ORIGINAL ARTICLE

Is microalbuminuria a risk factor for hypertension in childrenwith solitary kidney?

Ayoub Shirzai & Nurdan Yildiz & Nese Biyikli &Seyfettin Ustunsoy & Meryem Benzer & Harika Alpay

Received: 5 June 2012 /Revised: 3 June 2013 /Accepted: 17 June 2013 /Published online: 12 November 2013# IPNA 2013

AbstractBackground The correlations between ambulatory bloodpressure measurements (ABPM) and serum cystatin C (CysC), serum creatinine (Cr), microalbumin (MA), and β2-microglobulin (β2-MG) levels in 24 h (24-h) urine wereanalyzed in children with solitary kidney (SK) and comparedto healthy children.Methods Fifty children with normal functioning SK and 25controls were studied. The ABPM, serum Cys C, serum Cr,MA, and β2-MG levels in 24-h urine were measured in allchildren. Clinical symptoms and signs, laboratory results, uri-nary ultrasonography, voiding cystourethrography, andDimercaptosuccinic acid (DMSA) scintigraphy results wererecorded in the SK group. Four patients with Wilms’ tumorand two with renal scarring were excluded from the study.Results The mean ages of the SK group and controls were 9.6±3.6 and 9.3±3.3 years, respectively. The serumCys C and Crlevels, 24-h urinary β2-MG and MA levels were similar inboth groups (p >0.05). However, 24-h urinary MA excretionwas higher in patients living with SK more than 5 years (p =0.01). Standard deviation scores of ABPMparameters showedno significant correlation with serum Cr, serum Cys C, MA,and β2-MG in 24-h urine of both groups.Conclusions Children with SK have increased 24-h urinaryMA excretion in the long term, and need prolonged follow-up

to detect early deterioration of renal function and to preventend-organ damage later in life.

Keywords Solitary kidney . Hypertension . Renal functions .

Microalbuminuria . Cystatin C

Introduction

In patients with congenital solitary kidney (SK) or nephrectomy,a single kidney has to adapt to themaintenance of homoeostasis.In nephrectomized patients, the removal of the one kidney leadsto structural and functional changes in the remnant one [1]. Oneof the major functional changes is increased filtration and hy-pertrophy of the remaining glomeruli. Persistent hyperfiltrationmay lead to microalbuminuria, proteinuria, and focal segmentalhyalinizations of the renal glomeruli [2–5].

After nephrectomy in adulthood, some studies show anincreased incidence of hypertension and proteinuria [6, 7],whereas most reports have shown no additional risk [8].

Unilateral renal agenesis (URA) and unilateral multicysticdysplastic kidney (MCDK) result in a congenital renal massreduction. It has been shown that the congenitally reducednephron number is associated with increased blood pressure(BP), proteinuria, glomerulosclerosis, and impaired renal func-tion in animal models [9, 10]. However, in humans, there is stillcontroversy as to the effects of a reduced nephron mass on BPand renal function [11]. Some studies have not found anyabnormalities in children with SK, while some support thistheory [2, 12–14].

The aim of this study was to investigate the serum cystatinC (Cys C), serum creatinine (Cr), microalbumin (MA), andβ2microglobulin (β2-MG) levels in 24 h (24-h) urine andtheir relation to the ambulatory blood pressure monitoring(ABPM) parameters of children with SK in comparison tohealthy children.

A. Shirzai :N. Yildiz :N. Biyikli :M. Benzer :H. AlpayDepartment of Pediatric Nephrology, Marmara University MedicalFaculty, Istanbul, Turkey

S. UstunsoyDepartment of Biochemistry, Marmara University Medical Faculty,Istanbul, Turkey

N. Yildiz (*)Atasehir 48. Ada Mimoza2/6 D: 11, 34758 Istanbul, Turkeye-mail: nurdan.yildiz@marmara.edu.tr

Pediatr Nephrol (2014) 29:283–288DOI 10.1007/s00467-013-2641-2

Patients and methods

Patients

Fifty children and adolescents (21 girls and 29 boys) with an SKfollowed-up at the pediatric nephrology outpatient clinic wereincluded in the study. The clinical symptoms and signs, thelaboratory results, renal ultrasonography (USG), voidingcystourethrography (VCUG) and DMSA scintigraphy resultswere recorded in the SK group. Renal size percentiles evaluatedby USG were determined according to the standard growthchart of normal renal size vs. age [15]. Compensatory hypertro-phy was defined as measured renal size greater than the 95thpercentile. The study group consisted of patients with unilateralrenal agenesis (n = 22, 44 %), unilateral MCDK (n = 11, 22 %)and unilateral nephrectomy (n = 17, 34 %). Nephrectomieswere done for nonfunctional kidneys due to vesicoureteralreflux in four patients, ureteropelvic junction stenosis in five,renal atrophy in four, and Wilms’ tumor in four patients.Nephrectomized patients with MCDK were included inMCDK patients. Renal agenesis and MCDK were diagnosedby renal USG and confirmed by DMSA or Tc-99 m-diethylenetriamine pentaacetate (DTPA) scintigraphy in all pa-tients. Voiding cystourethrographywas performed in all childrenwith SK showing vesicoureteral reflux (VUR) (18, 36%). Six ofthese patients had VUR in their SK. Two patients had renalscarring in their SK demonstrated by DMSA scintigraphy. Fourchildren with Wilms tumor and two with renal scarringwere excluded from the study since their urine volume andconcentrating ability may be affected due to potential mildtubular dysfunction, which may be attributed to effects ofchemotherapy.

The patients with SK were also divided into two groupsaccording to length of time of living with an SK. Group 1included 18 patients who were living with an SK for less than5 years and group 2 included 26 patients who were living withan SK for more than 5 years.

The control group included 25 age-matched healthy chil-dren (16 girls, nine boys) with a pair of normal kidneysvisualized by renal USG. All patients and controls had anormal renal function defined as a glomerular filtration rate(GFR) of over 90 ml/min/1.73 m2.

Height was measured using a Harpenden stadiometer, andstandard deviation scores (SDS) were calculated using refer-ence growth charts of Turkish children [16]. Body mass index(BMI) was calculated by dividing body weight (kg) by height(m) squared.

None of the children received any antihypertensive andantiproteinuric drugs or drugs interfering with BP.

After a full explanation of the study was given to parentsand children, informed consent was obtained prior to thetesting. The study was approved by the local ethics committee

of the Faculty of Medicine, Marmara University, Istanbul,Turkey (MAR.0.01.02/AEK/678).

Study design

In all patients and controls, blood urea nitrogen (BUN), serumCr, uric acid, electrolytes, cholesterol, protein, albumin, CysC, urinalysis, 24-h urine protein, MA, andβ2-MG levels weredetermined by the standard methods and the results of bothgroups were compared.

SerumCys C (mg/l) and urinaryMA levels were determinedby the nephelometric method, serum Cr concentration by spec-trophotometric method, and urinary β2-MG levels by enzyme-linked two-site chemiluminescent immunometric assay.EstimatedGFRwas calculated from height and plasmaCr usingthe Schwartz formula [17]. Urinary MA and β2-MG levelswere presented as mg/m2/day and microgram (mcg)/m2/day.

Ambulatory BPmonitoring was performed over 24 h usinga SpaceLabs Monitor 90217 oscillometric device (SpaceLabsMedical Inc., Redmond, WA, USA) in all children. An appro-priate cuff, chosen out of three available sizes, was placed onthe non-dominant arm. Monitor use was explained to partic-ipants and their activities during ABPMwere recorded. Bloodpressure was automatically recorded every 20 min duringdaytime (08:00–22:00) and every 30 min during nighttime(22:00–08:00) in all children. The children were required togo to sleep at 22:00 by their parents and were asleep during thenighttime. Recordings with a minimum of 40 (43.5 %) ofsuccessful readings, including at least eight nighttime readingsand without breaks longer than 2 h were considered sufficient.Mean daytime and nighttime systolic BP (SBP) and diastolicBP (DBP) were calculated and compared with standards ob-tained in healthy children of the same sex and height providedby Soergel et al. [18]. The ABPM parameters were convertedto SDS, which were calculated for the normalization of BP forage and gender using the left main stem (LMS) method [19].Hypertension was defined as a systolic and/or diastolic BP>95th percentile according to the Fourth Report on high BP[20]. Hypertension on ABPMwas defined as mean systolic ordiastolic daytime or nighttime BP>95th percentile adjustedfor gender and body height according to reference values [18]and analyzed using the LMS method [19]. The percentage ofSBP and DBP readings above this value constituted a mea-surement of SBP and DBP load, respectively. The nocturnalblood pressure decrease (dipping) was defined as a fall in themean systolic and/or diastolic BP during nighttime of 10 % ormore of the corresponding daytime BP and it was calculatedas the day–night BP difference expressed as a percentage ofthe daytime BP mean. The non-dipping phenomenon wasdefined as dipping<10 % for systolic or diastolic BP.

Systolic BP, DBP, and mean arterial pressure (MAP) SDSvalues during daytime, nighttime, and over the 24-h span,

284 Pediatr Nephrol (2014) 29:283–288

dipping and BP load, were compared in children in both theSK and control groups. These values were also compared inchildren living with an SK more than 5 years and less than5 years. The relationships between ABPM SDS parametersand serum Cys C, serum Cr, MA, and β2-MG in the 24-hurine of the patients were evaluated.

Statistics

Ambulatory BP monitoring data were analyzed with theSpaceLabs ABPM Report Manager System. Data were de-scribed as frequencies andmeanswith standard deviation scores(SDS). To compare the ABPMdata of the patients with those ofthe healthy controls, the raw data of the original publication ofSoergel et al. [8] were used for statistical analysis.

All data were analyzed using the Statistical Packages for theSocial Sciences (SPSS Inc., Chicago, IL, USA) 15.0 package.A one-sample Kolmogorov–Smirnov test was used to deter-mine the normality of data. All data are expressed as mean±standard deviation (SD). The data not distributed normally wereexpressed as median (interquartile range, IQR). Differencesbetween the groups were analyzed using the Mann–WhitneyU test. The relationship between the variables was ana-lyzed with the Spearman’s correlation test in each group. A pvalue less than 0.05 was considered statistically significant.

Results

The mean ages of the SK group and control group were 9.6±3.6 (5–16) and 9.3±3.3 (5–10), years respectively. Age,weight, and BMI were not significantly different betweenpatients and controls. The demographic findings of the pa-tients are presented in Table 1. The time of living with SK was7.44±4.42 (range 0.3–15.8)years. Compensatory hypertrophywas seen in 36 (81.8 %) patients.

Ambulatory blood pressure monitoring

Ambulatory BP SDS parameters were normal according toABPM criteria in the SK group and controls (Table 2).

Twenty-four hour daytime and nighttime SBP, DBP, andMAP SDSs of the SK patients were not different from those ofhealthy controls (p >0.05). Daytime, nighttime, and 24-h SBPand DBP load of the patients were not statistically differentfrom those of controls (Table 2).

Themean nocturnal SBP and DBP dipping of childrenwithSK and controls were not different from the normal pediatricpopulation reported by Soergel et al. [18] and in addition werenot different in patients and controls (Table 2). Twenty-eightpatients with SK were non-dippers and all non-dippers werenormotensive.

Renal function

All children in the SK and control groups had normal renalfunction (eGFR>90 ml/min/1.73 m2). Serum Cys C levelswere 0.9±0.2 and 0.9±0.1 mg/l in SK group and controls,respectively. Serum Cr levels were 0.6±0.2 mg/dl in the SKgroup and 0.5±0.1 mg/dl in the control group (Table 1). Themean serum Cr and Cys C levels were not different in the SKgroup compared to the control group (p =0.640 and p =0.293).

Ambulatory BP SDS values showed no statistically signif-icant correlation with serum Cr and serum Cys C in childrenwith SK and healthy controls (p >0.05).

Urinary protein, microalbumin, and β2-microglobulinexcretion

Twenty-four hour urinary MA excretion was 115.8±203.2(range, 17.1–1,010) and 55.95±71.8 (range, 4.37–334) mg/m2/day in the SK and control groups, respectively. Twenty-four hour β2-MG excretion was 122.7±179.4 (range, 9.8–697.1) mcg/m2/day in the SK group and 80.5±79.1 (range,18–401.3) mcg/m2/day in controls. Twenty-four hour urinaryMA (p =0.078) and β2 MG (p =0.503) excretions were notdifferent in the two groups (Table 1). There were no significantrelationships between 24-h urinaryMA andβ2-MG excretionsin SK patients and controls (p >0.05). In SK patients, serumCrshowed significant correlation with MA and β2-MG levels in24-h urine (p =0.007 and p =0.006, respectively).

No significant correlation was found between 24-h urinaryMA or β2-MG excretion and ABPM SDS values in SKchildren (p >0.05).

There were 18 patients in group 1 who had been living withan SK for less than 5 years, and 26 patients in group 2 who hadbeen living with an SK for more than 5 years. Urinary MAexcretion in children in group 2 was significantly higher thanit was in group 1 (p =0.01), urinary β2 MG excretion was not

Table 1 Demographic data and renal functional parameters of SK andcontrol groups

SK group Control group

Male n (%) 18 (40.9) 9 (36.0)

Female n (%) 26 (59.1) 16 (64.0)

Age (years) 9.6±3.6 9.3±3.3

BMI (kg/m2) 17.4±3.9 17.9±3

Serum Cys C (mg/l) 0.9±0.2 0.9±0.1

Serum Cr (mg/dl) 0.6±0.2 0.5±0.1

24-h urine MA (mg/m2/day) 115.8±203.2 55.9±71.8

24-h urine β2 MG (mcg/m2/day) 122.73±179.4 80.5±79.1

SK Solitary kidney; BMI bodymass index; Cys cystatin; Cr creatinine;MA Microalbumin; β2MG β2 Microglobulin

Pediatr Nephrol (2014) 29:283–288 285

different in the two subgroups (p =0.628) (Table 3). Twenty-four hour daytime and nighttime SBP, DBP and MAP SDSs,serum Cr and Cys C were not different between group 1 andgroup 2 (p >0.05).

Discussion

The data from experimental and human studies showed thatreduced nephron mass leads to hyperfiltration and hy-pertrophy of the remaining nephrons, resulting in progressivedeterioration of renal function with proteinuria and hyperten-sion, known as Brenner’s theory [1, 8–10, 21, 22]. It isreported that unilateral nephrectomy in young rats leads to ahigher incidence of glomerular sclerosis than is observed inadult rats [23].

Unilateral renal agenesis and MCDK are human models of areduced nephron mass since birth and are considered to be riskfactors for hyperfiltration injury and progressive renal damage[1, 9, 10]. In adult studies, patients with URA hadmicroalbuminuria, renal dysfunction, and hypertension [24, 25].

There are limited data for children. Some studies havedemonstrated that children with URA have a higher risk ofdeveloping hypertension, proteinuria, or reduced renal func-tion whereas others have not found any abnormalities inchildren with a solitary kidney [2, 11, 12, 26, 27]. In childrenwith nephrectomy, only a few studies have shown that unilat-eral nephrectomy predisposes one to chronic impairment ofthe SK [8, 27, 28].

In our study, we found that all children with SK had normalrenal function. In most of the studies on children, renal func-tions were determined by a Cr-based formula. Creatinine-based

formulas have not been validated against gold-standard tech-niques in patients with SK.We investigated serum Cys C levelsas well as Cr and did not find a significant difference in eithereGFR or Cys C levels of the patients and controls. This is one ofthe crucial differences of our study when compared with others.Since the mean length of time living with an SK in our study is7.4 years, this may not be enough for the long-term evaluationof kidney function in these children.

Urinary MA excretion is an early indicator of hyperfiltrationinjury. The renal function may, however, remain stable for along time [5]. Proteinuria was reported in adults after nephrec-tomy [6, 7], whereas most reports have shown no additionalrisk. In recent years, many authors have reported an increasedincidence of hypertension and proteinuria in SK after donationfor transplantation [29, 30]. Kasiske et al. found that in normalindividuals kidney donation does not cause progressive renaldysfunction or an increased incidence of proteinuria, but it maybe associated with increased blood pressure in their meta-analysis of investigations [31]. Studies in children with SKhave reported contradictory findings on whether children withURA have a higher risk of developing hypertension, protein-uria, or reduced renal function [2, 14, 27, 28].

Reports concerning the function of the SK after surgicaltreatment of Wilms’ tumors in children are much more com-mon [28, 32]. Tullio et al. reported high MA excretion withnormal blood pressure in children nephrectomized due toWilms’ tumor [28]. We could not evaluate Wilms’ tumorpatients separately. We have only four patients with Wilms’tumor and omitted these patients since two had chemotherapy.On the other hand, it has been reported that children withunilateral nephrectomy had no evidence of hypertension orproteinuria, but did have decreased renal reserve capacity

Table 2 Ambulatory blood pres-sure monitoring SDS values ofthe patients and controls

SDS Standard deviation scores;SBP systolic blood pressure;DBP diastolic blood pressure;MAP mean arterial pressure

Variables SK group, n = 44 Control group, n = 25 P

24-h SBP/DBP SDS −0.95±0.87/−0.89±0.76 −0.96±0.68/−0.64±0.69 NS

Daytime/nighttime SBP SDS −0.94±0.86/−0.29±0.74 −1.04±0.9/−0.39±077 NS

Daytime/nighttime DBP SDS −0.96±0.66/0.04±0.82 −0.77±0.69/0.27±0.82 NS

24 h MAP SDS −0.43±0.73 −0.43±0.63 NS

Day-time/Night-time MAP SDS −0.50±0.79/0.5±0.69 −0.55±0.73/0.33±0.78 NS

SBP/DBP dipping (%) 12.85±6.08/8.94±4.85 14.48±5.8/11.01±4.90 NS

24 h SBP/DBP load (%) 11.17±11.52/12.85±11.33 12.5±3.83/15.1±5.85 NS

Daytime/nighttime SBP load (%) 9.97±12.07/13.07±11.66 10.2±5.73/10.82±5.53 NS

Daytime/nighttime DBP Load (%) 17.2±6.30/12.33±14.98 13.8±5.63/18.2±4.63 NS

Table 3 Comparison of serum Cr, Cys C, urinary MA and B-2-MG excretion in children living with SK less or more than 5 years

Follow-up Serum Cr (mean±SD) Serum Cys C (mean±SD) Urinary MA median (IQR) Urinary beta-2-MG median (IQR)

Group 1<5 years (n=18) 0.92±0.27 0.56±0.26 27.6 (18)* 41.2 (98.9)

Group 2 ≥5 years (n =26) 0.85±0.20 0.57±0.16 67.7 (121.1) 42.5 (57.8)

*p =0.01

Cr creatinine; Cys cystatin; MA microalbumin; MG microglobulin; SK solitary kidney

286 Pediatr Nephrol (2014) 29:283–288

[33]. Dursun et al. reported low GFR, high serum Cr levels,and hypertension in children with nephrectomy and URA,however, urinary MA excretion was not different from thatof controls [14]. In our study, we did not find significantdifferences in the urine MA and β2-MG excretion of patientswith SK and normal renal function. However, we did notcompare the patients with unilateral renal agenesis, unilateralMCDK and unilateral nephrectomy because of the limitednumber of patients in each group. On the contrary, we foundsignificant differences in urine MA excretion among patientsliving with an SK for more than 5 years. High urinary MAexcretion in these patients and its correlation with serum Crlevels may suggest that a mild renal dysfunction may developlater in the life of these children.

Schreuder et al. reported highMA excretion, low GFR, andhigh office BP in their patients with URA or MCDK. Bloodpressure measurements were not obtained by ABPM in theirpatients [13]. In contrast to the studies mentioned above, wehave demonstrated that children with SK, whether or not theyhad high urinary MA and β2 MG excretion, have ABPMpatterns similar to those of healthy children. There are fewreports that have utilized 24-h ABPM in SK children. Zahavet al. found higher SBP in children with SK than the controlsusing 24-h ABPM recording [12]. However, Seeman et al.reported that ABPM parameters and GFR were similar inchildren with normal SK and controls. They did not find anycorrelation between ABPM parameters and GFR or 24-h urineMA excretion [26]. Our results were similar to Seeman et al.,however they did not study serum Cys C, which is accepted asan early marker of decreased renal function, and tubularproteinuria in their study [26]. We also did not find a signif-icant correlation between serum Cys, 24-h urinary β2-MGexcretion, and ABPM parameters. The reasons for the dis-crepancy in the results of the published studies could be due todifferences in methodology and selection of patients.

It is reported that only children with renal abnormalities intheir SK had proteinuria, hypertension, and reduced renalfunction [26, 34]. The incidence of associated urologicalabnormalities is high in patients with congenital SK [35,36], so these patients with SK are at risk of developing renaldamage and progressive impairment of renal function. In ourstudy, children who had VUR have normal GFR and ABPMparameters, however, a limitation of our study is the smallnumber of the patients with renal abnormalities. Therefore,these data should be evaluated in larger series.

Our report is the first study investigating BP patterns usingABPM and their relationship with urinary MA and Β2-MGexcretion, serum Cr, Cys C, and eGFR in children with SK.Our study showed that SDS of ABPM parameters were nor-mal in children with SK and not different from controls with atleast an average of 7 years of living with SK. We did not findsignificant relationships between 24-h MA or Β2-MG excre-tion and ABPM SDS values. However, urinary MA and Β2-

MG excretions were significantly correlated with serum Crlevels, which were within normal ranges. We excluded biasfrom the different gender proportions in the groups byadjusting parameters for gender and height according to ref-erence values. According to our results, we may speculate thaturinary MA appeared due to hyperfiltration in the long-termbefore hypertension developed and GFR decreased. Thesedata emphasize the importance of monitoring urinary MAexcretion in children with SK to detect early deterioration ofkidney functions before hypertension develops in order toprevent end-organ damage later in life.

Brenner and Mackenzie stated that patients with URA tendto develop proteinuria or hypertension only after the thirddecade [10]. This theory is supported by several studies show-ing that there is a higher prevalence of albuminuria, hyperten-sion, and renal insufficiency in adult patients with URA than inthe normal population, and that these abnormalities are morefrequent after a longer follow-up period [2, 24, 37]. Afternephrectomy, the adaptive response in the remaining kidneydepends on the age at which the operation was performed [38].Some authors emphasize the fact that reduction in GFR in SKpatients may appear merely 15–25 years after nephrectomy [2,24]. However, other studies have demonstrated that adults whohave had SK since childhood display no adverse effects oflongstanding hyperfiltration [25, 39]. We found significantlyhigher urinary MA excretion in patients living with SK morethan 5 years than in patients livingwith SK less than 5 years. Asthis was a pediatric study, the time living with SK was less than20 years, and this relatively short period with SK was a limi-tation of our study. There is still controversy concerning theneed for large, long-term studies taking place over more thantwo decades in order to discern whether or not albumin excre-tion and renal function decrease or increase together with theextension of the follow-up period.

We conclude that children with SK have normal GFR andBP but may have higher urinary MA excretion in long-termfollow-up. Our results suggest that children with presumablynormal SK are at increased risk for the development ofhyperperfusion injury, which is expected with the presenceof MA excretion. Children with SK who have high levels ofurinaryMA need prolonged and careful follow-up in the long-term to detect early deterioration of renal function and toprevent end-organ damage later in life.

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