EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Antineutrophil cytoplasm antibody-associated systemic vasculitis is a rare disease that frequently leads to end-stage renal disease. Kidney transplant should be delayed until patients are in complete clinical remission for at least 6 months, but the persistence of antineutrophil cytoplasmic antibody titers should not delay transplant. Recurrence of disease after kidney transplant is rare, with only a few cases described in the literature with heterogenous clinical manifestations, therapeutic approaches, and prognosis. We describe the case of a young male patient with recurrent antineutrophil cytoplasmic antibody vasculitis, 5 years after kidney transplant, successfully treated with methylprednisolone pulses plus rituximab. Rituximab presents a new valid option for the treatment of antineutrophil cytoplasmic antibody vasculitis relapse in kidney grafts.

Key words : End-stage renal disease, Glomerulonephritis, Methylprednisolone, Relapse in kidney grafts, Renal vasculitis

Thirty to fifty percent of kidney transplant recipients have glomerular diseases as the underlying cause of end-stage renal disease.¹ After kidney transplant, recurrence of glomerular disease has been identified as an important contributor to allograft failure, but the rate of recurrence varies according to the primary entity.²

Glomerulonephritis secondary to renal vasculitis results in end-stage renal disease in 20% to 40% of patients with antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis.³ Renal transplant is a viable option in these patients but should be delayed for at least 6 months from initial presentation or most recent recurrence. The presence of a positive ANCA titer at transplant does not appear to predict recurrence, and allograft survival is similar to the general transplant population.⁴ In a small case series, ANCA vasculitis recurrence was infrequent and rarely associated with graft loss, but there are very few reports in literature and the appropriate management is not well established.⁵ We report a case of recurrent ANCA vasculitis on the kidney graft, successfully treated with rituximab.

Written informed consent was obtained from the patient for publication of this case report and the accompanying images. Procedures were in accordance with the regulations of the clinical research ethics committee and with those of the Code of Ethics of the World Medical Association (Declaration of Helsinki as revised in 2013).

A 40-year-old White male patient was diagnosed in 2015 with ANCA-myeloperoxidase (MPO)-associated vasculitis, with severe acute kidney injury and pulmonary hemorrhage, and treated with plasmapheresis, cyclophosphamide, and steroids. Renal disease remission did not occur, and he progressed to hemodialysis-dependent end-stage renal disease.

In May 2017, he received a deceased donor renal transplant from a 50-year-old donor with a total of 3 HLA mismatches (1 A, 1 B, and 1 DR) and a panel-reactive antibody test result of 4%. Induction immunosuppression with basiliximab was performed, and the maintenance immunosuppression consisted of prednisolone, tacrolimus, and mycophenolate mofetil. The immediate posttransplant period was complicated with allograft vein thrombosis, which was surgically treated, and his serum creatinine at discharge was 1.1 mg/dL, with normal urinalysis results and serum ANCA titer of 24 UI/mL (reference range, <10 UI/mL).

Five years after kidney transplant, he presented with de novo proteinuria of 3000 mg per 24 hours, despite blockade of the renin-angiotensin-aldosterone axis, active urinary sediment, and increasing titers of ANCA anti-MPO antibody (from 24 to 95 UI/mL in February 2022). Allograft function and serum albumin were maintained within the reference range (serum creatinine of 1.06 mg/dL), and donor-specific antibodies were negative as well as polyoma virus viremia. Physical examination was normal. Renal graft biopsy revealed a proliferative glomerulonephritis, with crescents in 20% of the glomeruli, interstitial fibrosis and tubular atrophy in 20% of the cortical area, and no significant inflammation, all of which are suggestive of a cellular or humoral rejection (Figure 1, Figure 2). Immunofluorescence was negative, including C4d or SV40 markers. The diagnosis of a relapsing necrotizing extracapillary proliferative ANCA-associated glomerulonephritis was established, and the patient started treatment with intravenous methylprednisolone (500 mg) for 3 consecutive days and rituximab (1 g) in 2 doses, 2 months apart. Infection prophylaxis with cotrimoxazole-trimethoprim and valganciclovir was maintained for 6 months.

During the first 6 months of follow-up, there was a progressive decrease of ANCA anti-MPO antibody levels (from 95 to 32 UI/mL) and proteinuria improvement (from 3 to 1 g/24 h), maintenance of a lower quantity of red blood cells in urinalysis, and normal graft function. At 1 year of follow-up, he presented with complete remission, with 24-hour proteinuria level at <500 mg/24 h, <10 red blood cells per field in urinalysis, and normal kidney function, with stable ANCA-MPO titers of 30 to 35 UI/mL. No infections or other side effects of rituximab and steroids were observed, and he has continued on immunosuppression with mycophenolate, tacrolimus, and low-dose prednisone.

Patients with systemic vasculitis are suitable candidates for kidney transplant and recurrence is unlikely, due to ongoing immunosuppression. A pooled analysis of multiple studies, from 1993 to 2018, found a relapse rate of 5.4%, which is significantly lower than native kidney relapses.⁶ The relapse rate in recent years, with the newer and more effective immunosuppression agents, is even lower, and graft survival is comparable to patients with other causes of end-stage renal disease.⁶

Given the scarcity of recurrent ANCA vasculitis in the kidney graft, there are so far no identified risk factors. In a multicentric cohort study that included 85 kidney transplant recipients with end-stage renal disease due to ANCA vasculitis, relapse was reported in 7 patients (relapse rate 0.02 patients/year). All flares occurred in the presence of circulating ANCA. There was a slight increased likelihood of relapse in patients with positive ANCA before kidney transplant, but there was no other factor associated with relapse, such as ANCA subtype, disease category, or time of remission before transplant.⁷

The new Kidney Disease: Improving Global Outcomes 2021 guidelines recommend that kidney transplant should be delayed until patients are in complete remission for 6 months, despite the persistence of ANCA antibodies. This recom-mendation differs from the 2012 guidelines that suggested a longer period of remission (1 year).⁴

The decision on the timing to kidney transplant is not only dependent on the risk of primary disease recurrence. Patients with end-stage renal disease secondary to ANCA-associated vasculitis frequently present with an aggressive disease and are submitted to high doses of immunosuppression, conferring frailty and fragility.⁸ A recent cohort that evaluated the causes of graft failure in kidney transplant recipients who developed end-stage renal disease due to ANCA vasculitis concluded that 65% of graft losses were secondary to death with functioning graft, and the most important causes of death were infection and malignancy.⁵

In our case reported case, the patient had disease remission of more than 1 year but had circulating ANCA titers at kidney transplant. We maintained ANCA screening annually, and the relapse was accompanied by a progressive increase in the serum titers. In most of the reported cases, the increase of ANCA titers was a sensitive marker of disease relapse.^5,6,9 Despite the histological evidence of crescentic glomerulonephritis, the clinical manifes-tations shown in our patient were relatively benign compared with the presentation in the native kidney and occurred later after kidney transplant. A recent study of a cohort of 59 patients who received kidney transplant to treat ANCA vasculitis compared patients with early relapse (n = 3) and late relapse (n = 3). Early recurrences occurred in the first 2 weeks after kidney transplant and presented as primary nonfunction and extrarenal manifestations, and all patients progressed toward end-stage renal disease. Late recurrence (65-67 months after kidney transplant) was clinically milder, with abnormal urinalysis results and a progressive increase in serum creatinine. The diagnosis was delayed in all patients, and, despite clinically less severe symptoms, all patients progressed to end-stage renal disease. Of note, patients with early relapses had higher ANCA titers before kidney transplant.⁹ We believe that the assessment of ANCA titers and urinalysis was essential to the decision to proceed with biopsy, which facilitated a prompt treatment.

The treatment of ANCA relapse in kidney transplant is not defined, and most authors base their approach on the recommendations for native kidneys. The most common treatment described in the literature is a combination of cyclophosphamide and methylprednisolone pulses, with or without plasma exchange.^9-11 More recently, rituximab treatment is gaining strength as first-line therapy in patients with ANCA-associated vasculitis in the native kidney.^4,10-13 Consequently, rituximab is also a valid option for the treatment of ANCA relapse in kidney graft, but very few cases are described in the literature (Table 1).^9,10,13,14

In our center in the last 10 years, this is the first case of ANCA vasculitis relapse among the 27 kidney transplant recipients with end-stage renal disease due to ANCA. Our patient was successfully treated with rituximab and methylprednisolone pulses, with complete laboratorial response and without infectious or neoplastic complications at 1 year of follow-up. The early diagnosis was of utmost importance, since there was an important dissociation between histological and clinical severity.

Volume: 21 Issue: 2 February 2023

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