Decreased Nephron Number Research Articles

In children born IUGR, normalization of weight by age 5 may be associated with hypertension

The Barker hypothesis suggests that IUGR fetuses undergo some form of in utero metabolic programming that ultimately leads to obesity and hypertension (HTN) in adulthood. However, hypertension can also be related to decreased nephron number. We hypothesized that, in children born IUGR, HTN may be related not just to obesity, but to “normalization” of weight (ie, an increase in weight –height from <10th percentile at birth to up to the 75th percentile at age 5), resulting in a body size out of proportion to renal function.

Acute Renal Failure in the Newborn

Acute renal failure in the newborn is a common problem and is typically classified as prerenal, intrinsic renal disease including vascular insults, and obstructive uropathy. In the newborn, renal failure may have a prenatal onset in congenital diseases such as renal dysplasia with or without obstructive uropathy and in genetic diseases such as autosomal recessive polycystic kidney disease. Acute renal failure in the newborn is also commonly acquired in the postnatal period because of hypoxic ischemic injury and toxic insults. Nephrotoxic acute renal failure in newborns is usually associated with aminoglycoside antibiotics and nonsteroidal anti-inflammatory medications used to close a patent ductus arteriosis. Alterations in renal function occur in approximately 40% of premature newborns who have received indomethacin and such alterations are usually reversible. Renal artery thrombosis and renal vein thrombosis will result in renal failure if bilateral or if either occurs in a solitary kidney. Cortical necrosis is associated with hypoxic/ischemic insults due to perinatal anoxia, placenta abruption and twin-twin or twin-maternal transfusions with resultant activation of the coagulation cascade. As in older children, hospital acquired acute renal failure is newborns is frequently multifactorial in origin. Although the precise incidence and prevalence of acute renal failure in the newborn is unknown, several studies have shown that acute renal failure is common in the neonatal intensive care unit. Recent interesting studies have demonstrated that some newborns may have genetic risks factors for acute renal failure. Once intrinsic renal failure has become established, management of the metabolic complications of acute renal failure continues to involve appropriate management of fluid balance, electrolyte status, acid-base balance, nutrition and the initiation of renal replacement therapy when appropriate. Renal replacement therapy may be provided by peritoneal dialysis, intermittent hemodialysis, or hemofiltration with or without a dialysis circuit. The preferential use of hemofiltration by pediatric nephrologists is increasing while the use of peritoneal dialysis is decreasing except for neonates and small infants. Peritoneal dialysis has been a major modality of therapy for acute renal failure in the neonate when vascular access may be difficult to maintain. In the newborn, the prognosis and recovery from acute renal failure is highly dependent upon the underlying etiology of the acute renal failure. Factors that are associated with mortality include multiorgan failure, hypotension, need for pressors, hemodynamic instability, and need for mechanical ventilation and dialysis. The mortality and morbidity of newborns with acute renal failure is much worse in neonates with multiorgan failure. Newborns who have suffered substantial loss of nephrons as may occur in cortical necrosis are at risk for late development of renal failure after apparent recovery from the initial insult. Similarly, hypoxic/ischemic and nephrotoxic injury to the developing kidney can result is decreased nephron number. Newborns with acute renal failure need life-long monitoring of their renal function, blood pressure, and urinalysis. Typically, the late development of chronic renal failure will first becomes apparent with the development of hypertension, proteinuria, and eventually an elevated blood urea nitrogen and creatinine.

Baa, Baa, black sheep, are your kidneys full?

The effect of genetic variance on blood pressure is about 50 %. Thus, environmental influences are major. Recent evidence has suggested that environment very early in life may influence blood pressure decades later. Barker and co-workers first proposed that intrauterine malnutrition, marked by low birth weight, predisposes persons to type 2 diabetes mellitus, hypertension, dyslipidaemia, and cardiovascular disease (Barker & Martyn, 1992; Barker et al. 1993). In this issue of The Journal of Physiology Wintour and colleagues observed that if pregnant sheep receive corticosteroids at days 26–28 during their gestation of 150 days, their offspring develop hypertension as adults (Dodic et al. 2002). Brenner & Chertow (1994) have suggested that reduction in the number of nephrons at birth leads to hyperperfusion of each nephron and resulting glomerular sclerosis, further nephron death, and a cycle of increasing blood pressure and nephron death. Glomerular filtration rate need not be reduced in this model, since the remaining (or the fewer) glomeruli do more filtration work and presumably increase in size. In rats, a decrease in nephron number of about 30 % was reported if the mothers received corticosteroids at days 11–16 of their 3-week pregnancy (Ortiz et al. 2001). A similar phenomenon has been described in rats that were food-restricted during pregnancy (Regina et al. 2001). Wintour et al. (2003) now report that dexamethasone treatment of pregnant ewes results in an increase in blood pressure of about a 10 mmHg in their offspring at 7 years of age and that their glomerular number is reduced about 40 %. The glomeruli in the dexamethasone offspring were larger and the proximal tubules were dilated, perhaps reflecting more filtrate per nephron.

Permeability factors in focal segmental glomerulosclerosis

The pathologic diagnosis of focal segmental glomerulosclerosis (FSGS) is associated with a syndrome of steroid-resistant nephrotic syndrome and progressive renal insufficiency. The incidence of FSGS has increased in recent years. Known causes of FSGS include genetic abnormalities, viral infections, decreased nephron number, and hyperperfusion/hyperfiltration. The etiology is unknown in the majority of cases. FSGS recurs after initial renal transplantation in as many as 30% to 50% of patients. Recent studies have verified the hypothesis that plasma of patients with FSGS contains a factor or factors that increase permeability of glomerular capillaries and cause proteinuria after injection into rats. Patients who experience posttransplant recurrence of FSGS and those with rapidly progressive disease exhibit this activity. Permeability activity has been verified in functional assays and defined by measurement of albumin permeability (P alb) or glomerular volume variation (GVV). Permeability activity is decreased by plasmapheresis or immunoadsorption and can be recovered from discarded plasma or eluate from adsorption materials. Studies from our laboratory indicate that permeability activity is carried by small, highly glycosylated, hydrophobic protein(s)/peptide(s). Normal plasma contains substances capable of blocking or inactivating the FSGS permeability factor. Pharmacologic agents including cyclosporine, indomethacin, and derivatives of Trypterigium wilfordii also block permeability activity in vitro. The observation that permeability activity can be blocked by diverse agents raises hope that specific therapy may be designed for FSGS. Future investigations will permit identification of the active FSGS permeability factor, of mechanisms that initiate and perpetuate proteinuria, and of interventions to prevent renal failure in native kidneys and recurrence of disease in renal allografts. © 2003 Elsevier Inc. All rights reserved.

In vitro studies on the roles of transforming growth factor-β1 in rat metanephric development

The development of the permanent kidney (metanephros) involves the interplay between both positive and negative regulatory molecules. Transforming growth factor-beta1 (TGF-beta 1) has previously been shown to negatively regulate ureteric duct growth. However, its potential role in nephron development and glomerulogenesis has been largely ignored. In situ hybridization and reverse transcription-polymerase chain reaction were employed to examine the temporal and spatial localization of TGF-beta 1 mRNA and a TGF-beta type I receptor (activin-like receptor kinase-5; ALK-5) mRNA in developing rat metanephroi. The addition of exogenous TGF-beta 1 to rat metanephric organ culture at different time points was used to examine the role of TGF-beta 1 in ureteric duct growth and nephron development. TGF-beta 1 mRNA did not colocalize with ALK-5 mRNA. Instead, TGF-beta1 mRNA colocalized with the TGF-beta type II receptor mRNA. The addition of recombinant human TGF-beta 1 to rat metanephric organ culture at the beginning of the culture period inhibited total metanephric growth and the growth of the ureteric tree, resulting in a decrease in nephron number. Similarly, the addition of TGF-beta 1 to metanephroi after 48 hours of culture inhibited ureteric duct growth, decreasing nephron number. The addition of TGF-beta 1 at days 0 or 2 of culture promoted hypertrophy of the renal capsule. These findings confirm that TGF-beta 1 inhibits ureteric duct growth and thereby nephron endowment in developing rat metanephroi in vitro. However, TGF-beta 1 does not appear to play a significant role in nephron development per se once the epithelial vesicle has formed.

Nephrotoxin exposure in utero reduces glomerular number in sclerosis-prone but not sclerosis-resistant mice

We have previously found that nephron number was not fixed, that is, there was a direct correlation between low birth weight and decreased nephron number in infants. In sclerosis-prone rats, we found that gentamicin exposure in utero induced a reduction in glomerular number and aggravated glomerulosclerosis in adults. In mice, we found that an inborn 50% reduction in nephron number, caused by the Os mutation, was associated with glomerulosclerosis in sclerosis-prone (ROP+/+) mice, but not in sclerosis-resistant (C57BL/6J) mice. Because the genetic background determined the response to decreased nephron number, we asked whether the susceptibility changes in glomerular number and glomerulosclerosis were linked. Gentamicin was administered before and after the onset of fetal nephrogenesis. (1) Prior to the onset of nephrogenesis, two groups of pregnant mice were treated from embryonic day (E) E8 to E12. In group A, early glomerular development was studied by placing ureteric ridges removed on E12 in vitro for four days, following which the ureteric bud branches and glomeruli were counted using lectin staining. In group B, nephron number was determined in spontaneously delivered 14-day-old (14PN) pups by counting glomeruli. (2) After the onset of nephrogenesis, to determine the direct effects of gentamicin on nephron induction, ureteric ridges were placed in organ culture at E12 of normal gestation, in the presence or absence of gentamicin. The number of glomeruli and ureteric bud branches were counted after six days in culture. A decrease in glomerular number and ureteric bud branches was observed in sclerosis-prone (ROP+/+) mice, irrespective of whether gentamicin was administered prior to or after the onset of nephrogenesis. Glomerular number and ureteric bud branching were not decreased by gentamicin in sclerosis-resistant (C57BL/6) mice. These data provide evidence that there is a positive correlation between the susceptibility to glomerulosclerosis in adulthood and a reduction in nephron number in utero. Thus, exposure to nephrotoxins in utero compounds the risk of renal failure as an adult in sclerosis-prone individuals.