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Unilateral anomalies of kidney development: why is left not right?
original article
http://www.kidney-international.org & 2011 International Society of Nephrology
Unilateral anomalies of kidney development: why is left not right? Michiel F. Schreuder1 1
Department of Pediatric Nephrology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Abnormal renal development results in congenital anomalies of the kidney and urinary tract. As many studies suggest that renal malformations are more often found on the left side, a meta-analysis was performed on the distribution of five different unilateral anomalies: multicystic dysplastic kidney, renal agenesis/aplasia, renal ectopia, pelviureteral junction obstruction, and non-obstructive non-refluxing megaureter. Of these anomalies, the left side was affected in 53%, 57%, 56.9%, 63.2%, and 62.5% of patients, respectively, significantly different when compared with an anticipated 50% of left-sided anomalies. An exception to this left-side predominance was found in females with combined genital anomalies and unilateral renal agenesis that commonly present on the right side. The exact mechanisms leading to these lateralizations remain to be determined but may involve vascular development, differential gene expression, or susceptibility to environmental factors such as hypoxia. This remains largely speculative, however, illustrating our limited knowledge of embryogenesis in general and nephrogenesis in particular. Kidney International (2011) 80, 740–745; doi:10.1038/ki.2011.204; published online 29 June 2011 KEYWORDS: kidney development; renal agenesis; renal development
Renal development is the process leading to the formation of nephrons, the functioning units of the kidney.1 This process is based on mutual induction by the metanephric mesenchyme and the ureteric bud. Malfunctioning of this process may lead to congenital anomalies of the kidney and urinary tract (CAKUT). Many renal malformations are based on genetic mutations (for an overview see NCPNephrol2). Although this could suggest that malformations are found either on both sides together or equally distributed over both sides, many studies seem to suggest that renal malformations are more often found on the left side. Indeed, a meta-analysis that we performed previously on unilateral multicystic dysplastic kidney (MCDK) did show that 53.1% of unilateral MCDK presented in the left kidney, significantly (Po0.02) more than the expected 50%.3 In addition, a recently described mutant rat strain with unilateral renal agenesis (URA) was found to have urogenital anomalies restricted to the left side.4 To study the side distribution of several renal malformations, I performed a meta-analysis of studies describing CAKUT. As this data showed that the left kidney shows developmental malformations more frequently than the right kidney, I briefly discuss possible explanations for this side difference. RESULTS Multicystic dysplastic kidney
As stated previously, we performed a meta-analysis on the incidence of associated urinary tract anomalies in patients with unilateral MCDK.3 On the basis of 58 papers, 53.1% (1663/3130) of unilateral MCDKs were located on the left side (Table 1). To exclude the influence of the timing of diagnosis (pre- vs. postnatal), a separate analysis of the 23 cohorts with a 100% prenatal diagnosis rate showed similar results (656/1211, 54.2%). Unilateral renal agenesis Correspondence: Michiel F. Schreuder, Department of Pediatric Nephrology, 804, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: [email protected] MFS was supported by an ERA-EDTA fellowship. Received 14 February 2011; revised 18 April 2011; accepted 10 May 2011; published online 29 June 2011 740
In total, 13 cohorts presented data on 1,165 patients with URA (Table 2); 56.7% showed agenesis/aplasia of the left kidney (z ¼ 4.57, Po0.0001 versus the expected 50%). As the literature study clearly showed that a subgroup consists of female patients with URA in combination with genital anomalies, for instance, as part of the Mayer–Rokitansky–Kuster–Hauser syndrome, papers presenting results solely Kidney International (2011) 80, 740–745
original article
MF Schreuder: Kidney development: why is left not right?
from this category of patients were excluded from this analysis. In patients with such combination of anomalies, a meta-analysis has previously shown that URA is on the right side in 67% (82/123) of cases.5
with unilateral renal ectopia, 56.9% was left sided (z ¼ 2.04, P ¼ 0.02). Including all bilateral cases, 142/252 (56.3%) of the ectopic kidneys originated from the left side (z ¼ 1.95, P ¼ 0.03).
Renal ectopia
Pelviureteral junction obstruction
Table 3 shows the data from six cohorts that were identified to present the side of the ectopic kidney. Of the 232 patients
Because of the expected high number of publications on pelviureteral junction obstruction (PUJO), only papers published in 1999 and onward were included, totaling 25 cohorts (Table 4). Of the unilateral PUJO cases, 63.2% were located on the left side (z ¼ 12.03, Po0.0001). Eight of the cohorts excluded patients with bilateral PUJO, and therefore these cohorts were excluded from the subsequent analysis. Combining the remaining 17 cohorts, 960 of the 1634 kidneys with PUJO were located on the left side (z ¼ 7.05, Po0.0001). Analysis using RevMan (Table 1) did show a significant heterogeneity of the published cohorts, hampering definitive interpretation of these data. Two papers presented data on the potential influence of the timing of diagnosis, showing similar results (overall 75/109 (68.8%) left sided in prenatal versus 38/59 (64.4%) left sided in postnatal diagnosed cases, w2: P ¼ 0.56).6,7
Table 1 | Results from the meta-analysis using Review Manager, showing the odds ratio for a specific unilateral congenital anomaly of the kidney and urinary tract to be located on the left side OR (95% CI) MCDK URA Ectopia PUJO Megaureter
1.12 1.31 1.32 1.71 1.67
P overall Heterogeneity, P effect I2 (%) heterogeneity
(1.02–1.24) 0.02 (1.11–1.54) 0.001 (0.92–1.91) 0.13 (1.40–2.08) o0.0001 (1.05–2.63) 0.03
0 0 0 54 0
0.99 0.95 0.84 0.0008 0.95
Abbreviations: CI, confidence interval; MCDK, multicystic dysplastic kidney; OR, odds ratio; PUJO, pelviureteral junction obstruction; URA, unilateral renal agenesis.
Table 2 | Demographic details of cohorts of patients with URA Publication
Cohort Agenesis of Proportion of Study size (N) left kidney (n) left-sided URA weighta (%)
Collins, 1932 (ref. 20) Emanuel, 1974 (ref. 21) Wilson, 1985 (ref. 22) Atiyeh, 1993 (ref. 23) Song, 1995 (ref. 24) Palmer, 1997 (ref. 25) Cascio, 1999 (ref. 26) Huang, 2001 (ref. 27) Guarino, 2005 (ref. 28) Dursun, 2005 (ref. 29) Krzemien, 2006 (ref. 30) Schreuder, 2008 (ref. 31) Wang, 2010 (ref. 32) Overall
556 74 88 16 51 14 46 75 50 87 21 39 48
318 47 51 6 29 6 27 37 29 46 13 27 25
0.57 0.64 0.58 0.38 0.57 0.43 0.59 0.49 0.58 0.53 0.62 0.69 0.52
1165
661
0.57 (95% CI 0.54–0.60) z=4.57, Po0.0001
47.8 6.2 7.5 1.3 4.4 1.2 3.9 6.6 4.3 7.6 1.8 3.2 4.2
Abbreviations: CI, confidence interval; URA, unilateral renal agenesis. a Weight according to the Review Manager random-effects meta-analysis.
Non-obstructive non-refluxing megaureter
Five cohorts were identified (Table 5) with 152 patients in total with a unilateral non-obstructive non-refluxing megaureter, of which 95 (62.5%) were localized on the left side (z ¼ 3.00, P ¼ 0.001). Including all bilateral cases yielded similar results (143 out of 248 renal units (57.7%), z ¼ 2.35, P ¼ 0.009). DISCUSSION
This analysis shows that most unilateral CAKUT affect the left kidney more frequently than the right. This is based on five different CAKUT diagnoses, with in total 107 cohorts and 7248 patients of whom 4,110 (56.7%, 95% confidence interval 55.6-57.8%) had a CAKUT on the left side. An exception to this left-side predominance is found in females with combined genital anomalies and URA that commonly present on the right side. It remains unclear what the exact mechanism is in explaining these lateralizations. Possible
Table 3 | Demographic details of cohorts of patients with renal ectopia Publication Donahoe, 1980 (ref. 33) Guarino, 2004 (ref. 34) Engelhardt, 2006 (ref. 35) Arena, 2007 (ref. 36) Glodny, 2008 (ref. 37) vd Bosch, 2010 (ref. 38) Overall
Ectopic left kidneya (n/N (proportion)) 7/16 50/92 11/15 32/56 6/12 26/41
(0.44) (0.54) (0.73) (0.57) (0.50) (0.63)
132/232 (0.57, 95% CI 0.51–0.63) z=2.04, P=0.02
Study weightb (%) 6.9 40.1 5.9 24.3 5.3 17.5
Ectopic left kidneyc (n/N (proportion)) 7/16 57/106 12/17 34/60 6/12 26/41
(0.44) (0.54) (0.71) (0.57) (0.50) (0.63)
142/252 (0.56, 95% CI 0.50–0.62) z=1.95, P=0.03
Abbreviation: CI, confidence interval. a Excluding bilateral cases. b Weight according to the Review Manager random-effects meta-analysis. c Including bilateral cases.
Kidney International (2011) 80, 740–745
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Table 4 | Demographic details of cohorts of patients with unilateral PUJO Publication
Left-sided PUJOa (n/N (proportion))
Study weightb (%)
Left-sided PUJOc (n/N (proportion))
55/89 (0.62) 58/79 (0.73) 74/100 (0.74) 64/85 (0.75) 54/75 (0.72) 33/39 (0.85) 6/11 (0.55) 38/69 (0.55) 38/53 (0.72) 52/74 (0.70) 57/84 (0.68) 61/100 (0.61) 28/54 (0.52) 9/16 (0.56) 233/343 (0.68) 120/173 (0.69) 86/188 (0.46) 57/99 (0.58) 31/49 (0.63) 3/13 (0.23) 60/88 (0.68) 13/32 (0.41) 25/60 (0.42) 12/14 (0.86) 43/84 (0.51)
4.8 4.3 4.8 4.4 4.3 2.8 1.2 4.3 3.6 4.3 4.6 5.0 3.8 1.6 7.0 6.0 6.2 5.0 3.5 1.2 4.7 2.7 4.0 1.0 4.7
NAd NAd 95/142 (0.67) 85/127 (0.67) 59/85 (0.69) 35/43 (0.81) 7/13 (0.54) 46/85 (0.54) NAd NAd 57/84 (0.68) NAd 42/82 (0.51) 9/16 (0.56) NAd 179/291 (0.62) 86/188 (0.46) 60/105 (0.57) NAd 4/15 (0.27) 115/198 (0.58) NAd 25/60 (0.42) 12/14 (0.86) 44/86 (0.51)
Capolicchio, 1999 (ref. 6) McAleer, 1999 (ref. 7) Subramaniam, 1999 (ref. 39) Kim, 2001 (ref. 40) Schuster, 2001 (ref. 41) Thompson, 2001 (ref. 42) Aziz, 2002 (ref. 43) Apocalypse, 2003 (ref. 44) Boubaker, 2003 (ref. 45) Braga, 2003 (ref. 46) Calisti, 2003 (ref. 47) Thorup, 2003 (ref. 48) Ylinen, 2004 (ref. 49) Reddy, 2005 (ref. 50) Chertin, 2006 (ref. 51) Ismail, 2006 (ref. 52) Romero, 2006 (ref. 53) Elmalik, 2008 (ref. 54) Chertin, 2009 (ref. 55) Gulur, 2009 (ref. 56) Karnak, 2009 (ref. 57) Lopez, 2009 (ref. 58) Ninan, 2009 (ref. 59) Deng, 2010 (ref. 60) Gupta, 2010 (ref. 61) Overall
1312/2075 (0.63, 95% CI 0.61–0.65) z=12.03, Po0.0001
960/1634 (0.59, 95% CI 0.56–0.61) z=7.05, Po0.0001
Abbreviations: CI, confidence interval; NA, not available; PUJO, pelviureteral junction obstruction. a Excluding bilateral cases. b Weight according to the Review Manager random-effects meta-analysis. c Including bilateral cases. d Bilateral cases were excluded in this study.
Table 5 | Demographic details of cohorts of patients with unilateral non-obstructive, non-refluxing megaureter Publication Anto´n-Pacheco Sa´nchez, 1995 (ref. 62) McLellan, 2002 (ref. 63) Chertin, 2008 (ref. 64) Arena, 1998 (ref. 65) Sheu, 1998 (ref. 66) Overall
Left-sided megauretera (n/N (proportion)) 13/20 25/39 30/53 13/20 14/20
(0.65) (0.64) (0.57) (0.65) (0.70)
Study weightb (%) 12.9 25.7 36.0 12.9 12.4
95/152 (0.63, 95% CI 0.55–0.70) z=3.00, P=0.001
Left-sided megaureterc (n/N (proportion)) 16/26 40/69 56/105 15/24 16/24
(0.62) (0.58) (0.53) (0.63) (0.67)
143/248 (0.58, 95% CI 0.52–0.64) z=2.35, P=0.009
Abbreviation: CI, confidence interval. a Excluding bilateral cases. b Weight according to the Review Manager random-effects meta-analysis. c Including bilateral cases.
causes can be found in the (development of the) vasculature, differential gene expression profiles, or susceptibility to environmental factors such as hypoxia. There is a known difference in shape and volume between both kidneys,8 illustrating the diversity in kidney development between the sides. An interesting dissimilarity between sides that illustrates possible gene differences is the finding of an autopsy study of 35 fetuses with trisomy 13 toward a tendency for the left kidney to be lighter.9 Other studies present evidence for an increased sensitivity to environmental influences with a higher susceptibility to hypoxia 742
of the right side of the body.10 In contrast, in a cohort of 20-year-old individuals born very prematurely, kidneys were significantly smaller than kidneys from term-born controls, a difference that was most pronounced in the left kidney.11 Another explanation for the difference between sides may be found in anatomical variations based on the liver (preventing the right kidney to ascend as far as the left during development12) or the vasculature.13 Indeed, there is a known difference in the origin and direction of the renal arteries between the sides.14 Kidney International (2011) 80, 740–745
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MF Schreuder: Kidney development: why is left not right?
Many other congenital malformation do show a laterality pattern,15,16 indicating that the difference in frequency of CAKUT between the sides is not a unique finding. This may have to do with an imbalance in factors that coordinate lateralization, including genes that are differentially expressed at both sides of the embryo at different times during development.17,18 However, the expression of such genes during nephrogenesis has not yet shown any explanation for the described differences between sides in the incidence of CAKUT. This analysis has some limitations. First, the case definition of the original publication was used, which could lead to a mixture of underlying diagnoses. Second, I did not attempt to contact authors of publications that did not provide information on the side of the CAKUT, nor did I elaborate on all of the reference lists of papers that were identified. This will have resulted in not all cohorts of CAKUT being included, and may have an effect on the exact percentage of CAKUT being on the left side. Finally, it cannot be excluded that there is a difference in presentation between a CAKUT on the left side versus the same diagnosis on the right side, which would lead to an increased presentation of patients with left-sided CAKUT. Analysis of cohorts with unilateral MCDK and PUJO that were detected prenatally (that is, before the onset of clinical signs) did show similar results, which illustrates that this is unlikely to have a significant impact on the results. In conclusion, unilateral CAKUT (MCDK, URA, renal ectopia, PUJO, and non-obstructive non-refluxing megaureter) do present more frequently on the left side. Explanations for this difference between sides remain largely unclear and speculative, illustrating our limited knowledge of embryogenesis in general and nephrogenesis specifically. As more insight into factors controlling kidney development may ultimately lead to optimization of nephrogenesis and/or prevention of CAKUT, this presents a relevant field for further research. MATERIALS AND METHODS For the meta-analysis, I selected several urinary tract malformations of interest, that is, unilateral MCDK, URA, unilateral renal ectopia, unilateral PUJO, and unilateral non-obstructive nonrefluxing megaureter. Only publications reporting over 10 cases were included. Owing to the high numbers of publications on PUJO, only papers published since 1999 were included. Extracted data included the total number of cases with unilateral urinary tract malformations that were described to fit the diagnosis of interest, and with bilateral anomalies in the categories renal ectopia, PUJO, and non-obstructive non-refluxing megaureter. Bilateral cases of renal agenesis or MCDK were not included, as this presents a lethal condition. Of the total numbers of unilateral cases, the number and proportion of patients with the malformation on the left side was noted. Of the total number of unilateral and bilateral cases, the total number and proportion of left renal units affected was noted. Some of the papers on PUJO excluded bilateral cases; these cohorts were excluded from the analysis that included the bilateral cases. Kidney International (2011) 80, 740–745
With these data, a cumulative meta-analysis was performed. To test my hypothesis that CAKUT is more frequently found on the left side than the expected 50%, two approaches were used. First of all, Review Manager (RevMan, version 5.0, The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen) was used. For each cohort entered, the control group consisted of the same number of patients as the publication and 50% of these were considered to have that specific unilateral CAKUT on the left side. In case of an odd number of cases in the cohort, the number in the control cohort was increased by one. Using RevMan, a pooled effect size of weighted mean differences for continuous data was calculated, together with a 95% confidence interval, based on a random-effects model. A random-effects model was chosen a priori as I had the impression that variation in the study populations would result in between-study heterogeneity beyond that of sampling variability. The weight (%) is based on study size and variation of the data (standard deviation). Second, the proportion of the anomalies on the left side was compared with the expected proportion (0.50), and a z value (with continuity correction) was calculated,19 with corresponding P-value to test the null hypothesis that the measured proportion (Pmeas) was identical to the expected proportion (Pexp): z¼
1 jPmeas Pexp j 2n seðPexp Þ
in which n indicates the total number of patients included and se(Pexp) indicates the standard error of the expected proportion, which can be calculated as follows: rffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi Pexp ð1 Pexp Þ se ðPexp Þ ¼ n The total measured proportions of left-sided CAKUT are presented, together with the 95% confidence interval. Statistical differences were considered significant if Po0.05 (two tailed). DISCLOSURE
The author declared no competing interests. ACKNOWLEDGMENTS
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Kidney International (2011) 80, 740–745
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MF Schreuder: Kidney development: why is left not right?
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Unilateral anomalies of kidney development: why is left not right? Michiel F. Schreuder1 1
Department of Pediatric Nephrology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Abnormal renal development results in congenital anomalies of the kidney and urinary tract. As many studies suggest that renal malformations are more often found on the left side, a meta-analysis was performed on the distribution of five different unilateral anomalies: multicystic dysplastic kidney, renal agenesis/aplasia, renal ectopia, pelviureteral junction obstruction, and non-obstructive non-refluxing megaureter. Of these anomalies, the left side was affected in 53%, 57%, 56.9%, 63.2%, and 62.5% of patients, respectively, significantly different when compared with an anticipated 50% of left-sided anomalies. An exception to this left-side predominance was found in females with combined genital anomalies and unilateral renal agenesis that commonly present on the right side. The exact mechanisms leading to these lateralizations remain to be determined but may involve vascular development, differential gene expression, or susceptibility to environmental factors such as hypoxia. This remains largely speculative, however, illustrating our limited knowledge of embryogenesis in general and nephrogenesis in particular. Kidney International (2011) 80, 740–745; doi:10.1038/ki.2011.204; published online 29 June 2011 KEYWORDS: kidney development; renal agenesis; renal development
Renal development is the process leading to the formation of nephrons, the functioning units of the kidney.1 This process is based on mutual induction by the metanephric mesenchyme and the ureteric bud. Malfunctioning of this process may lead to congenital anomalies of the kidney and urinary tract (CAKUT). Many renal malformations are based on genetic mutations (for an overview see NCPNephrol2). Although this could suggest that malformations are found either on both sides together or equally distributed over both sides, many studies seem to suggest that renal malformations are more often found on the left side. Indeed, a meta-analysis that we performed previously on unilateral multicystic dysplastic kidney (MCDK) did show that 53.1% of unilateral MCDK presented in the left kidney, significantly (Po0.02) more than the expected 50%.3 In addition, a recently described mutant rat strain with unilateral renal agenesis (URA) was found to have urogenital anomalies restricted to the left side.4 To study the side distribution of several renal malformations, I performed a meta-analysis of studies describing CAKUT. As this data showed that the left kidney shows developmental malformations more frequently than the right kidney, I briefly discuss possible explanations for this side difference. RESULTS Multicystic dysplastic kidney
As stated previously, we performed a meta-analysis on the incidence of associated urinary tract anomalies in patients with unilateral MCDK.3 On the basis of 58 papers, 53.1% (1663/3130) of unilateral MCDKs were located on the left side (Table 1). To exclude the influence of the timing of diagnosis (pre- vs. postnatal), a separate analysis of the 23 cohorts with a 100% prenatal diagnosis rate showed similar results (656/1211, 54.2%). Unilateral renal agenesis Correspondence: Michiel F. Schreuder, Department of Pediatric Nephrology, 804, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: [email protected] MFS was supported by an ERA-EDTA fellowship. Received 14 February 2011; revised 18 April 2011; accepted 10 May 2011; published online 29 June 2011 740
In total, 13 cohorts presented data on 1,165 patients with URA (Table 2); 56.7% showed agenesis/aplasia of the left kidney (z ¼ 4.57, Po0.0001 versus the expected 50%). As the literature study clearly showed that a subgroup consists of female patients with URA in combination with genital anomalies, for instance, as part of the Mayer–Rokitansky–Kuster–Hauser syndrome, papers presenting results solely Kidney International (2011) 80, 740–745
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MF Schreuder: Kidney development: why is left not right?
from this category of patients were excluded from this analysis. In patients with such combination of anomalies, a meta-analysis has previously shown that URA is on the right side in 67% (82/123) of cases.5
with unilateral renal ectopia, 56.9% was left sided (z ¼ 2.04, P ¼ 0.02). Including all bilateral cases, 142/252 (56.3%) of the ectopic kidneys originated from the left side (z ¼ 1.95, P ¼ 0.03).
Renal ectopia
Pelviureteral junction obstruction
Table 3 shows the data from six cohorts that were identified to present the side of the ectopic kidney. Of the 232 patients
Because of the expected high number of publications on pelviureteral junction obstruction (PUJO), only papers published in 1999 and onward were included, totaling 25 cohorts (Table 4). Of the unilateral PUJO cases, 63.2% were located on the left side (z ¼ 12.03, Po0.0001). Eight of the cohorts excluded patients with bilateral PUJO, and therefore these cohorts were excluded from the subsequent analysis. Combining the remaining 17 cohorts, 960 of the 1634 kidneys with PUJO were located on the left side (z ¼ 7.05, Po0.0001). Analysis using RevMan (Table 1) did show a significant heterogeneity of the published cohorts, hampering definitive interpretation of these data. Two papers presented data on the potential influence of the timing of diagnosis, showing similar results (overall 75/109 (68.8%) left sided in prenatal versus 38/59 (64.4%) left sided in postnatal diagnosed cases, w2: P ¼ 0.56).6,7
Table 1 | Results from the meta-analysis using Review Manager, showing the odds ratio for a specific unilateral congenital anomaly of the kidney and urinary tract to be located on the left side OR (95% CI) MCDK URA Ectopia PUJO Megaureter
1.12 1.31 1.32 1.71 1.67
P overall Heterogeneity, P effect I2 (%) heterogeneity
(1.02–1.24) 0.02 (1.11–1.54) 0.001 (0.92–1.91) 0.13 (1.40–2.08) o0.0001 (1.05–2.63) 0.03
0 0 0 54 0
0.99 0.95 0.84 0.0008 0.95
Abbreviations: CI, confidence interval; MCDK, multicystic dysplastic kidney; OR, odds ratio; PUJO, pelviureteral junction obstruction; URA, unilateral renal agenesis.
Table 2 | Demographic details of cohorts of patients with URA Publication
Cohort Agenesis of Proportion of Study size (N) left kidney (n) left-sided URA weighta (%)
Collins, 1932 (ref. 20) Emanuel, 1974 (ref. 21) Wilson, 1985 (ref. 22) Atiyeh, 1993 (ref. 23) Song, 1995 (ref. 24) Palmer, 1997 (ref. 25) Cascio, 1999 (ref. 26) Huang, 2001 (ref. 27) Guarino, 2005 (ref. 28) Dursun, 2005 (ref. 29) Krzemien, 2006 (ref. 30) Schreuder, 2008 (ref. 31) Wang, 2010 (ref. 32) Overall
556 74 88 16 51 14 46 75 50 87 21 39 48
318 47 51 6 29 6 27 37 29 46 13 27 25
0.57 0.64 0.58 0.38 0.57 0.43 0.59 0.49 0.58 0.53 0.62 0.69 0.52
1165
661
0.57 (95% CI 0.54–0.60) z=4.57, Po0.0001
47.8 6.2 7.5 1.3 4.4 1.2 3.9 6.6 4.3 7.6 1.8 3.2 4.2
Abbreviations: CI, confidence interval; URA, unilateral renal agenesis. a Weight according to the Review Manager random-effects meta-analysis.
Non-obstructive non-refluxing megaureter
Five cohorts were identified (Table 5) with 152 patients in total with a unilateral non-obstructive non-refluxing megaureter, of which 95 (62.5%) were localized on the left side (z ¼ 3.00, P ¼ 0.001). Including all bilateral cases yielded similar results (143 out of 248 renal units (57.7%), z ¼ 2.35, P ¼ 0.009). DISCUSSION
This analysis shows that most unilateral CAKUT affect the left kidney more frequently than the right. This is based on five different CAKUT diagnoses, with in total 107 cohorts and 7248 patients of whom 4,110 (56.7%, 95% confidence interval 55.6-57.8%) had a CAKUT on the left side. An exception to this left-side predominance is found in females with combined genital anomalies and URA that commonly present on the right side. It remains unclear what the exact mechanism is in explaining these lateralizations. Possible
Table 3 | Demographic details of cohorts of patients with renal ectopia Publication Donahoe, 1980 (ref. 33) Guarino, 2004 (ref. 34) Engelhardt, 2006 (ref. 35) Arena, 2007 (ref. 36) Glodny, 2008 (ref. 37) vd Bosch, 2010 (ref. 38) Overall
Ectopic left kidneya (n/N (proportion)) 7/16 50/92 11/15 32/56 6/12 26/41
(0.44) (0.54) (0.73) (0.57) (0.50) (0.63)
132/232 (0.57, 95% CI 0.51–0.63) z=2.04, P=0.02
Study weightb (%) 6.9 40.1 5.9 24.3 5.3 17.5
Ectopic left kidneyc (n/N (proportion)) 7/16 57/106 12/17 34/60 6/12 26/41
(0.44) (0.54) (0.71) (0.57) (0.50) (0.63)
142/252 (0.56, 95% CI 0.50–0.62) z=1.95, P=0.03
Abbreviation: CI, confidence interval. a Excluding bilateral cases. b Weight according to the Review Manager random-effects meta-analysis. c Including bilateral cases.
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Table 4 | Demographic details of cohorts of patients with unilateral PUJO Publication
Left-sided PUJOa (n/N (proportion))
Study weightb (%)
Left-sided PUJOc (n/N (proportion))
55/89 (0.62) 58/79 (0.73) 74/100 (0.74) 64/85 (0.75) 54/75 (0.72) 33/39 (0.85) 6/11 (0.55) 38/69 (0.55) 38/53 (0.72) 52/74 (0.70) 57/84 (0.68) 61/100 (0.61) 28/54 (0.52) 9/16 (0.56) 233/343 (0.68) 120/173 (0.69) 86/188 (0.46) 57/99 (0.58) 31/49 (0.63) 3/13 (0.23) 60/88 (0.68) 13/32 (0.41) 25/60 (0.42) 12/14 (0.86) 43/84 (0.51)
4.8 4.3 4.8 4.4 4.3 2.8 1.2 4.3 3.6 4.3 4.6 5.0 3.8 1.6 7.0 6.0 6.2 5.0 3.5 1.2 4.7 2.7 4.0 1.0 4.7
NAd NAd 95/142 (0.67) 85/127 (0.67) 59/85 (0.69) 35/43 (0.81) 7/13 (0.54) 46/85 (0.54) NAd NAd 57/84 (0.68) NAd 42/82 (0.51) 9/16 (0.56) NAd 179/291 (0.62) 86/188 (0.46) 60/105 (0.57) NAd 4/15 (0.27) 115/198 (0.58) NAd 25/60 (0.42) 12/14 (0.86) 44/86 (0.51)
Capolicchio, 1999 (ref. 6) McAleer, 1999 (ref. 7) Subramaniam, 1999 (ref. 39) Kim, 2001 (ref. 40) Schuster, 2001 (ref. 41) Thompson, 2001 (ref. 42) Aziz, 2002 (ref. 43) Apocalypse, 2003 (ref. 44) Boubaker, 2003 (ref. 45) Braga, 2003 (ref. 46) Calisti, 2003 (ref. 47) Thorup, 2003 (ref. 48) Ylinen, 2004 (ref. 49) Reddy, 2005 (ref. 50) Chertin, 2006 (ref. 51) Ismail, 2006 (ref. 52) Romero, 2006 (ref. 53) Elmalik, 2008 (ref. 54) Chertin, 2009 (ref. 55) Gulur, 2009 (ref. 56) Karnak, 2009 (ref. 57) Lopez, 2009 (ref. 58) Ninan, 2009 (ref. 59) Deng, 2010 (ref. 60) Gupta, 2010 (ref. 61) Overall
1312/2075 (0.63, 95% CI 0.61–0.65) z=12.03, Po0.0001
960/1634 (0.59, 95% CI 0.56–0.61) z=7.05, Po0.0001
Abbreviations: CI, confidence interval; NA, not available; PUJO, pelviureteral junction obstruction. a Excluding bilateral cases. b Weight according to the Review Manager random-effects meta-analysis. c Including bilateral cases. d Bilateral cases were excluded in this study.
Table 5 | Demographic details of cohorts of patients with unilateral non-obstructive, non-refluxing megaureter Publication Anto´n-Pacheco Sa´nchez, 1995 (ref. 62) McLellan, 2002 (ref. 63) Chertin, 2008 (ref. 64) Arena, 1998 (ref. 65) Sheu, 1998 (ref. 66) Overall
Left-sided megauretera (n/N (proportion)) 13/20 25/39 30/53 13/20 14/20
(0.65) (0.64) (0.57) (0.65) (0.70)
Study weightb (%) 12.9 25.7 36.0 12.9 12.4
95/152 (0.63, 95% CI 0.55–0.70) z=3.00, P=0.001
Left-sided megaureterc (n/N (proportion)) 16/26 40/69 56/105 15/24 16/24
(0.62) (0.58) (0.53) (0.63) (0.67)
143/248 (0.58, 95% CI 0.52–0.64) z=2.35, P=0.009
Abbreviation: CI, confidence interval. a Excluding bilateral cases. b Weight according to the Review Manager random-effects meta-analysis. c Including bilateral cases.
causes can be found in the (development of the) vasculature, differential gene expression profiles, or susceptibility to environmental factors such as hypoxia. There is a known difference in shape and volume between both kidneys,8 illustrating the diversity in kidney development between the sides. An interesting dissimilarity between sides that illustrates possible gene differences is the finding of an autopsy study of 35 fetuses with trisomy 13 toward a tendency for the left kidney to be lighter.9 Other studies present evidence for an increased sensitivity to environmental influences with a higher susceptibility to hypoxia 742
of the right side of the body.10 In contrast, in a cohort of 20-year-old individuals born very prematurely, kidneys were significantly smaller than kidneys from term-born controls, a difference that was most pronounced in the left kidney.11 Another explanation for the difference between sides may be found in anatomical variations based on the liver (preventing the right kidney to ascend as far as the left during development12) or the vasculature.13 Indeed, there is a known difference in the origin and direction of the renal arteries between the sides.14 Kidney International (2011) 80, 740–745
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Many other congenital malformation do show a laterality pattern,15,16 indicating that the difference in frequency of CAKUT between the sides is not a unique finding. This may have to do with an imbalance in factors that coordinate lateralization, including genes that are differentially expressed at both sides of the embryo at different times during development.17,18 However, the expression of such genes during nephrogenesis has not yet shown any explanation for the described differences between sides in the incidence of CAKUT. This analysis has some limitations. First, the case definition of the original publication was used, which could lead to a mixture of underlying diagnoses. Second, I did not attempt to contact authors of publications that did not provide information on the side of the CAKUT, nor did I elaborate on all of the reference lists of papers that were identified. This will have resulted in not all cohorts of CAKUT being included, and may have an effect on the exact percentage of CAKUT being on the left side. Finally, it cannot be excluded that there is a difference in presentation between a CAKUT on the left side versus the same diagnosis on the right side, which would lead to an increased presentation of patients with left-sided CAKUT. Analysis of cohorts with unilateral MCDK and PUJO that were detected prenatally (that is, before the onset of clinical signs) did show similar results, which illustrates that this is unlikely to have a significant impact on the results. In conclusion, unilateral CAKUT (MCDK, URA, renal ectopia, PUJO, and non-obstructive non-refluxing megaureter) do present more frequently on the left side. Explanations for this difference between sides remain largely unclear and speculative, illustrating our limited knowledge of embryogenesis in general and nephrogenesis specifically. As more insight into factors controlling kidney development may ultimately lead to optimization of nephrogenesis and/or prevention of CAKUT, this presents a relevant field for further research. MATERIALS AND METHODS For the meta-analysis, I selected several urinary tract malformations of interest, that is, unilateral MCDK, URA, unilateral renal ectopia, unilateral PUJO, and unilateral non-obstructive nonrefluxing megaureter. Only publications reporting over 10 cases were included. Owing to the high numbers of publications on PUJO, only papers published since 1999 were included. Extracted data included the total number of cases with unilateral urinary tract malformations that were described to fit the diagnosis of interest, and with bilateral anomalies in the categories renal ectopia, PUJO, and non-obstructive non-refluxing megaureter. Bilateral cases of renal agenesis or MCDK were not included, as this presents a lethal condition. Of the total numbers of unilateral cases, the number and proportion of patients with the malformation on the left side was noted. Of the total number of unilateral and bilateral cases, the total number and proportion of left renal units affected was noted. Some of the papers on PUJO excluded bilateral cases; these cohorts were excluded from the analysis that included the bilateral cases. Kidney International (2011) 80, 740–745
With these data, a cumulative meta-analysis was performed. To test my hypothesis that CAKUT is more frequently found on the left side than the expected 50%, two approaches were used. First of all, Review Manager (RevMan, version 5.0, The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen) was used. For each cohort entered, the control group consisted of the same number of patients as the publication and 50% of these were considered to have that specific unilateral CAKUT on the left side. In case of an odd number of cases in the cohort, the number in the control cohort was increased by one. Using RevMan, a pooled effect size of weighted mean differences for continuous data was calculated, together with a 95% confidence interval, based on a random-effects model. A random-effects model was chosen a priori as I had the impression that variation in the study populations would result in between-study heterogeneity beyond that of sampling variability. The weight (%) is based on study size and variation of the data (standard deviation). Second, the proportion of the anomalies on the left side was compared with the expected proportion (0.50), and a z value (with continuity correction) was calculated,19 with corresponding P-value to test the null hypothesis that the measured proportion (Pmeas) was identical to the expected proportion (Pexp): z¼
1 jPmeas Pexp j 2n seðPexp Þ
in which n indicates the total number of patients included and se(Pexp) indicates the standard error of the expected proportion, which can be calculated as follows: rffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi Pexp ð1 Pexp Þ se ðPexp Þ ¼ n The total measured proportions of left-sided CAKUT are presented, together with the 95% confidence interval. Statistical differences were considered significant if Po0.05 (two tailed). DISCLOSURE
The author declared no competing interests. ACKNOWLEDGMENTS
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