Deballi, P

Fung, JJ

Jain, A

McCauley, J

Starzl, TE

Todo, S

English

PubMed

Name not available

Changes in renal function after liver transplantation under FK 506

D-Scholarship@Pitt

EFFECTS ON THE KIDNEY-CLINICAL Changes in Renal Function After Liver Transplantation Under FK 506 J. McCauley. J.J. Fung. S. Todo. A. Jain. P. Oeballi. and T.E. Starzl SINCE its introduction into clinical trials. FK 506 has proven to be the most potent oral immunosuppres-sant available. 1-3 Our previous studies have documented the nephrotoxicity of FK 506. and have suggested that a reduction in renal blood flow is central to its pathogene-sis.4.S The clinical management has been constantly evolving. The starting dosage of FK 506 has gradually decreased and the IV infusion was changed from a 4-hour infusion to l~-hour infusIOns to attenuate the early perioperative nephrotoxicity. We will present. herein. the results of our experience with nephrotoxicity during the first year of primary hepatic transplantation under FK 506. This repre· sents the results of a high·dose period and the steepest slope of our learning curve in the use of FK 506. Current practices emphasize lower initial doses. lower FK 506 levels. and progressive dosage reductions. Maintaining the optimal drug level which minimizes nephrotoxicity while avoiding rejection. will likely be assisted by a computer-based artificial intelligence program which has only re-cently been developed at the University of Pittsburgh.1> PATIENTS AND METHODS All of the 28:! adult patIents receiving onhotopic liver transplants at the UniversllY of Pittsburgh between September 1989 and July 1990 were Included in this study. The immunosuppression sched· ules have been published elsewhere. and were under evolution during this study. In brief. FK 506 was administered at doses of 0.075 m!!lkg or 0.15 mg/kg IV over 4 hours. then repeated at 0.075 mg/kg every I ~ hours until oral conversion was possible. At that time patIents received 0.15 mg/kg per day. The oral and I V doses frequently overlapped for approximately 24 hours. Prednisone. with a 5-day IV burst. was employed in many patients. Others received between 200 mg or 20 mg/kg per day as the staning dose. Rejection episodes were treated with IV Solumedrol bolus. pred-nisone recycle. or OKT3. All patients received Bactrim (one single-strength tablet tWice per dayl and acyclovir adjusted to renal funclion. Plasma FK 506 levels were measured by enzyme Immunoassay. and done so dally while in hospllu'and during each clinic Visit. Standard laboratory studies included serum creatinine (Serl. BUN. electrolvtes. liver enzymes. cholesterol. uric acid. magne-sium. and total protein. among others. Values are expressed as mean !: standard deviation. Differences between means were deterrntned by Student's I test or analysis of vanance when appropnate. RESULTS The changes in SCr over time are depicted in Fig I. Invariably. SCr rose in the perioperative period. The change in SCr was generally mild to moderate: 76% of patients had values <~Kl mg/dL at 7 days postoperatively. Hemodialysis was required for the first time in 43 patients. Thirty-two patients were dialyzed within the first 30 days. and 11 patients after 30 days (range 38 to S68 days). Patients requiring late dialysis were typically recipients of multiple liver transplants. septic or developed acute tubu-lar necrosis (ATN) due to hypotension. or nephrotoxic antibiotics. Seventeen patients had either ARF or chronic renal failure at the time of transplantation. At latest follow·up, one patient requiring dialysis prior to transplan· tation is on regular dialysis, and is listed for a cadaveric renal transplant: one patient with early renal failure has required prolonged dialysis (6 months): and two patients ::; e. " ! OJ z i i= '" .. .. u 2." 2.00 1.10 1.00 0 ... 1--------------------i 0.00 ............ _.L...-...... _.L...-...... _'--...... _'--...... _'--........ ---' ·1 0 14 21 I. 10 120 110 170 110 410 140 DAYI Fig 1. SeR after liver transplantation. Error bars are!: SEM. From the Departments of Medicine and Surgery. University Health Center of Pittsburgh. University of Pittsburgh School of Medicine. and the Veterans Administration Medical Center. Pitts· burgh. Pennsylvania. Supported by research grants from the Velerans Administration and Project Grant No. 29961 from the Natlonallnstltules of Health. Bethesda. Maryland. Address reprint requests to Jerry McCauley. MD. Renal-Elec-trolyte Division. 11431 Scaife Hall. University of Pittsburgh School of Medicine. Pittsburgh. PA 15213. ~ 1991 by Appleton & Lange 0041·13451911$3.00/+0 TranspiantatJOtl ProctNIdIngS. Vol 23. No 6 (DecernbeI). 1991: pp 3143-3145 3143 3144 ~------------------------~~ 10 ~~----+---~ ... -+~~y~------~ Z 'W / \.. ! .. __ ... _ .. ,-f-'\-............. _-_. 40 ~ zaa ~K • 10 tL .••• _ .............. _ •• __ • •••• • __ •• _ .......................... _ ... . ~ : ~ f~~------------------------~ ~----------------------~Io __ leA" O1"~ 3ZI III K4-~~fDA~~ __ ~~4R~~«~~~=-~O~K~ __ ~ Z i U ~ C II. o fig 2. ERPF and GFR in one patient after liver transplantation. with late renal failure require regular dialysis. The latter two patients had renal insufficiency at the time of trans-plantation. Mean SCr on postoperative day 450 was 1.6 :t 0.6 mgldL (Fig 1). In selected patients. studies for effective renal plasma !low (ERPFl and glomerular filtration rate (GFR) were perfonned. Fig 2 illustrates the early changes in one patient. In essentially all patients. ERPF and GFR de-creased in parallel after transplantation. A significant fall in GFR without a proponionate decrease in ERPF was seen in patients with A TN from other causes. Hypomagnesemia was common after transplantation. Fig 3 illustrates the percentage of patients with hypo-magnesemia at selected times after transplantation. Ninety days after transplantation. 11.8% of patients had values < 1.0 mgldL. The prevalence of hypomagnesemia tended to decrease after 60 to 90 days. The hypomagnesemia was surprisingly well tolerated. even at levels less than 1.0 mgldL. No seizures. hypocalcemia. or hypokalemia could be attributed to hypomagnesemia. although it may have lowered the seizure threshold in several pauents with seizures from other causes. Hyperkalemia was also a common complication of FK S06 therapy. At latest follow-up. SS% of the patients require !ludroconisone acetate (F1orineO to control hyper-~ .. u c .. ~ ,. 20 J ........................................ __ .................................... •······· .. · ................ ·1 .1 • 7 14 I. .. .. , .. '" 'N a .. 4M ... DAft FlO 3. Pereenllge of patJents WIIt'I hypomagnesema (magne-Sium <'.3 mgtdL). McCAULEY. FUNG. TODO ET AL kalemia. These patients have been exquisitely sensitive to this agent. Common complications of this therapy. how-ever. were peripheral edema and worsening hypcnension due to sodium and water retention. Two patterns of hyperkalemia were seen: ( I) in association with hypcrchlo-remic metabolic acidosis (type IV RTA): and (2) in asso-ciation with renal insufficiency without acidosis. A very low incidence of hypenension. despite the hypenensive stimulus of ftudroconisone. was again appar-ent. At latest follow-up, 37 patients (16.4%) required antihypenensive medication. Of these. 30 (81.1%) require only one medication. 6 (16.2%) require two. and I (2.7%) requires three medications to control hypenension. Pa-tients with a previous history of hypenension. although nonnotensive immediately prior to transplantation. devel-oped elevated pressures once hepatic function improved. Serum creatinine was also greater in patients with a hypenensive history (1.8 :t 1.3 mgldL) than their nor-motensive counterpans (1.4 :t 0.6 mgldL). P < .OS. DISCUSSION The nephrotoxicity of FK 506 has been described previ-ously. The patients reponed in this series represent the results of empiric trials of FK S06 drug dosing and an earlier practice of maintaining relatively high oral doses months after transplantation. During this early learning phase. the standard dose and schedule of IV administration has changed. and the target FK 506 level has fallen dramatically. Although the patients in this series have received what will likely come to be regarded as very high doses of FK S06. renal function has been relatively well preserved compared to published trials with cyclosporine and in the randomized controllrial of liver transplants at the Univer-sity of Pittsburgh. 1 The mechanism of FK S06 nephrotoxicity is currently under exploration. Our studies demonstrate that ERPF and GFR both decrease after initiation of FK 506. and often parallel changes in FK 506 level-decreasing with high levels and increasing with lower levels. No precise linear relationship exists for SCr and FK 506 levels. but elevations in FK 506 are aSSOCiated with deterioration of renal function. Many of the findings of in vitro studies reponed are similar to those for CyA. but are usually milderK~·Di It is now cenain that the nephrotoxicity of FK 506 is dose-dependent and measures to decrease the quan-tity of drug reqUired will improve renal function . In the early phases of clinical use. the nephrotoxlCIlV of FK 506 has been clearly demonstrated. Although our clinical expenence. to date. suggests that FK 506 is approximately as nephrotOXIC as CyA when used at max-imai doses. It is likely that the measures now being planned will fL!nher reduce its seventy.7 Among these include. the addition of a third drug such as azathioprine or the newer agents in this class. This Will likely allow funher reduction in FK 506 doses. A novel computer-aSSisted drug prescnp-tion program is now being developed at the University of CHANGES IN RENAL FUNCTION UNDER FK 506 Pinsburgh.6 With this system. a user-defined target FK 506 level will be maintained by dose adjustments which correct for drug toxicity. Additional potential areas of study in-clude direct measures to reduce nephrotoxicity by pre-operative calcium channel blockade. or prostaglandin ad-ministration. among others. REFERENCES I. Stanl TE. Todo S. Fung JJ. et al: Lancet ti: 1000. 1989 !. Stan! TE. Abu·Elmagd. Tzakis A. et a1: Transplant Proc 23;914. 1991 3145 3. Fung JJ. Todo S. Jain A. et a1: Transplant Proc 22;6. 1990 4. McCauley J. Fung JJ. Jain A. et al: Transplant Proc 22:17. 1990 5. McCauley J. Fung JJ. Todo S. et al: Transplant Proc 23:1444. 1991 6. McMichaels J. et al: Transplant Proc (this issue I 7. Fung J. et al: Transplant Proc (this issue) 8. McCauley J. Farkus Z. Prasad S. et al: Transplant Proc (this issuel 9. McCauley J. Studer R. Craven P. et al: Transplant Proc (this issue) 

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Changes in renal function after liver transplantation under FK 506

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