Bioenergetics: the evolutionary basis of progressive kidney disease.

Chronic kidney disease (CKD) affects >10% of the world population, with increasing prevalence in middle age. The risk for CKD is dependent on the number of functioning nephrons through the life cycle, and 50% of nephrons are lost through normal aging, revealing their vulnerability to internal and external stressors. Factors responsible for CKD remain poorly understood, with limited availability of biomarkers or effective therapy to slow progression. This review draws on the disciplines of evolutionary medicine and bioenergetics to account for the heterogeneous nephron injury that characterizes progressive CKD following episodes of acute kidney injury with incomplete recovery. The evolution of symbiosis in eukaryotes led to the efficiencies of oxidative phosphorylation and the rise of metazoa. Adaptations to ancestral environments are the products of natural selection that have shaped the mammalian nephron with its vulnerabilities to ischemic, hypoxic, and toxic injury. Reproductive fitness rather than longevity has served as the driver of evolution, constrained by available energy and its allocation to homeostatic responses through the life cycle. Metabolic plasticity has evolved in parallel with robustness necessary to preserve complex developmental programs, and adaptations that optimize survival through reproductive years can become maladaptive with aging, reflecting antagonistic pleiotropy. Consequently, environmental stresses promote trade-offs and mismatches that result in cell fate decisions that ultimately lead to nephron loss. Elucidation of the bioenergetic adaptations by the nephron to ancestral and contemporary environments may lead to the development of new biomarkers of kidney disease and new therapies to reduce the global burden of progressive CKD.

Why is chronic kidney disease progressive? Evolutionary adaptations and maladaptations.

Despite significant advances in renal physiology, the global prevalence of chronic kidney disease (CKD) continues to increase. The emergence of multicellular organisms gave rise to increasing complexity of life resulting in trade-offs reflecting ancestral adaptations to changing environments. Three evolutionary traits shape CKD over the lifespan: 1) variation in nephron number at birth, 2) progressive nephron loss with aging, and 3) adaptive kidney growth in response to decreased nephron number. Although providing plasticity in adaptation to changing environments, the cell cycle must function within constraints dictated by available energy. Prioritized allocation of energy available through the placenta can restrict fetal nephrogenesis, a risk factor for CKD. Moreover, nephron loss with aging is a consequence of cell senescence, a pathway accelerated by adaptive nephron hypertrophy that maintains metabolic homeostasis at the expense of increased vulnerability to stressors. Driven by reproductive fitness, natural selection operates in early life but diminishes thereafter, leading to an exponential increase in CKD with aging, a product of antagonistic pleiotropy. A deeper understanding of the evolutionary constraints on the cell cycle may lead to manipulation of the balance between progenitor cell renewal and differentiation, regulation of cell senescence, and modulation of the balance between cell proliferation and hypertrophy. Application of an evolutionary perspective may enhance understanding of adaptation and maladaptation by nephrons in the progression of CKD, leading to new therapeutic advances.

The first randomized controlled trial in pediatric nephrology: the history of the International Study of Kidney Disease in Children (ISKDC).

The International Study of Kidney Disease in Children (ISKDC), begun in 1966, conducted the first international collaborative randomized blinded controlled trial in pediatric nephrology and one of the first in either pediatrics or nephrology. For this trial, the ISKDC developed the criteria, such as those for response and relapse, used today to describe the clinical course of the nephrotic syndrome, and the trial generated the nephropathologic terminology and criteria which largely remain the current standards. Over an approximately 20-year span, the ISKDC followed the natural history and evaluated the therapeutic effectiveness of therapies in over 500 children with the nephrotic syndrome from three continents. It published 14 peer-reviewed studies and several reports and commentaries, many of which helped create current standards of practice for therapy of childhood nephrotic syndrome and consequently remain highly cited today. The ISKDC continues to be an important model for subsequent collaborative studies and was the impetus for the development of regional and national pediatric nephrology societies leading to the recognition and growth of pediatric nephrology as a separate subspecialty. A higher resolution version of the Graphical abstract is available as Supplementary information.

Impact of early life development on later onset chronic kidney disease and hypertension and the role of evolutionary trade-offs.

NEW FINDINGS: What is the topic of this review? In this report, we summarize the latest clinical evidence linking developmental programming in the kidney to later life blood pressure and kidney disease. What advances does it highlight? Population-level studies now show convincingly that low birth weight, fetal growth restriction and preterm birth are associated with and have a synergistic impact on the risk of kidney disease in later life. A new approach also considers how evolutionary selection pressure might fail to select for long-term robustness of kidney function. ABSTRACT: The global burden of kidney disease is high and rising. The risk of kidney disease among individuals is highly variable, in part related to genetic and environmental factors, but also likely to be modulated by developmental programming of the number of nephrons and kidney function in fetal life. The number of nephrons varies widely across the population and is lower among those who were born small or preterm. Population registry evidence clearly shows an association between these birth circumstances and later-life risk of hypertension and kidney disease, not only for chronic kidney disease but also for acquired kidney disease, demonstrating an inherent susceptibility to kidney disease in these individuals. Gestational stressors impact kidney development, a process that is likely to be layered upon the evolutionary history of the kidney and how the organ has developed in response to selection pressure to support reproductive capacity in early adulthood, but not to withstand multiple stresses later in life. Reducing the global burden of kidney disease in future generations will require both individual- and population/environment-level risks to be addressed.

Evolution, kidney development, and chronic kidney disease.

There is a global epidemic of chronic kidney disease (CKD) characterized by a progressive loss of nephrons, ascribed in large part to a rising incidence of hypertension, metabolic syndrome, and type 2 diabetes mellitus. There is a ten-fold variation in nephron number at birth in the general population, and a 50% overall decrease in nephron number in the last decades of life. The vicious cycle of nephron loss stimulating hypertrophy by remaining nephrons and resulting in glomerulosclerosis has been regarded as maladaptive, and only partially responsive to angiotensin inhibition. Advances over the past century in kidney physiology, genetics, and development have elucidated many aspects of nephron formation, structure and function. Parallel advances have been achieved in evolutionary biology, with the emergence of evolutionary medicine, a discipline that promises to provide new insight into the treatment of chronic disease. This review provides a framework for understanding the origins of contemporary developmental nephrology, and recent progress in evolutionary biology. The establishment of evolutionary developmental biology (evo-devo), ecological developmental biology (eco-devo), and developmental origins of health and disease (DOHaD) followed the discovery of the hox gene family, the recognition of the contribution of cumulative environmental stressors to the changing phenotype over the life cycle, and mechanisms of epigenetic regulation. The maturation of evolutionary medicine has contributed to new investigative approaches to cardiovascular disease, cancer, and infectious disease, and promises the same for CKD. By incorporating these principles, developmental nephrology is ideally positioned to answer important questions regarding the fate of nephrons from embryo through senescence.

Changes in cell fate determine the regenerative and functional capacity of the developing kidney before and after release of obstruction.

Congenital obstructive nephropathy is a major cause of chronic kidney disease (CKD) in children. The contribution of changes in the identity of renal cells to the pathology of obstructive nephropathy is poorly understood. Using a partial unilateral ureteral obstruction (pUUO) model in genetically modified neonatal mice, we traced the fate of cells derived from the renal stroma, cap mesenchyme, ureteric bud (UB) epithelium, and podocytes using Foxd1Cre, Six2Cre, HoxB7Cre, and Podocyte.Cre mice respectively, crossed with double fluorescent reporter (membrane-targetted tandem dimer Tomato (mT)/membrane-targetted GFP (mG)) mice. Persistent obstruction leads to a significant loss of tubular epithelium, rarefaction of the renal vasculature, and decreased renal blood flow (RBF). In addition, Forkhead Box D1 (Foxd1)-derived pericytes significantly expanded in the interstitial space, acquiring a myofibroblast phenotype. Degeneration of Sine Oculis Homeobox Homolog 2 (Six2) and HoxB7-derived cells resulted in significant loss of glomeruli, nephron tubules, and collecting ducts. Surgical release of obstruction resulted in striking regeneration of tubules, arterioles, interstitium accompanied by an increase in blood flow to the level of sham animals. Contralateral kidneys with remarkable compensatory response to kidney injury showed an increase in density of arteriolar branches. Deciphering the mechanisms involved in kidney repair and regeneration post relief of obstruction has potential therapeutic implications for infants and children and the growing number of adults suffering from CKD.

The proximal tubule is the primary target of injury and progression of kidney disease: role of the glomerulotubular junction.

There is an alarming global increase in the incidence of end-stage kidney disease, for which early biomarkers and effective treatment options are lacking. Largely based on the histology of the end-stage kidney and on the model of unilateral ureteral obstruction, current investigation is focused on the pathogenesis of renal interstitial fibrosis as a central mechanism in the progression of chronic kidney disease (CKD). It is now recognized that cumulative episodes of acute kidney injury (AKI) can lead to CKD, and, conversely, CKD is a risk factor for AKI. Based on recent and historic studies, this review shifts attention from the glomerulus and interstitium to the proximal tubule as the primary sensor and effector in the progression of CKD as well as AKI. Packed with mitochondria and dependent on oxidative phosphorylation, the proximal tubule is particularly vulnerable to injury (obstructive, ischemic, hypoxic, oxidative, metabolic), resulting in cell death and ultimately in the formation of atubular glomeruli. Animal models of human glomerular and tubular disorders have provided evidence for a broad repertoire of morphological and functional responses of the proximal tubule, revealing processes of degeneration and repair that may lead to new therapeutic strategies. Most promising are studies that encompass the entire life cycle from fetus to senescence, recognizing epigenetic factors. The application of techniques in molecular characterization of tubule segments and the development of human kidney organoids may provide new insights into the mammalian kidney subjected to stress or injury, leading to biomarkers of early CKD and new therapies.

Prognostic factors and biomarkers of congenital obstructive nephropathy.

Congenital obstructive nephropathy (CON) is the leading cause of chronic kidney disease (CKD) in children. Anomalies of the urinary tract are often associated with abnormal nephrogenesis, which is compounded by obstructive injury and by maternal risk factors associated with low birth weight. Currently available fetal and postnatal imaging and analytes of amniotic fluid, urine, or blood lack predictive value. For ureteropelvic junction obstruction, biomarkers are needed for optimal timing of pyeloplasty; for posterior urethral valves, biomarkers of long-term prognosis and CKD are needed. The initial nephron number may be a major determinant of progression of CKD, and most patients with CON who progress to renal failure reach this point in adulthood, presumably compounded by episodes of acute kidney injury. Biomarkers of tubular injury may be of particular value in predicting the need for surgical intervention or in tracking progression of CKD, and must be adjusted for patient age. Discovery of new biomarkers may depend on "unbiased" proteomics, whereby patterns of urinary peptide fragments from patients with CON are analyzed in comparison to controls. Most promising are the analysis of urinary exosomes (restricting biomarkers to relevant tubular cells) and quantitative magnetic resonance imaging techniques allowing precise determination of nephron number and tubular mass. The greatest need is for large prospective multicenter studies with centralized biomarker sample repositories to follow patients with CON from fetal life through adulthood.

The swan-neck lesion: proximal tubular adaptation to oxidative stress in nephropathic cystinosis.

Cystinosis is an inherited disorder resulting from a mutation in the CTNS gene, causing progressive proximal tubular cell flattening, the so-called swan-neck lesion (SNL), and eventual renal failure. To determine the role of oxidative stress in cystinosis, histologic sections of kidneys from C57BL/6 Ctns(-/-) and wild-type mice were examined by immunohistochemistry and morphometry from 1 wk to 20 mo of age. Additional mice were treated from 1 to 6 mo with vehicle or mitoquinone (MitoQ), an antioxidant targeted to mitochondria. The leading edge of the SNL lost mitochondria and superoxide production, and became surrounded by a thickened tubular basement membrane. Progression of the SNL as determined by staining with lectin from Lotus tetragonolobus accelerated after 3 mo, but was delayed by treatment with MitoQ (38 ± 4% vs. 28 ± 1%, P < 0.01). Through 9 mo, glomeruli had retained renin staining and intact macula densa, whereas SNL expressed transgelin, an actin-binding protein, but neither kidney injury molecule-1 (KIM-1) nor cell death was observed. After 9 mo, clusters of proximal tubules exhibited localized oxidative stress (4-hydroxynonenal binding), expressed KIM-1, and underwent apoptosis, leading to the formation of atubular glomeruli and accumulation of interstitial collagen. We conclude that nephron integrity is initially maintained in the Ctns(-/-) mouse by adaptive flattening of cells of the SNL through loss of mitochondria, upregulation of transgelin, and thickened basement membrane. This adaptation ultimately fails in adulthood, with proximal tubular disruption, formation of atubular glomeruli, and renal failure. Antioxidant treatment targeted to mitochondria delays initiation of the SNL, and may provide therapeutic benefit in children with cystinosis.

Tubular obstruction leads to progressive proximal tubular injury and atubular glomeruli in polycystic kidney disease.

In polycystic kidney disease (PKD), renal parenchyma is destroyed by cysts, hypothesized to obstruct nephrons. A signature of unilateral ureteral obstruction, proximal tubular atrophy leads to formation of atubular glomeruli. To determine whether this process occurs in PKD, kidneys from pcy mice (moderately progressive PKD), kidneys from cpk mice (rapidly progressive PKD), and human autosomal dominant PKD were examined in early and late stages. Integrity of the glomerulotubular junction and proximal tubular mass were determined in sections stained with Lotus tetragonolobus lectin. Development of proximal tubular atrophy and atubular glomeruli was determined in serial sections of individual glomeruli. In pcy mice, most glomerulotubular junctions were normal at 20 weeks, but by 30 weeks, 56% were atrophic and 25% of glomeruli were atubular; glomerulotubular junction integrity decreased with increasing cyst area (r = 0.83, P < 0.05). In cpk mice, all glomerulotubular junctions were normal at 10 days, but by 19 days, 26% had become abnormal. In early-stage autosomal dominant PKD kidneys, 50% of glomeruli were atubular or attached to atrophic tubules; in advanced disease, 100% were abnormal. Thus, proximal tubular injury in cystic kidneys closely parallels that observed with ureteral obstruction. These findings support the hypothesis that, in renal cystic disorders, cyst-dependent obstruction of medullary and cortical tubules initiates a process culminating in widespread destruction of proximal convoluted tubules at the glomerulotubular junction.

The Fate of Nephrons in Congenital Obstructive Nephropathy: Adult Recovery is Limited by Nephron Number Despite Early Release of Obstruction.

PURPOSE: Urinary tract obstruction and reduced nephron number often occur together as a result of maldevelopment of the kidneys and the urinary tract. We determined the role of nephron number on adaptation of the remaining nephrons of mice subjected to neonatal partial unilateral ureteral obstruction followed through adulthood. MATERIALS AND METHODS: Wild-type and Os/+ mice (the latter with 50% fewer nephrons) underwent sham operation or partial unilateral ureteral obstruction in the first 2 days of life. Additional mice underwent release of unilateral ureteral obstruction at 7 days. All kidneys were harvested at 3 weeks (weaning) or 6 weeks (adulthood). Glomerular number and area, glomerulotubular junction integrity, proximal tubular volume fraction and interstitial fibrosis were measured by histomorphometry. RESULTS: In the obstructed kidney unilateral ureteral obstruction caused additional nephron loss in Os/+ but not in wild-type mice. Glomerular growth from 3 to 6 weeks was impaired by ipsilateral obstruction and not preserved by release in wild-type or Os/+ mice. Proximal tubular growth was impaired and interstitial collagen was increased by ipsilateral obstruction in all mice. These conditions were attenuated by release of unilateral ureteral obstruction in wild-type mice but were not restored in Os/+ mice. Unilateral ureteral obstruction increased interstitial collagen in the contralateral kidney while release of obstruction enhanced tubular growth and reduced interstitial collagen. CONCLUSIONS: Unilateral ureteral obstruction in early postnatal development impairs adaptation to reduced nephron number and induces additional nephron loss despite release of obstruction. Premature and low birth weight infants with congenital obstructive nephropathy are likely at increased risk for progression of chronic kidney disease.

Responses of proximal tubular cells to injury in congenital renal disease: fight or flight.

Most chronic kidney disease in children results from congenital or inherited disorders, which can be studied in mouse models. Following 2 weeks of unilateral ureteral obstruction (UUO) in the adult mouse, nephron loss is due to proximal tubular mitochondrial injury and cell death. In neonatal mice, proximal tubular cell death is delayed beyond 2 weeks of complete UUO, and release of partial UUO allows remodeling of remaining nephrons. Progressive cyst expansion develops in polycystic kidney disease (PKD), a common inherited renal disorder. The polycystic kidney and fibrosis (pcy)-mutant mouse (which develops late-onset PKD) develops thinning of the glomerulotubular junction in parallel with growth of cysts in adulthood. Renal insufficiency in nephropathic cystinosis, a rare inherited renal disorder, results from progressive tubular cystine accumulation. In the Ctns knockout mouse (a model of cystinosis), proximal tubular cells become flattened, with loss of mitochondria and thickening of tubular basement membrane. In each model, persistent obstructive or metabolic stress leads ultimately to the formation of atubular glomeruli. The initial "fight" response (proximal tubular survival) switches to a "flight" response (proximal tubular cell death) with ongoing oxidative injury and mitochondrial damage. Therapies should be directed at reducing proximal tubular mitochondrial oxidative injury to enhance repair and regeneration.

Transforming growth factor-ß1 receptor inhibition preserves glomerulotubular integrity during ureteral obstruction in adults but worsens injury in neonatal mice.

Unilateral ureteral obstruction (UUO), a widely used model of chronic kidney disease and congenital obstructive uropathy, causes proximal tubular injury and formation of atubular glomeruli. Because transforming growth factor-ß1 (TGF-ß1) is a central regulator of renal injury, neonatal and adult mice were subjected to complete UUO while under general anesthesia and treated with vehicle or ALK5 TGF-ß1 receptor inhibitor (IN-1130, 30 mg·kg(-1)·day(-1)). After 14 days, glomerulotubular integrity and proximal tubular mass were determined by morphometry of Lotus tetragonolobus lectin distribution, and the fraction of atubular glomeruli was determined by serial section analysis of randomly selected individual glomeruli. Glomerular area, macrophage infiltration, fibronectin distribution, and interstitial collagen were measured by morphometry. Compared with placebo, inhibition of TGF-ß1 by IN-1130 decreased apoptosis and formation of atubular glomeruli, prevented parenchymal loss, increased glomerular area and glomerulotubular integrity, and increased proximal tubule fraction of the adult obstructed kidney parenchyma from 17 to 30% (P < 0.05, respectively). IN-1130 decreased macrophage infiltration and fibronectin and collagen deposition in the adult obstructed kidney by ∼50% (P < 0.05, respectively). In contrast to these salutary effects in the adult, IN-1130 caused widespread necrosis in obstructed neonatal kidneys. We conclude that whereas IN-1130 reduces obstructive injury in adult kidneys through preservation of glomerulotubular integrity and proximal tubular mass, TGF-ß1 inhibition aggravates obstructive injury in neonates. These results indicate that while caution is necessary in treating congenital uropathies, ALK5 inhibitors may prevent nephron loss due to adult kidney disease.

Chronic unilateral ureteral obstruction in the neonatal mouse delays maturation of both kidneys and leads to late formation of atubular glomeruli.

Unilateral ureteral obstruction (UUO) in the adult mouse is the most widely used model of progressive renal disease: the proximal tubule is the nephron segment most severely affected and atubular glomeruli are formed after only 7 days of UUO. To determine the proximal nephron response to UUO in the maturing kidney, neonatal mice were examined 7 to 28 days following complete UUO under general anesthesia. Proximal tubular mass and maturation were determined by staining with Lotus tetragolonobus lectin. Superoxide was localized by nitroblue tetrazolium and collagen by Sirius red. Cell proliferation, cell death, PAX-2, megalin, α-smooth muscle actin (α-SMA), renin, and fibronectin were identified by immunohistochemistry. During the first 14 days of ipsilateral UUO, despite oxidative stress (4-hydroxynonenal staining), glomerulotubular continuity was maintained and mitochondrial superoxide production persisted. However, from 14 to 28 days, papillary growth was impaired and proximal tubules collapsed with increased apoptosis, autophagy, mitochondrial loss, and formation of atubular glomeruli. Fibronectin, α-SMA, and collagen increased in the obstructed kidney. Oxidative stress was present also in the contralateral kidney: renin was decreased, glomerulotubular maturation and papillary growth were delayed, followed by increased cortical and medullary growth. We conclude that neonatal UUO initially delays renal maturation and results in oxidative stress in both kidneys. In contrast to the adult, proximal tubular injury in the neonatal obstructed kidney is delayed at 14 days, followed only later by the formation of atubular glomeruli. Antioxidant therapies directed at proximal tubular mitochondria during early renal maturation may slow progression of congenital obstructive nephropathy.

Renal functional decline and glomerulotubular injury are arrested but not restored by release of unilateral ureteral obstruction (UUO).

Murine unilateral ureteral obstruction (UUO), a major model of progressive kidney disease, causes loss of proximal tubular mass and formation of atubular glomeruli. Adult C57BL/6 mice underwent a sham operation or reversible UUO under anesthesia. In group 1, kidneys were harvested after 7 days. In group 2, the obstruction was released after 7 days, and a physiological study of both kidneys was performed 30 days later. Renal blood flow (RBF), glomerular filtration rate (GFR), urine protein, and albumin excretion were measured after ligation of either the left or right ureter. Glomerular volume (periodic acid-Schiff), glomerulotubular integrity and proximal tubular mass (Lotus tetragonolobus lectin), and interstitial collagen (Sirius red) were measured by histomorphometry. Obstructed kidney weight was reduced by 15% at 7 days but was not different from sham after a 30-day recovery. Glomerular volume and proximal tubular area of the obstructed kidney were reduced by 55% at 7 days, but normalized after 30 days. Interstitial collagen deposition increased 2.4-fold after 7 days of UUO and normalized after release. However, GFR and RBF were reduced by 40% and urine albumin/protein ratio was increased 2.8-fold 30 days after release of UUO. This was associated with a 50% reduction in glomerulotubular integrity despite a 30-day recovery (P < 0.05 for all data). We conclude that release of 7-day UUO can arrest progression but does not restore normal function of the postobstructed kidney. Although the remaining intact nephrons have hypertrophied, glomerular injury is revealed by albuminuria. These results suggest that glomerulotubular injury should become the primary target of slowing progressive kidney disease.

CAKUT: A Pediatric and Evolutionary Perspective on the Leading Cause of CKD in Childhood.

The global prevalence of chronic kidney disease (CKD) is increasing rapidly, due to increasing environmental stressors through the life cycle. Congenital anomalies of kidney and urinary tract (CAKUT) account for most CKD in children, with a spectrum that can lead to kidney failure from early postnatal to late adult life. A stressed fetal environment can impair nephrogenesis, now recognized as a significant risk factor for the development of adult CKD. Congenital urinary tract obstruction is the leading cause of CKD due to CAKUT and can itself impair nephrogenesis as well as contribute to progressive nephron injury. Early diagnosis by ultrasonography in fetal life by an obstetrician/perinatologist can provide important information for guiding prognosis and future management. This review focuses on the critical role played by the pediatrician in providing timely evaluation and management of the patient from the moment of birth to the transfer to adult care. In addition to genetic factors, vulnerability of the kidney to CKD is a consequence of evolved modulation of nephron number in response to maternal signaling as well as to susceptibility of the nephron to hypoxic and oxidative injury. Future advances in the management of CAKUT will depend on improved biomarkers and imaging techniques.

Fight-or-flight: murine unilateral ureteral obstruction causes extensive proximal tubular degeneration, collecting duct dilatation, and minimal fibrosis.

Unilateral ureteral obstruction (UUO) is the most widely used animal model of progressive renal disease. Although renal interstitial fibrosis is commonly used as an end point, recent studies reveal that obstructive injury to the glomerulotubular junction leads to the formation of atubular glomeruli. To quantitate the effects of UUO on the remainder of the nephron, renal tubular and interstitial responses were characterized in mice 7 and 14 days after UUO or sham operation under anesthesia. Fractional proximal tubular mass, cell proliferation, and cell death were measured by morphometry. Superoxide formation was identified by nitro blue tetrazolium, and oxidant injury was localized by 4-hydroxynonenol and 8-hydroxydeoxyguanosine. Fractional areas of renal vasculature, interstitial collagen, α-smooth muscle actin, and fibronectin were also measured. After 14 days of UUO, the obstructed kidney loses 19% of parenchymal mass, with a 65% reduction in proximal tubular mass. Superoxide formation is localized to proximal tubules, which undergo oxidant injury, apoptosis, necrosis, and autophagy, with widespread mitochondrial loss, resulting in tubular collapse. In contrast, mitosis and apoptosis increase in dilated collecting ducts, which remain patent through epithelial cell remodeling. Relative vascular volume fraction does not change, and interstitial matrix components do not exceed 15% of total volume fraction of the obstructed kidney. These unique proximal and distal nephron cellular responses reflect differential "fight-or-flight" responses to obstructive injury and provide earlier indexes of renal injury than do interstitial compartment responses. Therapies to prevent or retard progression of renal disease should include targeting proximal tubule injury as well as interstitial fibrosis.

Evolution of the urinary proteome during human renal development and maturation: variations with gestational and postnatal age.

BACKGROUND: Low birth weight is associated with deficits in nephron number in the infant kidney and increased risk of adulthood hypertension and renal dysfunction. Urinary biomarkers may be potential indicators of renal reserve, but little is known about the influence of gestational and postnatal age on the expression of urinary proteins. The aims of this study were to determine the relationships between selected urinary proteins and renal maturation. We hypothesized that urinary protein patterns would change over time during late nephrogenesis and renal maturation. METHODS: Urine samples were collected at birth and over 12 mo from preterm (33-35 wk) and term (38-40 wk) infants. Candidate urinary proteins were identified by antibody array and quantified with enzyme-linked immunosorbent assay. RESULTS: Preterm infants at birth were found to have relatively elevated levels of insulin-like growth factor binding protein-1, -2, and -6, monocyte chemotactic protein-1, CD14, and sialic acid-binding Ig-like lectin 5. These markers gradually decline to levels similar to those of full-term infants by 2-6 mo of life. In contrast, many urinary markers in healthy full-term infants remain stable over the first year of life. CONCLUSION: Gestational and postnatal age must be considered when evaluating the utility of urinary biomarkers.