Cyclosporine-Induced Renal Macroangiopathy

Cyclosporine-Induced Renal Macroangiopathy Boutros Sawaya, MD, Robert Provenzano, MD, Warren L. Kupin, MD, and K. K. Venkat, MD • Although nephrotoxicity secondary to cyclosporine (CsA) is common and has a predilection for arterioles, stenosis of the major renal artery or its primary branches has not yet been described as a manifestation of CsA toxicity. A case of a primary cadaveric renal transplant recipient treated with CsA who developed significant deterioration of renal function associated with angiographic evidence of high-grade stenosis of all three major branches of the renal artery that resolved completely after discontinuation of the drug is reported. © 1988 by the National Kidney Foundation, Inc. INDEX WORDS: Cyclosporine nephrotoxicity; renal artery stenosis; renal transplant.

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N RENAL TRANSPLANT recipients cyclosporine (CsA) administration has been associated with a variety of changes in the renal vasculature. These vascular effects of CsA can be divided into three categories L2 : (1) a reversible dose-dependent arteriolar vasoconstriction associated with decreased renal blood flow; (2) an arteriolopathy characterized by luminal narrowing as a result of proteinaceous deposits within the intimal layer; and (3) the development of arteriolar and capillary thrombi, probably caused by increased platelet aggregation secondary to CsAinduced inhibition of endothelial prostacyclin synthetase. These vascular changes have not been reported with the long-term use of azathioprine (AZA) for maintenance immunosuppression. Amelioration of the first two vascular complications may occur with reduction or discontinuation of CsA, whereas successful treatment of the third vascular lesion has been reported only with intraarterial infusion of streptokinase. 3 We report a case of CsA-induced macrovascular stenosis involving all three primary branches of the allograft renal artery in a cadaveric renal transplant recipient. Complete resolution of these vascular changes occurred after discontinuation of CsA. CASE REPORT A 31-year-old white woman with end-stage renal disease secondary to chronic glomerulonephritis received a primary cadaveric renal transplant in November 1986. Initial immunosup-

From the Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit. Address reprint requests to Boutros Sawaya, MD, Division of Nephrology and Hypertension, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202. © 1988 by the National Kidney Foundation, Inc. 0272-6386/8811206-0011$3.00/0

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pression consisted of prophylactic Minnesota antilymphoblast globulin followed by maintenance therapy with CsA, AZA, and methylprednisolone (MP). A technetium-DTPA renogram performed eight days after transplantation while the patient was in an initial period of acute tubular necrosis (ATN) showed inadequate blood flow to the allograft. This was followed by a renal angiogram that demonstrated the patency of the main renal artery and its segmental branches without evidence of rejection (Fig I). The diminished blood flow initially demonstrated by the renogram was felt, in retrospect, to be caused by an insufficient bolus of technetium. During the third postoperative week a corticosteroid-resistant rejection episode developed that was successfully treated with 14 daily doses of OKT 3 monoclonal antibody. One week after completion of OKT 3 therapy the patient developed cytomegalovirus infection complicated by Legionella pneumonia. Erythromycin was started and all immunosupressive drugs were withdrawn except for a maintenance dose of 10 mg/d MP. Following the completion of 4 weeks of antibiotic therapy, the intravenous (IV) erythromycin was stopped and cyclosporine was restarted. The serum creatinine concentration progressively increased from a baseline value of 1.4 mg/dL (124 }Lmoll L) to 1.8 mg/dL (159 }LmoIlL) during the 2-week period following reinstitution of CsA (Fig 2). There was no significant change in the platelet count (range, 170 to 348,000) during this time. Isotopic studies of the transplanted kidney revealed a significant reduction in renal blood flow (Fig 3A) and the diagnosis of a recurrent rejection episode was considered. Despite three doses of IV MP (250 mg/d) and addition of AZA (1 mg/kg/d), renal function continued to deteriorate with a peak serum creatinine of 4.8 mg/dL (424 }LmoIlL) 4 weeks after restarting CsA. Plasma trough CsA levels were between 25 and 110 ng/mL (measured by radioimmunoassay) during the 4-week period of CsA therapy. The BP became increasingly difficult to control, requiring large doses of calcium channel blockers, beta blockers, and arterial vasodilators. This accelerated hypertension raised the possibility of renal artery stenosis and a follow-up renogram demonstrated a further significant decrease in blood flow to the allograft (Fig 3B). Subsequently, a renal angiogram performed on the 28th day after reinstitution of CsA therapy revealed significant stenosis of all three primary branches of the allograft renal artery (Fig 4). Percutaneous angioplasty and/or revascularization was not felt to be technically feasible. Because these lesions were thought to represent a form of CsA vasculopathy, CsA was discontinued while immunosuppression was maintained with AZA and MP.

American Journal of Kidney Diseases, Vol XII, No 6 (December), 1988: pp 534-537

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Fig 1. Arteriogram of the transplanted kidney eight days after transplantation demonstrated the pat· ency of the main renal artery with its segmental branches.

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Within 3 weeks of complete cessation of CsA, the serum creatinine decreased and stabilized at 1.4 mg/dL (124 JLmollL) (Fig 2). Follow-up isotopic (Fig 3C) and digital subtraction angiographic studies (Fig 5) performed 4 months after discontinuation of CsA showed marked improvement in the vascular stenosis with a return of renal blood flow to normal levels . At 1 year posttransplantation the serum creatinine level was 1.2 mg/ dL.

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Fig 2. Serial changes in serum creatinine, trough plasma CsA levels, platelet count, and mean arterial 8P during the final 2 weeks of CsA therapy and after discontinuation of the drug. Arrows indicate the time of the transplant renograms.

The acute form of CsA nephrotoxicity is primarily due to reversible renal arteriolar vasoconstriction.4 In some patients acute renal dysfunction results from the development of widespread thrombi in the small intrarenal branches of the renal artery and the glomerular capillaries. 5 The latter disorder may be associated with thrombocytopenia and microangiopathic hemolytic anemia resembling the hemolytic-uremic syndrome. CsA-related reversible stenosis of the primary branches of the main renal artery has not been reported previously. In our patient the renal angiogram revealed normal primary segmental arteries shortly after transplantation. Progressive renal dysfunction subsequently developed in the 13th postoperative week, 2 weeks after CsA therapy was restarted. This deteriora-

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Fig 4. Arteriogram of the transplanted kidney performed while the patient was on CsA demonstrated marked irregular stenosis of all three major branches of the renal artery.

tion in renal function was associated with the renal angiographic finding of stenosis in the three primary branches of the allograft renal artery. All angiographic studies were performed using standard views and magnifications, thereby effectively eliminating any artifactual changes in vascular caliber. Discontinuation of CsA resulted in virtually complete resolution of the stenotic lesions with return of renal function to baseline levels. This sequence of events suggests that the stenotic lesions were CsA related and contributed

Fig 5. Arteriogram of the transplanted kidney during normal renal function 4 months after discontinuation of CsA showed almost complete resolution of the stenotic lesions.

significantly to renal dysfunction. Although these lesions could have been caused by a vascular rejection, clinical improvement following a lowering of immunosuppressive agents would not have been expected. The normal appearance of the distal branches of the renal artery also makes it unlikely that the patient had transplant rejection. CsA vasculopathy may present itself as acute graft dysfunction secondary to the development of mirothrombi in the glomerular capillaries. This lesion has been classified as a variant of the hemolytic uremic syndrome. However, this disorder has not been associated with thrombotic involvement of the major renal vessels in the absence of diffuse distal disease. The other forms of CsA vasculopathy reported have been associated with a more chronic type of arteriolar narrowing characterized by increased hyaline deposition in the media and subintima. These lesions are unique to the small arteries and arterioles and have not been described in larger arteries. In this reported case the vascular lesions developed despite low CsA trough levels. Erythromycin has been reported to cause marked elevations in CsA concentrations because of inhibition of the hepatic P-4S0 enzyme system. Erythromycin had been completely discontinued at the time of CsA initiation and close follow-up of CsA levels prohibited the development of values within the nephrotoxic range. We hypothesize that the vascular damage resulting from the preceding severe rejection episode might have sensitized these renal

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CYCLOSPORINE-INDUCED RENAL MACROANGIOPATHY

vessels to CsA-related endothelial injury leading to platelet and thrombin deposition with luminal narrowing. However, it is not clear why the lesions affected only the larger branches of the renal artery while sparing the small intrarenal vessels . We conclude that CsA-induced vascular changes may

present as isolated narrowing of the major branches of the renal artery and that these lesions may be completely reversible with early discontinuation of CsA. This entity needs to be considered in the differential diagnosis of renal dysfunction in CsA-treated renal transplant recipients.

REFERENCES 1. Kahan BD: Cyclosporine nephrotoxicity: Pathogenesis, prophylaxis, therapy and prognosis. Am J Kidney Dis 8:323331, 1986 2. Mihatsch MJ , Thiel G, Baslan V: Morphological patterns in cyclosporin treated renal transplant recipients. Transplant Proc 17: 101-116,1985 (suppll) 3. Sommer BG, Innes JT, Whitehurst RM , et al: Cyclospor-

ine associated renal arteriopathy resulting in loss of allograft function . Am J Surg 149:756-764, 1985 4. Myers BD: CycJosporine nephrotoxicity. Kidney Int 30:964-974 , 1986 5. Van Buren D, Van Buren CT, Flechner SM, et al: De novo hemolytic uremic syndrome in renal transplant recipients immunosuppressed with cycJosporine. Surgery 98:54-62, 1985