Published ahead of print on January 7, 2009
Clin J Am Soc Nephrol 4: 10-13, 2009
© 2009 American Society of Nephrology
doi: 10.2215/CJN.06101108
Developmental Origins of Renal Disease: Should Nephron Protection Begin at Birth?
Susan P. Bagby
Department of Medicine, Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, Oregon
Correspondence: Dr. Susan P. Bagby, Professor of Medicine and Physiology/Pharmacology, Oregon Health and Science University, 3314 SW U.S. Veterans Hospital Road (PP262), Portland, OR 97239. Phone: 503-494-8490; Fax: 503-494-5330; E-mail: bagbys{at}ohsu.edu
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Introduction
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That an adverse environment early in life—in utero or in the early postnatal period—can create vulnerability to chronic disease in later life is no longer a surprise. Following the lead of Barker and colleagues beginning in the late 1980s, a burgeoning literature now documents the increased risk of later-life hypertension (1), diabetes (2), coronary disease (3), and obesity (4) conferred by low birth weight, a surrogate for poor intrauterine growth. However, solid data documenting clinical relevance of the "developmental origins of disease" concept to the kidney have been slower to emerge.
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Renal Development
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We know that the critical window of kidney development spans 9 to 35 wk gestational age (GA) (5), although the point of completion can vary from 32 to 35 wk (6,7). Nephrogenesis involves successive branching of the ingrowing ureteral bud, with new nephron units forming at branch tips via co-inductive crosstalk between the ureteral bud epithelium and surrounding undifferentiated mesenchyme. Of note, this process proceeds in concentric layers, such that newly forming nephrons are located in the outer layer, with the more mature nephron units occupying successively deeper layers. Fortunately, when growth rate is impaired during this fixed developmental window, the fetal kidney forms—not incomplete nephrons—but fewer layers of normal nephrons. Nonetheless, because no new nephrons form after 35 wk GA, nephron endowment is at that point fixed for life. Thus poor intrauterine growth during nephrogenesis may yield a nephron deficit as a permanent structural legacy.
As in postnatal life, the developing fetal kidney is exquisitely sensitive to body size such that fetal kidney weight reflects body weight and—on the basis of careful studies in humans (8,9) and nonhuman primates (10)—grows by adding new nephrons. Recent stereologic studies of autopsied kidneys have shown that, in humans born at term, nephron number is in fact strikingly proportional to birth weight (11). Thus, birth weight has emerged as our first clinical clue to nephron number. In contrast to the fetal kidney, the postnatal kidney grows to match body size by hypertrophy of existing nephrons; its size thus provides no indication of nephron number except in advanced disease states.
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The Kidney in Intrauterine Growth Restriction
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Although data remain sparse, we know that intrauterine growth restriction (IUGR) in humans (birth weight <10th centile for GA) can reduce nephron number (9). The altered renal shape observed in growth-restricted babies—a skinny, sausage-shaped kidney (12,13)—is compatible with fewer concentric layers. Brenner and colleagues (14,15) were the first to articulate the potential implications of fewer nephrons at birth for later renal disease, proposing that nephropenia as a consequence of IUGR could create a relative mismatch of body size to excretory capacity, setting the stage for afferent vasodilation, glomerular hypertension, and progressive loss of nephrons via glomerulosclerosis. In 1999, in Australian aborigines, Hoy and colleagues reported the first study linking low birth weight with increased risk of microalbuminuria (16). Subsequently this relationship of low birth weight and/or prematurity to increased risk of adverse renal outcomes has been reported for low-normal kidney function in young Norwegian adults (17), for microalbuminuria and abnormal GFR in Dutch adolescents (18), and for ESRD in U.S. (19) and Norwegian adults (20).
Surprisingly, however, no prior studies to date have looked at renal histopathologic outcomes in the setting of IUGR. In the current issue, Hodgin et al. (21) are thus the first to document the histopathologic diagnosis of focal segmental glomerular sclerosis (FSGS) in the context of premature and very-low-birth-weight (VLBW) subjects. On the basis of an index case, the authors compiled six premature/VLBW patients (average 1054 g) with histopathologic findings of FSGS, drawn from the Columbia Renal Pathology Laboratory archives over a 7-yr period. Patients were of diverse ethnicity with ages at study ranging 15 to 53 yrs. Clinically, each patient presented with proteinuria (1.3 to 6.0 g daily) but—typically for secondary forms of FSGS—without other features of nephrotic syndrome. Histopathologic features included glomerulomegaly and predominantly perihilar FSGS lesions with intermittent foot process effacement, attributes again suggestive of secondary FSGS due to a functional/structural mismatch. Renal function was well maintained: creatinine clearance ranged 71 to 132 cc/min. Although recent-onset hypertension was reported in four of six, none had longstanding hypertension. Importantly, other diagnoses associated with FSGS were excluded.
It is useful to put this series of patients into a broader context. Clearly it represents the extreme end of the low-birth-weight spectrum. It also includes prematurity, a factor that may convey risks independent of being small for gestational age (SGA) (13). For one, the early environments of these infants necessarily included the neonatal intensive care unit (NICU) experience—crucial to their survival but nonetheless fraught with frequent and variable nephrotoxic exposures. Even if nephron number were available, the NICU exposure would preclude our knowing to what degree any reduction in nephron number reflects primary failure of nephrogenesis versus secondary loss of nephrons due to exogenous postnatal insults. Nor can we necessarily extrapolate to full-term infants born SGA, because the presence/magnitude of nephron deficits may differ and/or other independent factors associated with immaturity may be operative.
That said, this seminal case series by Hodgin et al. is important for three reasons. First, as noted, it is the first to link a specific histopathologic diagnosis of FSGS to subjects born prematurely or of VLBW, in the absence of known causes of FSGS. Despite our widely held expectations that this should be the case, we now have proof of concept.
Second, although the six patients reported exhibit FSGS in a minority of glomeruli (5 to 16%), five of six show predominance of globally sclerotic glomeruli (11 to 41%). This suggests an actively progressive process. Moreover, given the inverse relationship between nephron number and glomerular volume in human kidneys (11), the associated glomerulomegaly in the FSGS patients provides indirect evidence for an underlying mismatch between body size and renal excretory capacity. Specifically, Hoy and colleagues, recently summarizing their findings on nephron number and glomerular volume in three populations (U.S. white, U.S. African American, Australian Aboriginal), noted that increased average glomerular volume, coupled with greater heterogeneity of glomerular size in individual subjects with increased mean glomeruli volume, together identify glomerular stress (22). The largest glomeruli within the widened spectrum may be most apt to lose podocyte integrity, sclerose, and eventually disappear (22). From a mismatch perspective, it may not be coincidental that, of the six patients reported by Hodgin et al., all but two approach or exceed the high end of the normal body mass index (BMI) range; thus several centiles of BMI have been crossed by their respective growth trajectories from VLBW at birth to the time of study. There is strong evidence that accelerated postnatal growth (i.e., crossing BMI centiles) in childhood (3 to 15 yrs) is a powerful enhancer of adult disease risk in subjects born small, specifically including risks of hypertension (23), diabetes (4), and obesity (24). It is feasible that a high-normal to overweight BMI level is a critical cofactor for the development of FSGS in premature/VLBW subjects.
Finally, the clinical and histopathologic findings reported by Hodgin et al. (21) suggest that prematurity/VLBW may yield FSGS directly, without an intermediary role for the later-life chronic hypertension, diabetes, and/or overt obesity that often follow low birth weight. Because the evidence linking hypertension, diabetes, and obesity with chronic kidney disease is well established, we expect that the renal risk from poor intrauterine growth will be in part mediated via one or more of these three outcomes. Epidemiologic studies examining the causes of renal disease in low-birth-weight subjects in fact suggest that birth weight confers increased risk within all of the causes of ESRD (20), supporting the concept that developmental effects convey vulnerability rather than disease per se. However, these observations derive largely from clinical, not histopathological, diagnoses of ESRD causes; they therefore cannot exclude the possibility that FSGS may precede—and itself confer an enhanced renal vulnerability to—hypertension, diabetes, and/or relative excess body mass. Thus, although the case series presented here cannot address relative probability, it nonetheless provides evidence for a fourth primary pathway of renal injury, operating via secondary FSGS in premature/VLBW subjects.
In the setting of babies born SGA, with or without prematurity, we would be wise to critically examine our preoccupation with prenatal nephrogenesis as the only culprit in developmental origins of renal disease. Of several reasons to question this assumption, the most important is the possibility that our focus on irreversible events in utero will ignore treatable postnatal factors. At least three postnatal stages deserve our attention in developing nephroprotective practices for babies born small. First, in the NICU setting, Rodriquez et al. demonstrated that, in the premature baby (<35 wk), nephrogenesis may (but does not always) proceed postnatally for up to 40 d after birth (25), although nephron number did not reach normal levels. The NICU environment uses standard pharmacologic interventions, many developed before our awareness of the potential for postnatal nephrogenesis. Some of those interventions (e.g., nonsteroidal anti-inflammatory drugs, gentamycin) involve known nephrotoxins and impair nephron number in neonatal rodents (26). In the premature babies studied by Rodriquez (25), postnatal nephrogenesis was less sustained in babies experiencing renal failure. Also in the NICU setting, even as we identify new requirements for normal nephrogenesis, optimum macro- and micronutrients for support of postnatal nephrogenesis has never been addressed. Introducing a second stage with renal effect, Schmidt et al. found that SGA babies not only had small kidneys at birth, but also had poor absolute and relative (to body weight) kidney growth over 0 to 18 mo of age (13). Whether this postnatal renal growth failure in babies born small reflects secondary loss of existing nephrons or failure of existing nephrons to appropriately hypertrophy with body growth is unknown, but understanding how poor intrauterine growth leads to poor early postnatal kidney growth may reveal unexpected therapeutic opportunities. A third developmental stage meriting nephroprotective attention is later childhood, where accelerated growth—the crossing of weight or BMI centiles—consistently amplifies cardiovascular disease risk in SGA babies. It will be important to learn whether early identification, together with aggressive control of blood pressure and normalization of late-childhood growth rate, will prevent or slow FSGS progression in those born premature and/or SGA.
There are clearly mechanisms other than reduced nephron number by which IUGR and/or prematurity contribute to adverse renal outcomes (27). Increased vascular responses to angiotensin II via oxidant-dependent pathways have been described in animal models of maternal nutrient restriction and are preventable via antioxidant intervention in utero or early postnatally (28). Proinflammatory molecules are upregulated in the kidney after maternal protein restriction (29). Such enhanced functional setpoints of potentially injurious pathways may be necessary cofactors that interact with a modest reduction in nephron number to generate overt renal disease.
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Practical Applications for the Nephrologist
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The current state of our knowledge suggests that prematurity and/or low birth weight constitute risk factors for adult renal disease. Routine addition of birth weight and GA to the clinical history can thus identify individual patients at risk for having reduced nephron numbers. Regular monitoring from birth for hypertension, microalbuminuria, and reduced GFR is imminently reasonable, and treatment indications and approaches in children must be tested and optimized. Favorable lifestyle practices to prevent overweight conditions and obesity may be uniquely important in this group and warrant education of parents and adult patients. In adolescents and adults born premature or SGA, blood pressure goals require re-examination with respect to long-term renal outcomes. Future research must define how postnatal nephrogenesis can be optimized in premature neonates, identify reversible factors in postnatal renal growth failure in SGA infants, and test whether modulating accelerated childhood growth and final BMI can improve renal outcomes. Ultimately, full understanding of the effect of low nephron number and its interactions with the postnatal environment awaits access to accurate and noninvasive measurements of nephron number in the clinical setting.
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Disclosures
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None.
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Footnotes
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Published online ahead of print. Publication date available at www.cjasn.org.
See related article, "Very Low Birth Weight is a Risk Factor for Secondary Focal Segmental Glomerulosclerosis," on pages 71–76.
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Introduction
Renal Development
