Background
Brenner and co-workers suggested that adverse intrauterine environment, for example due to placental insufficiency or maternal undernutrition, was associated with impaired nephron development and increased risk of hypertension and progressive kidney disease in adult life [
1]. Birthweight related parameters such as low birth weight (LBW) and small for gestational age (SGA) are strong surrogate markers for adverse intrauterine environment [
2,
3]. LBW has been associated with increased risk of hypertension [
4], albuminuria [
5,
6] and progressive chronic kidney disease [
7,
8]. Fewer studies have investigated effects of SGA, but in a previous study from Norway we showed that SGA was a stronger risk marker than LBW for development of ESRD in adult age [
9].
IgA nephropathy (IgAN) is the most frequent primary idiopathic glomerulonephritis worldwide [
10‐
12] and has a variable clinical course [
13‐
15]. In a previous study we showed that LBW and SGA were risk factors for progression to ESRD in IgAN patients [
16].
Several previous autopsy-based stereological and histomorphometric studies have reported strong correlations between LBW and reduced glomerular numbers as well as increased glomerular volume [
17‐
19]. A previous study has also shown that IgAN patients born SGA had increased risk for glomerulosclerosis and arterial hypertension [
20]. To our knowledge, the association between birth weight and glomerular histomorphometric changes among IgAN patients has not been investigated before.
In the present study we aimed to investigate how LBW and SGA in IgAN patients associate with specific glomerular morphological changes compared to IgAN without LBW and SGA. We hypothesized that LBW and SGA would be associated with fewer and larger glomeruli in line with the Brenner hypothesis but that the effects of LBW and SGA could be different. In our previous study cited above, associations were stronger in males, so gender differences were also investigated in the present study.
Discussion
The present study shows that young IgAN patients who were born with LBW and/or SGA had larger glomerular area at time of diagnosis than IgAN patients born with normal birth weight. The association was statistically significant in total cohort and in males. We consider larger glomerular area to be a marker of lower number of total glomeruli and the study thus suggests that larger glomeruli may at least in part, explain the higher risk of progressive renal disease in young IgAN patients with LBW and/or SGA in Norway [
16]. Furthermore, considering that our cohort comprised young adults with preserved renal function (low-risk group), our findings may indeed underestimate the importance of this association. LBW and/or SGA may thus represent a basic vulnerability (first hit) among IgAN patients upon which other insults (immunology, hypertension etc. as second hits) may accelerate progressive nephropathy.
As described, LBW and/or SGA were associated with larger glomeruli at time of diagnosis of IgAN. Importantly, this association showed a dose-response correlation between birthweight and glomerular area. Larger glomeruli were also associated with lower eGFR. Previous studies have shown that glomerular size is a sensitive measure of total kidney glomerular number [
18] and is proposed to be among the adaptive compensatory glomerular changes for congenital nephron deficit [
17,
18,
33]. LBW has also been associated with low nephron number [
34] and higher blood pressure [
35] as well as microalbuminuria and low glomerular filtration rate in those born very premature and after intrauterine growth retardation [
36]. In relation to IgAN in particular, a previous study has shown that progressive IgAN is associated with reduced glomerular density and increased glomerular volume [
37]. The present study thus links these findings and suggests that LBW and/or SGA increase risk of progressive IgAN, mechanisms might involve lower glomerular number or higher blood pressure [
1,
38]. These mechanisms might be important also in other kidney diseases as we previously have shown that LBW was associated with higher risk of ESRD in general, and also of ESRD due to glomerular disease [
7,
39]. In the present study, LBW was defined by the 10th percentile in our previous study and corresponded to 2.93 kg for men and 2.69 kg for women [
16]. As we observed a dose-response relationship between birth weight and glomerular size, we hypothesize that differences might have been larger if we had used a lower cut-off (WHO definition of LBW is < 2.5 kg). Neither LBW alone nor SGA alone were however significantly associated with larger glomeruli in Table
1 and we therefore decided to combine these groups in the remaining analyses. SGA and LBW may however partly be explained by different pathophysiological mechanisms and it is uncertain which is most strongly associated with later development of kidney disease [
16]. As differences between groups with LBW and/or SGA in Table
1 were negligible we believe that this is the best approach. It is interesting to note that the group with SGA but not LBW (mean birth weight of 2.9 kg) had nearly the same glomerular area as the groups with LBW (mean birth weights of 1.9 and 2.4 kg). It should however be noted that in the comparison of only IgAN patients with vs without LBW (excluding the group with SGA and without LBW), glomerular area was statistically significantly different. Whether birthweight or birthweight for gestational age represents the most powerful predictor of later kidney disease and morphology must be analysed further in future studies.
Brenner postulated that congenital nephron deficit would lead to large glomeruli with glomerular hyperfiltration that would progressively increase risk of glomerular damage. A previous study has reported higher mean percentage of sclerotic glomeruli among IgAN patients who had suffered intra-uterine growth retardation [
20]. Further, Ikezumi et al. reported association between LBW and development of focal segmental glomerulosclerosis in children and proposed that this was probably related to glomerular prematurity and podocytopenia [
38]. In fact, podocytopenia has been associated with increased disease severity in IgAN [
40] and in turn, compensatory podocyte hypertrophy has been associated with progressive glomerulosclerosis [
41]. In our paper, there were non-significant trends towards more glomerular sclerosis in those with low birth weight but the degree of glomerular sclerosis was mild in our study as we selected patients with preserved kidney function. In our opinion, our study supports the Brenner hypothesis that large glomeruli with hyperfiltration is a link between low birth weight (as a marker of congenital nephron deficit) and progressive kidney disease.
As mentioned above, the association between LBW and larger glomeruli was significant in males but not females. In our previous paper [
16] on IgAN, we reported that the association between LBW and ESRD was strong and significant in males but not females. The present study included a slightly higher proportion of female IgAN patients (53%) as compared to a previous study from the same registry (26%) [
42]. These findings of a possible gender difference are interesting and warrant further investigation to supplement previous human and experimental studies that also have suggested that females might be protected against both progressive nephropathy [
43‐
45] and intrauterine impaired nephron endowment or effects thereof [
46].
In adjusted analysis, maternal preeclampsia was associated with a significantly larger glomerular area. Previous studies have shown that pre-eclampsia is associated with placental insufficiency and increases risk of LBW and SGA offspring [
17,
47]. The present study suggests that the associated placental insufficiency might have especially important effects on kidney development. This finding is however limited by the small number of observations in this study (only four patients had a mother with preeclampsia) and should thus be interpreted with caution.
In this study, we report on glomerular morphology from kidney tissue specimens obtained from patients using percutaneous kidney biopsy needle as part of the routine clinical care. This method yields only a limited sample of glomeruli as compared to stereological methods using the physical dissector/fractionator method which is considered as the gold standard. Such stereological methods e.g. Cavalieri, Weibel-Gomez, Maximal Planar Area or Dissector Principle yield accurate estimation for glomerular size and density but are laborious, time consuming, costly and require the whole kidney tissue and are therefore of limited accessibility for routine studies [
48,
49]. A previous study has illustrated that reliable mean estimates of glomerular size can be obtained by measuring 9 or more glomeruli; in white patients, measuring fewer than 6 glomeruli reduced the precision [
32]. In the present study, even though some patients had fewer than 6 glomeruli, and fewer glomeruli would tend to lower precision of the mean, the glomerular size estimates were statistically significant between groups. Also, results for glomerular area were comparable in a sensitivity analysis where only patients with 9 glomeruli or more were included, although it did not reach statistical significance due to lower N. We would thus argue that estimates of glomerular area could be obtained also by measuring fewer glomeruli in studies with limited number of available patients and tissue.