P-ANCA Positive Renal Vasculitis in Association with Renal Cell Carcinoma and Prolonged Hydralazine Therapy

Abstract

Renal cell carcinoma and hydralazine drug therapy has each been reported as rare associations with pauci-immune renal vasculitis. We report a patient in whom both factors were operative simultaneously. A middle-aged man on long term hydralazine therapy presented with advanced renal failure. Serum was strongly positive for P-ANCA with high anti-myeloperoxidase (MPO) titre and renal biopsy showed focal necrotizing glomerulonephritis. A renal mass was identified on scanning and at left nephrectomy a large renal cell carcinoma was removed. In spite of an apparently curative operation and discontinuation of hydralazine, P-ANCA remains strongly positive, he has had no recovery of renal function and has progressed to dialysis dependence.

• P-ANCA vasculitis
• Renal cell carcinoma

Case Report

A 61-year-old man was referred by his General Practitioner to the Medical Admissions Unit in July 2000. He had recently suffered Campylobacter gastroenteritis in the community and was experiencing intense fatigue and dizziness although the diarrhea had settled. He reported weight loss of 1.5 stones over the previous eight months. The past medical history included longstanding hypertension for which he was taking indapamide and hydralazine 50 mg twice daily. He was diagnosed with superficial transitional cell carcinoma of bladder (G1pTa) in 1994 and had undergone trans-urethral resection. A superficial recurrence in 1998 had been treated with intravesical mitomycin C. The bladder was clear at routine surveillance in 1999. At that time serum creatinine was 172 μmol/L.

On presentation he was a slim but not cachectic man. Blood pressure was 126/71 without postural drop, pulse was 82/min and skin turgor appeared normal. The abdomen was soft and non-tender without organomegaly. There were no other specific features on examination.

Laboratory investigation revealed abnormal renal function (serum creatinine 651 μmol/L, urea 39 mmol/L), raised liver enzymes (alkaline phosphatase 542 IU/L, alanine aminotransferase 41 IU/L, total bilirubin 12 μmol/L, γ-glutamyltransferase 95 IU/L) and raised serum amylase (421 IU/L). He was anemic with hemoglobin 10.1 g/dL. Urine dipstick showed protein++, blood+, the MSU produced an intermediate growth of β hemolytic streptococcus Group B. An abdominal USS showed an 8 × 8 cm solid mass arising from the upper pole of the left kidney: the liver and right kidney were normal. An abdominal MRI was performed which suggested a well-demarcated tumour without involvement of the IVC nor evidence of renal vein thrombosis. The pancreas was normal. Immunological studies demonstrated a polyclonal increase in immunoglobulins, CRP was 30 mg/L, antinuclear antibody was positive at 1/80, and complement levels were normal. Anti-nuclear cytoplasmic antibody (ANCA) was strongly positive with a peri-nuclear pattern, and anti-MPO antibody was present at a titre of >100 U/mL. There was no reactivity to proteinase 3. Percutaneous renal biopsy was undertaken on the right kidney. On light microscopy a focal proliferative glomerulonephritis with associated focal segmental necrosis was seen. Complete glomerular sclerosis was apparent in 15% and there was accompanying interstitial fibrosis and patchy chronic inflammation. The vessels did not show arteritic change. Staining for complement and immunoglobulins on immunofluorescence was negative. He did not receive immunosuppression. Renal function slowly improved over the next five weeks, serum creatinine reaching 400 μmol/L. The liver enzymes and amylase also normalized. In September 2000 he underwent left radical nephrectomy: there was no evidence of local nor metastatic spread. Histology confirmed a clear cell carcinoma. Post-operatively he required five hemodialysis sessions but was discharged dialysis independent. He then attended the pre-dialysis clinic for 12 months prior to starting on the regular hemodialysis program in September 2001. He has remained well with no evidence of tumour recurrence. The P-ANCA has remained strongly positive at a titre of 1/640 at September 2001 and January 2002. Hydralazine was discontinued in November 2001. There has not been evidence of any renal recovery.

Discussion

This gentleman presented with a pauci-immune renal localized vasculitis with high titre anti-MPO antibody. It is interesting that this occurred in the setting of two processes that have each been implicated in the pathogenesis, namely renal cell carcinoma[[1]], [[2]], [[3]], [[4]] and hydralazine therapy.[[5]], [[6]], [[7]] We chose not to immunosuppress him in view of the advanced renal failure, the renal localized nature of the vasculitis, and the malignant associated condition. In spite of this he had a useful year without need for renal replacement therapy, and he remains well without evidence of tumor recurrence or systemic vasculitic features.

Renal cell carcinoma has been associated with various renal lesions including amyloidosis, membranous glomerulopathy,[[8]], [[9]] and mesangiocapillary glomerulonephritis.[[10]] Crescentic glomerulonephritis has been reported in association with multisystemic Wegeners Granulomatosis[[1]] or as renal localized disease,[[2]], [[3]], [[4]] with both C-ANCA and P-ANCA reactivities. It has not been clear from the literature whether the association has occurred by chance or whether this represents a para-neoplastic phenomenon. Putative mechanisms for the association have included immune complex deposition involving tumour-related or tubular antigens, and cytokine induced damage associated with tumour secretion. In one case resection of the renal tumour led to resolution of many features of Wegeners granulomatosis though the patient remained dialysis dependent.[[1]] In a further patient tumour removal led to reduced anti-MPO titre and amelioration of proteinuria.[[4]]

Our patient has had prolonged exposure to hydralazine. An association with a lupus-type syndrome has been long recognized, but it has only more recently been appreciated that the drug can cause a picture more typical of vasculitis,[[5]], [[6]], [[7]] which can be either multi-systemic or renal localized, as in this case. In many of the reported cases there has been strong P-ANCA activity with high anti-MPO titres. Discontinuation of the drug sometimes, but not always, leads to improvement in renal function and reduction in anti-MPO titre.

It is perhaps unfortunate that the continuation of hydralazine was overlooked in the clinic, but this has allowed the renal cell cancer and the drug to be individually assessed with regard to the clinical and immunological picture. The P-ANCA remained strongly positive 12 months following an apparently curative resection of the tumour. In addition the pattern has not altered three months after the discontinuation of hydralazine and there has been no resolution of nephropathy in that he remains dialysis dependent. What pathogenic process is continuing to stimulate ongoing production of anti-MPO antibodies remains uncertain and there must be some caution in presuming surgical cure and removal of all tumour tissue.

This case has highlighted an interesting and novel aggregation, in one patient, of two rare associations, P-ANCA reactive vasculitis in combination with, respectively, renal cell carcinoma and hydralazine therapy.