Blood Pressure and the Survival of Renal Allografts from Living Donors
Kevin C. Mange*,,
Harold I. Feldman*,,
Marshall M. Joffe*,
Kosunarty Fa and
Roy D. Bloom
*Center for Clinical Epidemiology and Biostatistics University of Pennsylvania School of Medicine; and Renal-Electrolyte and Hypertension Division Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
Correspondence to Dr. Kevin C. Mange, Room 902 Blockley Hall, 423 Guardian Drive, University of Pennsylvania, Philadelphia, PA 19104. Phone: 215-573-5039; Fax: 215-573-2265;
ABSTRACT. Levels of BP have been associated with increasingrates of renal allograft failure from cadaveric donors, independentof renal function. The effect of BP, a modifiable risk factor,on the failure rates of renal allografts from living donorsis unknown and maybe obscured by the rate of decline of renalfunction from this source of organs. A nonconcurrent cohortstudy collecting data from 392 recipients of a renal allograftfrom a living donor during 1990 to 2001 was performed. MultivariableCox regression models were fit by means of time-varying termsfor systolic BP (SBP), diastolic BP (DBP), mean arterial BP(MAP), pulse pressure, and renal function during the first yearafter transplantation to study the association of BP and thetime to allograft failure. Potential nonlinear relationshipswere considered by fractional polynomial terms. Recipient gender,preemptive transplantation, and time-varying terms for the naturallogarithm of creatinine clearance and acute rejection were retainedin the multivariable model. Including separate multivariablemodels with nonlinear terms for SBP (P = 0.02), for DBP (P =0.02), or for MAP (P = 0.05) during the first year significantlyimproved the fit of the respective models and confirmed thatthere is an association of BP and allograft failure independentof renal function. Pulse pressure had neither a linear nor nonlinearassociation with allograft failure. In this nonconcurrent study,the level of BP during the first year affected the survivalof renal allografts from living donors, independent of renalfunction. Further investigation is required to confirm the levelof BP that is optimal to prevent foreshortened duration of survival.E-mail: kmange@cceb.med.upenn.edu
Detecting a causal relationship between BP and the survivalof renal allografts is complex because renal insufficiency isa described cause of hypertension. Several prior investigationslimited to cadaveric renal allografts (CRT) have examined therelationship of BP and allograft survival conditional on a minimumduration of survival after transplantation (1–3). Investigatorsfrom the Collaborative Transplant Group studied CRT with a minimumsurvival of 1, 2, and 3 yr, and observed greater rates of allograftfailure with increasing BPs measured at these times (2). However,adjustment for the level of allograft function at the time ofBP measurements was not performed, leaving the relevance ofBP to survival separate from renal function unclear. The effectof the levels of BP on CRT survival, independent of renal function,was subsequently addressed by a study of 277 recipients of aCRT that accounted for allograft function at the beginning offollow-up (3). In this study, increases of 10 mmHg in systolicBP (SBP), diastolic BP (DBP), and mean arterial BP (MAP) at1 yr after transplantation increased the risk of allograft failureby 15%, 27%, and 30%, respectively, after adjustment for thelevel of allograft function.
Prior studies of the relationship of BP and CRT survival havenot considered BP early within the posttransplantation period.BP levels during the first year have been considered less clinicallyrelevant to the survival of CRT in the milieu of the more dominantinsults by immunological and ischemic processes. Nonetheless,it is plausible that the levels of BP within this time framesignificantly influence the survival of allografts, especiallythose transplanted from living donors, given the less prominentallograft injury from ischemia and immunological factors inthis population. Enhancing the understanding of factors thatinfluence the survival of renal allografts from living donors(LDRT) is of particular importance, given that living donorsare the fastest growing source of renal allografts in the UnitedStates (4). The extended duration of survival of these allograftsmay detract from the importance of BP and lead to an underappreciationof a modifiable clinical exposure, resulting in avoidable foreshortenedsurvival. The principal objective of this study was to assesswhether the level of BP within the first year after transplantationprovides predictive information, adjusted for the level of renalfunction, for LDRT survival.
Study Design
This nonconcurrent cohort study of recipients of renal allograftsfrom living donors during 1990 to 2001 at the Hospital of theUniversity of Pennsylvania was designed to examine the potentialassociation of BP during the first year after transplantationand long-term allograft survival. Data were abstracted frommedical records for inpatient admissions and outpatient clinicvisits at 2 wk and at 1, 2, 3, 6, 9, and 12 mo after transplantation.BP was measured during routine outpatient visits to the transplantclinic by an automated sphygmomanometer while the patient wasseated. Creatinine clearances by the Cockcroft-Gault formula(5) were calculated from the serum creatinine levels and bodyweights recorded at each of the clinic visits. The status ofallografts and of patients was verified with the United Networkfor Organ Sharing, and patient vital status was further confirmedusing the National Death Index. This study was approved by theInstitutional Review Board of the University of Pennsylvania.
Analytical Strategy
The primary outcome was allograft failure defined by the initiationof chronic dialysis, retransplantation, or death. Survival analysis,fitting Cox regression models, was used to examine the associationof BP and the time to allograft failure. Time-varying termswere constructed for SBP, DBP, MAP (2/3 DBP + 1/3 SBP), andpulse pressure (PP = SBP - DBP), as well as for renal functionduring the first year. The incorporation of time-varying dataon BP and renal function permitted investigation of the relationshipof recent BP and renal function on the subsequent rate of allograftfailure. Eligibility for inclusion in the multivariable modelwas explored in unadjusted models with P < 0.20 by the Waldtest as the threshold criterion for inclusion. Factors wereretained in the multivariable model if the addition of the variableresulted in P 0.10 by the likelihood ratio test (6). The assumptionof proportionality was examined by weighted testing of Schoenfeldresiduals (7,8).
Nonlinear associations of SBP, DBP, MAP, and PP with allograftfailure were explored in the Cox regression models by meansof fractional polynomials (9–11). This technique affordsflexibility in allowing for whole integer as well as fractionalpowers when examining continuous exposures. Fractional polynomialsalso have a primary advantage over percentile categorizationof BP levels by not requiring individuals within each groupto assume the mean value of BP of the categorical group, whichreduces power for detecting effects if the effect of the exposureis concentrated in the ends of the distribution or if exposureeffects are nonlinear (12,13). The multivariable models thatincluded polynomial terms with or without a linear term forBP were compared with a multivariable model that included onlya linear term for BP to determine which model better fit thedata. P 0.05 by the likelihood ratio test for this comparisonwas indicative of a nonlinear association. A similar strategywas used to allow for a nonlinear association of renal function(serum creatinine or estimated creatinine clearance) and allograftfailure. The possibility that BP at particular times withinthe first year had greater or lesser magnitudes of associationswith allograft failure was explored by fitting BP-by-time multiplicativeinteraction terms. Two-sided P values 0.05 were considered significantexcept were noted, and all analyses were performed using Stataversion 7 (Stata, College Station, TX).
Characteristics
There were a total of 392 recipients of a renal allograft froma living donor with a mean time of follow-up of 1050 d (range,39 to 4297 d). Donors were more frequently white women; recipientswere more frequently white men, and glomerulonephritis was themost common cause of end-stage renal disease (ESRD) (Table 1).Of the transplant pairs, 99.7% had a donor with the identicalrace of the recipient. The mean 5-yr allograft survival was77.8% (95% confidence interval, 72.0 to 83.0), consistent withreported national rates of allograft survival (4). Of the 72persons who had an allograft failure, 11 (15.6%) had a failuredue to death from any cause.
Unadjusted Analysis of Associations with Allograft Failure
Pressures throughout the first year are presented in Figure 1.Significant correlations existed between SBP and DBP (r =0.59, P < 0.0001), SBP and PP (r = 0.83, P < 0.0001),and MAP and PP (r = 0.46, P < 0.0001). A low correlationwas observed between DBP and PP (r = 0.04, P 0.08).
Figure 1. BPs throughout the first year after transplantation.
In Table 2, SBP measured during the first year was divided intocategories. Within each SBP category, the total amount of person-timespent by individuals is presented, along with the incidencerates of allograft failure. A comparison of the crude incidencerates across categories suggests that there is a potential associationbetween the levels of SBP and allograft failure. However, alinear relationship may not best characterize the effect ofBP. Similar observations were made for DBP and MAP.
Table 2. Unadjusted rates of allograft failure according to categories of systolic BP in the first year and duration of exposure
Constraining the associations of allograft failure with SBP,DBP, MAP, or PP (using time-varying terms) to a linear formrevealed that SBP and PP had unadjusted associations with allograftfailure that exceeded the criterion for inclusion in the multivariablemodel (P 0.17 and P 0.12, respectively) (Table 3). Nonetheless,linear and nonlinear associations of BP were still examinedin the multivariable models.
Table 3. Unadjusted analysis of factors associated with allograft failure
Allograft failure was observed to have significant unadjustedassociations with recipient gender and race, donor race, preemptivetransplantation, and the levels of HLA matching (Table 3). Renalfunction during the first year, reflected by a time-varyingterm for either serum creatinine or calculated creatinine clearance,was also associated with an increasing rate of failure.
Independent Associations of BP with Allograft Failure
Multivariable models separately containing a linear term forSBP, DBP, MAP, or PP were fit. Collinearity of variables (donorand recipient race, HLA matching and unrelated donor, and calculatedcreatinine clearance and serum creatinine) was accommodatedby alternatively fitting these variables into the multivariablemodel. The following variables subsequently satisfied criteriato be retained in the multivariable models: recipient gender,preemptive transplantation, unrelated donor or HLA matching,calculated creatinine clearance or serum creatinine, and acuterejection. Adjustment for either of the alternative collinearvariables did not affect the models. The time-varying termsfor BP did not suggest that there was an adjusted linear associationof SBP (P = 0.25), DBP (P = 0.23), MAP (P = 0.40), or PP (P= 0.38) with allograft failure. The use of fractional polynomialterms revealed that the addition of a variable representingthe time-varying natural logarithm (Ln) of SBP over the firstyear significantly improved the fit of the model (P = 0.02),incremental to a time-varying linear term (Table 4). Similarly,the model for MAP had an improved fit to the data when a time-varyingvariable representing the natural logarithm (Ln) of MAP overthe first year was included in addition to a time-varying linearterm, P = 0.03. For DBP, the final model did not include a linearterm, but rather two polynomials (square root of DBP, and Ln(DBP)x square root of DBP) for DBP varying over the first year bestfit the data (P = 0.05). An adjusted nonlinear association ofPP with allograft failure was not observed (P > 0.50). Thesemodels confirm that during the first year, SBP, DBP, and MAPhave associations with the rate of allograft failure, independentof the level of renal function at the time of BP measurement.The magnitude of collinearity between SBP and DBP resulted inunreliable estimates of each in a multivariable model that includedboth parameters. Fitting PP into the multivariable models didnot significantly change the adjusted estimates of the effectsfor SBP, DBP, or MAP. The BP-by-time interaction was nonsignificant(P > 0.50), suggesting that the magnitude of the BP associationwith allograft failure was unrelated to the time of BP measurementwithin the first year. Forcing the year of transplantation andthe type of calcineurin inhibitor administered at the time ofdischarge from the transplantation procedure did not affectthe models.
The graphs in Figure 2 combine the information from the modelsin Table 4 in order that the terms for BP can be jointly interpretedto provide an indication of the magnitude of the associationbetween varying levels of BP and the adjusted rate of allograftfailure. The lower 95% confidence limits of the adjusted hazardratios exceeded 1 when during the first year SBP was below 75mmHg and above 159 mmHg; when DBP was below 43 mmHg and above98 mmHg; and when MAP was below 56 mmHg and above 113 mmHg.
Figure 2. (a) Systolic BP during the first year and allograft failure. (b) Diastolic BP during the first year and allograft failure. (c) Mean arterial BP during the first year and allograft failure. All hazard ratios are adjusted for variables in Table 4.
A series of ancillary analyses was performed to evaluate thesensitivity of the primary observations to various assumptions.First, analyses were repeated considering death from any causeas a censoring event. Second, the level of allograft functionin the follow-up period immediately preceding the measurementof BP was considered instead of contemporaneous renal functionto evaluate for potential overadjustment for renal function,leading to underestimation of associations. Third, time-varyingindications of an occurrence of acute rejection during the follow-upperiod were included in multivariable models to account forthe transient elevations of BP and renal function resultingfrom episodic rejections, creating an overestimation of associations.In all supplemental analyses, the primary observations wererobust to varying assumptions.
This study demonstrates that among recipients of renal allograftsfrom living donors, BP throughout the first year after transplantationis an important determinant of allograft failure, independentof renal function. Furthermore, pressures at the times measuredthroughout the first year had equivalent importance to the rateof failure. These results are consistent with earlier studiesdemonstrating that BP later within the first year or later affectsallograft function among recipients of CRT (1–3).
The largest study of BP and allograft survival from the CollaborativeTransplant Group analyzed data from 29,751 recipients of CRTs.These investigators observed that SBP and DBP significantlypredicted allograft failure among cohorts with minimum survivaltimes (e.g., 1 yr, 2 yr, 3 yr). Limiting the observations fromthis large study was the lack of consideration for the levelof renal function at the time of BP measurements that mightexplain the observations, leaving unanswered the direction ofthe causal relationship. An earlier study that averaged MAPduring the first 6 mo after transplantation among recipientsof cadaveric allografts detected an increased risk of failurewith MAP after consideration of renal function, but the effectwas limited to African American recipients (1). Several otherinvestigations have explored the importance of BP, measuredat various times relative to transplantation, to allograft survival,but time-varying measures of BP and allograft function werenot considered in the analyses (14,15). Ultimately, one studythat examined recipients of cadaveric organs that had surviveda minimum of 6 or 12 mo confirmed the effect of BP on the long-termsurvival of CRTs, independent of renal function (3).
Unlike previous investigations of BP and allograft failure thatwere limited primarily to organs from cadaveric donors as wellas in the investigation of the nature of this relationship,this study considered a curvilinear association analogous toprior demonstrations of nonlinear associations of BP with otherclinical events (16–18). Allowing for nonlinearity precludedthe erroneous conclusion of no association of BP and survivalof allografts from living donors. The significant collinearityof pressures within subjects did not permit reliable estimationof separate effects of SBP and DBP in this observational study,as described in an earlier population-based study (19).
PP has been associated with outcomes in nontransplant populations(20–22), but not consistently (18). The lack of an independentrelationship and the insignificant contribution to rates ofallograft failure from PP within our study suggest that predictiveinformation for allograft failure is related predominantly tothe levels of SBP or DBP rather than to the difference betweenpressures. The unimportance of PP is likely related to the distributionof characteristics in this study population as well as to themagnitudes of proposed effects of PP. In comparison to the findingsof an association of PP with the rate of progression to ESRDamong nontransplanted individuals with type II diabetes andnephropathy in the Reduction of Endpoints in NIDDM with theAngiotensin II Antagonist Losartan (RENAAL) study, the presenttransplantation population under study was younger (40.2 yrversus 60.2 yr), 23.1% had diabetes, and less than 25% of thesubjects had a PP that exceeded the threshold PP (>70 mmHg)above which the risk for ESRD progression was significantlyassociated within the RENAAL study.
We can simply speculate to explain the form of BP relationshipsdepicted in Figure 2. It is plausible, and consistent with ananimal model of denervated renal allografts (23), that autoregulationof renal blood flow is impaired in renal allografts such thatbelow a range of flow there is chronic ischemia, above whichthe elevated pressure may ultimately lead to arteriolosclerosisand fibrosis. This hypothesis is further supported by data demonstratingpressure-dependent renal blood flow among humans who have chronicrenal disease (24). The persistence of a curvilinear associationin analyses that assigned death to be a censoring event arguesthat mortality from any cause does not explain the observationsmade in this investigation. Furthermore, the patients who hadSBP below the first percentile (SBP <91 mmHg) were not unusualin other clinical parameters that might suggest that comorbiditiesdetermined their risk for allograft failure indirectly throughthe level of BP. For example, these individuals had BP readingsrepeated over several clinic visits that confirmed their exposure;they tended to be have diabetes, and they had a mean weightof 139.3 lb and a mean serum creatinine of 1.2 mg/dl at theiroutpatient visits during the first year after transplantation.
Appreciating the existence of a relationship between BP andsurvival of allografts from LDRT independent of renal functionis important. The complex relationship between renal functionand BP and the duration of survival of allografts from livingdonors likely obscured whether or not the level of BP affectedallograft survival. This study, in conjunction with earlierstudies, provides substantive evidence that BP, a modifiablerisk factor, is significantly associated with the risk of allograftfailure. Interestingly, this association appears not be simplylinear in form. The nature of this relationship observed inthis study suggests that inadequate control of BP as well asoverzealous control may not be tolerated by the transplantedkidney, which has impaired autoregulation of perfusion pressure,leading to shortened survival.
There are several limitations to this study. First, we did notcollect data on the type and number of therapeutic agents forhypertension used by the subjects. This study, focusing on BP,would account mechanistically for these agents, and any effectof these medications on allograft failure would then be independentof level of BP and would have been unlikely to be detected inthis observational study. We cannot exclude the notion thatthere maybe further association of the types of BP-loweringagents and allograft failure. Second, BP beyond the first yearwas not considered in these analyses. The analyses cannot refutethat BP within the first year may rather be an indication ofthe level of BP later in the posttransplantation period thatmay also be a relevant period causally related to allograftfailure. Third, data about the presence of protein in the urineof subjects were not routinely collected during this study period.There exists the possibility that the effect of the level ofBP may be related to the daily excretion of urinary protein.Last, the design of this study included the use of multivariableadjustment procedures, but residual confounding from factorsthat do not correlate with the factors studied cannot be excluded.
In conclusion, this study confirmed that in recipients of renalallografts from the most rapidly growing source of donors inthe United States, BP during the first year after transplantation,independent of renal function, affects the rate of allograftfailure. The optimal level of BP and the antihypertensive regimento achieve these levels to reduce rates of failure remain tobe determined in clinical trials.
Acknowledgments
This study was supported by an unrestricted grant from FujisawaHealthcare. We thank Angela Starnes for her administrative assistance.
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Received for publication April 1, 2003.
Accepted for publication October 8, 2003.
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Abstract
Introduction
0.10 by the likelihood ratio test (6). The assumption of proportionality was examined by weighted testing of Schoenfeld residuals (7,8). 
