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CLINICAL STUDIES
Evaluation of Renal Function in Transplant
Patients on Tacrolimus Therapy
Sangeeta Agarwala, PhD, Emma Culligan, RN, Ashok Jain, MD, Jerry McCauley, MD, Ron Shapiro, MD, Pradip Chakrabarti, MD, Gilbert Burckart, PharmD, and Raman Venkataramanan, PhD Glomerular filtration rate (GFR), as measured by 24-hour lower (p < 0.05) at 3 months (212 ± 42) compared to 1 month creatinine clearance and clearance of iothalamate, and effec- (306 ± 118) after transplantation. In liver transplant patients, tive renal plasma flow (ERPF), as measured by the clearance GFR and ERPF were below normal despite normal serum of para-aminohippuric acid (PAH), were evaluated at 2 creatinine concentrations, but there was no difference in GFR weeks, 1 month, and 3 months after transplantation in 8 renal or ERPF at 1 month and 1 year after transplantation. Al- transplant patients and at 1 month and 1 year after trans- though below normal, renal function was well preserved in plantation in 9 liver transplant patients receiving tacrolimus transplant patients while receiving chronic tacrolimus ther- (Prograf ®) therapy. In renal transplant patients, there was a apy over the study period. Dosage alterations of renally elimi- significant increase in GFR after transplantation. There was nated drugs may be required for drugs with a narrow thera- no change in GFR at 1 and 3 months as compared to 2 weeks after transplantation, while ERPF (ml/min/1.73 m2) was Journal of Clinical Pharmacology, 2002;42:798-805
2002 the American College of Clinical Pharmacology
Organ transplantation is an acceptedtherapeutic ter surgery andbecause of the use of nephrotoxic
option for patients with an end-stage organ dis- ease. After transplantation, patients often receive mul- Tacrolimus andcyclosporine are currently the two tiple drug therapy that includes immunosuppressive primary immunosuppressive drugs used to prevent agents, antibiotics, antifungal agents, antiviral agents, organ rejection. Tacrolimus (Prograf ®, Fujisawa, Chi- andantihypertensive agents. Many of these drugs are cago), a relatively new immunosuppressive drug, was excretedprimarily through the kidney, andthe func- isolatedfrom the fungus Streptomyces tsukubaensis in tional status of the kidney in transplant patients is very 1984,1 andclinical trials were initiatedin 1989 by important in determining the kinetics and dynamics of Starzl andcoworkers.2 The 1-year patient andgraft sur- renally excreteddrugs. In transplant patients, renal vival under tacrolimus immunosuppression are 88% function may be compromisedby factors such as and82% after liver transplantation,3 and95%4 to 96%5 ischemia/reperfusion injury to the kidney during or af- and89%4 to 91.2%,5 respectively, after renal transplan-tation. Despite the significant improvement in patientandorgan survival, a major side effect of tacrolimustherapy is nephrotoxicity. Clinically, nephrotoxicity From the Department of Pharmaceutical Sciences and Pharmacy andTherapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, inducedby tacrolimus is often inferredbasedon an in- Pennsylvania (Dr. Agarwala, Ms. Culligan, Dr. Burckart, Dr.
crease in serum creatinine or bloodurea nitrogen Venkataramanan) and the Thomas Starzl Transplantation Institute, School (BUN) or, occasionally, by a reduction in creatinine of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr. Jain, Dr.
clearance or histological changes in the kidney.6,7 McCauley, Dr. Shapiro, Dr. Chakrabarti). This publication was supported These parameters, however, do not provide an accurate by funds received from NIH/NCRR/GCRC grant 5M01 RR00056, NIH estimate of the functional capacity of the kidney.
grant DK34475, and a U.S. Pharmacopoeia (USP) fellowship. Submitted Limitedinformation is available on the quantitative as- for publication September 15, 2000; revised version accepted April 19,2002. Address for reprints: Dr. Raman Venkataramanan, 718 Salk Hall, pects of kidney function in transplant patients treated School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261.
with tacrolimus. The objectives of this study were to as- 798 • J Clin Pharmacol 2002;42:798-805
RENAL FUNCTION IN PATIENTS ON TACROLIMUS THERAPY sess renal function quantitatively in kidney and liver Table I Renal Transplant Patients:
transplant patients receiving tacrolimus as their pri- mary immunosuppressive therapy andto characterizethe time course of changes in renal function following Renal Transplant
MATERIAL AND METHODS
The protocol for this study was approved by the institu- tional review board, and the study was conducted at the General Clinical Research Center at the University of Pittsburgh. Patients were randomly selected, and re- cruitedfor the study with the approval of their primary physician if they met the inclusion andthe exclusion criteria. The study protocol was explained to the pa- tients, andinformedconsent was obtainedfrom each Indications for transplantation (n) Study Population
The demographics and characteristics of the patients enrolledin this study are shown in Tables I andII. Eight renal transplant patients (4 male, 4 female) and9 livertransplant patients (7 male, 2 female) were recruitedforthe study. Male and female transplant patients, be-tween the ages of 18 and60 years, with no secondaryorgan involvement were included in this study. Thetypical dosing regimen for tacrolimus in these patients Table II Liver Transplant Patients:
was 0.2 to 0.3 mg/kg/day in two divided doses. Liver transplant patients were requiredto have a serumcreatinine of less than 1.5 mg/dl at the time of recruit- Liver Transplant
ment, andthe renal transplant patients were required to have primary renal allograft function. Patients were excludedif they were pregnant, hada hematocrit of less than 25%, or were allergic to iodine or hippurate.
At the time of the study, all the patients were receiving tacrolimus as their primary immunosuppressive ther- apy andwere not on any other concurrent medication that wouldeither be nephrotoxic or induce or inhibit Study Protocol
The study was performed at approximately 2 weeks, 1 month, and3 months after renal transplantation and approximately 1 month and1 year after liver transplan- tation. These days were chosen so as to coincide with the patient’s routine clinical visits. On the day of thestudy, the subjects were asked to eat a light breakfastconsisting of apple/orange juice, muffins, toast, or ce-real with their morning medications andwere askedto tacrolimus, andthe study was startedwithin 2 to 3 refrain from taking any caffeine-containing products.
hours thereafter. All subjects were fastedfor approxi- Patients were askedto take their morning d mately 2 to 3 hours prior to starting the study and for at least 3 hours after initiation of the administration of the Statistical Analysis
renal function markers. Exceptions were made for dia-betic patients, who were given crackers andjuice as Results were reportedas mean ± standard deviation (SD). The data for renal transplant patients were ana- Each subject was askedto collect urine for 24 hours, lyzedby using repeated-measures ANOVA (Figures 1, approximately 24 to 36 hours prior to the start of the 2 [discussed below]). A paired t-test was usedfor analy- study. On the morning of the study, a blood sample was sis of data from liver transplant patients (Figures 3, 4 withdrawn, andthe subject was askedto voidbefore [discussed below]). A repeated-measures ANOVA was starting the infusion of the renal markers. Diuresis was usedfor testing statistical significance for the estimated initiatedby consumption of 200 ml of water orally creatinine clearance in Figure 3. An unpaired t-test was prior to starting the study and every half hour thereaf- usedfor comparison of GFR andERPF between renal ter. A priming dose of 217 mg iothalamate and 3 mg/kg andliver transplant patients in Figure 5. The statistical para-aminohippuric acid(PAH) was given intrave- package usedwas SAS, version 6.12. A p-value ≤ 0.05 nously over 5 minutes. This was followedby a continu- was considered statistically significant.
ous infusion of iothalamate andPAH for 2.5 hours toachieve target steady-state concentrations of 30 µg/ml and15 µg/ml, respectively. Bloodsamples were with-drawn at 1, 1.5, 2, and 2.5 hours after initiation of infu- Renal Transplant Patients
sion, andtimedurine sample were collectedat half-hour intervals.
Seven cadaveric and1 living relatedrenal allograft re-cipients completedthe study at 2 weeks and1 month.
Laboratory Analysis
The living relatedrecipient didnot complete the studyat 3 months when she was diagnosed to have acute re- Iothalamate andPAH were analyzedin plasma and jection. The data given below are for all 8 patients at 2 urine by high-performance liquidchromatography weeks and1 month andfor 7 patients at 3 months. The (HPLC). Two hundred µl of plasma andurine samples pretransplant serum creatinine concentrations of 7.3 ± were mixedwith 100 µl of para-amino benzoic acidin 3.6 mg/dl improved to 1.4 ± 0.3 within 2 weeks after water (50 µg/ml or 100 µg/ml) as the internal standard transplantation in these patients. Serum creatinine re- andsubjectedto protein precipitation with 100 µl of mainedstable andwithin the normal range during the perchloric acid. The samples were vortexedandthen entire 3-month study period after transplantation (Ta- centrifugedfor 10 minutes at 3000 rpm. The ble III). The estimatedcreatinine clearance by the supernatant was injectedonto a reverse-phase HPLC Cockcroft andGault methodincreasedfrom 10.3 ± 3.7 column. The mobile phase for PAH consistedof disod- ml/min to 54 ± 8.8 ml/min at 2 weeks after transplanta- ium citrate, hydrochloric acid, and di-n-butylamine tion andremainedstable thereafter (54 ± 12.1 at month adjusted to a pH of 2.5. For iothalamate, 35 ml of 1 and51 ± 7.3 at month 3). The GFR as measuredby acetonitrile were added to 965 ml of the mobile phase 24-hour creatinine clearance andiothalamate clear- describedabove. The flow rate was 1 ml/min, andthe ance didnot change over the 3-month time period(Fig- UV detector was set at 254 nm. The standard curve was ure 1). However, ERPF as measuredby PAH clearance linear in the concentration range of 7.5 µg/ml to 100 at 3 months was similar to values at 2 weeks but was µg/ml for both markers in plasma andurine. The lower (p < 0.05) comparedto the values at 1 month (Fig- interassay andintra-assay coefficients of variation for ure 2). Filtration fraction (GFR/ERPF) remainedcon- PAH andiothalamate were less than 6.3% andless than stant over 3 months. The fractional excretion of sodium 6.5%, respectively, in the urine andless than 3.5% and (FeNa%) that is reflective of tubular function was un- changedover time (Table III). Poor correlations were Glomerular filtration rate (GFR) andeffective renal observedwhen estimatedcreatinine clearance was cor- plasma flow (ERPF) were calculatedas the renal clear- relatedwith 24-hour creatinine clearance (r2 = 0.1, p = ance of iothalamate andPAH correctedto body surface 0.1) andiothalamate clearance (r2 = 0.31, p = 0.007). In area, respectively. The renal clearance was calculated addition, the 24-hour creatinine clearance showed a as the amount excretedin urine/AUC for each collec- poor correlation with iothalamate clearance (r2 = 0.19, tion interval. The average of the renal clearances over p = 0.04). Renal function as evaluatedby 24-hour the collection intervals of 60 to 90 minutes, 90 to 120 creatinine clearance, iothalamate clearance, andPAH minutes, and120 to 150 minutes was calculatedfor clearance was below normal at all the time points 800 • J Clin Pharmacol 2002;42:798-805
RENAL FUNCTION IN PATIENTS ON TACROLIMUS THERAPY Table III Renal Transplant Patients:
Biochemical Parameters andTacrolimus Therapy Parameters
Figure 1. Glomerular filtration rate (GFR) as measured by 24-hour creatinine clearance and iothalamate clearance in renal transplant patients. Results are expressed as mean ± SD. GFR was evaluated by 24-hour creatinine clearance (dark bars) and iothalamate clearance(open bars) at 2 weeks, 1 month, and 3 months after renal Data are mean ± standard deviation. BUN, blood urea nitrogen; FeNa%,fractional excretion of sodium; FKWB concentrations, whole-blood con- a. p < 0.05 as comparedto pretransplant.
b. p < 0.05 as comparedto 2 weeks and1 month.
Figure 2. Scatter plot of effective renal plasma flow (ERPF) as mea-sured by p-aminohippurate (PAH) clearance in renal transplant pa- The dose of tacrolimus was lower (p < 0.05) at 3 tients. ERPF was measured at 2 weeks, 1 month, and 3 months after months as comparedto 2 weeks and1 month. The renal transplantation. *p < 0.05 versus 1 month. whole-bloodtrough concentrations of tacrolimusshowed a tendency to decrease with time, but this didnot achieve statistical significance (Table III). No signif-icant correlation was obtainedwhen whole-bloodcon- points, the serum creatinine was within the normal centrations of tacrolimus or the dose of tacrolimus range. However, serum creatinine was significantly were correlatedwith 24-hour creatinine clearance, the higher (p < 0.05) at 1 month and1 year comparedto clearance of iothalamate, or the clearance of PAH.
pretransplant values (Table IV). The estimatedcreatinine clearance was significantly reduced at both Liver Transplant Patients
1 month and1 year as comparedto pretransplant val-ues. Renal function as evaluatedby estimated All 9 liver transplant patients recruitedwere evaluated creatinine clearance (Cockcroft andGault equation), at 1 month and1 year after transplantation. At all time 24-hour creatinine clearance, iothalamate clearance, Table IV Liver Transplant Patients:
Biochemical Parameters andTacrolimus Therapy Parameters
Figure 3. Glomerular filtration rate (GFR) as measured by esti- mated creatinine clearance, 24-hour creatinine clearance, and iothalamate clearance. GFR was evaluated by estimated creatinine clearance (ml/min, hollow bars) based on serum creatinine(Cockcroft and Gault equation), 24-hour creatinine clearance (ml/min/m2, gray bars), and iothalamate clearance (ml/min/m2, dark bars). *p < 0.05 versus pretransplant. Renal and Liver Transplant Patients
Data are means ± standard deviations. BUN, blood urea nitrogen; FeNa%, A comparison of GFR andERPF as measuredby fractional excretion of sodium; FKWB concentrations, whole-blood con- iothalamate andPAH clearance demonstratedthat the values were similar at 1 month between the two patient a. p < 0.05 as comparedto pretransplant.
b. p < 0.05 as comparedto 1 year.
DISCUSSION
andPAH clearance were below normal (Figures 3, 4).
In organ transplant patients, renal function may be in- There was no difference in any of these parameters over fluenced by intraoperative conditions, hemodynamic 1 year. The filtration fraction andthe FeNa% didnot changes, and the use of nephrotoxic drugs. In addition, change over 1 year (Table IV). As with renal transplant prolongedpreservation time, reperfusion injury, and patients, poor correlation was observedbetween esti- rejection will also affect renal function in renal trans- matedcreatinine clearance and24-hour creatinine plant patients. Transplant patients are often on chronic clearance (r2 = 0.2, p = 0.05) or iothalamate clearance (r2 = therapy with tacrolimus or cyclosporine andare at risk 0.45, p = 0.002) andbetween 24-hour creatinine clear- for developing renal impairment. Initial observations ance andiothalamate clearance (r 2 = 0.25, p = 0.04).
suggestedtacrolimus to be less nephrotoxic when com- The dose of tacrolimus was significantly (p < 0.05) paredwith cyclosporine andwith a lower incidence of higher at 1 month than at 1 year. The whole-bloodcon- rejection andhypertension.8,9 However, with addi- centrations of tacrolimus were not significantly differ- tional studies, tacrolimus was reported to be as ent but showeda trendto decrease at 1 year (Table IV).
nephrotoxic as cyclosporine.5,7 Limitedquantitative in- No correlation was observedbetween whole-blood formation is available on the functional capacity of the concentrations of tacrolimus and24-hour creatinine kidney after transplantation. The objective of the cur- clearance or iothalamate clearance or PAH clearance.
rent study was to characterize the time course of Similar results were seen when the three functional pa- changes in kidney function following transplantation rameters (24-hour creatinine clearance, iothalamate using exogenous markers andto understandthe func- clearance, andPAH clearance) were correlatedwith tional status of the kidney in transplant patients on tacrolimus dose at 1 month and 1 year.
chronic tacrolimus therapy. Renal transplant patients 802 • J Clin Pharmacol 2002;42:798-805
RENAL FUNCTION IN PATIENTS ON TACROLIMUS THERAPY Figure 5. Mean renal hemodynamics (glomerular filtration rate[GFR] and effective renal plasma flow [ERPF]) at 1 month after renal and liver transplantation. GFR and ERPF were evaluated byiothalamate and p-aminohippurate clearance, respectively, in the re- nal (dark bars, n = 8) and liver transplant patients (hollow bars, n =9), respectively. studies in our laboratory have shown markedly lowerclearance of cefotaxime andceftizoxime (two drugs Figure 4. Scatter plot of glomerular filtration rate (GFR) as mea- primarily excretedby the kidney) in liver transplant sured by iothalamate clearance in liver transplant patients (top patients, despite normal serum creatinine concentra- panel). GFR was evaluated at 1 month and 1 year after liver trans-plantation. Scatter plot of effective renal plasma flow (ERPF) as mea- tions.12 Similarly, the half-lives of gentamicin and sured by p-aminohippurate (PAH) clearance in liver transplant pa- vancomycin were prolongedin liver transplant pa- tients (bottom panel). ERPF was evaluated at 1 month and 1 year tients beyondwhat wouldbe expectedbasedon serum creatinine concentrations.13 Therefore, in the presentstudy, renal function was evaluated by creatinine clear-ance as estimatedusing the Cockcroft andGault equa-tion, as measureddirectly by collecting a 24-hour urine were studiedat 2 weeks, 1 month, and3 months after sample andby determining the clearance of two exoge- transplantation, which allowedus to evaluate the re- covery of renal function after renal transplantation and Very few studies have measured the functional as- the effect of tacrolimus therapy on a newly trans- pects of the kidney in renal transplant patients. To our plantedkidney. Liver transplant patients were evalu- knowledge, this is the first report in which serial evalu- atedfor the effects of acute andchronic tacrolimus ther- ation of renal function has been conducted with exoge- apy at 1 month and1 year, respectively.
nous markers in kidney transplant patients on Serum creatinine is commonly usedas an index of tacrolimus therapy. The estimatedcreatinine clearance renal function in patients. In the current study, serum significantly improvedafter renal transplantation. Glo- creatinine returnedto normal or near-normal values merular filtration rate as measuredby estimated within 2 weeks after renal transplantation. In liver creatinine clearance (Cockcroft andGault method transplant patients, the serum creatinine increased1 24-hour creatinine clearance, andiothalamate clear- month after transplantation but was well within the ance was lower in kidney transplant patients as com- normal range throughout the study. Serum creatinine paredto normal subjects but remainedstable over 3 has been reportedto be an insensitive indicator of kid- months comparedto baseline values at 2 weeks. The ney function in patients with kidney disease or after re- compromisedrenal function in the renal transplant nal transplantation andalso to provide no information patients is similar to the observation of Rostaing and about tubular function in these patients.10,11 Previous coworkers,14 who reporteddecreasedrenal hemody- namics at 3 months after transplantation in patients on cessive damage to the kidneys during or after liver sur- tacrolimus therapy. In comparison to subjects who gery, are possibilities that couldhave contributedto the have undergone unilateral nephrectomy, however, the renal hemodynamic values were only marginally lower It was not possible to distinguish between decreased in kidney transplant patients. It is well documented that after uninephrectomy, the remaining kidney hy- cause of lower clearance of PAH. Afferent arteriolar pertrophies to compensate for the loss of renal func- constriction may have been responsible for the ob- tion.15,16 Studies in subjects after uninephrectomy or in served decrease in renal hemodynamics in both patient living related kidney transplant donors have shown populations.22 This is supportedby the unchangedfil- that within the first few weeks after nephrectomy, GFR tration fraction in both renal andliver transplant pa- andrenal plasma flow in the remnant kidney increase tients. Afferent vasoconstriction has been docu- by approximately 40%. The GFR andERPF then lie be- tween 65% and70% of prenephrectomy values in andis thought to occur with tacrolimus-ind In liver transplant patients on tacrolimus therapy, Tacrolimus is a drug with a narrow therapeutic in- McCauley andcoworkers6 have reporteda parallel de- dex, and therapeutic drug monitoring is essential to en- cline in GFR andERPF. A 9% and42% reduction in sure maximum graft survival andminimal toxicity.23,24 GFR andERPF, comparedwith expectedvalues in nor- Initial studies in which tacrolimus was measured in mal subjects as measuredby the single injection of ra- plasma reportedboth good25 andpoor correlations26 dioactive iothalamate and orthoiodo-hippurate, has with tacrolimus toxicity. Subsequently, whole blood also been reportedin liver transplant patients.19 has been usedas the matrix of choice, andpositive cor- relations have been reportedbetween tacrolimus blood GFR andERPF as measuredby iothalamate andPAH concentrations andtoxicity in liver andrenal trans- clearance at 1 month after liver transplantation. There plant patients.27,28 In both of these studies, a large num- is limitedinformation available on serial evaluation of ber of patients were studied, and the trough tacrolimus GFR andERPF in liver transplant patients. The lower bloodconcentrations over a 7-day periodbefore the on- GFR that was observedin the present study is in accor- set of adverse effects were correlated with toxicity. In dance with previous clinical studies, where GFR as our study, there was a poor correlation between the functional hemodynamics and the dose or the diethylenetriamine penta-acetic acid (DTPA) measure- whole-bloodconcentrations of tacrolimus on the day of ments was diminishedat 1 month and1 year after liver the study, presumably due to smaller sample size and Both GFR andERPF were similar in the renal and In conclusion, renal andliver transplant patients liver transplant patient populations at 1 month after have a reducedGFR andERPF as measuredby exoge- transplantation. The kidney transplant donors were se- nous markers. The functional parameters were lower lectedfor kidney donation only when they hadgoodre- than normal in both patient populations despite nor- nal function. The expectation was that better renal mal serum creatinine concentrations. When renal func- function wouldbe observedin liver transplant patients tion was comparedto patients who have undergone who were screenedfor preexisting renal impairment unilateral nephrectomy, renal function in the (as measuredby serum creatinine andestimated tacrolimus-treatedrenal transplant patients appeared creatinine clearance) andwho have two functioning to be preserved. In comparison to the initial postopera- kidneys as compared to the renal transplant patients tive baseline values, renal hemodynamics remained with one functioning (transplanted) kidney. However, stable despite chronic tacrolimus therapy. Judicious the liver transplant patients were relatively older (48 ± monitoring of tacrolimus bloodconcentrations andad- 6 years) than the kidney transplant donors (36 ± 16 justments in tacrolimus dose may play a role in pre- years), which may be one of the factors that couldac- venting severe deterioration in renal function in trans- count for the similar renal function that was observed plant patients. Whether preservation of functional in the two patient populations. As liver andrenal trans- hemodynamics plays a role in preventing chronic tox- plant patients were not receiving any other concurrent icity in the long term due to tacrolimus therapy is an nephrotoxic drug therapy at the time of the study, other area that warrants further investigation. In general, in factors, such as mildpreexisting hepatorenal syn- transplant patients with tacrolimus therapy, dosing drome that was not detectable with routine clinical regimen changes are needed only for renally elimi- measures/biopsy examination or hypoperfusion or ex- nated drugs that have a narrow therapeutic index.
804 • J Clin Pharmacol 2002;42:798-805
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