Diurnal Blood Pressure Changes One Year after Kidney Transplantation: Relationship to Allograft Function, Histology, and Resistive Index
Hani M. Wadei*,
Hatem Amer*,
Sandra J. Taler*,
Fernando G. Cosio*,
Matthew D. Griffin*,
Joseph P. Grande,
Timothy S. Larson*,
Thomas R. Schwab*,
Mark D. Stegall and
Stephen C. Textor*
* Department of Medicine, Division of Nephrology and Hypertension, Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, and Department of Surgery, Division of Transplantation Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota
Address correspondence to: Dr. Hani M. Wadei, Mayo Clinic Jacksonville, 4205 Belfort Road, Suite 1100, Jacksonville FL 32216. Phone: 904-296-9075; Fax: 904-296-5499; E-mail: wadei.hani{at}mayo.edu
Received for publication November 28, 2006.
Accepted for publication February 20, 2007.
Loss of circadian BP change has been linked to target organdamage and accelerated kidney function loss in hypertensivepatients with and without chronic kidney disease. AmbulatoryBP–derived data from 119 consecutive kidney transplantrecipients who presented for the first annual evaluation wereexamined in relation to allograft function, histology, and ultrasoundfindings. A total of 101 (85%) patients were receiving antihypertensivemedications (median 2), and 85 (71%) achieved target awake averagesystolic BP (SBP) of <135 mmHg. A day–night changein SBP by 10% or more (dippers) was detected in 29 (24%). Dippingstatus was associated with younger recipient age, lack of diabetes,low chronic vascular score, and low resistive index. Nondippersand reverse dippers had lower GFR compared with dippers (P =0.04). For every 10% nocturnal drop in SBP, GFR increased by4.6 ml/min per 1.73 m2 (R = 0.3, P = 0.003). Nondippers andreverse dippers were equally common in recipients with normalhistology and in those with pathologic findings on surveillancebiopsy. On multivariate analysis, percentage of nocturnal fallin SBP and elevated resistive index independently correlatedwith GFR. This study indicates that lack of nocturnal fall inSBP is related to poor allograft function, high chronic vascularscore, and high resistive index irrespective of allograft fibrosis.Further studies are needed to determine whether restorationof normal BP pattern will confer better allograft outcome.
Evaluation of kidney allografts 1 yr after transplantation providesan opportunity to study the effects of early injury and to anticipatelong-term outcomes. Early fibrosis is common and sometimes portendsloss of allograft function that limits the long-term viabilityof the kidney (1). Whereas immunologic injury and early rejectionepisodes have major effects on long-term graft function, nonimmunologicfactors such as arterial BP warrant careful evaluation. Previousstudies indicated that clinic BP levels 1 yr after transplantationpredict future graft function, even when corrected for GFR (2).However, BP measurements vary widely depending on methods ofmeasurement, study conditions, and time of day (3). How bestto evaluate treated levels of arterial pressure in transplantrecipients is not well understood.
BP normally exhibits a diurnal rhythm, with higher awake andlower nocturnal periods. On average, normal individuals reducemean systolic BP (SBP) and diastolic BP (DBP) by 10% or moreduring the overnight period ("dippers"), even if sleeping isnot consistently achieved. Failure to have a circadian fallin BP is designated as a "nondipper" status. Nondippers havemore severe target injury, including a higher rate of strokes,dementia, left ventricular hypertrophy, and microalbuminuria(4–6). Even with normal average pressure levels, nondipperswith type 1 diabetes are more likely to develop diabetic nephropathyduring subsequent years (7). Studies suggest that nondippingaccelerates loss of GFR in individuals with and without chronickidney disease (CKD) (8,9). Previous studies indicated thatdisturbances in circadian BP patterns develop in liver, kidney,and cardiac transplant recipients, sometimes persisting forseveral years (10–12).
Resistive index (RI) is promoted as a general marker of vascularcompliance (13,14). In kidney transplant recipients, elevatedRI is a predictor of renal allograft survival and death fromcardiovascular disease (15). However, elevated RI is not necessarilyrelated to biopsy findings, which leaves open the question ofhow elevated RI is involved in allograft dysfunction (16).
We sought to evaluate BP measurements systematically in mostlytreated transplant recipients who returned for scheduled reviewof renal allograft function 1 yr after transplantation. Thesesstudies included routine clinic BP measurements (Dinamap), standardizedBP protocols using American Heart Association (AHA) trainednurses, and ambulatory BP monitoring (ABPM) with day and nightsegments. Additional studies included measurement of GFR byiothalamate clearance, histologic assessment with surveillancebiopsy, and ultrasound evaluation of the allograft. We wishedto examine the hypothesis that circadian BP measurements relateto allograft function, RI and histologic findings even at thisrelatively early time point.
Study Population
Included in this analysis were 119 consecutive kidney transplantrecipients who underwent ABPM between August 2004 and August2005 as part of their first annual posttransplantation evaluation.Review and analysis of the clinical records from these patientswas undertaken with the approval from the Mayo InstitutionalReview Boards. ABPM was obtained using an overnight automatedABPM monitor (Spacelabs, Issaquah, WA) as described previously(11). Briefly, the 18-h monitoring period was selected to determineawake and inactive nocturnal BP profiles without interferingwith other posttransplantation studies during morning and earlyafternoon. Each monitor consisted of an appropriately sizedinflatable cuff, worn on the nondominant arm. BP was measuredautomatically and stored every 10 min during awake hours andevery 20 min during nocturnal hours. Two 5-h period blocks forawake and nocturnal measurements were selected for the analysis.A 2-h interval between the awake and nocturnal data periodswas excluded from analysis to eliminate the variable effectsof sleep initiation (17). For ensuring accuracy, BP measurementswere calibrated against manual auscultatory measurements atthe outset by trained technicians. On the basis of percentagereduction in the circadian BP, patients were grouped into dippers(SBP 10%), nondippers (SBP between 0 and 9%), or reverse dippers(nocturnal rise in SBP). Clinic BP measurements were obtainedby clinic staff using an automated oscillometric device (Dinamap;Critikon, Tampa, FL), during a quiet sitting at a recordingstation. Standardized BP was obtained by a hypertension therapynurse who was trained to apply AHA standards regarding patientpositioning and measurement of auscultatory BP. Care was takento ensure at least 5 min of quiet rest, using AHA standardsfor arm support, cuff size, and body positioning (18). The meanof three seated BP measurements was recorded. Body surface areaand body mass index were determined using height and weightmeasurements.
Graft function was assessed by serum creatinine and GFR determinationusing the clearance of subcutaneous nonradiolabeled iothalamateduring water diuresis (19). Results were corrected for bodysurface area and expressed as ml/min per 1.73 m2. A total of109 recipients had iothalamate GFR values available at both3 wk and 1 yr after transplantation. GFR was estimated by 24-hurinary creatinine clearance in another four patients. Urinaryprotein and microalbumin excretion was measured from a 24-hurine collection. Transplant renal ultrasound including segmentalDoppler flow velocities was undertaken in 117 patients. RI atthe arcuate arteries was determined at the upper, middle, andlower zones using the formula [peak systolic velocity –end diastolic velocity/peak systolic velocity]. The resultsfrom the three readings were averaged and recorded. A percutaneousallograft surveillance biopsy was obtained on 112 recipients.These biopsies were obtained as part of the routine care ofrenal transplant patients at Mayo Clinic, Rochester, and werenot related to graft dysfunction. Biopsy specimens were evaluatedby routine light microscopy by an experienced renal pathologistand were scored using the Banff ’97 classification (20).For the purpose of this analysis, acute and chronic scores forinflammation and tubular injury were combined (i+t and ci+ct).Data regarding recipient's demographics, donor characteristics(donor age and gender), type and dosage of immunosuppressionmedications, and type of hypertensive medications were obtainedfrom patients’ charts and electronic medical records.Recipients with biopsy-proven acute rejection episodes and polyomavirus-associatednephropathy (PVAN) diagnosed in the first posttransplantationyear were identified. PVAN diagnosis was based on the demonstrationof BKV DNA by in situ hybridization performed on paraffin-embeddedsections as described previously (21).
Immunosuppression consisted of intravenous methylprednisolonefor 4 d. Induction therapy with rabbit anti-thymocyte globulin1.5 mg/kg per d for a total of four to six doses was given in117 followed by oral immunosuppression with prednisone taperedto 5 mg/d by 3 mo, mycophenolate mofetil 750 mg twice dailyand either tacrolimus (target trough level 10 to 12 ng/ml [AbbottIMX whole-blood assay] for 3 mo and 6 to 8 ng/ml thereafter)or sirolimus (target trough level 15 to 20 mg/ml for 3 mo and8 to 15 ng/ml thereafter). Two patients received FTY-720 followedby prednisone and microemulsion cyclosporine.
Statistical Analyses
Results are presented as counts and percentages for qualitativedata and means and SD for quantitative data. Means of normallydistributed data were compared by t test and for more than twogroups by ANOVA. Data that were not normally distributed werecompared by nonparametric tests. 2 was used for 2 x 2 tableassociations. For analysis of the effect of different clinicalvariables on 1-yr iothalamate clearance, a univariate analysiswas conducted first. Variables that were significant in theunivariate analysis were included in a stepwise logistic regressionmodel that included the 1-yr iothalamate clearance as the dependentvariable.
Demographic information, including age, gender, body mass indexand pretransplantation clinical features, iothalamate GFR 3wk after transplantation, and donor information, for the 119studied patients is summarized in Table 1. The study cohortconsisted mainly of white patients, and the majority (76%) receiveda living-donor kidney transplant. The mean GFR at 3 wk was 56.6± 16.0 ml/min per 1.73 m2. Table 2 summarizes clinicalinformation that was obtained at the visit 1 yr after transplantation.The predominant immunosuppressive regimen was prednisone, tacrolimus,and mycophenolate mofetil (92%), and the mean GFR was 58.5 ±17.8 ml/min per 1.73 m2. At the time of ABPM evaluation, 101(85%) recipients were receiving antihypertensive therapy thatconsisted of a median of two BP medications (range 1 to 5).
Table 2. Clinical, ultrasound, and histologic findings 1 y after transplantationa
Target BP (defined as awake average SBP <135 mmHg) was achievedin the majority (71%) of patients. Clinic BP were higher thaneither ABPM or standardized BP values (P < 0.001 for both),whereas awake average SBP was not different from standardizedSBP readings (NS). Forty-one percent of clinic BP levels wereconsidered above target, whereas 29% of awake ABPM values failedto reach BP goal.
On the basis of the circadian change in SBP, 29 (24%) patientswere dippers (mean ± SD SBP 13.7 ± 3.8%), 50 (42%)were nondippers (mean ± SD SBP change 5.2 ± 2.4%),and 40 (34%) were reverse dippers (mean ± SD SBP change–9.1 ± 8.4%). ABPM-derived BP measurements andclinical characteristics for patients within these groups aresummarized in Tables 3 and 4. Office BP readings did not regularlyrelate to dipper status. SBP was higher only in the reversedipper group, but other SBP and DBP readings did not differ.The dipper status in transplant recipients reflected both progressivelylower awake readings (see Table 3 for both SBP and DBP) andprogressively higher nocturnal readings. Factors that were associatedwith a dipper status included younger recipient age and lowarcuate artery RI. Absence of diabetes and lower chronic vascular(cv) score trended to associate with dipper status but did notreach statistical significance (P = 0.06 and 0.07, respectively).The type of transplant, preemptive transplantation, recipientgender, calcineurin inhibitor–free immunosuppression,average trough tacrolimus level, class of antihypertensive medications,the degree of proteinuria, donor age, and donor gender did notcorrelate with the circadian BP rhythm.
Table 4. Clinical, ultrasound, histologic, and donor characteristics according to dipping statusa
Relationship between Circadian BP Change and 1-Yr GFR
Iothalamate GFR did not differ between dippers and the othertwo groups at an early (3 wk) time point. When measured 1 yrafter transplantation, nondippers and reverse dippers had lowerGFR compared with dippers (iothalamate clearance for dipperswas 64.1 ± 21.5 ml/min per 1.73 m2, for nondippers was59.5 ± 16.9 ml/min per 1.73 m2, and for reverse dipperswas 53.2 ± 14.5 ml/min per 1.73 m2; P = 0.04; Figure 1).The relationship between GFR as measured by iothalamate clearanceand the percentage of day–night SBP change is demonstratedin Figure 2. Iothalamate clearance correlated with the percentageof nocturnal fall in SBP (R = 0.3, P = 0.003). For every 10%nocturnal drop from the awake average SBP, GFR increased by4.6 ml/min per 1.73 m2.
Figure 1. Relationship between 1-yr iothalamate clearance and dipper status: Plot of the iothalamate GFR for dippers, nondippers, and reverse dippers. GFR progressively declined in nondippers and reverse dippers compared with dippers (P = 0.04). For each group, the GFR mean ± SD is provided.
Figure 2. Relationship between percentage of nocturnal fall in systolic BP (SBP) and 1-yr GFR: Scatter plot of the 1-yr GFR in relation to percentage of nocturnal fall in SBP in 119 kidney transplant recipients. There was a positive correlation between 1-yr GFR and nocturnal fall in SBP (R = 0.3, P = 0.003). For every 10% nocturnal fall in SBP, the GFR increased by 4.6 ml/min per 1.73 m2.
Relationship between Nocturnal Fall in SBP, GFR, and Pathologic Findings 1 Yr after Transplantation
To determine whether the correlation between percentage of nocturnalfall in SBP and GFR was affected by findings on surveillancebiopsy, we examined the relationship between percentage of nocturnalfall in SBP and GFR separately in those with normal or abnormalbiopsies. A total of 112 recipients had surveillance allograftbiopsies at 1 yr of follow-up. For the purpose of this analysis,biopsies were classified into four groups: Normal (n = 48),chronic allograft nephropathy (CAN; n = 45; 32 were grade 1,11 were grade 2, and two were grade 3), biopsies with inflammation(n = 12; four showed acute cellular rejection [three Banff 1Aand 1 Banff 1B], two borderline rejection, four interstitialnephritis, and two PVAN), and biopsies with glomerular disease(n = 7; four had transplant glomerulopathy, two had FSGS, andone had membranous nephropathy). The day–night fall inSBP and the proportion of dippers were similar between thosewith CAN and those with normal histologic findings, indicatingthat dipper status was not related to allograft fibrosis. Similarly,the proportion of dippers was not different in those with biopsyevidence of inflammation or transplant glomerulopathy. Of the48 patients with normal biopsies, 47 had iothalamate clearanceavailable at both 3 wk and 1 yr after transplantation. Noneof these recipients experienced acute rejection, whereas onerecipient developed PVAN that cleared during the course of thefirst year. Kidney transplant recipients with normal histologicfindings demonstrated a direct correlation between day–nightSBP change and cv score on surveillance biopsy (R = 0.4, P =0.002). Importantly, there was also a direct correlation betweenday–night SBP change and GFR at 1 yr (R = 0.4, P = 0.006;Figure 3). No such relationship was evident in the 3-wk measurementof GFR (R = 0.2; NS). Other factors that affected 1-yr GFR includedGFR 3 wk after transplantation, diabetes, donor age, and RI.On multivariate analysis, dismissal GFR was the only predictorof 1-yr function. Because early GFR may relate to late (1 yr)GFR, 3-wk GFR was excluded from the regression model. Afterexclusion of 3-wk GFR, percentage of nocturnal fall in SBP (P= 0.006) and RI (P = 0.068) were independently related to 1-yrGFR (Table 5). SBP that was obtained by different BP measurementtechniques, including awake average SBP and clinic and standardizedSBP, did not relate directly to allograft GFR. No correlationwas observed between nocturnal fall in SBP and cv score or GFRin recipients with biopsies that demonstrated CAN, inflammation,or glomerular disease, likely reflecting the detrimental effectof the underlying pathology on GFR (R = 0.2, P = 0.14).
Figure 3. Relationship between percentage of nocturnal fall in SBP and 1-yr GFR in recipients with normal histologic findings. Scatter plot of 1-yr GFR in relation to percentage of nocturnal fall in SBP in 47 recipients with normal histologic findings on 1-yr surveillance biopsy. There was a strong correlation between 1-yr GFR and percentage of nocturnal fall in SBP in this subset of patients (R = 0.4, P = 0.006). This correlation was still present on a multivariate analysis that included GFR as the dependent variable as indicated in the Results section.
The results of our study both identify correlates of abnormalday–night BP change and relate these measurements to allograftfunction and histology 1 yr after transplantation in 119 kidneytransplant recipients. The majority of these patients were receivingantihypertensive medications, with 85 (71%) achieving targetBP levels. Older recipients, presence of diabetes, high cv score,and elevated RI tended to associate with abnormal circadianBP rhythms. Nocturnal fall in SBP and GFR were related withworse allograft function in those with abnormal circadian BPchange. These changes were most evident in those with a paradoxicrise in nocturnal BP. Perhaps most important, recipients withnormal allograft histology at 1 yr after transplantation demonstrateda direct correlation between the percentage of nocturnal fallin SBP and GFR as measured by iothalamate clearance. Doppler-derivedRI was also independently related to iothalamate clearance,indicating that there is a relationship among diurnal BP pattern,GFR, cv changes, and elevated RI independent of allograft fibrosis.
Our results extend previous observations from reports that studiedABPM in kidney transplant recipients who were maintained mainlyon cyclosporine-based immunosuppression. These reports indicateda prevalence of abnormal diurnal variation that ranged from25 to 100% (10,22–24). For some of these reports, disturbancesin day–night change in SBP are related to cyclosporinedosage and poor allograft function (25–27). A recent studyby Covic et al. (22) identified an abnormal BP pattern in all20 studied cyclosporine-treated and rejection-free kidney transplantrecipients without diabetes 1 mo after transplant who laternormalized the BP pattern in eight (40%) by 1 yr. These authorsattributed the recovery of diurnal pattern to the reductionin immunosuppression level. The prevalence of abnormal day–nightBP pattern in tacrolimus-treated kidney transplant patientshas not been examined in large series. Our results indicatedthat abnormal BP diurnal variation was common, affecting 75%of tacrolimus-treated kidney transplant recipients who otherwisehad stable allograft function 1 yr after transplantation. Ourfindings also indicated that the average trough tacrolimus leveldid not relate to the day–night BP pattern, unlike reportsfrom cyclosporine-based regimens. Whether the use of calcineurininhibitor–free and/or steroid free immunosuppression protocolswill favorably affect the diurnal SBP pattern in transplantrecipients has not been tested and merits evaluation in futuretrials.
Older age is associated with lack of normal nocturnal fall inSBP in kidney transplant recipients (10). In addition to recipient'sage, our study identified diabetes, elevated RI, and lower GFRas correlates of abnormal day–night SBP change. The findingthat nondipper status is associated with diabetes is recognizedas a feature of autonomic dysfunction, regardless of renal function(28). Although the relationship between diabetes and abnormalBP pattern did not reach statistical significance in this study(P = 0.06), this is probably because of the small sample size.RI is promoted as a general marker of vascular compliance (13,14).An elevated RI is associated with older recipient age and increasedpulse pressure and is a predictor of renal allograft survivaland death from cardiovascular disease (13,15,16,29). The correlationbetween elevated RI and lack of nocturnal fall in SBP in ourcohort has at least two possible explanations. First, loss ofnormal day–night BP change may be a manifestation of decreasedvascular compliance as evidenced by elevated RI. Alternatively,identified (old age, increased pulse pressure, low GFR) or unidentifiedfactors may be simultaneously responsible for both abnormaldiurnal BP pattern and elevated RI. We cannot distinguish whichone of these explanations is operative, but we interpret ourresults to demonstrate that loss of normal SBP diurnal variationand elevated RI are related. Remarkably, RI was similar betweenpatients with normal and pathologic biopsies with early CANand had no evident correlation with the Banff ’97 acuityor chronicity indices (data not shown). These results indicatedthat elevated RI in our patients was not necessarily a reflectionof parenchymal renal injury but rather was a reflection of vasculardisease primarily. This interpretation is supported by previousstudies that showed no correlation between high RI and protocolbiopsy findings in 87 kidney transplant recipients (16). Heineet al. (30,31) documented a direct relationship between elevatedRI and subclinical extrarenal atherosclerotic vascular diseasein both kidney transplant recipients and patients with CKD.Regardless of the interpretation, our study identified elevatedRI as an independent predictor of GFR 1 yr after transplantationin recipients with normal histologic findings and with no historyof rejection. This observation highlights the potential importanceof elevated RI in identifying a group of transplant patientswho are at risk for early loss of kidney function and mightbenefit from therapeutic interventions, possibly directed towardimproving vascular compliance (32).
Is the loss of circadian BP rhythm a pathogenic factor involvedin allograft function loss? Loss of circadian BP changes hasbeen linked to target organ damage and accelerated kidney functionloss in hypertensive patients with and without CKD (9,33,34).Although uncontrolled systemic hypertension is related to poorallograft and patient survival after kidney transplantation,loss of normal nocturnal fall in SBP, independent of BP control,has not been fully defined as a promoter of kidney functionattrition after transplantation (2,35,36). Haydar et al. (37)studied the role of ABPM-derived BP values that were obtainedat 2 to 34 wk after transplantation in predicting renal functiondecline in 177 kidney transplant recipients. After 48 to 287wk of follow-up, last serum creatinine correlated only withearly transplant kidney function with no observed differencebetween dippers and nondippers. Although the results are consistentwith lack of a protective effect of a dipper status, it shouldbe noted that the time points at which ABPM was obtained aswell as the follow-up periods were widely variable between patients.Moreover, serum creatinine rather than GFR was used for allograftmonitoring. Our results indicate that nondipper status and reversedipper status confer worse allograft function at 1 yr from transplantationin this homogeneously monitored group of patients with ABPMand iothalamate clearance obtained at a fixed time point aftertransplantation. Moreover, the percentage of nocturnal fallin SBP was an independent correlate to 1-yr GFR, especiallyin recipients with normal allograft histology. Our data cannotestablish whether the nocturnal rise in SBP is itself the injuriousfactor or patients who develop poor allograft function manifestfirst with loss of circadian change in SBP. However, the findingof more pronounced vascular injury as indicated by higher RIand a trend toward a higher cv score (P = 0.07) in nondippersand reverse dippers makes us hypothesize that lack of nocturnalfall in SBP has a detrimental effect on allograft function,at least in recipients with normal histology. It is also noteworthyto mention that awake SBP obtained by different BP measurementtechniques did not relate directly to allograft GFR at thisearly time point. These data support the contention that ABPMshould be a preferred method to evaluate systemic hypertensionin kidney transplant patients and that its benefits extend beyondthe diagnosis of hypertension or monitoring antihypertensivetherapy. Whether implementing protocols that are targeted directlyto control nighttime hypertension or identifying and treatingother factors that induce nocturnal hypertension (e.g., sleepapnea) will confer functional benefit is an important questionthat merits consideration in future trials.
Our study represents the largest comprehensive series to datethat correlates ABPM values with allograft kidney function,histologic changes, and ultrasound findings. It must be recognizedthat our data are limited to the studied population, which consistedmainly of white patients who received living-donor kidney transplants.The population that was selected for review comprised a consecutivegroup of kidney transplant recipients without evident selectionbias. The clinical features, pretransplantation diagnosis, andimmunosuppression were consistent with other temporal cohortsfrom our institution (38–40). We also sampled a periodin our practice during which the annual follow-up was homogeneousand consistent among patients. These data provide informationregarding the relationships between diurnal BP measurementsand early allograft structure and function. Whether such relationshipswill extend to long-term injury or progressive allograft dysfunctionis an important question that cannot be addressed with thisstudy.
Taken together, our results identified a relationship betweenloss of nocturnal fall in SBP and low GFR, increased cv score,and high RI 1 yr after transplantation. These findings suggestthat in addition to immunologic injury and early allograft fibrosis,nocturnal hypertension can be added as cause of early allograftdysfunction. Therapeutic measures that aim to diagnose and treatabnormal BP diurnal variation in kidney transplant patientsare needed to determine whether normalization of the BP patternwill translate into functional or survival benefit.
We acknowledge the contributions of Kerrie E. Lansing, clinicalresearch coordinator, Kidney Pancreas Transplant Program, MayoClinic Jacksonville, for assistance in the statistical analysisand Muhammed AbuAttieh, MD, for his effort in data collection.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Top
Abstract
Introduction
SBP 
10%), nondippers (
2 was used for 2 x 2 table associations. For analysis of the effect of different clinical variables on 1-yr iothalamate clearance, a univariate analysis was conducted first. Variables that were significant in the univariate analysis were included in a stepwise logistic regression model that included the 1-yr iothalamate clearance as the dependent variable. 
