Successful treatment of recurrence of immunotactoid glomerulopathy in a kidney allograft recipient
Xavier Carles1,
Lionel Rostaing1,,
Anne Modesto2,
Claudine Orfila3,
Jean-Marc Cisterne1,
Marie-Bernadette Delisle3 and
Dominique Durand1
1 Department of Nephrology/Hypertension/Haemodialysis/Transplantation,
2 Department of Immunology and
3 Department of Pathology, CHU Rangueil, Toulouse, France
Keywords: cyclophosphamide; cyclosporin A; fibrillary glomerulonephritis; immunotactoid glomerulopathy; monoclonal gammopathy; renal transplantation
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Introduction
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Glomerulopathy characterized by deposits of fibrillary material was first reported in 1977 [1]. Fibrillary immunotactoid glomerulopathy is a clinicopathological entity characterized by extracellular deposition of non-branching microfibrils or microtubules (Congo-red and thioflavin T negative) within the mesangium and capillary walls of renal glomeruli. It is clinically characterized by the presence of glomerular proteinuria (often in the nephrotic range), microscopic haematuria, and often hypertension. It can lead to chronic renal failure. Based on the size and the arrangement of the microfibrils or microtubules in intraglomerular deposit, fibrillary immunotactoid glomerulopathies have been divided into two distinct entities: fibrillary glomerulopathy (FG) is characterized by small, randomly organized fibrils (
30 nm in diameter), whereas immunotactoid glomerulopathy (ITG) is typified by larger fibrils and often organized in parallel arrays (
30 nm in diameter) [2,3]. Patients with FG are less likely than those with ITG to have associated haematopoietic disease, i.e. monoclonal gammopathies; they also have poorer renal survival [2]. The two above-mentioned entities are primarily renal in most cases. Despite the fact that there is limited information about kidney transplantation in the context of end-stage renal failure related to fibrillar immunotactoid glomerulopathies, the few reports available indicated that fibril deposition recurred in more than 50% of patients, although the allograft functioned satisfactorily for a few years [46]. We report the case of a patient with ITG who had an early recurrence of this disease after renal transplantation but who responded favourably to an increase in immunosuppressive therapy.
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Case
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A 30-year-old woman was first seen in our department in August 1988 for nephrotic syndrome, hypertension, microscopic haematuria, cutaneous vasculitis, and IgA lambda monoclonal gammopathy. The case study work-up led to the diagnosis of immunotactoid glomerulopathy. This observation has already been reported [7]. The patient progressively developed chronic renal failure, leading to chronic haemodialysis in February 1992. In February 1996 she received a well-matched (1A1B2DR) cadaveric kidney transplant. Immunosuppression was quadruple and sequential, including (i) prednisone 1 mg/kg/day tapered to 10 mg/day 90 days post-transplantation; (ii) azathioprine 2 mg/kg/day; (iii) thymoglobulins (Mérieux, France) 75 mg/day for 7 days; and (iv) cyclosporin A (CsA) 4 mg/kg/day, introduced at day 6 post-transplantation and aiming at trough levels of around 150 ng/ml. The post-transplant course was uneventful; the serum creatinine at discharge was 1.52 mg/dl.
In December 1996 the patient became pregnant: at that time the serum creatinine was 1.2 mg/dl (creatinine clearance at 104 ml/min), proteinuria was negative, and blood pressure was spontaneously normal. During pregnancy proteinuria appeared in March 1997 onwards and was mild at around 12 g/day. Blood pressure and serum creatinine were normal until the beginning of July 1997. Thereafter, hypertension developed and was treated with labetalol; serum creatinine increased progressively. The pregnancy was terminated by caesarean section in August 1997 at 33 weeks of amenorrhoea, because of pre-eclampsia (serum creatinine at 3.85 mg/dl, nephrotic syndrome, and uncontrolled hypertension). During the days following delivery the serum creatinine stabilized at around 3.3 mg/dl, and hypertension was better controlled with isradipine and labetalol. Serum complement (CH50, C3, C4) was normal; HCV and CMV serological tests as well as ANA and ANCA were negative. There was a mild anaemia (Hb at 8.9 g/dl), schistocytes were negative, platelets were at 291 000/mm3, and liver enzymes as well as LDH were within the normal ranges. The CsA whole-blood trough level was at 105 ng/ml.
Four weeks later since renal failure persisted (serum creatinine at 3.2 mg/dl), a transplant biopsy was performed (see Figure 1
): the specimen disclosed 17 glomeruli. There was diffuse mesangial hypertrophy, associated with hypercellularity and thickening of the glomerular basement membranes. In five (30%) of the glomeruli there was segmental or extensive extracapillary proliferation. Most of the glomeruli showed large intracapillary hyaline deposits, which stained positive for periodic acidSchiff staining. In the interstitium, a mild fibrosis was present without evidence of acute rejection. Congo-red staining was negative and there was no abnormal birefringence. Using immunofluorescence, endomembranous deposits stained with anti-IgG and anti-C3 sera were observed. Using electron microscopy, we found the same findings as in native kidneys, i.e. organized deposits of fibrillar structures (see Figure 2
).

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Fig. 1. First post-transplant renal biopsy. Magnification of one glomerulus showing mesangial proliferation and huge thickening of capillary walls by interposition of hyaline material. Masson's trichrome (x300).
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Fig. 2. Electron micrograph of the first post-transplant renal biopsy showing foot process fusion and narrowing of the glomerular capillary lumen due to subendothelial and mesangial deposits of numerous fibrils (x21 600).
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Because of the severity of the recurrence of the initial disease, the patient was treated with six plasma exchanges, three methylprednisolone pulses of 10 mg/kg each followed by prednisolone at 1 mg/kg/day; azathioprine was withdrawn and replaced by monthly cyclophosphamide pulses (1 g each). CsA was continued although at a lower dosage (2 mg/kg/day). One month after the beginning of this therapeutic scheme, the serum creatinine was 0.9 mg/dl but nephrotic-range proteinuria persisted. In February 1998, after 6 months of intensive therapy, the serum creatinine was 1.3 mg/dl, proteinuria was mild (2 g/day), and the blood pressure was normal with isradipine. A new transplant biopsy disclosed 14 glomeruli, of which two were obsolescent. There were neither intraglomerular deposits nor crescents. All glomeruli showed an increase in mesangial matrix. Interstitial fibrosis was mild, as on the previous biopsy. Immunofluorescence results of the biopsy were unchanged from the previous one. Cyclophosphamide was stopped and replaced by mycophenolate mofetil 2 g/day, and prednisolone (0.5 mg/kg/day at that time) was progressively decreased. By November 1999 the serum creatinine was normal (1.1 mg/dl) and proteinuria was very mild (0.2 g/day).
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Discussion
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The morphological features of immunotactoid glomerulopathies were initially reported in 1980 by Schwartz and Lewis [8], for Congo-red negative extracellular organized microtubular deposits with an average diameter of 3250 nm. Although this disease is rare, to date some cases have been reported in the literature [2]. Little is know about the response to therapy in patients with immunotactoid glomerulopathies. It appears that steroids alone, steroids with plasma exchanges, and steroids with cyclophosphamide do not generally alter the clinical course of the disease [9]. However, at least two reports described partial remission with long-term alternate-day prednisone [10] or low-dose prednisolone [11].
In contrast to ESRD patients with amyloidosis (primary or AL amyloid), where patient survival is notoriously poor, ESRD patients with FG/ immunotactoid glomerulopathies have to be considered for renal transplantation, even if the number of published cases is very small. To the best of our knowledge, 10 cases (11 with ours) have been reported to date [46]. In half of them immunosuppression was based on CsA, whereas in the others it relied on azathioprine plus steroids. The rate of recurrence is at least 64%; two patients had no renal allograft biopsies, and finally two patients had no recurrence as evidenced by transplant biopsy. However, despite this high rate of relapse, Pronovost et al. [6] showed that the rate of deterioration of renal function was invariably slower in allografts than in native kidneys (mean slope 1/creatinine vs time: allografts 0.036±0.01; native kidneys 0.301±0.18). This might be related to chronic immunosuppressive therapy. Nevertheless, in the literature there is only one report of treatment of a recurrence of immunotactoid glomerulopathy. This occurred 18 months post-transplantation [4]: since that patient presented at the same time with evidence of acute rejection, he received methylprednisolone pulses, without success. Our patient's case is striking in the way that: (i) the relapse occurred early after transplantation; (ii) the patient experienced subacute renal failure with crescents at the renal biopsy; and (iii) the outcome was favourable after increasing immunosuppression.
Meanwhile, it is noteworthy that the recurrence of the disease took place during the patient's pregnancy. De novo immunotactoid glomerulopathy of the kidney allograft has been reported and was possibly related to cytomegalovirus infection [12]. As with the initial episode of the disease 9 years before in the native kidneys, our patient responded very well to plasma exchanges, methylprednisolone, and cyclophosphamide pulses. As she had IgA monoclonal gammopathy, after the end of cyclophosphamide pulses we added mycophenolate mofetil, a new immunosuppressive drug known to decrease the synthesis of antibodies by B lymphocytes [13] and also to be efficient in some primary glomerular diseases [14]. However, the follow-up of this patient is too short to draw firm conclusions from our observations, although they show that the recurrence of immunotactoid glomerulopathy on kidney allografts can be successfully managed by increasing and adapting immunosuppression. Finally, the results of a long-term follow-up are obviously needed to draw more definitive conclusions.
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Acknowledgments
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The authors thank Miss Danièle Mencia for secretarial assistance.
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Notes
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Correspondence and offprint requests to: Prof. Lionel Rostaing, UTO, CHU Rangueil, 1 Avenue Jean Poulhès, F-31403 Toulouse Cédex 4, France. 
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References
|
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-
Rosenmann E, Eliakim M. nephrotic syndrome associated with amyloid-like glomerular deposits. Nephron1977; 18: 301308[ISI][Medline]
-
Fogo A, Qureshi N, Horn RG. Morphologic and clinical features of fibrillary glomerulonephritis versus immunotactoid glomerulopathy. Am J Kidney Dis1993; 22: 367377[ISI][Medline]
-
Alpers CE. Glomerulopathies of dysproteinemias, abnormal immunoglobulin deposition, and lymphoproliferative disorders. Curr Opin Nephrol Hypertens1994; 3: 349355[Medline]
-
Cadnapaphornchai P, Sillix D. Recurrence of monoclonal gammopathy-related glomerulonephritis in renal allograft. Clin Nephrol 1989; 31: 156159[ISI][Medline]
-
Korbet MS, Rosenberg BF, Schwartz MM, Lewis EJ. Course of renal transplantation in immunotactoid glomerulopathy. Am J Med 1990; 89: 9195[ISI][Medline]
-
Pronovost PH, Brady HR, Gunning ME, Espinoza O, Rennke HG. Clinical features, predictors of disease progression and results of renal transplantation in fibrillary/immunotactoid glomerulopathy. Nephrol Dial Transplant1996; 11: 837842[Abstract]
-
Orfila C, Meeus F, Bernadet P, Lepert JC, Suc JM. Immunotactoid glomerulopathy and cutaneous vasculitis. Am J Nephrol 1991; 11: 6772[ISI][Medline]
-
Schwartz MM, Lewis EJ. The quarterly case: Nephrotic syndrome in a middle aged woman. Ultrastruct Pathol1980; 1: 5782
-
Korbet SM, Schwartz MM, Lewis EJ. Immunotactoid glomerulopathy. Am J Kidney Dis1991; 17: 247257[ISI][Medline]
-
Rosenmann E, Brisson ML, Bercovitch DD et al. Atypical membranous glomerulonephritis with fibrillar sub-epithelial deposits in a patient with malignant lymphoma. Nephron1988; 48: 226230[ISI][Medline]
-
Minami J, Ishimitsu T, Inenaga T et al. Immunotactoid glomerulopathy: report of a case. Am J Kidney Dis1997; 30: 160163[ISI][Medline]
-
Rao KV, Hafner GP, Crary GS, Anderson WR, Crosson JT. De novo immunotactoid glomerulopathy of the renal allograft: possible association with cytomegalovirus infection. Am J Kidney Dis1994; 24: 97103[ISI][Medline]
-
Grailer A, Nichols J, Hullett D, Sollinger HW, Burlingham WJ. Inhibition of human B cell responses in vitro by RS-61443, cyclosporine A and DAB 486 IL2. Transplant Proc1991; 23: 314315[ISI][Medline]
-
Briggs WA, Choi MJ, Scheel PJ Jr. Successful mycophenolate mofetil treatment of glomerular disease. Am J Kidney Dis1998; 31: 213217[ISI][Medline]
Received for publication: 28. 8.99
Revision received 18. 1.00.