- Email: [email protected]
Familial Factors, Low Birth Weight, and Development of ESRD: A Nationwide Registry Study
Original Investigation Familial Factors, Low Birth Weight, and Development of ESRD: A Nationwide Registry Study Paschal Ruggajo, MD,1,2 Rannveig Skrunes, MD,2,3 Einar Svarstad, MD, PhD,2,3 Rolv Skjærven, PhD,4,5 Anna Varberg Reisæther, MD, PhD,6 and Bjørn Egil Vikse, MD, PhD 2,7 Background: Previous studies have demonstrated that low birth weight (LBW) is associated with higher risk for end-stage renal disease (ESRD). However, both LBW and ESRD cluster in families. The present study investigates whether familial factors explain the association between LBW and ESRD. Study Design: Retrospective registry-based cohort study. Setting & Participants: Since 1967, the Medical Birth Registry of Norway has recorded medical data for all births in the country. Sibling data are available through the Norwegian Population Registry. Since 1980, all patients with ESRD in Norway have been registered in the Norwegian Renal Registry. Individuals registered in the Medical Birth Registry with at least 1 registered sibling were included. Predictor: LBW in the participant and/or LBW in at least 1 sibling. Outcome: ESRD. Results: Of 1,852,080 included individuals, 527 developed ESRD. Compared with individuals without LBW and with no siblings with LBW, individuals without LBW but with a sibling with LBW had an HR for ESRD of 1.20 (95% CI, 0.91-1.59), individuals with LBW but no siblings with LBW had an HR of 1.59 (95% CI, 1.182.14), and individuals with LBW and a sibling with LBW had an HR of 1.78 (95% CI, 1.26-2.53). Similar results were observed for individuals who were small for gestational age (SGA). Separate analyses for the association of age 18 to 42 years and noncongenital ESRD showed stronger associations for SGA than for LBW, and the associations were not statistically significant for age 18 to 42 years for LBW. Limitations: Follow-up only until 42 years of age. Conclusions: LBW and SGA are associated with higher risk for ESRD during the first 40 years of life, and the associations were not explained by familial factors. Our results support the hypothesis that impaired intrauterine nephron development may be a causal risk factor for progressive kidney disease. Am J Kidney Dis. 67(4):601-608. ª 2016 by the National Kidney Foundation, Inc. INDEX WORDS: Low birth weight (LBW); end-stage renal disease (ESRD); index; sibling; genetic factors; small for gestational age (SGA); placental insufficiency; intrauterine growth restriction; early determinants of disease; prenatal exposure delayed effects.
B
arker et al1 proposed the hypothesis that malnutrition in utero could result in permanent physiologic and metabolic changes in adult life that would increase the risk for chronic adult diseases. A related hypothesis by Brenner et al2 postulated that intrauterine malnutrition could cause lower nephron number, predicting later hypertension and kidney disease. Other studies have shown that infants with low birth weight (LBW) have reduced nephron numbers compared with infants with normal birth weight.3,4 Studies have also demonstrated associations between LBW and higher blood pressure5-8 and risk for end-stage renal disease (ESRD).6-8 Contrasting views exist on mechanisms underlying the association between LBW and future hypertension and kidney disease.9-11 On the one hand, direct mechanisms are suggested by strong associations between birth weight and nephron number,3,12 as well as by associations between intrauterine malnutrition and cardiovascular risk factors in extreme situations such as the Dutch hunger crisis13 and in animal model experiments.14,15 On the other hand, LBW,16,17 cardiovascular risk factors,18,19 and chronic kidney Am J Kidney Dis. 2016;67(4):601-608
diseases20,21 show clear familial aggregation and it is therefore possible that genetic or environmental factors strongly confound the association. The association between LBW and hypertension is the most studied and established association in this field. A meta-analysis of several small twin studies From the 1Department of Internal Medicine, MUHAS, Dar es Salaam, Tanzania; 2Department of Clinical Medicine, University of Bergen; 3Department of Medicine, Haukeland University Hospital; 4 Department of Global Health and Primary Health Care, University of Bergen; 5Medical Birth Registry of Norway, Norwegian Institute of Public Health, Bergen; 6Department of Transplantation Medicine, Rikshospitalet, Oslo University Hospital, Oslo; and 7Department of Medicine, Haugesund Hospital, Haugesund, Norway. Received July 1, 2015. Accepted in revised form November 16, 2015. Originally published online December 31, 2015. Address correspondence to Paschal Ruggajo, MD, c/o Bjorn Egil Vikse, MD, PhD, Department of Medicine, Haugesund Hospital, Postcode 5528, Haugesund, Norway. E-mail: prugajo@ yahoo.com 2016 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2015.11.015 601
Ruggajo et al
suggested important confounding by familial factors.22,23 A larger Swedish twin study argued for the opposite.9 However, to our knowledge, no studies have investigated the possible confounding role of familial factors in the association between LBW and later ESRD. The Medical Birth Registry of Norway has registered data for all births in Norway since 1967, and sibling data have been registered in the Norwegian Population Registry. Since 1980, all patients with ESRD in Norway have been registered in the Norwegian Renal Registry. We linked these registries and studied how risk for ESRD was affected by whether the individuals or at least 1 sibling had LBW or was small for gestational age (SGA). We hypothesized that if genetic factors were a confounding factor, risk for ESRD would be higher in individuals who had siblings with LBW, and that the association between LBW and ESRD would be attenuated by including data for siblings with LBW, independent of ESRD. It has been debated whether LBW or SGA is the best predictor of later disease, and both factors were therefore included in the analyses.24,25
METHODS Study Participants Since 1967, extensive data for maternal disease and conditions of the newborn have been registered in the Medical Birth Registry of Norway for all births of 16 weeks’ gestation or longer. Maternal and paternal national identification numbers have been registered in the Norwegian Population Registry for almost all individuals born since 1953. We defined individuals with the same mother and father as siblings. Since 1980, data (including date of onset and cause of ESRD) for all patients developing ESRD have been registered in the Norwegian Renal Registry. The national Cause of Death Registry contains data for all deaths; for this study, data were available through December 2009. Data from the registries were linked based on the 11-digit national identification number. All individuals registered in the Medical Birth Registry from 1967 to 2009 who had at least 1 sibling registered in the Medical Birth Registry during the same period were included. Individuals with no siblings (504,531 individuals in total, of whom 164 had ESRD), individuals with 7 or more siblings (5,063 individuals, of whom 4 had ESRD), individuals who either themselves or at least 1 of their siblings were the result of a multiple gestation (92,247 individuals, of whom 20 had ESRD), and individuals with missing birth weight data (7,122 individuals, of whom 4 developed ESRD) were excluded. Individuals who died before 1980 (8,315 participants) were also excluded. The study protocol was approved and consent was waived by the regional ethics committee (approval number 2009/90).
Explanatory Variables Birth weight less than the sex-specific 10th percentile (male, 2.87 kg; female, 2.80 kg) was considered LBW. Gestational age was based on the last menstrual period (period 1967-1999) and routine ultrasonographic examination in gestational weeks 17 through 20 (period from 1999 onward). Preterm birth was defined as gestational age less than 37 weeks. Birth weight less than the 10th percentile for gestational age using previously published sexspecific reference values in Norway26 defined SGA. In the Medical 602
Birth Registry, gestational age data were available for w94.5% of all included individuals and 92% of individual-sibling groups. Maternal preeclampsia was defined as increased blood pressure to .140/90 mm Hg and proteinuria after 20 weeks’ gestation. We defined pregestational maternal disease as maternal diabetes mellitus, kidney disease, rheumatic disease, or essential hypertension diagnosed before pregnancy.27
Outcome Variables The outcome was the development of ESRD, and onset was defined as the date of initiating dialysis treatment or undergoing kidney transplantation. Individuals with kidney failure who did not receive long-term dialysis treatment or undergo kidney transplantation were not recorded as having an outcome. Individuals who did not develop ESRD were followed up until June 30, 2009, or date of death. Causes of ESRD were divided into 4 categories: glomerular disease (primary glomerulonephritis, inflammatory vascular disease, and systemic autoimmune disease), congenital or hereditary disease (congenital kidney or urinary tract malformations, cystic kidney disease, and other heritable causes of kidney disease), diabetic nephropathy, and other causes (upper urinary tract infections and other primary tubulointerstitial nephropathies, hypertensive nephropathy, renal vascular disease, rare causes, and unknown cause).
Statistical Analyses Data were analyzed in a cohort design with birth-related variables for the individual and/or sibling(s) as exposure variables and ESRD as the outcome variable. Hazard ratio (HR) estimates were obtained by Cox regression statistics, and start of follow-up was set at the date of birth. The main explanatory variable was LBW of the included individual and/or at least 1 sibling, but risk estimates associated with SGA and preterm birth of the individual and/or at least 1 sibling were also analyzed. Because no cases with ESRD had been registered between 1967 and 1979, individuals born in this period were left truncated in the survival analyses before January 1980. Consequently, the counting process formulation of proportional hazards (Cox regression) was applied. This method does not include index individuals with siblings in the analysis until an event could be registered. If not otherwise stated, mean 6 standard deviation or HR estimates with 95% confidence intervals (CIs) are given; P , 0.05 was considered statistically significant, and all tests were 2 tailed. Analyses were performed using the STATA MP edition 13.0 statistical package (StataCorp LP).
RESULTS Study Participants A total of 1,852,080 individuals were included in the present study, and 527 of these developed ESRD during follow-up. By definition, 10% of the included individuals had LBW, and 13.5% of the included individuals had at least 1 sibling with LBW; corresponding numbers for SGA were 9.8% and 13.1%. Mean number of siblings was 1.7 6 1.0 (standard deviation), and mean follow-up was 20.9 6 12.0 (maximum, 42.1) years. Characteristics of included individuals for 4 subgroups based on whether the individual or at least 1 of his or her siblings had LBW are shown in Table 1; identical analyses for SGA are presented in Table S1 (provided as online supplementary material). Risks Associated With Own Birth-Related Variables At ages 10, 20, 30, and 40 years, 0.01%, 0.02%, 0.04%, and 0.09% of individuals had developed Am J Kidney Dis. 2016;67(4):601-608
Low Birth Weight, Sibship, and ESRD Table 1. Characteristics of Included Individuals and Their Mothers’ Pregnancy Health According to Whether at Least 1 Sibling Had LBW, Norway 1967-2009 Neither Individual Nor Sibling With LBW
Sibling With LBW, Individual Not LBW
Individual With LBW, Sibling Not LBW
Individual and Sibling With LBW
1,492,968 387 12.4
178,720 57 14.8
110,577 49 20.9a
69,815 34 23.1a
676 1.68 6 0.97 20.9 6 11.9 4.60% 1.62% 0.67% 1.99% 2.14%
128 2.00 6 1.16a 21.5 6 11.7a 13.0%a 2.78%a 0.71% 2.62%a 2.39%a
54 1.56 6 0.89a 21.2 6 12.5a 56.8%a 31.5%a 4.8%a 8.17%a 2.65%a
52 1.82 6 1.05a 21.1 6 12.3a 68.3%a 32.0%a 4.1%a 7.89%a 3.24%a
Total no. No. with ESRD No. with ESRD, per 1,000,000 person-y at risk No. of siblings with ESRD No. of siblings Follow-up, y SGA (,10th percentile) Preterm birth 5-min Apgar score , 7 Maternal preeclampsia Maternal diseaseb
Note: Unless otherwise indicated, values given as mean 6standard deviation. Abbreviations: ESRD, end-stage renal disease; LBW, low birth weight; SGA, small for gestational age. a P , 0.001. b Defined as maternal diabetes mellitus, kidney disease, rheumatic disease, or essential hypertension diagnosed before pregnancy.
ESRD. Compared with individuals with birth weight above the 10th percentile, LBW was associated with a higher HR of 1.63 (95% CI, 1.29-2.06) for the development of ESRD. Corresponding HRs for individuals with SGA and preterm birth were 1.67 (95% CI, 1.30-2.07) and 1.36 (95% CI, 0.94-1.99), respectively (Fig 1). When analyses for LBW and SGA were repeated in term births, being LBW was associated
Figure 1. Cumulative risk for end-stage renal disease (ESRD) in individuals according to whether the individual was [A] low birth weight (LBW) or [B] small for gestational age (SGA). Am J Kidney Dis. 2016;67(4):601-608
with an HR of 1.56 (95% CI, 1.18-2.07) and SGA was associated with an HR of 1.64 (95% CI, 1.30-2.07). LBW was associated with a similar HR of ESRD in males and females. In separate analyses using 2.5 kg as the cutoff for defining LBW, LBW was associated with an HR of 2.25 (95% CI, 1.59-3.19). Risks Associated With Birth-Related Variables in Siblings Compared with individuals who did not have siblings with LBW, having at least 1 sibling with LBW was associated with an HR of 1.31 (95% CI, 1.051.64) for the development of ESRD. Similar, but weaker, trends were observed for SGA and preterm birth. As shown in Tables 1 and S1, LBW and SGA aggregated in families. This slightly higher risk in siblings could thus be explained by LBW in the individuals themselves, and in further analyses, we analyzed the combined effects. Compared with individuals without LBW and with no siblings with LBW, individuals without LBW but with a sibling with LBW had an HR of ESRD of 1.20 (95% CI, 0.91-1.59), individuals with LBW but no siblings with LBW had an HR of 1.59 (95% CI, 1.18-2.14), and individuals with LBW and a sibling with LBW had an HR of 1.78 (95% CI, 1.26-2.53; Table 2; Fig 2). After adjustments for birth year, sex, maternal disease, maternal preeclampsia, and number of recorded siblings, virtually identical results were found. Identical analyses for SGA showed HRs of 1.00 (95% CI, 0.73-1.36), 1.49 (95% CI, 1.10-2.03), and 1.73 (95% CI, 1.21-2.48), respectively, and analyses for preterm birth showed HRs of 1.23 (95% CI, 0.87-1.76), 1.32 (95% CI, 0.85-2.04), and 1.42 (95% CI, 0.63-3.18). Results were similar in males and females. In a separate analysis using 2.5 kg as the cutoff for defining LBW, HRs were 1.46 (95% CI, 603
Ruggajo et al Table 2. Risk for ESRD According to Whether Included Individual or at Least 1 Sibling Had LBW, SGA, or Preterm Birth, Norway 1967-2009 Adjusted Modela
Unadjusted Model Individual
Not LBW LBW Not SGA SGA Not preterm birth Preterm birth
Sibling
Total No.
No. With ESRD
Not LBW LBW Not LBW LBW Not SGA SGA Not SGA SGA Not preterm birth Preterm birth Not preterm birth Preterm birth
1,492,968 178,720 110,577 69,815 1,378,340 160,133 102,930 61,235 1,538,469 101,435 62,029 19,393
387 57 49 34 351 44 47 33 426 33 21 6
HR (95% CI)
1.00 1.20 1.59 1.78 1.00 1.00 1.49 1.73 1.00 1.23 1.32 1.42
(reference) (0.91-1.59) (1.18-2.14) (1.26-2.53) (reference) (0.73-1.36) (1.10-2.03) (1.21-2.48) (reference) (0.87-1.76) (0.85-2.04) (0.63-3.18)
P
0.2 0.02 0.01 0.9 0.007 0.002 0.2 0.2 0.4
HR (95% CI)
1.00 1.20 1.60 1.78 1.00 1.00 1.51 1.75 1.00 1.22 1.29 1.34
(reference) (0.91-1.58) (1.19-2.15) (1.25-2.52) (reference) (0.73-1.36) (1.11-2.06) (1.22-2.50) (reference) (0.86-1.75) (0.83-2.00) (0.60-3.00)
P
0.2 0.002 0.001 0.9 0.007 0.002 0.3 0.3 0.5
Abbreviations: CI, confidence interval; ESRD, end-stage renal disease; HR, hazard ratio; LBW, low birth weight; SGA, small for gestational age. a Adjusted for birth year, sex, maternal disease (defined as as maternal diabetes mellitus, kidney disease, rheumatic disease, or essential hypertension diagnosed before pregnancy), maternal preeclampsia, and number of recorded siblings, categorized as 1, 2, or 3 or more.
1.00-2.12), 2.27 (95% CI, 1.53-3.38), and 2.42 (95% CI, 1.20-4.86), respectively. Furthermore, analyzing the risk for developing ESRD by decremental birth weight in the individual and/or sibling(s) suggested stronger effects with individual birth weight , 2.25 kg, but there was no added effect of decremental birth weight in siblings. In analyses using the 20th percentile as the cutoff, results were weaker
than in our main analyses, most likely due to dilution of effects. As expected and shown in Table 1, individuals who had more siblings had a higher probability of having at least 1 sibling with LBW, SGA, or preterm birth. This could affect the analyses and we therefore chose to separately analyze individuals who had only 1 or 2 or more siblings. These analyses showed that number of recorded siblings did not significantly modify the HRs described. Risks Associated With Preterm Birth and Effect of Age Period
Figure 2. Cumulative risk for end-stage renal disease (ESRD) in individuals according to whether the individual or at least 1 of his or her siblings was [A] low birth weight (LBW) or [B] small for gestational age (SGA). 604
Compared with individuals born at term who were not SGA, individuals born preterm and not SGA had an HR for ESRD of 1.09 (95% CI, 0.69-1.73), individuals born at term with SGA had an HR of 1.54 (95% CI, 1.20-1.96), and individuals born with SGA and preterm had the highest risk for developing ESRD with an HR of 4.03 (95% CI, 2.08-7.80; Table 3). A similar analysis for LBW stratified by term status yielded a nonsignificant increase in risk. Because the associations could be age dependent, the associations between birth-related variables and differing risk for ESRD were further analyzed in the periods before age 18 years and age 18 to 42 years (ie, childhood vs adulthood). In these analyses, LBW was more strongly associated with risk for ESRD during the first 18 years of life; the HR was 2.72 (95% CI, 1.88-3.92) during the first 18 years of life and 1.23 (95% CI, 0.90-1.68) for age 18 to 42 years. For SGA, the corresponding results were 1.93 (95% CI, 1.282.91) and 1.53 (95% CI, 1.15-2.03). The effects of combinations of LBW/SGA with preterm birth are Am J Kidney Dis. 2016;67(4):601-608
Low Birth Weight, Sibship, and ESRD Table 3. HRs for Risk for ESRD According to Whether the Individuals Had LBW, SGA, or were Born Preterm, Norway 1967-2009 Total Follow-up Period Total No.
No. With ESRD
Not LBW, term birth 1,566,298 Not LBW, preterm birth 27,807 LBW, term birth 117,804 LBW, preterm birth 54,645 Not SGA, term birth 1,515,611 Not SGA, preterm birth 72,700 SGA, term birth 160,073 SGA, preterm birth 11,505
Age 18-42 y P
HR (95% CI)
418 4 55 24 389 19 77 9
1.00 0.54 1.56 1.89 1.00 1.09 1.54 4.03
(reference) (0.20-1.45) 0.2 (1.18-2.07) 0.002 (1.25-2.86) 0.002 (reference) (0.69-1.73) 0.7 (1.20-1.96) 0.001 (2.08-7.80) ,0.001
Total No.
No. With ESRD
889,187 15,777 72,782 26,388 849,180 37,132 104,517 4,979
303 3 32 13 274 10 52 6
P
HR (95% CI)
1.00 0.57 1.21 1.42 1.00 0.81 1.41 4.02
(reference) (0.18-1.77) (0.84-1.75) (0.82-2.48) (reference) (0.43-1.53) (1.05-1.90) (1.79-9.03)
0.3 0.3 0.2 0.5 0.02 0.001
Note: Analyses performed for total follow-up period and separately for the period of age 18 to 42 years. Abbreviations: CI, confidence interval; ESRD, end-stage renal disease; HR, hazard ratio; LBW, low birth weight; SGA, small for gestational age.
shown for adult age in Table 4, and as shown in the table, SGA is a stronger risk factor for ESRD in adult age than is LBW. Further analyses of the results in Table 3 with subgroups for siblings with LBW/SGA showed no effect of sibling LBW/SGA. Risk for ESRD Due to Different Causes Among the 527 individuals who developed ESRD, 228 developed ESRD due to glomerular disease; 155, congenital or inherited causes; 49, diabetic nephropathy; and 9, other causes. Table 4 shows risks for specific causes of ESRD for LBW and SGA. The numbers of cases in several subgroups were low with imprecise estimates of HR; however, there was a trend toward a stronger association between LBW and ESRD due to congenital or inherited causes than with other causes of ESRD, but the same trend was not seen for SGA. It is possible that congenital urinary tract malformations and hereditary kidney disease might cause LBW. We therefore chose to analyze risk for ESRD that was not caused by congenital or inherited disease separately. In these analyses, which were performed identically as the analyses described
for Tables 2 and 4, HRs for LBW were 1.03 (95% CI, 0.73-1.45), 1.30 (95% CI, 0.89-1.90), and 1.41 (95% CI, 0.89-2.22), and for SGA were 0.97 (95% CI, 0.67-1.41), 1.48 (95% CI, 1.03-2.12), and 1.65 (95% CI, 1.08-2.54). Among individuals who developed ESRD during the first 18 years of life, 33.1% developed ESRD due to glomerular disease; 52.8%, congenital or inherited disease; 0.0%, diabetic nephropathy; and 14.1%, other causes; corresponding percentages for the age group 18 to 42 years were 47.2%, 19.1%, 13.2%, and 20.5%, respectively.
DISCUSSION The present study shows that LBW is associated with higher risk for the development of ESRD during the first 40 years of life. This association is not attenuated after including data for LBW in siblings, and LBW in siblings is not significantly associated with higher risk for ESRD. In the main analyses, similar results were seen for LBW and SGA. However, LBW seemed in further analyses to be more strongly associated with ESRD due to congenital or hereditary disease during the first 18 years of life,
Table 4. HR for Different Causes of ESRD According to Birth Characteristic, Norway 1980-2009 Congenital or Inherited Disease
Glomerular Disease Individual
Sibling
n
HR (95% CI)
P
n
Not LBW Not LBW 173 1.00 (reference) 101 LBW 23 1.08 (0.70-1.67) 0.7 21 LBW Not LBW 22 1.60 (1.03-2.50) 0.04 19 LBW 10 1.17 (0.62-2.22) 0.6 14 Not SGA Not SGA 150 1.00 (reference) 99 SGA 20 1.05 (0.66-1.68) 0.8 13 SGA Not SGA 28 2.08 (1.39-3.12) ,0.001 13 SGA 13 1.59 (0.90-2.80) 0.1 10
HR (95% CI)
1.00 1.72 2.49 2.92 1.00 1.07 1.58 1.99
P
Diabetes n
HR (95% CI)
Other Causes P
(reference) 43 1.00 (reference) (1.08-2.76) 0.02 1 0.19 (0.03-1.38) 0.1 (1.52-4.07) ,0.001 2 0.55 (0.13-2.29) 0.4 (1.67-5.11) ,0.001 3 1.37 (0.43-4.41) 0.6 (reference) 34 1.00 (reference) (0.60-1.91) 0.8 1 0.23 (0.03-1.70) 0.2 (0.88-2.82) 0.1 2 0.61 (0.14-2.54) 0.5 (1.04-3.83) 0.04 6 3.07 (1.29-7.30) 0.01
n
70 12 6 7 68 10 4 4
HR (95% CI)
1.00 1.42 1.08 2.04 1.00 1.18 0.66 1.09
(reference) (0.77-2.62) (0.47-2.49) (0.94-4.45) (reference) (0.61-2.31) (0.24-1.81) (0.40-3.00)
P
0.3 0.9 0.07 0.6 0.4 0.9
Abbreviations: CI, confidence interval; ESRD, end-stage renal disease; HR, hazard ratio; LBW, low birth weight; SGA, small for gestational age. Am J Kidney Dis. 2016;67(4):601-608
605
Ruggajo et al
whereas the association between SGA and ESRD remained important also in adulthood and for all causes of ESRD. The most important finding of the present study is that having been born with LBW or SGA is associated with higher risk for ESRD, and that these associations are not explained by familial aggregation of LBW or SGA. Individuals who themselves were not LBW but who had a sibling with LBW had a nonsignificantly increased HR of 1.20 (95% CI, 0.911.59), and identical analyses for SGA showed an HR of 1.00 (95% CI, 0.73-1.36). Both these HRs were much less than the HRs for individuals who themselves had LBW or SGA (1.5-1.8) and we therefore conclude that having a sibling with LBW or SGA does not confer an increased risk for ESRD at age younger than 40 years. As discussed in the introduction, a plausible explanation for the association between LBW/SGA and adult disease could be familial aggregation of genetic or environmental factors; however, our results point toward a causal effect of intrauterine growth restriction. In numerous previous studies, LBW has been linked to moderately higher blood pressure,28 impaired glucose homeostasis,29 microalbuminuria,30 impaired vascular resistance,31 and endothelial dysfunction.32 All these factors are known risk factors for progression to ESRD. Additionally, LBW has been shown to be associated with progressive immunoglobulin A nephropathy and membranous nephropathy.33,34 Results from the present study have confirmed those of previous studies that have shown associations between LBW and ESRD.4,6-8,35 In a previous Norwegian study,8 it was suggested that LBW seemed to be more predictive for the development of ESRD than SGA. However, in the present study, SGA and LBW were similarly associated with ESRD in the main analyses, but SGA was a stronger risk factor than LBW at age 18 to 42 years and in the analyses of noncongenital and nonhereditary kidney disease. Because the present and previous8 studies were based on almost the same population, the different findings were unexpected. However, the difference could stem from the different inclusion criteria and follow-up periods between the 2 studies. Because the effects of prenatal programming are expected to increase with age, we regard noncongenital ESRD in adult age as a more interesting outcome than all-cause ESRD, and the present study suggests that SGA is a stronger risk factor than LBW for this outcome. Whereas LBW could be explained merely by short gestational age in many cases, SGA is more often explained by compromised intrauterine nutrition. Interestingly, the effect of SGA was significantly stronger in those with preterm birth versus those with term birth, whereas the effect of 606
LBW was similar in those with preterm or term birth. Our findings thus suggest that placental insufficiency, as indicated by SGA, might be an important explanatory factor for impaired nephron development, and that the effect might be especially important if born preterm. It could be that the pathophysiologic background for a higher risk for glomerular and hypertensive nephropathy is that LBW or SGA are associated with a reduced number of hypertrophied glomeruli,4,36,37 as well as mild to moderate elevations of blood pressure.38,39 Stronger effects would thus be expected with advancing age, although that could not be investigated in the present study, which only has follow-up data up to a maximum age of 42 years. To our knowledge, the association between LBW and ESRD has not been investigated at more than 50 years of age,4,6-8,12,24,35 except in 1 Japanese study of elderly patients on hemodialysis therapy that suggested increased risk for diabetic nephropathy in people with LBW.40 The findings in younger individuals and the presumed pathophysiologic background argues that LBW or SGA should be regarded as a risk factor for progressive kidney disease also in older age. In this study, LBW was defined as less than the 10th percentile (w2.8 kg) in order to have adequate numbers of outcomes in subgroups of LBW. In separate analyses in which we defined LBW as ,2.5 kg, even stronger effect estimates were seen. There are important international variations in average birth weight, and although birth weight has been shown to be associated with glomerular number,4,36 our results of a dose-response relationship for birth weight and SGA being a stronger predictor of noncongenital ESRD suggest that degree of intrauterine growth restriction might be the determining factor. The global incidence of LBW (defined as birth weight , 2.5 kg) is 15% and varies widely between developed and developing countries.41 For example, 3.3% had birth weight , 2.5 kg in the present Norwegian study, whereas a report from Sub-Saharan Africa describes a prevalence of 13% to 15%.42 According to the Innocenti Report from UNICEF (United Nations Children’s Fund), Norway was ranked sixth for low incidence of birth weight , 2.5 kg, third for material well-being in children, and seventh for health and safety in children.43 In developing countries such as Tanzania, maternal undernutrition is a major determinant of intrauterine growth restriction and subsequent LBW.44 It is uncertain whether the cause of intrauterine growth restriction, such as maternal undernutrition in developing countries or placental dysfunction in developed countries, affects nephron development differently. Because maternal undernutrition probably was very uncommon in the present Norwegian study, it cannot shed further light on this Am J Kidney Dis. 2016;67(4):601-608
Low Birth Weight, Sibship, and ESRD
topic. However, the important consequence might be that maternal undernutrition in developing countries might be a major cause of impaired nephron development and future risk for hypertension and kidney disease in these populations.45 The complete national inclusion and registration of end points is the key strength of our study; it yielded a large number of participants with prospective registration of birth-related variables extracted from very reliable registries. This allowed for a cohort design that we believe is a strong study design. Furthermore, the study used a clinically highly significant outcome. A limitation is that ESRD is a rare outcome, and despite the more than 1.85 million included individuals, only 527 individuals developed ESRD, an adequate number for investigation of risk factors for our main outcome, but too few for reliable analyses of risk factors for specific ESRD causes. Cause of ESRD was reported by the treating nephrologist, but it was not possible to review the medical charts to validate these reports. Because the total emigration rate from Norway during the study period was only 0.1% (data from the Norwegian Population Registry), we believe that we have nearly complete follow-up of our population. A limitation is also that individuals were included from 1967 to 2009, but outcomes were not registered until 1980. This limitation was compensated for by the statistical method that does not include individuals in the analyses until an outcome could be registered. Risks associated with siblings having LBW, SGA, or preterm birth were defined by at least 1 having the given risk factor. The probability of this of course increased with increasing numbers of recorded siblings and therefore, one could expect that this would affect the associated risks. To investigate this, we performed both stratified and adjusted analyses and could not find evidence that our main results were affected. We conclude that intrauterine growth restriction seems to be associated with increased risk for ESRD during the first 40 years of life. Because this effect cannot be explained by familial genetic or environmental factors, our study suggests a causal effect of intrauterine growth restriction. We further conclude that SGA is a stronger predictor than LBW for the risk for noncongenital and nonhereditary causes of ESRD at the age of 18 to 42 years. In general, our study strengthens the hypothesis of impaired nephron development in utero as an important risk factor for kidney disease in adult life and points to the importance of relating birth weight to gestational age in future studies.
ACKNOWLEDGEMENTS Aspects of this work were presented in abstract form at the 51st European Renal Association2European Dialysis and Transplant Assocation Congress, May 31 to June 3, 2014, Amsterdam, the Netherlands. Support: None. Am J Kidney Dis. 2016;67(4):601-608
Financial Disclosure: The authors declare that they have no relevant financial interests. Contributions: Research idea and study design; PR, BEV, ES; data acquisition; BEV, AVR; data analysis/interpretation; PR, BEV, RoS; statistical analysis; PR, BEV, RoS, RaS; supervision or mentorship; BEV, ES. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. PR and BEV take responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained. Peer Review: Evaluated by 3 external peer reviewers, a Statistical Editor, a Co-Editor, and the Editor-in-Chief.
SUPPLEMENTARY MATERIAL Table S1: Characteristics of included individuals and maternal health according to whether they or $1 sibling had SGA. Note: The supplementary material accompanying this article (http:dx.doi.org/10.1053/j.ajkd.2015.11.015) is available at www. ajkd.org
REFERENCES 1. Barker DJ, Osmond C, Winter P, Margetts B, Simmonds S. Weight in infancy and death from ischaemic heart disease. Lancet. 1989;334:577-580. 2. Brenner BM, Garcia DL, Anderson S. Glomeruli and blood pressure. Less of one, more the other? Am J Hypertens. 1988;1: 335-347. 3. Hinchliffe S, Sargent P, Howard C, Chan Y, Van Velzen D. Human intrauterine renal growth expressed in absolute number of glomeruli assessed by the disector method and Cavalieri principle. Lab Invest. 1991;64:777-784. 4. Manalich R, Reyes L, Herrera M, Melendi C, Fundora I. Relationship between weight at birth and the number and size of renal glomeruli in humans: a histomorphometric study. Kidney Int. 2000;58:770-773. 5. Zarrati M, Shidfar F, Razmpoosh E, et al. Does low birth weight predict hypertension and obesity in schoolchildren? Ann Nutr Metab. 2013;63:69-76. 6. Lackland DT, Egan BM, Fan ZJ, Syddall HE. Low birth weight contributes to the excess prevalence of end-stage renal disease in African Americans. J Clin Hypertens. 2001;3: 29-31. 7. Fan ZJ, Lackland DT, Lipsitz SR, Nicholas JS. The association of low birthweight and chronic renal failure among Medicaid young adults with diabetes and/or hypertension. Public Health Rep. 2006;121:239-244. 8. Vikse BE, Irgens LM, Leivestad T, Hallan S, Iversen BM. Low birth weight increases risk for end-stage renal disease. J Am Soc Nephrol. 2008;19:151-157. 9. Bergvall N, Iliadou A, Johansson S, et al. Genetic and shared environmental factors do not confound the association between birth weight and hypertension: a study among Swedish twins. Circulation. 2007;115:2931-2938. 10. Lie RT. Intergenerational exchange and perinatal risks: a note on interpretation of generational recurrence risks. Paediatr Perinatal Epidemiol. 2007;21:13-18. 11. Hübinette A, Cnattingius S, Ekbom A, de Faire U, Kramer M, Lichtenstein P. Birthweight, early environment, and genetics: a study of twins discordant for acute myocardial infarction. Lancet. 2001;357:1997-2001. 607
Ruggajo et al 12. Giapros V, Drougia A, Hotoura E, Papadopoulou F, Argyropoulou M, Andronikou S. Kidney growth in small-forgestational-age infants: evidence of early accelerated renal growth. Nephrol Dial Transplant. 2006;21:3422-3427. 13. Roseboom TJ, Van Der Meulen JH, Ravelli AC, Osmond C, Barker DJ, Bleker OP. Effects of prenatal exposure to the Dutch famine on adult disease in later life: an overview. Mol Cell Endocrinol. 2001;185:93-98. 14. Langley-Evans SC. Critical differences between two low protein diet protocols in the programming of hypertension in the rat. Int J Food Sci Nutr. 2000;51:11-17. 15. Kwong WY, Wild AE, Roberts P, Willis AC, Fleming TP. Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension. Development. 2000;127:4195-4202. 16. Wang X, Zuckerman B, Coffman GA, Corwin MJ. Familial aggregation of low birth weight among whites and blacks in the United States. N Engl J Med. 1995;333:1744-1749. 17. La Batide-Alanore A, Trégouët D-A, Jaquet D, Bouyer J, Tiret L. Familial aggregation of fetal growth restriction in a French cohort of 7,822 term births between 1971 and 1985. Am J Epidemiol. 2002;156:180-187. 18. ten Kate LP, Boman H, Daiger SP, Motulsky AG. Familial aggregation of coronary heart disease and its relation to known genetic risk factors. Am J Cardiol. 1982;50:945-953. 19. Knuiman MW, Divitini ML, Welborn TA, Bartholomew HC. Familial correlations, cohabitation effects, and heritability for cardiovascular risk factors. Ann Epidemiol. 1996;6: 188-194. 20. Lei H-H, Perneger TV, Klag MJ, Whelton PK, Coresh J. Familial aggregation of renal disease in a population-based casecontrol study. J Am Soc Nephrol. 1998;9:1270-1276. 21. Satko SG, Sedor JR, Iyengar SK, Freedman BI. Familial clustering of chronic kidney disease. Semin Dial. 2007;20(3): 229-236. 22. McNeill G, Tuya C, Smith W. The role of genetic and environmental factors in the association between birthweight and blood pressure: evidence from meta-analysis of twin studies. Int J Epidemiol. 2004;33:995-1001. 23. Kramer MS. Invited commentary: association between restricted fetal growth and adult chronic disease: is it causal? Is it important? Am J Epidemiol. 2000;152:605-608. 24. Schmidt IM, Chellakooty M, Boisen KA, et al. Impaired kidney growth in low-birth-weight children: distinct effects of maturity and weight for gestational age. Kidney Int. 2005;68:731-740. 25. Keijzer-Veen MG, Schrevel M, Finken MJ, et al. Microalbuminuria and lower glomerular filtration rate at young adult age in subjects born very premature and after intrauterine growth retardation. J Am Soc Nephrol. 2005;16:2762-2768. 26. Skjaerven R, Gjessing HK, Bakketeig LS. Birthweight by gestational age in Norway. Acta Obstet Gynecol Scand. 2000;79: 440-449. 27. Vikse BE, Irgens LM, Leivestad T, Skjærven R, Iversen BM. Preeclampsia and the risk of end-stage renal disease. N Engl J Med. 2008;359:800-809.
608
28. Law CM, Shiell AW. Is blood pressure inversely related to birth weight? The strength of evidence from a systematic review of the literature. J Hypertens. 1996;14:935-942. 29. Nelson RG, Morgenstem H, Bennett PH. Birth weight and renal disease in Pima Indians with type 2 diabetes mellitus. Am J Epidemiol. 1998;148:650-656. 30. Steinberg HO, Tarshoby M, Monestel R, et al. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest. 1997;100:1230-1239. 31. Yudkin J, Phillips D, Stanner S. Proteinuria and progressive renal disease: birth weight and microalbuminuria. Nephrol Dial Transplant. 1996;12:10-13. 32. Goodfellow J, Bellamy MF, Gorman ST, et al. Endothelial function is impaired in fit young adults of low birth weight. Cardiovasc Res. 1998;40:600-606. c M, Kenda RB, et al. Effect of intrauterine 33. Zidar N, Cavi growth retardation on the clinical course and prognosis of IgA glomerulonephritis in children. Nephron. 1998;79:28-32. 34. Duncan R, Bass P, Garrett P, Dathan J. Weight at birth and other factors influencing progression of idiopathic membranous nephropathy. Nephrol Dial Transplant. 1994;9:875. 35. Ichikawa T, Fukuda M, Wakamatsu-Yamanaka T, et al. Low birth weight and end-stage renal disease: demographic analysis by region in Japan. Clin Exp Nephrol. 2012;16:596-603. 36. Hughson M, Farris AB, Douglas-Denton R, Hoy WE, Bertram JF. Glomerular number and size in autopsy kidneys: the relationship to birth weight. Kidney Int. 2003;63:2113-2122. 37. Hughson M, Douglas-Denton R, Bertram J, Hoy W. Hypertension, glomerular number, and birth weight in African Americans and white subjects in the Southeastern United States. Kidney Int. 2006;69:671-678. 38. Eriksson J, Forsén T, Tuomilehto J, Osmond C, Barker D. Fetal and childhood growth and hypertension in adult life. Hypertension. 2000;36:790-794. 39. Huxley R, Neil A, Collins R. Unravelling the fetal origins hypothesis: is there really an inverse association between birthweight and subsequent blood pressure? Lancet. 2002;360:659-665. 40. Nagai K, Saito C, Yamagata K. Birth weight and end-stage diabetic nephropathy in later life: a Japanese multicenter study. Ther Apher Dial. 2014;18:111-112. 41. Abitbol CL, Rodriguez MM. The long-term renal and cardiovascular consequences of prematurity. Nat Rev Nephrol. 2012;8:265-274. 42. Wardlaw TM. Low Birthweight: Country, Regional and Global Estimates. New York: UNICEF; 2004. 43. UNICEF. An Overview of Child Well-Being in Rich Countries: A Comprehensive Assessment of the Lives and Well-Being of Children and Adolescents in the Economically Advanced Nations, Report Card 7. Florence: Innocenti Research Centre; 2007. 44. Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S, Murray CJ. Selected major risk factors and global and regional burden of disease. Lancet. 2002;360:1347-1360. 45. Luyckx VA, Bertram JF, Brenner BM, et al. Effect of fetal and child health on kidney development and long-term risk of hypertension and kidney disease. Lancet. 2013;382:273-283.
Am J Kidney Dis. 2016;67(4):601-608
B
arker et al1 proposed the hypothesis that malnutrition in utero could result in permanent physiologic and metabolic changes in adult life that would increase the risk for chronic adult diseases. A related hypothesis by Brenner et al2 postulated that intrauterine malnutrition could cause lower nephron number, predicting later hypertension and kidney disease. Other studies have shown that infants with low birth weight (LBW) have reduced nephron numbers compared with infants with normal birth weight.3,4 Studies have also demonstrated associations between LBW and higher blood pressure5-8 and risk for end-stage renal disease (ESRD).6-8 Contrasting views exist on mechanisms underlying the association between LBW and future hypertension and kidney disease.9-11 On the one hand, direct mechanisms are suggested by strong associations between birth weight and nephron number,3,12 as well as by associations between intrauterine malnutrition and cardiovascular risk factors in extreme situations such as the Dutch hunger crisis13 and in animal model experiments.14,15 On the other hand, LBW,16,17 cardiovascular risk factors,18,19 and chronic kidney Am J Kidney Dis. 2016;67(4):601-608
diseases20,21 show clear familial aggregation and it is therefore possible that genetic or environmental factors strongly confound the association. The association between LBW and hypertension is the most studied and established association in this field. A meta-analysis of several small twin studies From the 1Department of Internal Medicine, MUHAS, Dar es Salaam, Tanzania; 2Department of Clinical Medicine, University of Bergen; 3Department of Medicine, Haukeland University Hospital; 4 Department of Global Health and Primary Health Care, University of Bergen; 5Medical Birth Registry of Norway, Norwegian Institute of Public Health, Bergen; 6Department of Transplantation Medicine, Rikshospitalet, Oslo University Hospital, Oslo; and 7Department of Medicine, Haugesund Hospital, Haugesund, Norway. Received July 1, 2015. Accepted in revised form November 16, 2015. Originally published online December 31, 2015. Address correspondence to Paschal Ruggajo, MD, c/o Bjorn Egil Vikse, MD, PhD, Department of Medicine, Haugesund Hospital, Postcode 5528, Haugesund, Norway. E-mail: prugajo@ yahoo.com 2016 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2015.11.015 601
Ruggajo et al
suggested important confounding by familial factors.22,23 A larger Swedish twin study argued for the opposite.9 However, to our knowledge, no studies have investigated the possible confounding role of familial factors in the association between LBW and later ESRD. The Medical Birth Registry of Norway has registered data for all births in Norway since 1967, and sibling data have been registered in the Norwegian Population Registry. Since 1980, all patients with ESRD in Norway have been registered in the Norwegian Renal Registry. We linked these registries and studied how risk for ESRD was affected by whether the individuals or at least 1 sibling had LBW or was small for gestational age (SGA). We hypothesized that if genetic factors were a confounding factor, risk for ESRD would be higher in individuals who had siblings with LBW, and that the association between LBW and ESRD would be attenuated by including data for siblings with LBW, independent of ESRD. It has been debated whether LBW or SGA is the best predictor of later disease, and both factors were therefore included in the analyses.24,25
METHODS Study Participants Since 1967, extensive data for maternal disease and conditions of the newborn have been registered in the Medical Birth Registry of Norway for all births of 16 weeks’ gestation or longer. Maternal and paternal national identification numbers have been registered in the Norwegian Population Registry for almost all individuals born since 1953. We defined individuals with the same mother and father as siblings. Since 1980, data (including date of onset and cause of ESRD) for all patients developing ESRD have been registered in the Norwegian Renal Registry. The national Cause of Death Registry contains data for all deaths; for this study, data were available through December 2009. Data from the registries were linked based on the 11-digit national identification number. All individuals registered in the Medical Birth Registry from 1967 to 2009 who had at least 1 sibling registered in the Medical Birth Registry during the same period were included. Individuals with no siblings (504,531 individuals in total, of whom 164 had ESRD), individuals with 7 or more siblings (5,063 individuals, of whom 4 had ESRD), individuals who either themselves or at least 1 of their siblings were the result of a multiple gestation (92,247 individuals, of whom 20 had ESRD), and individuals with missing birth weight data (7,122 individuals, of whom 4 developed ESRD) were excluded. Individuals who died before 1980 (8,315 participants) were also excluded. The study protocol was approved and consent was waived by the regional ethics committee (approval number 2009/90).
Explanatory Variables Birth weight less than the sex-specific 10th percentile (male, 2.87 kg; female, 2.80 kg) was considered LBW. Gestational age was based on the last menstrual period (period 1967-1999) and routine ultrasonographic examination in gestational weeks 17 through 20 (period from 1999 onward). Preterm birth was defined as gestational age less than 37 weeks. Birth weight less than the 10th percentile for gestational age using previously published sexspecific reference values in Norway26 defined SGA. In the Medical 602
Birth Registry, gestational age data were available for w94.5% of all included individuals and 92% of individual-sibling groups. Maternal preeclampsia was defined as increased blood pressure to .140/90 mm Hg and proteinuria after 20 weeks’ gestation. We defined pregestational maternal disease as maternal diabetes mellitus, kidney disease, rheumatic disease, or essential hypertension diagnosed before pregnancy.27
Outcome Variables The outcome was the development of ESRD, and onset was defined as the date of initiating dialysis treatment or undergoing kidney transplantation. Individuals with kidney failure who did not receive long-term dialysis treatment or undergo kidney transplantation were not recorded as having an outcome. Individuals who did not develop ESRD were followed up until June 30, 2009, or date of death. Causes of ESRD were divided into 4 categories: glomerular disease (primary glomerulonephritis, inflammatory vascular disease, and systemic autoimmune disease), congenital or hereditary disease (congenital kidney or urinary tract malformations, cystic kidney disease, and other heritable causes of kidney disease), diabetic nephropathy, and other causes (upper urinary tract infections and other primary tubulointerstitial nephropathies, hypertensive nephropathy, renal vascular disease, rare causes, and unknown cause).
Statistical Analyses Data were analyzed in a cohort design with birth-related variables for the individual and/or sibling(s) as exposure variables and ESRD as the outcome variable. Hazard ratio (HR) estimates were obtained by Cox regression statistics, and start of follow-up was set at the date of birth. The main explanatory variable was LBW of the included individual and/or at least 1 sibling, but risk estimates associated with SGA and preterm birth of the individual and/or at least 1 sibling were also analyzed. Because no cases with ESRD had been registered between 1967 and 1979, individuals born in this period were left truncated in the survival analyses before January 1980. Consequently, the counting process formulation of proportional hazards (Cox regression) was applied. This method does not include index individuals with siblings in the analysis until an event could be registered. If not otherwise stated, mean 6 standard deviation or HR estimates with 95% confidence intervals (CIs) are given; P , 0.05 was considered statistically significant, and all tests were 2 tailed. Analyses were performed using the STATA MP edition 13.0 statistical package (StataCorp LP).
RESULTS Study Participants A total of 1,852,080 individuals were included in the present study, and 527 of these developed ESRD during follow-up. By definition, 10% of the included individuals had LBW, and 13.5% of the included individuals had at least 1 sibling with LBW; corresponding numbers for SGA were 9.8% and 13.1%. Mean number of siblings was 1.7 6 1.0 (standard deviation), and mean follow-up was 20.9 6 12.0 (maximum, 42.1) years. Characteristics of included individuals for 4 subgroups based on whether the individual or at least 1 of his or her siblings had LBW are shown in Table 1; identical analyses for SGA are presented in Table S1 (provided as online supplementary material). Risks Associated With Own Birth-Related Variables At ages 10, 20, 30, and 40 years, 0.01%, 0.02%, 0.04%, and 0.09% of individuals had developed Am J Kidney Dis. 2016;67(4):601-608
Low Birth Weight, Sibship, and ESRD Table 1. Characteristics of Included Individuals and Their Mothers’ Pregnancy Health According to Whether at Least 1 Sibling Had LBW, Norway 1967-2009 Neither Individual Nor Sibling With LBW
Sibling With LBW, Individual Not LBW
Individual With LBW, Sibling Not LBW
Individual and Sibling With LBW
1,492,968 387 12.4
178,720 57 14.8
110,577 49 20.9a
69,815 34 23.1a
676 1.68 6 0.97 20.9 6 11.9 4.60% 1.62% 0.67% 1.99% 2.14%
128 2.00 6 1.16a 21.5 6 11.7a 13.0%a 2.78%a 0.71% 2.62%a 2.39%a
54 1.56 6 0.89a 21.2 6 12.5a 56.8%a 31.5%a 4.8%a 8.17%a 2.65%a
52 1.82 6 1.05a 21.1 6 12.3a 68.3%a 32.0%a 4.1%a 7.89%a 3.24%a
Total no. No. with ESRD No. with ESRD, per 1,000,000 person-y at risk No. of siblings with ESRD No. of siblings Follow-up, y SGA (,10th percentile) Preterm birth 5-min Apgar score , 7 Maternal preeclampsia Maternal diseaseb
Note: Unless otherwise indicated, values given as mean 6standard deviation. Abbreviations: ESRD, end-stage renal disease; LBW, low birth weight; SGA, small for gestational age. a P , 0.001. b Defined as maternal diabetes mellitus, kidney disease, rheumatic disease, or essential hypertension diagnosed before pregnancy.
ESRD. Compared with individuals with birth weight above the 10th percentile, LBW was associated with a higher HR of 1.63 (95% CI, 1.29-2.06) for the development of ESRD. Corresponding HRs for individuals with SGA and preterm birth were 1.67 (95% CI, 1.30-2.07) and 1.36 (95% CI, 0.94-1.99), respectively (Fig 1). When analyses for LBW and SGA were repeated in term births, being LBW was associated
Figure 1. Cumulative risk for end-stage renal disease (ESRD) in individuals according to whether the individual was [A] low birth weight (LBW) or [B] small for gestational age (SGA). Am J Kidney Dis. 2016;67(4):601-608
with an HR of 1.56 (95% CI, 1.18-2.07) and SGA was associated with an HR of 1.64 (95% CI, 1.30-2.07). LBW was associated with a similar HR of ESRD in males and females. In separate analyses using 2.5 kg as the cutoff for defining LBW, LBW was associated with an HR of 2.25 (95% CI, 1.59-3.19). Risks Associated With Birth-Related Variables in Siblings Compared with individuals who did not have siblings with LBW, having at least 1 sibling with LBW was associated with an HR of 1.31 (95% CI, 1.051.64) for the development of ESRD. Similar, but weaker, trends were observed for SGA and preterm birth. As shown in Tables 1 and S1, LBW and SGA aggregated in families. This slightly higher risk in siblings could thus be explained by LBW in the individuals themselves, and in further analyses, we analyzed the combined effects. Compared with individuals without LBW and with no siblings with LBW, individuals without LBW but with a sibling with LBW had an HR of ESRD of 1.20 (95% CI, 0.91-1.59), individuals with LBW but no siblings with LBW had an HR of 1.59 (95% CI, 1.18-2.14), and individuals with LBW and a sibling with LBW had an HR of 1.78 (95% CI, 1.26-2.53; Table 2; Fig 2). After adjustments for birth year, sex, maternal disease, maternal preeclampsia, and number of recorded siblings, virtually identical results were found. Identical analyses for SGA showed HRs of 1.00 (95% CI, 0.73-1.36), 1.49 (95% CI, 1.10-2.03), and 1.73 (95% CI, 1.21-2.48), respectively, and analyses for preterm birth showed HRs of 1.23 (95% CI, 0.87-1.76), 1.32 (95% CI, 0.85-2.04), and 1.42 (95% CI, 0.63-3.18). Results were similar in males and females. In a separate analysis using 2.5 kg as the cutoff for defining LBW, HRs were 1.46 (95% CI, 603
Ruggajo et al Table 2. Risk for ESRD According to Whether Included Individual or at Least 1 Sibling Had LBW, SGA, or Preterm Birth, Norway 1967-2009 Adjusted Modela
Unadjusted Model Individual
Not LBW LBW Not SGA SGA Not preterm birth Preterm birth
Sibling
Total No.
No. With ESRD
Not LBW LBW Not LBW LBW Not SGA SGA Not SGA SGA Not preterm birth Preterm birth Not preterm birth Preterm birth
1,492,968 178,720 110,577 69,815 1,378,340 160,133 102,930 61,235 1,538,469 101,435 62,029 19,393
387 57 49 34 351 44 47 33 426 33 21 6
HR (95% CI)
1.00 1.20 1.59 1.78 1.00 1.00 1.49 1.73 1.00 1.23 1.32 1.42
(reference) (0.91-1.59) (1.18-2.14) (1.26-2.53) (reference) (0.73-1.36) (1.10-2.03) (1.21-2.48) (reference) (0.87-1.76) (0.85-2.04) (0.63-3.18)
P
0.2 0.02 0.01 0.9 0.007 0.002 0.2 0.2 0.4
HR (95% CI)
1.00 1.20 1.60 1.78 1.00 1.00 1.51 1.75 1.00 1.22 1.29 1.34
(reference) (0.91-1.58) (1.19-2.15) (1.25-2.52) (reference) (0.73-1.36) (1.11-2.06) (1.22-2.50) (reference) (0.86-1.75) (0.83-2.00) (0.60-3.00)
P
0.2 0.002 0.001 0.9 0.007 0.002 0.3 0.3 0.5
Abbreviations: CI, confidence interval; ESRD, end-stage renal disease; HR, hazard ratio; LBW, low birth weight; SGA, small for gestational age. a Adjusted for birth year, sex, maternal disease (defined as as maternal diabetes mellitus, kidney disease, rheumatic disease, or essential hypertension diagnosed before pregnancy), maternal preeclampsia, and number of recorded siblings, categorized as 1, 2, or 3 or more.
1.00-2.12), 2.27 (95% CI, 1.53-3.38), and 2.42 (95% CI, 1.20-4.86), respectively. Furthermore, analyzing the risk for developing ESRD by decremental birth weight in the individual and/or sibling(s) suggested stronger effects with individual birth weight , 2.25 kg, but there was no added effect of decremental birth weight in siblings. In analyses using the 20th percentile as the cutoff, results were weaker
than in our main analyses, most likely due to dilution of effects. As expected and shown in Table 1, individuals who had more siblings had a higher probability of having at least 1 sibling with LBW, SGA, or preterm birth. This could affect the analyses and we therefore chose to separately analyze individuals who had only 1 or 2 or more siblings. These analyses showed that number of recorded siblings did not significantly modify the HRs described. Risks Associated With Preterm Birth and Effect of Age Period
Figure 2. Cumulative risk for end-stage renal disease (ESRD) in individuals according to whether the individual or at least 1 of his or her siblings was [A] low birth weight (LBW) or [B] small for gestational age (SGA). 604
Compared with individuals born at term who were not SGA, individuals born preterm and not SGA had an HR for ESRD of 1.09 (95% CI, 0.69-1.73), individuals born at term with SGA had an HR of 1.54 (95% CI, 1.20-1.96), and individuals born with SGA and preterm had the highest risk for developing ESRD with an HR of 4.03 (95% CI, 2.08-7.80; Table 3). A similar analysis for LBW stratified by term status yielded a nonsignificant increase in risk. Because the associations could be age dependent, the associations between birth-related variables and differing risk for ESRD were further analyzed in the periods before age 18 years and age 18 to 42 years (ie, childhood vs adulthood). In these analyses, LBW was more strongly associated with risk for ESRD during the first 18 years of life; the HR was 2.72 (95% CI, 1.88-3.92) during the first 18 years of life and 1.23 (95% CI, 0.90-1.68) for age 18 to 42 years. For SGA, the corresponding results were 1.93 (95% CI, 1.282.91) and 1.53 (95% CI, 1.15-2.03). The effects of combinations of LBW/SGA with preterm birth are Am J Kidney Dis. 2016;67(4):601-608
Low Birth Weight, Sibship, and ESRD Table 3. HRs for Risk for ESRD According to Whether the Individuals Had LBW, SGA, or were Born Preterm, Norway 1967-2009 Total Follow-up Period Total No.
No. With ESRD
Not LBW, term birth 1,566,298 Not LBW, preterm birth 27,807 LBW, term birth 117,804 LBW, preterm birth 54,645 Not SGA, term birth 1,515,611 Not SGA, preterm birth 72,700 SGA, term birth 160,073 SGA, preterm birth 11,505
Age 18-42 y P
HR (95% CI)
418 4 55 24 389 19 77 9
1.00 0.54 1.56 1.89 1.00 1.09 1.54 4.03
(reference) (0.20-1.45) 0.2 (1.18-2.07) 0.002 (1.25-2.86) 0.002 (reference) (0.69-1.73) 0.7 (1.20-1.96) 0.001 (2.08-7.80) ,0.001
Total No.
No. With ESRD
889,187 15,777 72,782 26,388 849,180 37,132 104,517 4,979
303 3 32 13 274 10 52 6
P
HR (95% CI)
1.00 0.57 1.21 1.42 1.00 0.81 1.41 4.02
(reference) (0.18-1.77) (0.84-1.75) (0.82-2.48) (reference) (0.43-1.53) (1.05-1.90) (1.79-9.03)
0.3 0.3 0.2 0.5 0.02 0.001
Note: Analyses performed for total follow-up period and separately for the period of age 18 to 42 years. Abbreviations: CI, confidence interval; ESRD, end-stage renal disease; HR, hazard ratio; LBW, low birth weight; SGA, small for gestational age.
shown for adult age in Table 4, and as shown in the table, SGA is a stronger risk factor for ESRD in adult age than is LBW. Further analyses of the results in Table 3 with subgroups for siblings with LBW/SGA showed no effect of sibling LBW/SGA. Risk for ESRD Due to Different Causes Among the 527 individuals who developed ESRD, 228 developed ESRD due to glomerular disease; 155, congenital or inherited causes; 49, diabetic nephropathy; and 9, other causes. Table 4 shows risks for specific causes of ESRD for LBW and SGA. The numbers of cases in several subgroups were low with imprecise estimates of HR; however, there was a trend toward a stronger association between LBW and ESRD due to congenital or inherited causes than with other causes of ESRD, but the same trend was not seen for SGA. It is possible that congenital urinary tract malformations and hereditary kidney disease might cause LBW. We therefore chose to analyze risk for ESRD that was not caused by congenital or inherited disease separately. In these analyses, which were performed identically as the analyses described
for Tables 2 and 4, HRs for LBW were 1.03 (95% CI, 0.73-1.45), 1.30 (95% CI, 0.89-1.90), and 1.41 (95% CI, 0.89-2.22), and for SGA were 0.97 (95% CI, 0.67-1.41), 1.48 (95% CI, 1.03-2.12), and 1.65 (95% CI, 1.08-2.54). Among individuals who developed ESRD during the first 18 years of life, 33.1% developed ESRD due to glomerular disease; 52.8%, congenital or inherited disease; 0.0%, diabetic nephropathy; and 14.1%, other causes; corresponding percentages for the age group 18 to 42 years were 47.2%, 19.1%, 13.2%, and 20.5%, respectively.
DISCUSSION The present study shows that LBW is associated with higher risk for the development of ESRD during the first 40 years of life. This association is not attenuated after including data for LBW in siblings, and LBW in siblings is not significantly associated with higher risk for ESRD. In the main analyses, similar results were seen for LBW and SGA. However, LBW seemed in further analyses to be more strongly associated with ESRD due to congenital or hereditary disease during the first 18 years of life,
Table 4. HR for Different Causes of ESRD According to Birth Characteristic, Norway 1980-2009 Congenital or Inherited Disease
Glomerular Disease Individual
Sibling
n
HR (95% CI)
P
n
Not LBW Not LBW 173 1.00 (reference) 101 LBW 23 1.08 (0.70-1.67) 0.7 21 LBW Not LBW 22 1.60 (1.03-2.50) 0.04 19 LBW 10 1.17 (0.62-2.22) 0.6 14 Not SGA Not SGA 150 1.00 (reference) 99 SGA 20 1.05 (0.66-1.68) 0.8 13 SGA Not SGA 28 2.08 (1.39-3.12) ,0.001 13 SGA 13 1.59 (0.90-2.80) 0.1 10
HR (95% CI)
1.00 1.72 2.49 2.92 1.00 1.07 1.58 1.99
P
Diabetes n
HR (95% CI)
Other Causes P
(reference) 43 1.00 (reference) (1.08-2.76) 0.02 1 0.19 (0.03-1.38) 0.1 (1.52-4.07) ,0.001 2 0.55 (0.13-2.29) 0.4 (1.67-5.11) ,0.001 3 1.37 (0.43-4.41) 0.6 (reference) 34 1.00 (reference) (0.60-1.91) 0.8 1 0.23 (0.03-1.70) 0.2 (0.88-2.82) 0.1 2 0.61 (0.14-2.54) 0.5 (1.04-3.83) 0.04 6 3.07 (1.29-7.30) 0.01
n
70 12 6 7 68 10 4 4
HR (95% CI)
1.00 1.42 1.08 2.04 1.00 1.18 0.66 1.09
(reference) (0.77-2.62) (0.47-2.49) (0.94-4.45) (reference) (0.61-2.31) (0.24-1.81) (0.40-3.00)
P
0.3 0.9 0.07 0.6 0.4 0.9
Abbreviations: CI, confidence interval; ESRD, end-stage renal disease; HR, hazard ratio; LBW, low birth weight; SGA, small for gestational age. Am J Kidney Dis. 2016;67(4):601-608
605
Ruggajo et al
whereas the association between SGA and ESRD remained important also in adulthood and for all causes of ESRD. The most important finding of the present study is that having been born with LBW or SGA is associated with higher risk for ESRD, and that these associations are not explained by familial aggregation of LBW or SGA. Individuals who themselves were not LBW but who had a sibling with LBW had a nonsignificantly increased HR of 1.20 (95% CI, 0.911.59), and identical analyses for SGA showed an HR of 1.00 (95% CI, 0.73-1.36). Both these HRs were much less than the HRs for individuals who themselves had LBW or SGA (1.5-1.8) and we therefore conclude that having a sibling with LBW or SGA does not confer an increased risk for ESRD at age younger than 40 years. As discussed in the introduction, a plausible explanation for the association between LBW/SGA and adult disease could be familial aggregation of genetic or environmental factors; however, our results point toward a causal effect of intrauterine growth restriction. In numerous previous studies, LBW has been linked to moderately higher blood pressure,28 impaired glucose homeostasis,29 microalbuminuria,30 impaired vascular resistance,31 and endothelial dysfunction.32 All these factors are known risk factors for progression to ESRD. Additionally, LBW has been shown to be associated with progressive immunoglobulin A nephropathy and membranous nephropathy.33,34 Results from the present study have confirmed those of previous studies that have shown associations between LBW and ESRD.4,6-8,35 In a previous Norwegian study,8 it was suggested that LBW seemed to be more predictive for the development of ESRD than SGA. However, in the present study, SGA and LBW were similarly associated with ESRD in the main analyses, but SGA was a stronger risk factor than LBW at age 18 to 42 years and in the analyses of noncongenital and nonhereditary kidney disease. Because the present and previous8 studies were based on almost the same population, the different findings were unexpected. However, the difference could stem from the different inclusion criteria and follow-up periods between the 2 studies. Because the effects of prenatal programming are expected to increase with age, we regard noncongenital ESRD in adult age as a more interesting outcome than all-cause ESRD, and the present study suggests that SGA is a stronger risk factor than LBW for this outcome. Whereas LBW could be explained merely by short gestational age in many cases, SGA is more often explained by compromised intrauterine nutrition. Interestingly, the effect of SGA was significantly stronger in those with preterm birth versus those with term birth, whereas the effect of 606
LBW was similar in those with preterm or term birth. Our findings thus suggest that placental insufficiency, as indicated by SGA, might be an important explanatory factor for impaired nephron development, and that the effect might be especially important if born preterm. It could be that the pathophysiologic background for a higher risk for glomerular and hypertensive nephropathy is that LBW or SGA are associated with a reduced number of hypertrophied glomeruli,4,36,37 as well as mild to moderate elevations of blood pressure.38,39 Stronger effects would thus be expected with advancing age, although that could not be investigated in the present study, which only has follow-up data up to a maximum age of 42 years. To our knowledge, the association between LBW and ESRD has not been investigated at more than 50 years of age,4,6-8,12,24,35 except in 1 Japanese study of elderly patients on hemodialysis therapy that suggested increased risk for diabetic nephropathy in people with LBW.40 The findings in younger individuals and the presumed pathophysiologic background argues that LBW or SGA should be regarded as a risk factor for progressive kidney disease also in older age. In this study, LBW was defined as less than the 10th percentile (w2.8 kg) in order to have adequate numbers of outcomes in subgroups of LBW. In separate analyses in which we defined LBW as ,2.5 kg, even stronger effect estimates were seen. There are important international variations in average birth weight, and although birth weight has been shown to be associated with glomerular number,4,36 our results of a dose-response relationship for birth weight and SGA being a stronger predictor of noncongenital ESRD suggest that degree of intrauterine growth restriction might be the determining factor. The global incidence of LBW (defined as birth weight , 2.5 kg) is 15% and varies widely between developed and developing countries.41 For example, 3.3% had birth weight , 2.5 kg in the present Norwegian study, whereas a report from Sub-Saharan Africa describes a prevalence of 13% to 15%.42 According to the Innocenti Report from UNICEF (United Nations Children’s Fund), Norway was ranked sixth for low incidence of birth weight , 2.5 kg, third for material well-being in children, and seventh for health and safety in children.43 In developing countries such as Tanzania, maternal undernutrition is a major determinant of intrauterine growth restriction and subsequent LBW.44 It is uncertain whether the cause of intrauterine growth restriction, such as maternal undernutrition in developing countries or placental dysfunction in developed countries, affects nephron development differently. Because maternal undernutrition probably was very uncommon in the present Norwegian study, it cannot shed further light on this Am J Kidney Dis. 2016;67(4):601-608
Low Birth Weight, Sibship, and ESRD
topic. However, the important consequence might be that maternal undernutrition in developing countries might be a major cause of impaired nephron development and future risk for hypertension and kidney disease in these populations.45 The complete national inclusion and registration of end points is the key strength of our study; it yielded a large number of participants with prospective registration of birth-related variables extracted from very reliable registries. This allowed for a cohort design that we believe is a strong study design. Furthermore, the study used a clinically highly significant outcome. A limitation is that ESRD is a rare outcome, and despite the more than 1.85 million included individuals, only 527 individuals developed ESRD, an adequate number for investigation of risk factors for our main outcome, but too few for reliable analyses of risk factors for specific ESRD causes. Cause of ESRD was reported by the treating nephrologist, but it was not possible to review the medical charts to validate these reports. Because the total emigration rate from Norway during the study period was only 0.1% (data from the Norwegian Population Registry), we believe that we have nearly complete follow-up of our population. A limitation is also that individuals were included from 1967 to 2009, but outcomes were not registered until 1980. This limitation was compensated for by the statistical method that does not include individuals in the analyses until an outcome could be registered. Risks associated with siblings having LBW, SGA, or preterm birth were defined by at least 1 having the given risk factor. The probability of this of course increased with increasing numbers of recorded siblings and therefore, one could expect that this would affect the associated risks. To investigate this, we performed both stratified and adjusted analyses and could not find evidence that our main results were affected. We conclude that intrauterine growth restriction seems to be associated with increased risk for ESRD during the first 40 years of life. Because this effect cannot be explained by familial genetic or environmental factors, our study suggests a causal effect of intrauterine growth restriction. We further conclude that SGA is a stronger predictor than LBW for the risk for noncongenital and nonhereditary causes of ESRD at the age of 18 to 42 years. In general, our study strengthens the hypothesis of impaired nephron development in utero as an important risk factor for kidney disease in adult life and points to the importance of relating birth weight to gestational age in future studies.
ACKNOWLEDGEMENTS Aspects of this work were presented in abstract form at the 51st European Renal Association2European Dialysis and Transplant Assocation Congress, May 31 to June 3, 2014, Amsterdam, the Netherlands. Support: None. Am J Kidney Dis. 2016;67(4):601-608
Financial Disclosure: The authors declare that they have no relevant financial interests. Contributions: Research idea and study design; PR, BEV, ES; data acquisition; BEV, AVR; data analysis/interpretation; PR, BEV, RoS; statistical analysis; PR, BEV, RoS, RaS; supervision or mentorship; BEV, ES. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. PR and BEV take responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained. Peer Review: Evaluated by 3 external peer reviewers, a Statistical Editor, a Co-Editor, and the Editor-in-Chief.
SUPPLEMENTARY MATERIAL Table S1: Characteristics of included individuals and maternal health according to whether they or $1 sibling had SGA. Note: The supplementary material accompanying this article (http:dx.doi.org/10.1053/j.ajkd.2015.11.015) is available at www. ajkd.org
REFERENCES 1. Barker DJ, Osmond C, Winter P, Margetts B, Simmonds S. Weight in infancy and death from ischaemic heart disease. Lancet. 1989;334:577-580. 2. Brenner BM, Garcia DL, Anderson S. Glomeruli and blood pressure. Less of one, more the other? Am J Hypertens. 1988;1: 335-347. 3. Hinchliffe S, Sargent P, Howard C, Chan Y, Van Velzen D. Human intrauterine renal growth expressed in absolute number of glomeruli assessed by the disector method and Cavalieri principle. Lab Invest. 1991;64:777-784. 4. Manalich R, Reyes L, Herrera M, Melendi C, Fundora I. Relationship between weight at birth and the number and size of renal glomeruli in humans: a histomorphometric study. Kidney Int. 2000;58:770-773. 5. Zarrati M, Shidfar F, Razmpoosh E, et al. Does low birth weight predict hypertension and obesity in schoolchildren? Ann Nutr Metab. 2013;63:69-76. 6. Lackland DT, Egan BM, Fan ZJ, Syddall HE. Low birth weight contributes to the excess prevalence of end-stage renal disease in African Americans. J Clin Hypertens. 2001;3: 29-31. 7. Fan ZJ, Lackland DT, Lipsitz SR, Nicholas JS. The association of low birthweight and chronic renal failure among Medicaid young adults with diabetes and/or hypertension. Public Health Rep. 2006;121:239-244. 8. Vikse BE, Irgens LM, Leivestad T, Hallan S, Iversen BM. Low birth weight increases risk for end-stage renal disease. J Am Soc Nephrol. 2008;19:151-157. 9. Bergvall N, Iliadou A, Johansson S, et al. Genetic and shared environmental factors do not confound the association between birth weight and hypertension: a study among Swedish twins. Circulation. 2007;115:2931-2938. 10. Lie RT. Intergenerational exchange and perinatal risks: a note on interpretation of generational recurrence risks. Paediatr Perinatal Epidemiol. 2007;21:13-18. 11. Hübinette A, Cnattingius S, Ekbom A, de Faire U, Kramer M, Lichtenstein P. Birthweight, early environment, and genetics: a study of twins discordant for acute myocardial infarction. Lancet. 2001;357:1997-2001. 607
Ruggajo et al 12. Giapros V, Drougia A, Hotoura E, Papadopoulou F, Argyropoulou M, Andronikou S. Kidney growth in small-forgestational-age infants: evidence of early accelerated renal growth. Nephrol Dial Transplant. 2006;21:3422-3427. 13. Roseboom TJ, Van Der Meulen JH, Ravelli AC, Osmond C, Barker DJ, Bleker OP. Effects of prenatal exposure to the Dutch famine on adult disease in later life: an overview. Mol Cell Endocrinol. 2001;185:93-98. 14. Langley-Evans SC. Critical differences between two low protein diet protocols in the programming of hypertension in the rat. Int J Food Sci Nutr. 2000;51:11-17. 15. Kwong WY, Wild AE, Roberts P, Willis AC, Fleming TP. Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension. Development. 2000;127:4195-4202. 16. Wang X, Zuckerman B, Coffman GA, Corwin MJ. Familial aggregation of low birth weight among whites and blacks in the United States. N Engl J Med. 1995;333:1744-1749. 17. La Batide-Alanore A, Trégouët D-A, Jaquet D, Bouyer J, Tiret L. Familial aggregation of fetal growth restriction in a French cohort of 7,822 term births between 1971 and 1985. Am J Epidemiol. 2002;156:180-187. 18. ten Kate LP, Boman H, Daiger SP, Motulsky AG. Familial aggregation of coronary heart disease and its relation to known genetic risk factors. Am J Cardiol. 1982;50:945-953. 19. Knuiman MW, Divitini ML, Welborn TA, Bartholomew HC. Familial correlations, cohabitation effects, and heritability for cardiovascular risk factors. Ann Epidemiol. 1996;6: 188-194. 20. Lei H-H, Perneger TV, Klag MJ, Whelton PK, Coresh J. Familial aggregation of renal disease in a population-based casecontrol study. J Am Soc Nephrol. 1998;9:1270-1276. 21. Satko SG, Sedor JR, Iyengar SK, Freedman BI. Familial clustering of chronic kidney disease. Semin Dial. 2007;20(3): 229-236. 22. McNeill G, Tuya C, Smith W. The role of genetic and environmental factors in the association between birthweight and blood pressure: evidence from meta-analysis of twin studies. Int J Epidemiol. 2004;33:995-1001. 23. Kramer MS. Invited commentary: association between restricted fetal growth and adult chronic disease: is it causal? Is it important? Am J Epidemiol. 2000;152:605-608. 24. Schmidt IM, Chellakooty M, Boisen KA, et al. Impaired kidney growth in low-birth-weight children: distinct effects of maturity and weight for gestational age. Kidney Int. 2005;68:731-740. 25. Keijzer-Veen MG, Schrevel M, Finken MJ, et al. Microalbuminuria and lower glomerular filtration rate at young adult age in subjects born very premature and after intrauterine growth retardation. J Am Soc Nephrol. 2005;16:2762-2768. 26. Skjaerven R, Gjessing HK, Bakketeig LS. Birthweight by gestational age in Norway. Acta Obstet Gynecol Scand. 2000;79: 440-449. 27. Vikse BE, Irgens LM, Leivestad T, Skjærven R, Iversen BM. Preeclampsia and the risk of end-stage renal disease. N Engl J Med. 2008;359:800-809.
608
28. Law CM, Shiell AW. Is blood pressure inversely related to birth weight? The strength of evidence from a systematic review of the literature. J Hypertens. 1996;14:935-942. 29. Nelson RG, Morgenstem H, Bennett PH. Birth weight and renal disease in Pima Indians with type 2 diabetes mellitus. Am J Epidemiol. 1998;148:650-656. 30. Steinberg HO, Tarshoby M, Monestel R, et al. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest. 1997;100:1230-1239. 31. Yudkin J, Phillips D, Stanner S. Proteinuria and progressive renal disease: birth weight and microalbuminuria. Nephrol Dial Transplant. 1996;12:10-13. 32. Goodfellow J, Bellamy MF, Gorman ST, et al. Endothelial function is impaired in fit young adults of low birth weight. Cardiovasc Res. 1998;40:600-606. c M, Kenda RB, et al. Effect of intrauterine 33. Zidar N, Cavi growth retardation on the clinical course and prognosis of IgA glomerulonephritis in children. Nephron. 1998;79:28-32. 34. Duncan R, Bass P, Garrett P, Dathan J. Weight at birth and other factors influencing progression of idiopathic membranous nephropathy. Nephrol Dial Transplant. 1994;9:875. 35. Ichikawa T, Fukuda M, Wakamatsu-Yamanaka T, et al. Low birth weight and end-stage renal disease: demographic analysis by region in Japan. Clin Exp Nephrol. 2012;16:596-603. 36. Hughson M, Farris AB, Douglas-Denton R, Hoy WE, Bertram JF. Glomerular number and size in autopsy kidneys: the relationship to birth weight. Kidney Int. 2003;63:2113-2122. 37. Hughson M, Douglas-Denton R, Bertram J, Hoy W. Hypertension, glomerular number, and birth weight in African Americans and white subjects in the Southeastern United States. Kidney Int. 2006;69:671-678. 38. Eriksson J, Forsén T, Tuomilehto J, Osmond C, Barker D. Fetal and childhood growth and hypertension in adult life. Hypertension. 2000;36:790-794. 39. Huxley R, Neil A, Collins R. Unravelling the fetal origins hypothesis: is there really an inverse association between birthweight and subsequent blood pressure? Lancet. 2002;360:659-665. 40. Nagai K, Saito C, Yamagata K. Birth weight and end-stage diabetic nephropathy in later life: a Japanese multicenter study. Ther Apher Dial. 2014;18:111-112. 41. Abitbol CL, Rodriguez MM. The long-term renal and cardiovascular consequences of prematurity. Nat Rev Nephrol. 2012;8:265-274. 42. Wardlaw TM. Low Birthweight: Country, Regional and Global Estimates. New York: UNICEF; 2004. 43. UNICEF. An Overview of Child Well-Being in Rich Countries: A Comprehensive Assessment of the Lives and Well-Being of Children and Adolescents in the Economically Advanced Nations, Report Card 7. Florence: Innocenti Research Centre; 2007. 44. Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S, Murray CJ. Selected major risk factors and global and regional burden of disease. Lancet. 2002;360:1347-1360. 45. Luyckx VA, Bertram JF, Brenner BM, et al. Effect of fetal and child health on kidney development and long-term risk of hypertension and kidney disease. Lancet. 2013;382:273-283.
Am J Kidney Dis. 2016;67(4):601-608