Early posttransplantation hypertension and poor long-term renal allograft survival in pediatric patients

Early posttransplantation hypertension and poor long-term renal allograft survival in pediatric patients

EARLY POSTTRANSPLANTATION HYPERTENSION AND POOR LONG-TERM RENAL ALLOGRAFT SURVIVAL IN PEDIATRIC PATIENTS MARK M. MITSNEFES, MD, PHILIP R. KHOURY, MS, ...

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EARLY POSTTRANSPLANTATION HYPERTENSION AND POOR LONG-TERM RENAL ALLOGRAFT SURVIVAL IN PEDIATRIC PATIENTS MARK M. MITSNEFES, MD, PHILIP R. KHOURY, MS, AND PAUL T. MCENERY, MD

Objective

To evaluate the effect of early hypertension on long-term allograft survival in children with kidney trans-

plantation.

Study design Data from a total of 159 patients (mean age, 12.8 ± 4.8 years) who underwent kidney transplantation between 1978 and 1998 and whose allograft was functioning for at least 1 year were analyzed retrospectively. Patients were divided according to the presence of hypertension within the first year after transplantation. Primary outcome was time of allograft failure (death, return to dialysis, or retransplantation). Results

Kaplan-Meier analysis showed that systolic (P < .0001) and diastolic (P = .016) hypertension was associated with overall worse allograft survival. Children with systolic hypertension had a significantly higher graft failure rate regardless of the type of donor, cause of kidney failure, presence or absence of acute rejection, and allograft function at 1 year after transplantation. The multivariate Cox regression model proved that systolic hypertension was a significant and independent risk factor for poor graft survival (hazard ratio [HR], 1.79; P < .0001). Other predictors included allograft function at 1 year after transplantation (HR, 0.97; P < .0001), acquired cause of end-stage kidney disease (HR, 1.96; P = .01) and age < 6 years (HR, 2.61; P = .045).

Conclusions Early posttransplantation systolic hypertension strongly and independently predicts poor long-term graft survival in pediatric patients. (J Pediatr 2003;143:98-103)

ypertension is a frequent complication in children and adolescents with kidney transplantation. The report from North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) demonstrates that the prevalence of hypertension in pediatric renal allograft recipients is between 70% and 80%.1 In adults with kidney transplantation, it is generally accepted that high blood pressure (BP) is associated with accelerated graft failure.2-5 As in adults, high BP in children with kidney transplantation is associated with allograft dysfunction. Recently we showed that in these patients, higher BP within the first months after transplantation is associated with worse allograft function at 1 year.6 Some pediatric data suggest that a higher number of antihypertensive medications after kidney transplantation is associated with increased rate of graft failure.7 A higher number of medications could be a marker for hypertension, which is more difficult to control, but this could also represent more aggressive management of BP to keep it under control. The effect of actual BP on longterm graft function in children after kidney transplantation remains uncertain. The purpose of this study was to evaluate the effect of early hypertension on allograft survival in children with kidney transplantation, by using BP measurements obtained within the first year after transplantation.

H

METHODS Data were obtained retrospectively from the medical records of all 217 patients who underwent kidney transplantation at Cincinnati Children’s Hospital Medical Center BP CAD DBP

98

Blood pressure Cadaveric donor Diastolic blood pressure

ESRD LRD SBP

End-stage renal disease Live related donor Systolic blood pressure

From the Division of Nephrology and Hypertension, Department of Pediatrics, University of Cincinnati College of Medicine and The Children’s Hospital Research Foundation, Cincinnati, Ohio. Submitted for publication Oct 17, 2002; revisions received Feb 7, 2003, and Feb 28, 2003; accepted Apr 3, 2003. Reprint requests: Mark M. Mitsnefes, MD, Division of Nephrology and Hypertension, MLC: 7022, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail: [email protected]. Copyright Ó 2003, Mosby, Inc. All rights reserved. 0022-3476/2003/$30.00 + 0 10.1016/S0022-3476(03)00209-9

Table I. Patient characteristics at 1-year after transplantation Variable Age (y) < 6, n (%) $6, n (%) Follow-up time (y) Sex, n (%) male Race, n (%) White Black Primary kidney disease, n (%) Acquired Dysplasia/obstructive uropathy Metabolic Prior dialysis, n (%) First transplant, n (%) Patients with acute rejections, n (%) Donor type, n (%) LD eGFR, mL/min/1.73 m2 <50, n (%)* 50-75, n (%) >75, n (%)* Calcineurin inhibitors, n (%)

Normotensive Hypertensive n = 60 (38%) n = 99 (62%) 12.9 ± 4.8 4 (7) 56 (93) 8.3 ± 4.8 38 (63)

11.2 ± 4.6 14 (14) 85 (86) 6.3 ± 4.9 59 (60)

53 (88) 7 (12)

82 (82) 17 (18)

18 (30) 38 (63)

39 (39) 50 (51)

4 (6) 47 (79) 45 (75) 26 (43)

10 (10) 82 (83) 69 (70) 39 (39)

27 (45) 74.4 ± 22.3 7 (11) 19 (32) 34 (57) 37 (62)

36 (36) 69.8 ± 25.3 28 (28) 33 (33) 38 (38) 68 (68)

Data presented as mean ± SD or %. Hypertension defined as mean indexed SBP or DBP, or both $ 1.0. *Significant difference (P < .05) between normotensive and hypertensive children.

between 1978 and 1998. In 56 patients, the allograft failed within the first year after transplantation; they were excluded from the study. Two medical records were unavailable for analysis. Data from 159 pediatric patients whose allograft was functioning for at least 1 year were included in the final analysis. The medical records were reviewed for age, sex, race, and cause of end-stage kidney (renal) disease (ESRD), allograft source: live related donor (LRD) and cadaveric donor (CAD), prior dialysis and number of previous transplantations, the number of patients having acute rejections and immunosuppression protocol within the first year after transplantation. An acute rejection episode was defined as a biopsy-proven diagnosis or acute increase in serum creatinine concentration that decreased in response to pulse steroid therapy. The data related to antihypertensive medications were also collected from medical records. Clinical and laboratory data were collected including height, weight, and serum creatinine level at 1 year after kidney transplantation. Estimated glomerular filtration rate (eGFR) was calculated by means of the Schwartz formula.8 Each patient had two BP measurements during each clinic visit. Auscultation was used before 1997, and an automated Early Posttransplantation Hypertension and Poor Long-term Renal Allograft Survival in Pediatric Patients

BP device (Dinamap Inc) has been used after December 1996. The mean value for systolic (SBP) and diastolic (DBP) BP from each visit was calculated. There were 34 ± 19 numbers of BP measurements within the first year after transplantation. The mean of recorded SBP and DBP was calculated and used for final analysis. SBP and DBP were indexed to the age-, sex-, and height-specific 95th percentile value for BP standard for each subject (measured SBP or DBP was divided by the age-, sex-, and height-specific 95th percentile SBP or DBP).9 This standardizes BP for differences in age and size and takes into account relative severity of hypertension. For example, indexed BP of 1.1 means that an person’s actual BP is 10% above the 95th percentile for their age, sex, and height. Even though height at 1 year after transplantation was used to determine the 95th BP percentiles, it is unlikely that children had significant changes in their 95th percentile BP levels since the time of transplantation. Hypertension was defined as mean SBP, DBP, or both equal or greater than the 95th percentile for sex, age, and height10 or mean indexed SBP and DBP or both $1.0. Patients were divided into 2 groups according to the presence of hypertension within the first year after transplantation. Primary outcome was time of allograft failure: death, return to dialysis, or retransplantation. Contrast between hypertensive and normotensive patients was assessed by the log-rank test. The primary survival analysis included the Kaplan-Meier method. The multivariate Cox regression model was then used to assess independent predictors for graft survival. Potential variables included indexed SBP and DBP, eGFR, donor type (LRD, CAD), use of calcineurin inhibitors (yes, no), cause of ESRD (congenital, acquired), acute rejection (yes, no), age (<6, $6 years), sex, and race.

RESULTS Descriptive Data Ninety-nine (62%) patients had either systolic or diastolic, or combined hypertension; 77 (48%) children had only systolic hypertension, and 81 (51%) had only diastolic hypertension at 1 year after transplantation. Comparison between normotensive and hypertensive patients at 1 year after transplantation is shown in Table I. The majority of recipients in both groups were male and white. The most common primary kidney disease causing ESRD in the study patients included renal dysplasia/obstructive uropathy. Most of the patients had prior chronic dialysis and were the first-time recipients of kidney transplantation. Most of the patients in both groups had estimated GFR >50 mL/min per 1.73 m2. Hypertensive patients more frequently had poor allograft function (GFR < 50 mL/min per 1.73 m2) than normotensive children. In contrast, children with normal BP more frequently had GFR >75 mL/min per 1.73 m2 at 1 year after transplantation than hypertensive children. Two thirds of the study patients had triple induction immunosuppressive therapy, including steroids, calcineurin inhibitors (cyclosporine or tacrolimus), and azathioprine or mycophenolate 99

Table II. Use of antihypertensive medications at 1 year after renal transplantation* Antihypertensive medications

Normotensive Hypertensive

None, n (%) One antihypertensive, n (%) Two antihypertensives, n (%) >Two antihypertensives, n (%) Calcium channel blocker, n (%) b-blocker, n (%) Diuretic, n (%) Vasodilator, n (%) ACE inhibitor, n (%)

6 (10) 27 (45) 18 (30) 9 (15)

4 (4) 33 (34) 36 (37) 25 (25)

33 (62)

53 (56)

26 (49) 24 (44) 11 (21) 4 (7)

46 (48) 55 (58) 27 (28) 3 (3)

ACE inhibitor, angiotensin converting enzyme inhibitor. *Data regarding the class of antihypertensive drugs reflect children who were taking BP medications: 54 normotensive and 95 hypertensive children.

mofetil. One third of these children did not receive calcineurin inhibitors. Data on BP medications at 1 year after transplantation are presented in Table II. The majority (90%) of normotensive patients were taking antihypertensive medications. Forty-five percent of normotensive children required more than one antihypertensive medication to control their BP. Almost two thirds of hypertensive children were taking two or more BP medications. Even though hypertensive patients had a tendency to take more BP medications than normotensive patients, the difference was not significant (P > .05). There also was no significant difference between the two groups regarding the class of antihypertensive medications used (P > .05). The management of hypertension has changed over the study period. Before 1989, only 3% of hypertensive children and 2% of normotensive children used calcium channel blockers (CCB), whereas from 1989 to 1998, 94% of normotensive and 91% of hypertensive children were taking CCB.

Survival Analysis Initial analysis (Kaplan-Meier method) showed that systolic (P < .0001) and diastolic (P = .016) hypertension were significantly associated with overall worse allograft survival (Fig 1). Children with systolic hypertension had a significantly higher graft failure rate than children without hypertension, regardless of donor type (LRD, P = .006; CAD, P < .001), cause of ESRD (acquired, P < .0001; congenital, P < .01), age at transplantation (<6 years, P = .02; $6 years, P < .001), use of calcineurin inhibitors (yes, P < .001; no, P = .02), and presence (P < .0001) or absence (P < .001) of acute rejection within the first year of transplantation. Graft survival was significantly worse even in patients with good allograft function but high SBP (eGFR 50-75 mL/min per 1.73 m2, P = .017, eGFR >75 mL/min per 1.73 m2, P < .001) at 1 year after transplantation (Fig 2). The analysis of graft survival in ‘‘low-risk’’ transplant recipients (LRD, no rejection, and GFR 100

Mitsnefes, Khoury, and McEnery

Fig 1. Allograft survival by 1-year indexed SBP and DBP.

$0 mL/min per 1.73 m2) still showed a significant association of SBP with long-term graft outcome (P < .001). For DBP, significant relations between diastolic hypertension and graft survival were found for older children (P = .02), patients with acquired kidney disease (P < .001), and those who had acute rejection (P < .002). To determine whether BP has an independent effect on long-term graft outcome, the data were analyzed by a Cox proportional hazards model (Table III). The analysis showed that high SBP was a significant risk factor for poor graft survival: For each 10% increase in indexed SBP, there was a significant increase in the rate of graft failure. Other risk factors included acute rejection within the first year after The Journal of Pediatrics  July 2003

Table III. Multivariate proportional hazards analysis of determinants of graft survival Hazard ratio (95% CI)

P value

0.74

2.1 (1.62-2.73)

< .0001

0.70 0.61

2.0 (1.26-3.21) 1.84 (1.15-2.96)

.003 .01

0.96

2.6 (1.06-6.43)

.037

Variable

Estimate

Indexed SBP, per 10% increase Acute rejection Acquired cause of ESRD Age <6 y

Table IV. Multivariate proportional hazards analysis of determinants of graft survival adjusted for the baseline allograft function Variable Indexed SBP, per 10% increase eGFR, mL/min/1.73 m2 Acquired cause of ESRD Age <6 y

Estimate

Hazard ratio (95% CI) P value

0.58

1.79 (1.37-2.33)

< .0001

ÿ0.03

0.97 (0.96-0.98)

< .0001

0.67

1.96 (1.22-3.14)

.01

0.96

2.61 (1.01-6.76)

.045

transplantation, acquired cause of ESRD, and young age at time of transplantation. To adjust for the baseline allograft function, we included eGFR to Cox proportional analysis (Table IV). Even after adjustment, indexed SBP remained in the final regression model as a significant and independent predictor of graft failure (P < .0001). Separate analysis performed for DBP (indexed SBP was not in the model) showed that higher indexed DBP predicted impaired graft survival after adjustment for 1-year eGFR (hazard ratio of 1.06, confidence intervals: 1.05-1.11, P < .0001).

DISCUSSION

Fig 2. Allograft survival by 1-year indexed SBP and 1-year graft function. Early Posttransplantation Hypertension and Poor Long-term Renal Allograft Survival in Pediatric Patients

The results of the current study underscore the importance of BP as an independent predictor of graft survival in pediatric patients with kidney transplantation. We demonstrated that for each 10% increase in SBP at 1 year after kidney transplantation there is a doubled risk for subsequent graft failure. The results of this analysis are in agreement with adult studies. Over the last decade there has been an accumulating body of evidence demonstrating the association between increased BP and allograft failure in adults.2-5,11-15 However, there have been very few studies assessing the effect of hypertension on allograft survival in pediatric kidney transplantation recipients. Sorof et al7 analyzed data from 5251 pediatric kidney transplantations, using the NAPRTCS database. They showed that increased use of antihypertensive medications (database does not have 101

actual BP values) was associated with higher rates of graft failure in these children. However, the use of BP medications as a marker of hypertension has significant limitations. Specifically, there is no conclusion that can be drawn about the level of BP control or which patient had hypertension. Most of our studied patients were taking BP medications at 1 year after kidney transplantation regardless of their BP control. Some of these children had normal BP, which indicated successful treatment of previously elevated BP, but others were hypertensive, which suggested the difficulty to control BP even using numerous antihypertensives. Even though there was no significant difference in the number or class of antihypertensives between normotensive and hypertensive children, we could not rule out that hypertensive patients required higher doses of BP medications. In any case, our study demonstrates significant limitation of the use of BP medications as a marker of hypertension. In the current study, we used actual BP values indexed according to children’s age, sex, and height (see METHODS section). This allowed us to assess BP in children of different body sizes and to avoid a bias related to the definition of hypertension as the use of the antihypertensive medications. Furthermore, CCB and ACE inhibitors have been used for their renoprotective effects in the absence of hypertension.16-18 At this center, almost all kidney transplantation recipients (since 1989) are routinely taking a CCB, especially during the first year after transplantation, independent of the presence of hypertension. Not surprisingly, there was no difference in CCB use between normotensive and hypertensive children in this study. The effect of BP on allograft outcome in our study was independent of other known risk factors, such as young age, black race, acquired renal disease as a cause of ESRD, acute rejection, and cadaveric kidney transplantation.19,20 It has also been shown that in adults with introduction of calcineurin inhibitors, the prevalence of post kidney transplantation hypertension rose to 60% to 70%.21 In our analysis, the confounding effect of calcineurin inhibitors did not change the outcome of the study. A negative effect of high SBP on long-term outcome was seen even in ‘‘low-risk’’ children, those with LRD transplantation, no acute rejection, and relatively good allograft function (GFR >50 mL/min per 1.73 m2) at 1 year after transplantation. This is important because some earlier studies argued that increased BP is not the cause but simply a marker of chronic allograft dysfunction that might develop as a result of the presence of the above-described risk factors.3,12,22,23 This might be true for our patients with significant allograft dysfunction, but observations that hypertension was associated with graft failure in recipients with relatively good GFR at 1 year after transplantation strongly suggest a causal relation between high BP and poor graft survival. Recently, Mange et al5 studied the relation between BP and graft survival in 277 adult cadaveric transplantation recipients by taking into an account the baseline graft function. In their study, the effect of high systolic, diastolic, and mean arterial BP at 1 year after transplantation was independent of baseline allograft function in predicting poor long-term allograft survival. As in that study, 102

Mitsnefes, Khoury, and McEnery

in our study the effect of BP remained independent after adjustment for the baseline graft function. These results strongly suggest that hypertension might be a powerful risk factor for the development and progression of chronic renal allograft dysfunction in pediatric patients. There are limitations of this study. First, there was a lack of standardization for BP measurement. Most of the measurements were done by auscultation, but the measurements after 1997 were done by oscillometric device. Second, the use of mean values of BP may limit our ability to truly represent average daily BP. Future studies should rely on ambulatory BP monitoring. Third, we were unable to evaluate the renoprotective effect of antihypertensive medications on allograft function. Fourth, it is possible that we did not fully control for all confounding variables for graft failure. Fifth, from our retrospective study we could not conclude which BP level is safe and what should be the target BP to prevent hypertension-related graft injury. In the study of adults with kidney transplantation, Opelz et al2 showed that even a minimal increase in SBP above the reference level of 140 mm Hg was associated with a poor long-term outcome. The relative risk of graft failure increased from 1.16 in patients with SBP of 140 to 149 mm Hg to 2.06 in those patients with SBP above 180 mm Hg. The National Kidney Foundation Task Force on cardiovascular disease recommends that target BP should be #130/85 mm Hg for adult kidney transplantation recipients without proteinuria and #125/75 mm Hg for proteinuric patients.24 These numbers are 10% to 15% below the reference values of 140/90. However, there are no controlled trials demonstrating that achieving the target BP will lead to improving long-term outcome in kidney transplantation recipients. There are no data available in regard to the target BP in children with chronic kidney disease. The effect of optimal BP on delay in the progression of chronic kidney failure is currently being determined in the European pediatric multicenter study. In this 3-year trial, children with chronic renal insufficiency treated with an ACE inhibitor (ramipril) are randomly assigned to a target BP below 50th percentile or between 50th and 95th percentiles, based on the 24-hour ambulatory BP monitoring standards.25 The results of this trial will not be available until 2004. Should the same strategy in the management of BP in pediatric patients with kidney transplantation be adopted or whether there are any benefits of aggressive BP control for graft survival in these children is yet to be determined in prospective interventional studies.

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Early Posttransplantation Hypertension and Poor Long-term Renal Allograft Survival in Pediatric Patients

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