When is one kidney not enough?

Most renal failure in children results from congenital anomalies of the kidney and urinary tract (CAKUTs). Sanna-Cherchi et al. predict that by 30 years of age, nearly 50% of patients with a solitary kidney would be receiving dialysis. This outcome differs markedly from that of renal-transplant donors, who have no increased risk for renal failure. Because morbidity from CAKUTs may not develop until adulthood, these patients should be closely followed throughout life

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

Unilateral ureteral obstruction in neonatal rats leads to renal insufficiency in adulthood

Unilateral ureteral obstruction in neonatal rats leads to renal insufficiency in adulthood.BackgroundAlthough unilateral ureteropelvic junction obstruction is the most common cause of congenital obstructive nephropathy in infants and children, management remains controversial, and follow-up after pyeloplasty is generally limited to the pediatric ages. We have developed a model of temporary unilateral ureteral obstruction (UUO) in the neonatal rat: One month following the relief of five-day UUO, the glomerular filtration rate (GFR) of the postobstructed kidney was normal despite a 40% reduction in the number of glomeruli and residual vascular, glomerular, tubular, and interstitial injury.MethodsTo determine whether hyperfiltration and residual injury of remaining nephrons leads to progression of renal insufficiency in later life, 31 rats were sham operated or subjected to left UUO at one day of age, with relief of UUO five days later, and were studied at one year of age. GFR was measured by inulin clearance, and the number of glomeruli, tubular atrophy, glomerular sclerosis, and interstitial fibrosis were measured by histomorphometry in sham, obstructed (UUO), and intact opposite kidneys. Intrarenal macrophages and α-smooth muscle actin were identified by immunohistochemistry.ResultsDespite relief of UUO, ultimate growth of the postobstructed kidney was impaired. The number of glomeruli was reduced by 40%, and GFR was decreased by 80%. However, despite significant compensatory growth of the opposite kidney, there was no compensatory increase in GFR, and proteinuria was increased. Moreover, glomerular sclerosis, tubular atrophy, macrophage infiltration, and interstitial fibrosis were significantly increased not only in the postobstructed kidney, but also in the opposite kidney.ConclusionsAlthough GFR is initially maintained following relief of five-day UUO in the neonatal rat, there is eventual profound loss of function of the postobstructed and opposite kidneys because of progressive tubulointerstitial and glomerular damage. These findings suggest that despite normal postoperative GFR in infancy, children undergoing pyeloplasty for ureteropelvic junction obstruction should be followed into adulthood. Elucidation of the cellular response to temporary UUO may lead to improved methods to assess renal growth, injury, and functional reserve in patients with congenital obstructive nephropathy

Selectins mediate macrophage infiltration in obstructive nephropathy in newborn mice11See Editorial by Kipari and Hughes, p. 760.

Selectins mediate macrophage infiltration in obstructive nephropathy in newborn mice.BackgroundUrinary tract obstruction during development leads to tubular atrophy and causes interstitial fibrosis. Macrophage infiltration into the interstitium plays a central role in this process. Selectins, a family of three adhesion molecules, are involved in leukocyte recruitment to sites of inflammation and immune activity. We investigated the role of selectins in obstructive nephropathy in newborn mice.MethodsTriple selectin-deficient mice (EPL-/-), L-selectin deficient mice (L-/-) and wild type mice (WT) were subjected to complete unilateral ureteral obstruction (UUO) or sham operation within the first 48 hours of life, and were sacrificed 5 and 12 days later. Kidneys were removed, and sections were stained for macrophage infiltration (mAb F4/80), apoptosis (TUNEL), tubular atrophy (periodic acid-Schiff) and interstitial fibrosis (Masson trichrome).ResultsSelectin deficient mice showed a marked reduction in macrophage infiltration into the obstructed kidney compared to WT at day 5 and day 12 after UUO. Tubular apoptosis was strongly reduced in EPL-/- at day 5 after UUO, and in EPL-/- and L-/- at day 12 after UUO when compared to WT. The number of apoptotic tubular cells was correlated with macrophage infiltration, suggesting that macrophages stimulate tubular apoptosis in obstructive nephropathy. In addition, tubular atrophy and interstitial fibrosis were significantly diminished in EPL-/- and L-/- compared to WT at day 12 after UUO.ConclusionFollowing UUO, selectins mediate macrophage infiltration into the obstructed kidney, which in turn may induce tubular apoptosis, tubular atrophy and interstitial fibrosis

Neonatal ureteral obstruction stimulates recruitment of renin-secreting renal cortical cells

Neonatal ureteral obstruction stimulates recruitment of renin-secreting renal cortical cells. Unilateral ureteral obstruction (UUO) in the neonate increases ipsilateral renal renin gene expression, an effect which is mediated by renal nerves. To determine whether neonatal UUO alters the number of renal cortical cells secreting renin and whether this change is modulated by renal nerve activity, newborn Sprague-Dawley rats were subjected to left UUO, right uninephrectomy, or sham operation and studied four weeks thereafter. To evaluate the importance of renal nerves in this response, an additional group of animals underwent chemical sympathectomy with guanethidine. Ureteral obstruction was associated with marked reduction in renal mass in the obstructed kidney and contralateral compensatory hypertrophy, changes which were not altered by sympathectomy. Renin messenger RNA and renal renin content were elevated in the obstructed kidney. The number of cells secreting renin, measured by the reverse hemolytic plaque assay, was markedly increased in the obstructed kidney (45 ± 18 plaques/slide vs. 11 ± 1 plaques/slide in sham animals), but not in the opposite kidney or following uninephrectomy. This effect was not significantly altered by sympathectomy. There was no change in the amount of renin secreted per cell or in the secretory response to Ca++. These results show that UUO results in recruitment of cells not previously secreting renin by a mechanism independent of renal nerve activity. This recruitment occurs without alteration of the quantity of renin secreted per cell or in the normal regulatory effect of Ca++ on renin secretion. An increase in the number of renin-secreting cells may contribute to the activation of the renin-angiotensin system, and thus to the vasoconstriction observed following ureteral obstruction

Unilateral ureteral obstruction impairs renal antioxidant enzyme activation during sodium depletion

Unilateral ureteral obstruction impairs renal antioxidant enzyme activation during sodium depletion.BackgroundObstructive nephropathy leads to progressive renal tubular atrophy and interstitial fibrosis and is associated with sodium wasting and sodium depletion. Renal damage resulting from unilateral ureteral obstruction (UUO) may be aggravated by reactive oxygen species (ROS), which are produced by a variety of processes. Ideally, deleterious effects of ROS are attenuated by antioxidant enzymes, including the superoxide dismutases, glutathione peroxidases, catalase, and glutathione-S-transferases. The general paradigm is that tissue damage occurs when ROS production is greater than the protective capacity of the antioxidant enzymes.MethodsThis study was designed to investigate the response of renal antioxidant enzymes to UUO and sodium depletion. Adult, male Sprague-Dawley rats received normal-sodium or sodium-depleted diets and were subjected to UUO or sham operation. Obstructed (UUO), intact opposite, or sham-operated kidneys were harvested after 14days, and antioxidant enzyme activities were measured in kidney homogenates. Thiobarbituric acid reactive substances were measured in these homogenates at 3 and 14days after UUO or sham operation as an index of ROS production.ResultsRenal interstitial area, a measure of fibrosis, was increased by UUO and was doubled in sodium-depleted animals. Sodium depletion increased manganese superoxide dismutase, glutathione peroxidases, and glutathione-S-transferase activities in sham-operated kidneys but not in UUO kidneys. Relative to intact opposite kidneys, UUO kidneys had reduced activities of catalase, manganese superoxide dismutase, and glutathione-S-transferase in normal-sodium animals and all antioxidant enzymes tested in sodium-depleted animals. Renal thiobarbituric acid reactive substances were increased by three days of UUO and were increased further by 14days of sodium depletion.ConclusionIn summary, sodium depletion increased several renal antioxidant enzymes, consistent with a stress response to increased ROS production. Further, UUO not only reduced antioxidant enzyme activities but also inhibited increases seen with sodium depletion. We conclude that suppression of renal antioxidant enzyme activities by UUO contributes to the progression of renal injury in obstructive nephropathy, a process exacerbated by sodium depletion

Growth factor-mediated phosphorylation of proapoptotic BAD reduces tubule cell death in vitro and in vivo

Growth factor-mediated phosphorylation of proapoptotic BAD reduces tubule cell death in vitro and in vivo.BackgroundExogenous growth factors administered during unilateral ureteral obstruction (UUO) in neonatal rats significantly reduce apoptosis and tubular atrophy. Because the mechanism underlying these salutary effects is largely unknown, we investigated signaling pathways potentially activated by growth factors to determine their roles in therapeutic action.MethodsMechanical strain was applied to confluent cultures of immortalized rat proximal tubule cells to simulate obstruction-induced stretch injury in vivo. Growth factors, inhibitory antibodies or pharmacological inhibitors were added to cultures that were subsequently processed for TUNEL analysis or immunoblots to identify signaling pathways that could be modulating cell survival. For in vivo studies, kidneys harvested from rats ± UUO ± epidermal growth factor (EGF) were fixed or frozen for immunohistochemistry or immunoblot analysis.ResultsTreatment with EGF or insulin-like growth factor-1 (IGF-1) during stretch decreased apoptosis by 50% (P < 0.001). Neutralizing antibodies (Abs) directed against either growth factor or its receptor blocked the reduction in apoptosis. Stretch decreased BAD phosphorylation by ∼50% (P < 0.001) relative to unstretched cells and each growth factor restored phosphorylation to basal levels. Kinase-specific inhibitors that blocked growth factor-mediated BAD phosphorylation promoted apoptosis in vitro. BAD phosphorylation decreased by ∼50% (P < 0.001) in the tubules of obstructed hydronephrotic rat kidneys and administration of EGF restored BAD phosphorylation to basal levels.ConclusionsSignaling pathways converging at BAD phosphorylation are key to growth factor-mediated attenuation of stretch-induced apoptosis in vitro and in vivo

Aql X-1 in Outburst and Quiescence

We present photometry and spectroscopy of the soft x-ray transient Aql X-1. Optical photometry during an active state shows a strong (0.6 mag peak-to-peak) modulation at a period of 19 hours. Infrared (K'-band) photometry during a quiescent state limits any ellipsoidal variations to <0.07 mag (peak-to-peak), which implies an inclination i<31 (90% limit). Spectroscopy in a quiescent state shows at most very small radial velocity variations, which implies a very low inclination of i<12 (90% limit). The low inclination is rather unexpected given the large photometric modulation seen in the active state. The upper limit to the equivalent width of the anomalous Li 6707A line is <0.3A, which is similar to the measured strength of this line in several other x-ray transients.Comment: Accepted for publication in ApJ, 12 pages, 5 figure

Coronal X-Ray Emission from the Stellar Companions to Transiently Accreting Black Holes

Observations of soft X-ray transients (SXTs) in quiescence have found that the binaries harboring black holes are fainter than those that contain a neutron star. Narayan and collaborators postulated that the faint X-ray emission from black hole binaries was powered by an advection dominated accretion flow (ADAF). We explore an alternative explanation for the quiescent X-ray emission from the black hole systems: coronal emission from the rapidly rotating optical companion. This is commonly observed and well studied in other tidally locked binaries, such as the RS CVns. We show that two of the three X-ray detected black hole binaries (A0620-00 and GRO J1655-40) exhibit X-ray fluxes entirely consistent with coronal emission. The X-ray spectra of these objects should be best fit with thermal Raymond-Smith models rich in lines when coronal emission predominates. One black hole system (V404 Cyg) is too X-ray bright to be explained as coronal emission. The quiescent X-ray emission from the neutron star binaries is far too bright for coronal emission. It might be that all SXT's have variable accretion rates in quiescence and that the basal quiescent X-ray flux is set by either coronal emission from the companion or -- when present -- by thermal emission from the neutron star. We also show that the lithium abundances in the black hole systems are comparable to those in the RS CVns, reducing the need for production mechanisms that involve the compact object.Comment: ApJ, accepted (v541; Oct 1, 2000); Changes to figures and tables, minor modifications to text. Uses emulateapj.sty. 14 pages, 3 figure