Pediatric Urology Ambulatory Blood Pressure Monitoring in Children With Vesicoureteral Reflux Sevgi Yavuz, Ali Anarat, and Aysun Karabay Bayazıt OBJECTIVE METHODS
RESULTS
CONCLUSION
To assess the value of ambulatory blood pressure monitoring (ABPM) for identifying the risk of hypertension (HT) in children with vesicoureteral reflux (VUR). Seventy-six children with primary VUR were enrolled. Patients were divided into 2 groups according to renal scarring (RS). Serum creatinine, urine protein, and urine creatinine were measured. All patients underwent ABPM and casual blood pressure (BP) examination. ABPM measurements were standardized to age, gender, and height by Lambda-Mu-Sigma method. Urine protein and creatinine concentrations were statistically higher in RS (þ) group than RS () group (P ¼ .05). Casual systolic and diastolic BP standard deviation score (SDS) values were not statistically different between RS (þ) and RS () groups. Day, night and 24-hour systolic BP SDS, day and 24-hour mean arterial blood pressure SDS values were significantly higher in RS (þ) group than that of RS () group (P ¼ .015, P ¼ .031, P ¼ .013, P ¼ .07, and P ¼ .021, respectively). All ABPM values significantly increased in patients with severe RS compared with ones with mild and moderate RS (P .05). ABPM is more sensitive than casual BP measurements and might be used for early identification of HT in VUR patients. The severity of RS increases the risk of HT in children with VUR. Controlling HT with proteinuria would decrease the progression of renal damage in VUR. UROLOGY 83: 899e903, 2014. 2014 Elsevier Inc.
V
esicoureteral reflux (VUR) is a common entity in pediatric urology practice. Despite the recent diagnostic and curative advances, it remains as one of the major causes of chronic kidney disease (CKD) in children. Reflux nephropathy (RN) refers the renal scarring (RS) that occurs as a result of pyelonephritis or primary renal dysplasia. The exact pathophysiology for the development of RN is unclear, and prediction of RN remains of interest. Potential long-term sequelae of RN include hypertension (HT), loss of renal function, and CKD.1,2 Proteinuria and HT, both indicators of renal damage, accelerate the progression of RN to CKD.1-3 HT in RN is thought to be related with reninaldosteron-angiotensin system (RAS) abnormalities and segmental ischemia.3,4 The degree of renal parenchymal damage, involvement of unilateral or bilateral kidneys, and age of the patient influence the frequency of HT.5 Given the close relationship between HT and RN, the authors recommend close monitoring of blood pressure (BP) in those children.2-5 Office measurement of BP is practical and inexpensive. However, it might not Financial Disclosure: The authors declare that they have no relevant financial interests. From the Division of Pediatric Nephrology, Cukurova University School of Medicine, Adana, Turkey Reprint requests: Sevgi Yavuz, M.D., Division of Pediatric Nephrology, Cukurova University School of Medicine, 01330 Adana, Turkey. E-mail: [email protected] Submitted: August 28, 2013, accepted (with revisions): October 8, 2013
ª 2014 Elsevier Inc. All Rights Reserved
properly demonstrate the white-coat and masked HT. Ambulatory blood pressure monitoring (ABPM) permits the evaluation of BP throughout the day, quantifies circadian BP variability, detects masked HT, and also eliminates the white coat effect. ABPM correlates better with end organ damage.6,7 ABPM has been widely used for the assessment of HT in adults. However, its routine application in pediatric clinical settings is limited. It is another debate how to analyze ABPM results, as BP range varies with size and maturity in childhood.6,7 The currently accepted normal values for pediatric ABPM are based on 2 studies conducted in the same pediatric cohort, including approximately 1200 Central European Caucasian children.8,9 These ABPM studies implemented regression methods to compute 95th percentile BP thresholds. Soergel et al8 assumed normally distributed BP, whereas Wühl et al9 used Lambda-Mu-Sigma (LMS) correction to normalize data before applying regression analysis. The LMS technique allowed direct calculation of standard deviation scores (SDS) of mean BP for gender and height.8-10 Recently, American Heart association adapted Wühl’s limits and updated recommendations for standard assessment of ABPM in children and adolescents.11 In the face of the advantages of ABPM, we aimed to assess the value of ABPM using LMS method for identifying the risk of HT in children with VUR. 0090-4295/14/$36.00 http://dx.doi.org/10.1016/j.urology.2013.10.008
899
MATERIALS AND METHODS
Table 1. Characteristics of study patients with and without renal scarring
Study Population Seventy-six children with primary VUR were enrolled in our study in Cukurova University Hospital. The exclusion criteria were age younger than 5 years, height below 120 cm, additional urinary tract abnormality or other chronic disease, and use of current antihypertensive medication or other BP-affecting drugs. Age, gender, and anthropometric data were recorded. The presence of VUR was determined using voiding cystourethrogram and graded from I to V according to International Reflux Study Group.12 The grade of reflux was summed up if bilateral. The severity of reflux was graded in 3 groups. Grade 1-2, grade 3-6, grade VUR 7 was considered as mild, moderate, and severe, respectively.13 RS was evaluated with 99mTc-dimercaptosuccinic acid (DMSA) syntigraphy. RS was defined as decreased uptake with loss of normal renal contour on the follow-up DMSA syntigraphy.14 The renal cortex was divided into 12 segments. The affected renal parenchymal segments were assessed using the DMSA grading system of Ziessman and Majd as none (no segments affected), mild (1-2 segments affected), moderate (2-3 segments affected), and severe (4 segments affected).15 The project was approved by the ethics committee of Cukurova University Hospital, and written informed consent was received from at least one of the parents in all cases.
Study Design On the day of ABPM, all patients supplied blood and urine samples for measurement of serum creatinine (Scr), urine protein (Up), and creatinine (Ucr), which were concurrently determined by turbidimetric assay on a Beckman Coulter AU analyzer (Beckman Coulter, CA). Estimated glomerular filtration rates (eGFR) of the patients were calculated based on the new Schwartz formula (eGFR [mL/min/1.73 m2] ¼ 0.413 height [cm]/Scr [mg/dL]).16 Children were divided into 2 groups according to the presence of RS. The patients with RS were redivided into 3 groups as mild, moderate, and severe based on the grade of RS.15 Office BP was measured 3 times consecutively by a mercury sphygmomanometer after 5 minutes rest time. The average of the values was used in analysis. To standardize BP for differences in age and height, z scores were calculated according to data given in the Forth Report of Task Force.17 Twenty-four-hour ABPM was performed using a noninvasive oscillometric device (SpaceLabs Monitor 90207; Spacelabs Inc, Reymond, WA). The size of the cuff was selected according to the recommendations of the Forth Report of the National High Blood Pressure Education Program Working Group in the USA.17 An appropriate cuff was wrapped around the nondominant arm. The device was programmed to measure BP every 15-20 minutes during daytime and every 30 minutes during the night. The sleep and awakeness periods of the patients were recorded as daytime and night. According to the reference values for gender and height taken from the article of Wühl et al, data were analyzed by LMS method that uses the formula as follows: Z score ðSDSÞ ¼ ðY = MðtÞÞLðtÞ 1=LðtÞ SðtÞ Y is the patients’ individual systolic BP, diastolic BP, mean arterial blood pressure (MAP) measurements, M(t) is median of Y, L(t) is the corresponding measure of skewness, S(t) is the 900
Parameter
RS () (n ¼ 28)
RS (þ) (n ¼ 48)
Age (y) 9.55 2.9 9.86 3.2 Gender (girl/boy) 17/11 32/16 Height 138.7 16.5 134.6 13.9 Weight 34.5 13.6 33.8 13.8 Grade of VUR, n (%) Mild (1-2) 16 13 Moderate (3-6) 10 29 Severe (7) 2 6 Scr (mg/dL) 0.48 0.48 0.73 0.76 eGFR (mL/min/ 152.9 56.6 112 46.6 1.73 m2) Up/Ucr (mg/g) 0.15 0.26 0.37 0.56
P Value .67 .63 .26 .82 .03 .12 .01 .05
eGFR, estimated glomerular filtration rate; RS, renal scarring; Scr, serum creatinine; Up/Ucr, urine protein/urine creatinine; VUR, vesicoureteral reflux.
coefficient of variation corresponding L(t).9 Mean SDS values of daytime, nighttime, and 24-hour ABPM measurements in study groups and subgroups were compared.
Data Analyses The statistical analysis was performed by SPSS version 16.0 for Windows (SPSS; Chicago, IL). The normality of distribution of measured parameters in the 2 groups was controlled with Kolmogorov-Smirnov test. Normally distributed data were compared using t test, and results were expressed as means standard deviations. For variables with a skewed distribution, descriptive results were presented as median and ranges. The Mann-Whitney U and Kolmogorov-Smirnov tests were used to assess the differences between groups. One-way analysis of variance and/or Kruskall-Wallis tests were used to compare the results between subgroups. Categorical variables were expressed as proportions and compared with using Chi-square test. For all tests, P value .05). Night MAP SDS values were only statistically significant between mild and moderate RS subgroups (P ¼ .035). All ABPM values were statistically higher in patients with severe RS compared with ones with mild and moderate RS (P .05).
COMMENT RN is the most common cause of HT in children.4,5 Currently, no clear-cut guidelines based on long-term prospective studies are available on how to follow-up children with VUR for the development of HT. It is well known that casual BP evaluation might fail to detect HT and end organ failure.6,7 Similarly, in the present study, casual BP measurements were all within normal ranges and did not differ with presence or the grade of RS. However, our ABPM data demonstrated that the risk of HT was higher in the presence of RS, and this risk was increased with the severity of RS. These findings suggested that the children with VUR, particularly the ones with severe RS might benefit from close monitoring with ABPM. Retrospective studies have shown that HT affects at least 10% of children with RN.18,19 In the present study, nearly 15% of our patients found to have HT using ABPM. In a similar study, Patzer et al20 reported much higher percentage of HT (28%). This discrepancy might UROLOGY 83 (4), 2014
be because of higher RS rates in previous study compared with our study (96% vs 63%). However, Wennerstr€ om et al21 found a 9% incidence of HT in patients with RS. However, their mean age was older than our group and HT definitions and also reference groups were so different from ours. Published data of ABPM in VUR and RN are limited. Similar to the present study, Patzer et al used LMS method and indicated a significant positive correlation between the extent of RS and systolic-diastolic BP SDS values.18 In another study, reference values for ABPM were based on the data that provided from a sample of 241 healthy Mediterranean children. As observed in our study, all children with RN were found to be normotensive, whereas daytime, nighttime, and 24-hour systolic and diastolic BP measurements and BP loads were significantly increased in patients with severe RN.22 Recently, Fidan et al23 identified more patients as hypertensive with ABPM compared with casual office BP measurements. They also found 24-hour systolic and diastolic BP measurements and BP loads higher in children with high grade of RS. In the present study, systolic, diastolic, and MAP readings during daytime, nighttime, and 24 hour were significantly elevated in children with moderate and severe scarring as well. The results of the present and previous studies confirmed the predisposing role of RS in the pathophysiology of HT in children and also showed the superiority of ABPM to clinical BP measurements in diagnosing HT in the same patient group. It is worthy of note that either frequency of HT or measurement of BP SDS was not affected by the grade of VUR in our study. Similarly, BP was independent of severity of VUR in the report of Patzer et al.18 After a follow-up of 10 years, Wolfish et al24 similarly concluded that severity of reflux was not associated with development of HT. In contrast, Fidan et al23 found increased HT rates in parallel with increasing degree of VUR. This might be explained using different classifications for defining the severity of VUR in previous studies. Proteinuria is a hallmark of permanent kidney injury. Several studies have already demonstrated a correlation 901
between proteinuria and a risk for CKD in RN.25-27 In agreement with classical published data, significant proteinuria was evident in our patients with RS. Despite the increase in Up/Ucr and BP SDS values, renal function tests did not differ according to the presence of RS. This finding supported the early indicative role of proteinuria for determining the candidates of CKD in VUR and RN. In addition, reduction of proteinuria and BP levels seemed to be a rational approach for preventing CKD in VUR patients, as it was outlined in published reports for slowing the progression of CKD.28 In this setting, RAS antagonists would be a good choice, particularly when the preliminary roles of RAS abnormalities were considered. This study has some limitations. The sample size is relatively small and represented from a single center. Because reference ABPM data was determined for children older than 5 years and taller than 120 cm, our results might not be accurate for younger and shorter children. In addition, BP loads were not calculated because we used LMS method.
CONCLUSION The severity of RS increases the risk of HT in children with VUR. The degree of VUR seems not to be affecting the BP values. ABPM is more sensitive than casual BP measurements and might be used for early detection of HT in patients with VUR. Controlling HT with proteinuria would slow the progression of renal damage in VUR. References
Figure 1. Comparison of systolic blood pressure (BP), diastolic BP, and mean arterial pressure (MAP) standard deviation score (SDS) values in patients according to renal scarring (RS).
902
1. Brakeman P. Vesicoureteral reflux, reflux nephropathy, and endstage renal disease. Adv Urol 2008:508949. 2. Cendron M. Reflux nephropathy. J Pediatr Urol. 2008;4:414-421. 3. Mattoo TK. Vesicoureteral reflux and reflux nephropathy. Adv Chronic Kidney Disease. 2011;18:348-354. 4. Jacobson SH, Ekl€of O, Lins LE, et al. Long-term prognosis of postinfectious renal scarring in relation to radiological findings in childhood-a 27-year follow-up. Pediatr Nephrol. 1992;6:19-24. 5. Smith EA. Pyelonephritis, renal scarring, and reflux nephropathy: a pediatric urologist’s perspective. Pediatr Radiol. 2008;38:76-82. 6. Flynn JT. Ambulatory blood pressure monitoring in children: imperfect yet essential. Pediatr Nephrol. 2011;26:2089-2094. 7. Chadhuri A. Pediatric ambulatory blood pressure monitoring: diagnosis of hypertension. Pediatr Nephrol 28:995e999. 8. Soergel M, Kirschtein M, Busch C, et al. Oscillometric twenty-fourhour ambulatory blood pressure values in healthy children and adolescents: a multicenter trial including 1141 subjects. J Pediatr. 1997;130:178-184. 9. Wühl EA, Witte K, Soergel M, et al. German Working Group on Pediatric Hypertension. Distribution of 24-h ambulatory blood pressure in children: normalized reference values and role of body dimensions. J Hypertens. 2002;20:1995-2007. 10. Bell CS, Poffenbarger TS, Samuels JA. Ambulatory blood pressure status in children: comparing alternate limit sources. Pediatr Nephrol. 2011;26:2211-2217. 11. Urbina E, Alpert B, Flynn J, et al. Ambulatory blood pressure monitoring in children and adolescents: recommendations for standard assessment. Hypertension. 2008;52:433-451. 12. Lebowitz RL, Olbing H, Parkkulainen KV, et al. International system of radiographic grading of vesicoureteral reflux. International Reflux Study in Children. Pediatr Radiol. 1985;15:105-109.
UROLOGY 83 (4), 2014
13. Gokce I, Alpay H, Biyikli N, et al. Urinary levels of interleukin-6 and interleukin-8 in patients with vesicoureteral reflux and renal parenchymal scar. Pediatr Nephrol. 2010;25:905-912. 14. Rushton HG. The evaluation of acute pyelonephritis and renal scarring with technetium 99m-dimercaptosuccinic acid renal scintigraphy: evolving concepts and future directions. Pediatr Nephrol. 1997;11:108-120. 15. Ziessman HA, Majd M. Importance of methodology on 99mtechnetium dimercapto-succinic acid scintigraphic image quality: imaging pilot study for RIVUR (Randomized Intervention for Children with Vesicoureteral Reflux) multicenter investigation. J Urol. 2009;182:272-279. 16. Schwartz GJ, Munoz A, Schneider MF, et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009;20: 629-637. 17. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114: 555-576. 18. Lahdes-Vasama T, Niskanen K, R€onnholm K. Outcome of kidneys in patients treated for vesicoureteral reflux (VUR) during childhood. Nephrol Dial Transplant. 2006;21:2491-2497. 19. Smellie JM, Prescod NP, Shaw PJ, et al. Childhood reflux and urinary tract infection: a follow-up of 10-41 years in 226 adults. Pediatr Nephrol. 1998;12:727-736.
UROLOGY 83 (4), 2014
20. Patzer L, Seeman T, Luck C, et al. Day-and night-time blood pressure elevation in children with higher grades of renal scarring. J Pediatr. 2003;142:117-122. 21. Wennerstr€om M, Hansson S, Hedner T, et al. Ambulatory blood pressure 16-26 years after the first urinary tract infection in childhood. J Hypertens. 2000;18:485-491. 22. Lama G, Tedesco MA, Graziano L, et al. Reflux nephropathy and hypertension: correlation with the progression of renal damage. Pediatr Nephrol. 2003;18:241-245. 23. Fidan K, Kandur Y, Buyukkaragoz B, et al. Hypertension in pediatric patients with renal scarring in association with vesicoureteral reflux. Urology. 2013;81:173-177. 24. Wolfish NM, Delbrouck NF, Shanon A, et al. Prevalence of hypertension in children with primary vesicouretral reflux. J Pediatr. 1993;123:559-563. 25. Ardissino G, Avolio L, Dacco V, et al. Long-term outcome of vesicoureteral reflux associated chronic renal failure in children. Data from the ItalKid Project. J Urol. 2004;172:305-310. 26. Neild GH, Thomson G, Nitsch D, et al. Renal outcome in adults with renal insufficiency and irregular asymmetric kidneys. BMC Nephrol. 2004;5:12. 27. el-Khatib MT, Becker GJ, Kincaid-Smith PS. Reflux nephropathy and primary vesicoureteral reflux in adults. Q J Med. 1990;77:12411253. 28. Wühl E, Schaefer F. Therapeutic strategies to slow chronic kidney disease progression. Pediatr Nephrol. 2008;23:705-716.
903
RESULTS
CONCLUSION
To assess the value of ambulatory blood pressure monitoring (ABPM) for identifying the risk of hypertension (HT) in children with vesicoureteral reflux (VUR). Seventy-six children with primary VUR were enrolled. Patients were divided into 2 groups according to renal scarring (RS). Serum creatinine, urine protein, and urine creatinine were measured. All patients underwent ABPM and casual blood pressure (BP) examination. ABPM measurements were standardized to age, gender, and height by Lambda-Mu-Sigma method. Urine protein and creatinine concentrations were statistically higher in RS (þ) group than RS () group (P ¼ .05). Casual systolic and diastolic BP standard deviation score (SDS) values were not statistically different between RS (þ) and RS () groups. Day, night and 24-hour systolic BP SDS, day and 24-hour mean arterial blood pressure SDS values were significantly higher in RS (þ) group than that of RS () group (P ¼ .015, P ¼ .031, P ¼ .013, P ¼ .07, and P ¼ .021, respectively). All ABPM values significantly increased in patients with severe RS compared with ones with mild and moderate RS (P .05). ABPM is more sensitive than casual BP measurements and might be used for early identification of HT in VUR patients. The severity of RS increases the risk of HT in children with VUR. Controlling HT with proteinuria would decrease the progression of renal damage in VUR. UROLOGY 83: 899e903, 2014. 2014 Elsevier Inc.
V
esicoureteral reflux (VUR) is a common entity in pediatric urology practice. Despite the recent diagnostic and curative advances, it remains as one of the major causes of chronic kidney disease (CKD) in children. Reflux nephropathy (RN) refers the renal scarring (RS) that occurs as a result of pyelonephritis or primary renal dysplasia. The exact pathophysiology for the development of RN is unclear, and prediction of RN remains of interest. Potential long-term sequelae of RN include hypertension (HT), loss of renal function, and CKD.1,2 Proteinuria and HT, both indicators of renal damage, accelerate the progression of RN to CKD.1-3 HT in RN is thought to be related with reninaldosteron-angiotensin system (RAS) abnormalities and segmental ischemia.3,4 The degree of renal parenchymal damage, involvement of unilateral or bilateral kidneys, and age of the patient influence the frequency of HT.5 Given the close relationship between HT and RN, the authors recommend close monitoring of blood pressure (BP) in those children.2-5 Office measurement of BP is practical and inexpensive. However, it might not Financial Disclosure: The authors declare that they have no relevant financial interests. From the Division of Pediatric Nephrology, Cukurova University School of Medicine, Adana, Turkey Reprint requests: Sevgi Yavuz, M.D., Division of Pediatric Nephrology, Cukurova University School of Medicine, 01330 Adana, Turkey. E-mail: [email protected] Submitted: August 28, 2013, accepted (with revisions): October 8, 2013
ª 2014 Elsevier Inc. All Rights Reserved
properly demonstrate the white-coat and masked HT. Ambulatory blood pressure monitoring (ABPM) permits the evaluation of BP throughout the day, quantifies circadian BP variability, detects masked HT, and also eliminates the white coat effect. ABPM correlates better with end organ damage.6,7 ABPM has been widely used for the assessment of HT in adults. However, its routine application in pediatric clinical settings is limited. It is another debate how to analyze ABPM results, as BP range varies with size and maturity in childhood.6,7 The currently accepted normal values for pediatric ABPM are based on 2 studies conducted in the same pediatric cohort, including approximately 1200 Central European Caucasian children.8,9 These ABPM studies implemented regression methods to compute 95th percentile BP thresholds. Soergel et al8 assumed normally distributed BP, whereas Wühl et al9 used Lambda-Mu-Sigma (LMS) correction to normalize data before applying regression analysis. The LMS technique allowed direct calculation of standard deviation scores (SDS) of mean BP for gender and height.8-10 Recently, American Heart association adapted Wühl’s limits and updated recommendations for standard assessment of ABPM in children and adolescents.11 In the face of the advantages of ABPM, we aimed to assess the value of ABPM using LMS method for identifying the risk of HT in children with VUR. 0090-4295/14/$36.00 http://dx.doi.org/10.1016/j.urology.2013.10.008
899
MATERIALS AND METHODS
Table 1. Characteristics of study patients with and without renal scarring
Study Population Seventy-six children with primary VUR were enrolled in our study in Cukurova University Hospital. The exclusion criteria were age younger than 5 years, height below 120 cm, additional urinary tract abnormality or other chronic disease, and use of current antihypertensive medication or other BP-affecting drugs. Age, gender, and anthropometric data were recorded. The presence of VUR was determined using voiding cystourethrogram and graded from I to V according to International Reflux Study Group.12 The grade of reflux was summed up if bilateral. The severity of reflux was graded in 3 groups. Grade 1-2, grade 3-6, grade VUR 7 was considered as mild, moderate, and severe, respectively.13 RS was evaluated with 99mTc-dimercaptosuccinic acid (DMSA) syntigraphy. RS was defined as decreased uptake with loss of normal renal contour on the follow-up DMSA syntigraphy.14 The renal cortex was divided into 12 segments. The affected renal parenchymal segments were assessed using the DMSA grading system of Ziessman and Majd as none (no segments affected), mild (1-2 segments affected), moderate (2-3 segments affected), and severe (4 segments affected).15 The project was approved by the ethics committee of Cukurova University Hospital, and written informed consent was received from at least one of the parents in all cases.
Study Design On the day of ABPM, all patients supplied blood and urine samples for measurement of serum creatinine (Scr), urine protein (Up), and creatinine (Ucr), which were concurrently determined by turbidimetric assay on a Beckman Coulter AU analyzer (Beckman Coulter, CA). Estimated glomerular filtration rates (eGFR) of the patients were calculated based on the new Schwartz formula (eGFR [mL/min/1.73 m2] ¼ 0.413 height [cm]/Scr [mg/dL]).16 Children were divided into 2 groups according to the presence of RS. The patients with RS were redivided into 3 groups as mild, moderate, and severe based on the grade of RS.15 Office BP was measured 3 times consecutively by a mercury sphygmomanometer after 5 minutes rest time. The average of the values was used in analysis. To standardize BP for differences in age and height, z scores were calculated according to data given in the Forth Report of Task Force.17 Twenty-four-hour ABPM was performed using a noninvasive oscillometric device (SpaceLabs Monitor 90207; Spacelabs Inc, Reymond, WA). The size of the cuff was selected according to the recommendations of the Forth Report of the National High Blood Pressure Education Program Working Group in the USA.17 An appropriate cuff was wrapped around the nondominant arm. The device was programmed to measure BP every 15-20 minutes during daytime and every 30 minutes during the night. The sleep and awakeness periods of the patients were recorded as daytime and night. According to the reference values for gender and height taken from the article of Wühl et al, data were analyzed by LMS method that uses the formula as follows: Z score ðSDSÞ ¼ ðY = MðtÞÞLðtÞ 1=LðtÞ SðtÞ Y is the patients’ individual systolic BP, diastolic BP, mean arterial blood pressure (MAP) measurements, M(t) is median of Y, L(t) is the corresponding measure of skewness, S(t) is the 900
Parameter
RS () (n ¼ 28)
RS (þ) (n ¼ 48)
Age (y) 9.55 2.9 9.86 3.2 Gender (girl/boy) 17/11 32/16 Height 138.7 16.5 134.6 13.9 Weight 34.5 13.6 33.8 13.8 Grade of VUR, n (%) Mild (1-2) 16 13 Moderate (3-6) 10 29 Severe (7) 2 6 Scr (mg/dL) 0.48 0.48 0.73 0.76 eGFR (mL/min/ 152.9 56.6 112 46.6 1.73 m2) Up/Ucr (mg/g) 0.15 0.26 0.37 0.56
P Value .67 .63 .26 .82 .03 .12 .01 .05
eGFR, estimated glomerular filtration rate; RS, renal scarring; Scr, serum creatinine; Up/Ucr, urine protein/urine creatinine; VUR, vesicoureteral reflux.
coefficient of variation corresponding L(t).9 Mean SDS values of daytime, nighttime, and 24-hour ABPM measurements in study groups and subgroups were compared.
Data Analyses The statistical analysis was performed by SPSS version 16.0 for Windows (SPSS; Chicago, IL). The normality of distribution of measured parameters in the 2 groups was controlled with Kolmogorov-Smirnov test. Normally distributed data were compared using t test, and results were expressed as means standard deviations. For variables with a skewed distribution, descriptive results were presented as median and ranges. The Mann-Whitney U and Kolmogorov-Smirnov tests were used to assess the differences between groups. One-way analysis of variance and/or Kruskall-Wallis tests were used to compare the results between subgroups. Categorical variables were expressed as proportions and compared with using Chi-square test. For all tests, P value .05). Night MAP SDS values were only statistically significant between mild and moderate RS subgroups (P ¼ .035). All ABPM values were statistically higher in patients with severe RS compared with ones with mild and moderate RS (P .05).
COMMENT RN is the most common cause of HT in children.4,5 Currently, no clear-cut guidelines based on long-term prospective studies are available on how to follow-up children with VUR for the development of HT. It is well known that casual BP evaluation might fail to detect HT and end organ failure.6,7 Similarly, in the present study, casual BP measurements were all within normal ranges and did not differ with presence or the grade of RS. However, our ABPM data demonstrated that the risk of HT was higher in the presence of RS, and this risk was increased with the severity of RS. These findings suggested that the children with VUR, particularly the ones with severe RS might benefit from close monitoring with ABPM. Retrospective studies have shown that HT affects at least 10% of children with RN.18,19 In the present study, nearly 15% of our patients found to have HT using ABPM. In a similar study, Patzer et al20 reported much higher percentage of HT (28%). This discrepancy might UROLOGY 83 (4), 2014
be because of higher RS rates in previous study compared with our study (96% vs 63%). However, Wennerstr€ om et al21 found a 9% incidence of HT in patients with RS. However, their mean age was older than our group and HT definitions and also reference groups were so different from ours. Published data of ABPM in VUR and RN are limited. Similar to the present study, Patzer et al used LMS method and indicated a significant positive correlation between the extent of RS and systolic-diastolic BP SDS values.18 In another study, reference values for ABPM were based on the data that provided from a sample of 241 healthy Mediterranean children. As observed in our study, all children with RN were found to be normotensive, whereas daytime, nighttime, and 24-hour systolic and diastolic BP measurements and BP loads were significantly increased in patients with severe RN.22 Recently, Fidan et al23 identified more patients as hypertensive with ABPM compared with casual office BP measurements. They also found 24-hour systolic and diastolic BP measurements and BP loads higher in children with high grade of RS. In the present study, systolic, diastolic, and MAP readings during daytime, nighttime, and 24 hour were significantly elevated in children with moderate and severe scarring as well. The results of the present and previous studies confirmed the predisposing role of RS in the pathophysiology of HT in children and also showed the superiority of ABPM to clinical BP measurements in diagnosing HT in the same patient group. It is worthy of note that either frequency of HT or measurement of BP SDS was not affected by the grade of VUR in our study. Similarly, BP was independent of severity of VUR in the report of Patzer et al.18 After a follow-up of 10 years, Wolfish et al24 similarly concluded that severity of reflux was not associated with development of HT. In contrast, Fidan et al23 found increased HT rates in parallel with increasing degree of VUR. This might be explained using different classifications for defining the severity of VUR in previous studies. Proteinuria is a hallmark of permanent kidney injury. Several studies have already demonstrated a correlation 901
between proteinuria and a risk for CKD in RN.25-27 In agreement with classical published data, significant proteinuria was evident in our patients with RS. Despite the increase in Up/Ucr and BP SDS values, renal function tests did not differ according to the presence of RS. This finding supported the early indicative role of proteinuria for determining the candidates of CKD in VUR and RN. In addition, reduction of proteinuria and BP levels seemed to be a rational approach for preventing CKD in VUR patients, as it was outlined in published reports for slowing the progression of CKD.28 In this setting, RAS antagonists would be a good choice, particularly when the preliminary roles of RAS abnormalities were considered. This study has some limitations. The sample size is relatively small and represented from a single center. Because reference ABPM data was determined for children older than 5 years and taller than 120 cm, our results might not be accurate for younger and shorter children. In addition, BP loads were not calculated because we used LMS method.
CONCLUSION The severity of RS increases the risk of HT in children with VUR. The degree of VUR seems not to be affecting the BP values. ABPM is more sensitive than casual BP measurements and might be used for early detection of HT in patients with VUR. Controlling HT with proteinuria would slow the progression of renal damage in VUR. References
Figure 1. Comparison of systolic blood pressure (BP), diastolic BP, and mean arterial pressure (MAP) standard deviation score (SDS) values in patients according to renal scarring (RS).
902
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