0041-1337/98/6601-59$03.00/0 TRANSPLANTATION Vol. 66, 59 – 66, No. 1, July 15, 1998 Copyright © 1998 by Williams & Wilkins Printed in U.S.A. CHRONIC RENAL FAILURE FOLLOWING LIVER TRANSPLANTATION ARETROSPECTIVE ANALYSIS NEIL C. FISHER, 1,2 PETER G. NIGHTINGALE, 3 BRIDGET K. GUNSON, 1 GRAHAM W. LIPKIN, 4 AND JAMES M. NEUBERGER 1 Liver and Renal Units, Queen Elizabeth Medical Centre and Wolfson Computer Laboratory, University of Birmingham Medical School, Birmingham B15 2TH, United Kingdom Background. Liver transplant recipients are at risk of chronic renal disease, principally as a result of nephrotoxicity of the commonly used immunosuppres- sive agents cyclosporine and tacrolimus. We have in- vestigated the incidence of chronic renal failure and its risk factors in our transplant population, which was treated predominantly with cyclosporine. Methods. A single-center retrospective study was done of 883 consecutive adult patients receiving a first liver transplant between 1982 and 1996. Potential risk factors for the development of chronic renal failure were recorded, including serial measurements of cy- closporine therapy and renal function. Results. Severe chronic renal failure (serum creati- nine level >250 M/L for at least 6 months) developed in 25 patients, representing 4% of patients surviving 1 year or more. Twelve of these patients developed end- stage renal failure and mortality was 44%. The pre- dominant cause of renal failure was cyclosporine nephrotoxicity. Serum creatinine as early as 3 months after surgery was strongly associated with the even- tual development of severe chronic renal failure (P0.001), and this group could be further subdivided into two groups with differing risk factors. The first group had early (<1 year) renal dysfunction, with older age (P0.03), cytomegalovirus infection (P0.03), need for perioperative renal replacement therapy (P0.06), and regrafting (P0.06) as risk fac- tors for eventual renal failure; the second group had late-onset (>1 year) renal dysfunction, with cyclospor- ine levels at 1 month after surgery (P0.007) and daily and cumulative cyclosporine dosage at 5 years (P0.01 for both) as risk factors. Conclusions. With improved survival of liver trans- plant recipients, chronic renal failure has become an important cause of morbidity and is associated with a high mortality. Many patients at risk of severe chronic renal failure may be identified at an early stage. Treat- ment regimens that avoid or prevent cyclosporine-in- duced nephrotoxicity are urgently required for this population. Immunosuppressive therapy is routinely given after liver transplantation and cyclosporine (CsA*) is one of the most widely used agents. The introduction of CsA for renal trans- plantation led to improved graft survival compared with prednisolone and azathioprine-based regimens (1), and this benefit is assumed to hold true for liver transplantation (2). One of the principal side effects of CsA is nephrotoxicity; this is not clearly related to dosage or trough blood levels (3, 4). The possibility that CsA may lead to chronic renal failure (CRF) and end-stage renal failure (ESRF) was first reported in long-term survivors of heart transplantation (5). Renal transplant recipients treated with CsA are also at higher risk of renal impairment and cardiovascular disease compared with those receiving prednisolone and/or azathioprine, de- spite improved early graft survival (1, 6). Likewise, liver transplant recipients receiving CsA therapy may develop CRF and ESRF, although there are few publications relating to their incidence in long-term survivors (7, 8). The presence of hepatorenal syndrome at the time of transplantation is a risk factor for future ESRF (8); however, despite the potential for other renal diseases, such as IgA nephropathy, to occur in association with liver disease (9), no other risk factors for CRF following transplantation have been described. We have observed the development of ESRF in several long-term survivors of liver transplantation treated with CsA but without other obvious risk factors. Therefore, we con- ducted a retrospective analysis to define the incidence of CRF and ESRF in our liver transplant population, which was treated primarily with CsA-based immunosuppression, and to identify risk factors for the development of severe CRF. PATIENTS AND METHODS Patients. From January 1982 to March 1996, 883 adults received a first liver transplant at our center. The median age was 48 years (range: 16 –73 years), and the ratio of men to women was 40:60. The most common indications for transplantation were primary biliary cirrhosis (36%), fulminant liver failure (15.6%), primary sclerosing cholangitis (11%), cryptogenic cirrhosis (6.5%), alcoholic liver disease (6.4%), autoimmune chronic active hepatitis (6.1%), primary or sec- ondary hepatic malignancy (3.4%), and hepatitis B or C infection (3.3% and 3.5%, respectively). After stabilization of graft function and immunosuppressive therapy, patients were followed for a max- imum of 6 monthly intervals on an outpatient basis, with prospective recording of clinical and laboratory information onto a database. 1 Liver Unit, Queen Elizabeth Medical Centre. 2 Address correspondence to: Dr J.M. Neuberger, Liver Unit, Queen Elizabeth Hospital, Birmingham B15 2TH, UK. 3 Wolfson Computer Laboratory, University of Birmingham Med- ical School. 4 Renal Unit, Queen Elizabeth Medical Centre. * Abbreviations: CMV, cytomegalovirus; CRF, chronic renal fail- ure; CsA, cyclosporine; ESRF, end-stage renal failure; HUS, hemo- lytic-uremic syndrome. 59