ESQUIVEL, CO

GORDON, RD

IWATSUKI, S

KLINTMALM, GBG

SHAW, BW

STARZL, TE

English

PubMed

Iwatsuki, S

Esquivel, CO

Klintmalm, GBG

Gordon, RD

Shaw, BW

Starzl, TE

Name not available

Nephrotoxicity of cyclosporine in liver transplantation

D-Scholarship@Pitt

Nephrotoxicity of Cyclosporine in Liver Transplantation S. Iwatsuki, C.O. Esquivel. G.B.G. Klintmalm, R.D. Gordon, B.W. Shaw, Jr, and T.E. Starzl SINCE the introduction of cyclosporine (CsA)-steroid therapy for our liver trans-plant recipients in March 1980, the survival rates have increased significantly as shown in Fig 1. The effective and relatively safe immu-nosuppression provided by CsA is undoubt-edly the most important factor in the improved success rate. l k~Dphrotoxicity is a troublesome side effect of CsA. The distinction between nephrotoxic-ity and rejection poses a major diagnostic dilemma in renal transplantation,2 but not after extrarenal organ transplantation. How-ever, end-stage liver diseases often predispose to renal dysfunction, and extensive surgical intervention also can cause acute renal impairment. Thus, a different kind of "arti-~ fact" may exist in the assessment of drug J; :1, ne~~~~o:~~i~r~er transplantation provides a I reasonable model to study some aspects of the t:nephrotoxicity of CsA. In this report, acute :~: and chronic renal dysfunction among our liver 4 transplant recipients will be described. ........ "-~ esA-STEROID THERAPY A brief description of our management ~D practices is in order. If there are several hours i.'·,.... with which to prepare a recipient for liver I transplantation, an initial loading dose Of 17.5 4t mg/kg of esA is administered orally.;If the 1, oral loading is possible, CsA is usually not ;(,; given again until the operation is completed at D~D which time the venous.route is used. If there is :+ d. not enough time before surgery for oral load-~i ing, all therapy is withheld until 2 mg/kg of intravenous (IV) CsA is administered over a K~I" period of two to three hours after revasculari-, zation of the graft. If the recipient becomes hemodynamically stable and is producing an adequate amount of urine, the IV dose is repeated every eight to 12 hours in the early postoperative period. The IV medication is continued, even after the resumption of oral intake. Although oral CsA (17.5 mg/kg/d in two divided doses) is administered as soon as can be tolerated postoperatively, the intestinal absorption of the drug is usually poor for a few weeks after liver transplantation. Therefore, during the early postoperative period, CsA is administered IV as well as orally (double-route therapy) to maintain adequate trough levels of the drug (usually 800 ± 200 ng/mL of whole blood measured by radioimmunoas-say [RIA]). When an adequate blood level of the drug can be maintained by the double-route therapy, the IV doses of CsA are grad-ually tapered and discontinued at the same time that oral doses are increased accord-ingly. Often, oral doses > 17.5 mg/kg/ dare required during the early posttransplant period to maintain an adequate blood level. However, if renal dysfunction exists, the dose of CsA is reduced and the whole blood trough levels are allowed to drift to as low or lower than 300 ng/mL. Then, additional doses of steroids may be required to prevent the graft rejection. More recently, monoclonal anti-body therapy has been used. With the improvement of renal function, the dose of CsA is gradually increased to reach a thera-peutic drug level consistent in that patient with satisfactory renal function. When satisfactory and stable graft function is obtained (usually a month or two after From the Department of Surgery, University of Pitts-burgh Health Center. Pittsburgh. Supported by a research grant from the Veterans Administration and by project grant No. AM·29961 from the National Institutes of Health. Address reprint requests to Dr Shunzaburo Iwatsuki, Department of Surgery, 3601 Fifth Ave. Room 103. Folk Clinic, Pittsburgh, PA 152 I 3. © 1985 by Grune & Stratton. Inc. 0041-/345/85//704-1021 $03.00/0 Transplantation Proceedings, Vol XVII, No 4, Suppl 1 (August), 1985 191 192 PERCENT SURVIVAL 1007...,,---------------·-----, 90 70 60 50 6;, 4,0 b "B·,,"'0·····e-,···-e··. __ e-.... -e. ____ e-. ___ -e _____ e .... -€l 30 20 IWATSUKI ET AL ~ 10 l lD---KKKKKKKKt-KK--D--D---D-D--D--D--D----D--D-~~~--D--D~ l o 2 3 4, 5 6 7 8 9 10 Fig 1. Actuarial survival after liver I YEARS transplantation, '. transplantation), long-term dose adjustments Immediately before liver transplantation, .' are directed by side effects of CsA, such as three adult and two pediatric patients had I,"", .... ;.. nephrotoxicity, tremor, gum hyperplasia, hir- abnormal renal functions (BUN level> 50 r .::i sutism, and hypertension, rather than relying mg/IOO mL and/or serum creatinine> 2 solely on blood concentrations of the drug. / mg/100 mL). One of the adult and one of the Corticosteroids are used in combination pediatric patients were receiving hemodialysis with CsA not only as rejection therapy, but (Table 1). ~i also as a maintenance immunosuppressive Before the introduction of CsA, acute renal therapy. Steroid therapy is begun immedi- dysfunction postoperatively was often ob-ately before the revascularization of the graft served. Massive transfusion during surgery, with a bolus of IV methylprednisolone. After failure of prompt graft function, and infec· the operation, a five-day burst of prednisone tious complications were predisposing factors. or methylprednisolone is started at 200 mg/d Without these complications, severe renal in adults. The dose is reduced by daily decre- dysfunction was uncommon with conventional inents of 40 mg to a maintenance dose of 20 triple-drug immunosuppressive therapy (aza-mg/ d for adults. In children, smaller doses of thioprine, steroids, and antilymphocyte globu-steroids are used. The maintenance dose of lin [ALG]). In order to eliminate the transient prednisone at one month is 15 to 20 mg/d for and mild renal dysfunction inherent in liver adults and 5 to 15 mg/d for children. Further transplant surgery, acute renal dysfunction reductions of prednisone depend on graft postoperatively is defined as follows in this function. report: for adult recipients, BUN level of 100 ACUTE RENAL DYSFUNCTION DURING A ONE-YEAR SAMPLE From Jan 1 to Dec 31, 1984, 135 patients with various end-stage liver diseases received their first liver grafts while receiving CsA-steroid therapy at the University Health Cen-ter of Pittsburgh (Pittsburgh). Seventy-one of the 135 patients were adults (18 years old or older), and the remaining 64 patients were children (under 18 years old). As of March 1, 1985,58 (82%) of the 71 adults and 57 (89%) of the 64 children are alive. mg/ 1 00 mL or greater and/or serum creati-nine level of 5 mg/ I 00 mL or greater; and for Table 1. Incidence of Renal Dysfunction Before and After Liver Transplantation Abnormal Renal Acute Renal Function Before DysfunctIon After liver Transplant Liver Transplant (%) (%) Adults (<:o18y,) 3/7114) 15/71 (21) Children «18 yr) 2/64 (3) 14/64 (22) Total 5/135 (4) 29/135 (21) .l I·'·.····!· " I '. ' t· , . '. CsA NEPHROTOXICITY IN LIVER GRAFTS pediatric recipients, BUN level of 70 mg/mL or greater and/or serum creatinine level of 3 mg/mL or greater .during the first three months after liver transplantation. There were 15 (21 %) of the 71 adult and 14 (22%) of the 64 pediatric liver recipients who developed severe acute renal dysfunction as just defined above (Table 1). In response to the complication, esA was administered in quantities far less than the usual early mainte-nance doses, and the trough levels were kept <500 ng/mL of whole blood measured by RIA. Among the 15 adult recipients, only three had abnormal renal function before trans-plantation and one was already receiving hemodialysis. Five of the 15 adult recipients required hemodialysis after liver transplanta-tion, and all died within three months. These five patients had very poor liver graft func-tion. Four of them received second grafts, and r, two of the four received the third grafts within ~ two months. ~I '* Among the remaining ten adult patients (of !t\ the 15 with renal failure), only two had abnor-~ < mal kidney function before transplantation I and both regained near-normal renal function ~I after liver transplantation. They are alive and .,¥, I ~egl in the fourth and 12th months. q~K<?I~her I, eIght patients had normal renal function ~KK before transplantation. Five of them died in ~ three months with liver failure and infectious jl. Jij complications. In the end, ten (67%) of the 15 ~K patients who developed severe renal dysfunc-I'" tion postoperatively died despite the drastic ....• decrease of or temporary withdrawal o~CsAK , 193 Liver failure and infectious complications were almost always present. Among the 14 pediatric recipients with postoperative renal dysfunction, only two had abnormal renal function before transplanta-tion. One patient was already receiving acute hemodialysis and the other was receiving chronic dialysis because of renal cystic dis-ease. For the latter patient, both kidney and liver were transplanted from the same donor. The patient with acute preoperative renal failure (from Wilson's disease) was dialyzed four times after liver transplantation. The liver-kidney recipient did not need dialysis. Both patients are living and well with good renal functions in the fourth and sixth months. The remaining 12 children developed severe renal dysfunction after transplantatio[' Although all 12 patients had a BUN level of 70 mg/ 1 00 mL or greater, only four of then~ had a serum creatinine level of 2 mg/100 mL or greater. None of the 12 required hemodial-ysis after transplant and only three have died as of March 1, 1985. The three patients who died had very poor liver function, and two of them had severe infectious complications as well. The other nine patients are all alive and well with good renal as well as hepatic func-tion. Thus, severe acute renal dysfunction after liver transplantation was always associated with preexisting renal failure, difficult sur-gery, poor liver function, and/or infectious complications. In the absence of these prob-lems, nephrotoxicity of CsA did not cause Table 2. Renal Function and CsA Dose After Liver Transplantation in Adults and Children Creatinine mg % CsA mg/kg/d Pediatric (age < 18 yr) BUN mg/l00 mL Creatinine mg % CsA mg/kg/d Before Transplant 2mo 6mo lyr 2 yr 3yr 4yr 17.7 ± 17.0 37.0 ± 21.6 40.5 ± 43.9 37.7 ± 31.1 33.7 ± 12.9 26.1 ± 8.5 20.8 ± 5.1 1.1±O.8 1.5±0.6 1.7±O.6 1.7±0.6 1.8±0.6 1.5±0.3 1.3±0.4 13.9 ± 7.4 8.2 ± 3.8 6.1 ± 2.0 5.0 ± 1.9 4.9 ± 1.9 6.2 ± 2.7 18.4 ± 24.7 24.8 ± 16.3 24.2 ± 11.2 20.8 ± 9.5 0.8 ± 1.8 0.5 ± 0.3 0.7 ± 0.4 0.6 ± 0.4 23.3 ± 14.7 17.0 ± 9.2 14.6 ± 8.9 22.2 ± 9.1 0.7 ± 0.3 9.3 ± 2.3 25.9 ± 10.2 21.5 ± 9.2 0.6 ± 0.4 0.8 ± 0.2 9.0 ± 6.3 8.7 ± 1.8 194 significant morbidity when the dose was adjusted properly during the first three months after liver transplantation. CHRONIC RENAL DYSFUNCTION IN CHRONIC SURVIVORS From March 1980 to February 1984, 178 patients with various end-stage liver diseases received the first liver grafts while receiving CsA-steroid therapy. One hundred thirty-six (76%) of the 178 recipients survived one to five years after transplant as of March 1985. Sixty-nine of the 136 one-year survivors were adults; and remaining 57 were children. BUN and serum creatinine levels and the oral doses of CsA (mg/kg/d) were analyzed before transplantation; at 2, 6, and 12 months; and yearly up to five years to study chronic nephrotoxicity of CsA when the doses were adjusted by close monitoring of renal function as mentioned earlier. The mean values with SDs are shown in Table 2. Among the 69 adult one-year survivors, there were five patients who had abnormal renal function (serum creatinine level 2 mg/ 100 mL or greater) before transplantation; none were on hemodialysis. In three of these five patients, renal function improved after liver transplantation to serum creatinine levels <2 mg/IOO mL, but in two, the improvement was limited to serum creatinine levels of 2.5 mg/IOO mL and 3.5 mg/IOO mL under CsA-steroid therapy. Sixty-five of the 69 adult patients had nor-mal or near normal renal functions (serum creatinine level <2 mg/ 1 00 mL) before trans-plantation. Only one of the 65 patients devel-oped severe renal failure after transplantation that necessitated hemodialysis for a month. This patient had been an insulin-dependent IWATSUKI ET AL diabetic for 15 years before transplantation. He received reduced doses of CsA for the first two days and for two weeks in the second month after transplantation. During the other postoperative times, he was given azathio-prine-steroid therapy because of renal failure. The patient's renal function slowly deterio-rated on azathioprine-prednisone therapy but did no~ require hemodialysis other than dur-ing th~ immediate postoperative period. He died of.' a myocardial infarction after one year. "-The rest of adult survivors did not develop t chronic progressive renal dysfunction under .1·.'::. CsA-steroid therapy during one to five years. The numbers of adult one-year survivors who had abnormal renal functions (BUN level >501>m.g%, creatinine level >2 mg/IOO mL)'f before and after liver transplantation are sum-marized in Table 3. The incidence of renal! dysfunction increased after transplantation} under CsA-steroid therapy. However, it grad- , ually decreased with reduction of esA dosage 'I during the observation of up to five years. Among the 57 pediatric one-year survivors, I seven children had abnormal renal functions I (creatinine level >1 mg/IOO mL) before l transplantation, but only one of them was . receiving hemodialysis. None required hemo- I dialysis after transplant. In all of these seven 1 children, renal function improved after liver transplantation under CsA-prednisone thera-py. In the remaining 50 children, the serum creatinine level was < I mg/ I 00 mL before transplant. None of the 57 children developed chronic, progressive renal dysfunction while receiving CsA-steroid therapy during one to five years. The numbers of pediatric one-year survi-vors who had abnormal (BUN level >30 mg/ I 00 mL, creatinine level > 1.0 mg/ 1 00 Table 3. Incidence of Renal Dysfunction Among 69 Adult One-Year Survivors After liver Transplentation With CsA-Steroid Therapy Before Transplant 2ma 6ma 1 yr 2 yr 3 yr 4 yr 5 yr Serum creatinine"" 1 mgt' 00 ml 5/69 19/69 18/69 18/69 8/34 2/17 1/6 0/1 % 7 28 26 26 24 12 17 0 BUN;;,: 30 mg/dL 3/69 12/69 8/69 9/69 3/34 0/10 0/6 0/1 % 4 17 12 13 9 0 0 0 lK~: CsA NEPHROTOXICITY IN LIVER GRAFTS 195 Table 4. Incidence of Renal Dysfunction Among 57 Pediatric One-Year Survivors After Liver Transplantation With CsA-Steroid Therapy Before Transplant 2mo 6 me 1yr 2 yr 3 yr 4yr Serum creatinine ~ 1 mg/l00 mL 7/57 4/57 12/57 8/57 2/28 1/11 0/2 % 12 7 21 14 7 9 0 BUN ~ 30 mg/dL 6/57 17/57 16/57 8/57 3/28 1/11 0/2 % 11 mL) before and after liver transplantation are summarized in Table 4. The incidence of renal dysfunction increased after transplant under CsA-steroid therapy, but it gradually de-creased with reduction of CsA dosage during the observation of up to five years. DISCUSSION 30 28 14 11 9 0 major causes of renal impairment. The dose of CsA must be carefully adjusted to avoid neph-rotoxicity. Daily monitoring of the drug level is helpful in adjusting the dose particularly during the immediate and early posttrans-plant period. Recently, chronic and irreversible renal damages were reported both in heart8 and Acute and reversible nephrotoxicity of CsA kidney9 transplantation under long-term CsA was recognized Soon after the introduction of therapy. Histologic changes characterized by this effective and safe immunosuppressive tubulointerstitial fibrosis were thought to be agent in clinical organ transplantation.3- 7 progressive. In the present clinical study of i Severe renal dysfunction during the early chronic renal dysfunction in 136 liver trans-~ postoperative period of liver transplantation is plants receiving CsA therapy for one to five I' an ominous prognostic sign often accompa- years, we could neither find an example of ',0 nied by unstable hemodynamics, poor liver chronic, progressive renal dysfunction, nor ~ " function, and/or infectious complications. In could we find any evidence of increasing inci-i our study of acute renal dysfunction, 13 (45%) dence of chronic, renal impairment (Tables 2 t of the 29 recipients who had severe renal through 4). Although recipients of different ~Df failure died within three months after trans- organs were studied, the lack of chronic, pro-f plantation.' ... ~ .... gressive renal dysfunction in our liver recip-I .. DKDKF~ .... ' CsA is an additional cause of acute renal ients was probably due to our policy of dose " dysfunction in liver transplantation, in which adjustment to avoid nephrotoxicity rather " hemodynamic instability, massive operative than to maintain any specific trough level of i ;nt",ent;on, and "ry poo, H", funct;~::::ob:~:: CsA. i I. StaTZI TE. Iwatsuki S. Van Thiel DH.; et al: 6. Starzl TE. Klintmalm GBG, Wei! R III. et al: Surg " Hepatology 2:614. 1982 . GynecolObstet 153:486. 1981 !~~ 2. StaTZI TE. Hakala TR. Rosenthal JT. et al: Surg "r, Gynecol Obstet 154:819,1982 3. Caine RY. White DJG, Thiru S, et al: Lancet 2:1323, 1978 4. Caine RY, RoBes K. White DJG, et al: Lancet 2:1033.1979 5. Starz] TE. Weil RIll. Iwatsuki S, et al: Surg Gynecol Obstet 151: 17. 1980 7. Caine RY. White DJG, Evans DB, et al: Br Med J 282:934, 1981 8. Myers'BD, Ross J. Newton L. et al: N Eng! J Med 311:699,1984 9. Klintma!m GBG. Bohman S, Sundolin B. et al: Lancet 2:950. 1984 

NEPHROTOXICITY OF CYCLOSPORINE IN LIVER-TRANSPLANTATION

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NEPHROTOXICITY OF CYCLOSPORINE IN LIVER-TRANSPLANTATION

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