g/L. Liver function tests and cyclosporin through levels were normal. Immunologic studies indicated a negative anti–glomerular basement membrane (GBM) antibody test by enzyme-linked immunosorbent assay, negative antineutrophil cytoplasmatic antibody test by indirect immunofluorescence, normal total complement activity, with normal C1q, C4, and C3 serum levels, and a negative C1q-binding assay, no cryoglobulins, and normal levels of immunoglobulin (Ig) isotypes without paraproteins. No IgM or IgG antibodies were found against cytomegalovirus or EpsteinBarr virus, and no hepatitis B surface antigen could be detected. The antistreptolysin titer was less than 100 U/mL. His sinuses and lungs were radiologically normal. An electrocardiogram disclosed a normal sinus rhythm. Ultrasonography showed a renal allograft of normal size and no hydronephrosis. Scintigraphy showed no signs of renal infarction. The clinical differential diagnosis included proliferative glomerulonephritis (recurrent or de novo), (late) acute rejection, or cyclosporin toxicity with hematuria possibly accentuated by anticoagulant therapy. After correction of hemostasis parameters, a renal biopsy was performed.

Renal Biopsy Findings The specimen received for light microscopical examination consisted of a sample of medulla and cortex containing a total of 13 glomeruli, one of which was globally sclerotic. The remaining glomeruli all showed in periodic acid-Schiff and silver-methenamine stains a mild mesangial expansion and hypercellularity, focally with some extension along the glomerular capillary walls (Fig 1). The GBM showed no abnormalities. No endocapillary proliferative lesions or crescents were present in glomeruli. There was a mild fibrosis of Bowman’s capsule in some glomeruli. As illustrated in Fig 2, several red blood cell casts were noted in the lumens of groups of tubules. The cortical interstitium showed a mild degree of fibrosis with focally some tubular atrophy, in approximate proportion with the degree of global glomerular sclerosis. Atrophic tubules were surrounded by small amounts of lymphocytes, but there were no signs of tubulitis. Several interstitial small arteries showed mild intimal fibrosis. No signs of vasculitis or endovasculitis were seen. A Congo red stain for amyloid was negative. We found no histological signs of cyclosporine A toxicity, such as arteriolar hyalinosis or isometric vacuolization of tubular epithelial cells.1 The specimen received for immunofluorescence contained 10 glomeruli. As shown in Fig 3, immunofluorescence studies showed 2 to 3⫹ (on a 0 to 3⫹ scale) granular deposits of IgA in the mesangial areas of all glomeruli present, with focal extensions along the glomerular capillary walls. Complement factor 3 (C3) was present in a similar intensity and distribution pattern as IgA. No specific staining was seen for IgM, IgG, and C1q. Anti-kappa and lambda light chain antisera showed trace mesangial staining that was

American Journal of Kidney Diseases, Vol 33, No 1 (January), 1999: pp 166-169


Fig 1. Glomerulus showing mild mesangial matrix expansion and hypercellularity. (Silver-methenamine, original magnification ⴛ400.)

equal for both. No specific deposits of immunoglobulins or complement components were seen in tubular basement membranes, interstitium, or extraglomerular blood vessels.

Clinicopathologic Diagnosis The diagnosis was (recurrent) IgA nephropathy with hematuria aggravated by anticoagulant therapy, with secondary sledging of erythrocytes in tubules as the probable cause of the acute nonoliguric renal insufficiency, mild arteriosclerosis, and focal global glomerulosclerosis, compatible with the age of the patient.

Clinical Course After the biopsy results came in, maintenance immunosuppressive therapy was continued. Therapy consisted of attempting to wash out the obstructing red blood cells with loop diuretics and fluids. After 4 days, gross hematuria was no longer apparent, and renal function gradually recovered to baseline over a period of 10 weeks. At present, approximately 6 months later, the patient has stable renal function. Microscopic hematuria and mild proteinuria are still present.

Fig 2. Considerable amounts of erythrocytes are present in tubules in allograft biopsy taken 8 months after renal transplantation. (Hematoxylin and eosin, original magnification ⴛ400.)


Fig 3. Immunofluorescence micrograph showing deposits of IgA in an irregular granular pattern predominantly in the mesangium. (Original magnification ⴛ400.)


Renal allograft dysfunction may be caused by acute rejection, chronic rejection, cyclosporine (CyA) or tacrolimus toxicity, and other causes such as recurrent renal disease. To establish the correct diagnosis, a renal biopsy is still the ‘‘gold standard.’’ However, an allograft biopsy is not routinely considered by all centers at the onset of renal dysfunction. The initial response to graft dysfunction is then empirical steroid therapy or CyA dose reduction.2 Nevertheless, in a recent study by Al-Awwa et al,2 prediction of the diagnosis in cases of renal allograft dysfunction was shown to be poor when based only on clinical data. These authors concluded that the renal biopsy is essential for establishing the correct diagnosis of renal allograft dysfunction and the appropriate management thereof.2 Moreover, there is current agreement that in the design of prospective clinical trials in renal transplantation, patients should be assigned to various treatment groups based on histological diagnosis of allograft rejection.3 A similar notion was recently put forward with regard to acute renal failure in native kidneys, in which early renal biopsy is often mandatory and may be the only key to diagnosis.4 This case illustrates the value of the renal biopsy in cases of late acute renal allograft dysfunction. Moreover, this case shows the necessity of complete workup of the biopsy when the clinical situation is not typical of rejection or CyA toxicity. In this case, the presence of hematuria with red cell casts in the urinary sediment


pointed to the possibility of glomerulonephritis. The serological tests were all unrevealing. A renal biopsy, obtained before the results of these tests became available, showed mild mesangial hypercellularity and matrix expansion. None of the 13 glomeruli showed extracapillary proliferation. The tubules were filled with red blood cells, but no conspicuous abnormalities were apparent in the interstitium. Tubulointerstitial nephritis was not present. Immunofluorescence studies showed mesangial deposition of IgA and C3 but not of IgG, IgM, or C1q. These findings established the diagnosis of IgA nephropathy. A biopsy specimen obtained 2 months after transplantation showed no deposits. In the absence of any clinical manifestations of systemic lupus erythematosus, alcohol-induced liver disease, celiac disease, ankylosing spondylitis, or any other disorder known to be associated with glomerular IgA deposits, the diagnosis was specified as (recurrent) primary IgA nephropathy. Primary IgA nephropathy, the most common form of glomerulonephritis worldwide, is well known to recur in normal kidneys transplanted into IgA nephropathy recipients.5 However, the current case manifested some unusual aspects of IgA nephropathy that deserve further consideration. Recurrence of IgA nephropathy after renal transplantation may develop in most, if not all, patients, when the time of follow-up is long enough.6 Proteinuria with or without microscopic hematuria appears to be the most common initial manifestation of recurrent IgA nephropathy.7,8 Initially, in analogy to native IgA nephropathy, recurrence has been described as a mild disease, but more recently a less favorable course has been suggested.8-10 In clinical practice, the finding of recurrent IgA nephropathy must be interpreted with the caveat in mind that mechanisms related to chronic alloreactive damage may have amplified recurrence-related graft damage in an additive or even synergistic manner.11 Isolated cases with a rapidly progressive course and crescent formation have been described, but gross hematuria is rare. In general, the presentation of IgA nephropathy with gross hematuria, oliguria, and an acute reduction in glomerular filtration rate is associated with crescent formation on renal biopsy in 79% to 100% of patients.12 Frequently, however, even in this setting the number of glomeruli with crescents is insuffi-


cient to account for the severity of the renal failure. When renal failure occurs, therefore, it is generally attributed to acute tubular damage and obstruction secondary to glomerular bleeding.13 In accordance with this notion, in the current case we found no glomerular proliferative lesions, significant interstitial pathological condition, or even histological signs of CyA toxicity that might explain the acute renal insufficiency. Therefore, the histological picture could not account for the considerable and acute renal insufficiency that accompanied the gross hematuria in this patient. In tubules, considerable amounts of erythrocytes were present. Taken together, these observations suggest that the use of anticoagulant therapy may have led to aggravation of the erythrocyturia, resulting in sludging of the erythrocytes, obstruction of tubules, and acute renal failure. To the best of our knowledge, this is the first case to be reported with recurrent primary IgA nephropathy and reversible acute renal failure caused by glomerular bleeding. On a more general note, these findings may explain the fact that gross hematuria is frequently not associated with a less favorable prognosis. CONCLUSIONS

This case illustrates the importance of biopsy in cases of renal allograft insufficiency. In this patient, biopsy findings led to the diagnosis of IgA nephropathy with sludging of erythrocytes in tubules as the most probable cause of acute non-oliguric renal insufficiency, and to the exclusion of other possible causes of renal insufficiency. Supporting our diagnosis, renal function recovered without treatment other than hydration and forced diuresis. This case history supports the notion that patients with renal allograft failure should not be treated empirically with steroid therapy or cyclosporin A dose reduction. Immunofluorescence investigation should be performed on renal transplant biopsy specimens when the clinical situation suggests it is not merely a case of ruling rejection in or out. REFERENCES 1. Mihatsch MJ, Antonovych T, Bohman S-O, Habib R, Helmchen U, Noel LH, Olsen S, Sibley RK, Kemeny E, Feutren G: Cyclosporin A nephropathy: Standardization of the evaluation of kidney biopsies. Clin Nephrol 41:23-32, 1994 2. Al-Awwa IA, Hariharan S, First MR: Importance of


allograft biopsy in renal transplant recipients: Correlation between clinical and histological diagnosis. Am J Kidney Dis 31:S15-S18, 1998 3. Gaber LW: Role of renal allograft biopsy in multicenter clinical trials in transplantation. Am J Kidney Dis 31:S19S25, 1998 4. Quaschning T, Baudenbacher H, Gassel AM, Wanner C: The patient with asymptomatic acute renal failure renal biopsy gives the diagnosis. Nephrol Dial Transplant 13:21472148, 1998 5. Berger J, Noel LH, Nabarra B: Recurrence of mesangial IgA nephropathy after renal transplantation. Contrib Nephrol 40:195-197, 1984 6. Van der Boog PJM, de Fijter JW, Bruijn JA, van Es LA: Recurrence of IgA nephropathy after renal transplantation. Ann Intern Med (in press) 7. Bachman U, Biava C, Amend W, Feduska N, Melzer J, Salvatierra O, Vincenti F: The clinical course of IgA nephropathy and Henoch-Schonlein purpura following renal transplantation. Transplantation 42:511-515, 1986 8. Park SB, Joo I, Suk J, Cho WH, Park CH, Kim SP,


Park KK, Kim HC: IgA nephropathy in renal transplant recipients: Is it a significant cause of allograft failure? Transplant Proc 28:1540-1542, 1996 9. Ohmacht C, Kliem V, Burg M, Nashan B, Schlitt HJ, Brunkhorst R, Koch KM, Floege J: Recurrent immunoglobulin A nephropathy after renal transplantation: A significant contributor to graft loss. Transplantation 64:1493-1496, 1997 10. Bumgardner GL, Amend WC, Ascher NL, Vincent FG: Single-center long-term results of renal transplantation for IgA nephropathy. Transplantation 65:1053-1060, 1998 11. Floege J, Burg M, Kliem V: Recurrent IgA nephropathy after kidney transplantation: Not a benign condition. Nephrol Dial Transplant 13:1933-1935, 1998 12. Bennett WM, Kincaid-Smith P: Macroscopic hematuria in mesangial IgA nephropathy: Correlation with glomerular crescents and renal dysfunction. Kidney Int 23:393-400, 1983 13. Praga M, Gutierrez-Millet V, Navas JJ, Ruilope LM, Morales JM, Alcazar JM, Bello I, Rodicio JL: Acute worsening of renal function during episodes of macroscopic hematuria in IgA nephropathy. Kidney Int 28:69-74, 1985