Embryonic kidney function in a chronic renal failure model in rodents.

BACKGROUND: Rapid advancements have been made in alternative treatments for renal diseases. Our goal for renal regeneration is to establish a kidney graft derived from human embryonic tissues. In this study, we investigated the effects of host renal failure on the structure and activity of transplanted embryonic kidney and bladder, and found that diuretics effectively induced urine production in the transplanted kidney. METHODS: Uremic conditions were reproduced using a 5/6 renal infarction rat model. An embryonic kidney plus bladder (embryonic day 15) was isolated from a pregnant Lewis rat and transplanted into the para-aortic area of a 5/6 renal-infarcted Lewis rat. Following growth, the embryonic bladder was successfully anastomosed to the host ureter. RESULTS: We assessed graft function in terms of survival rates and found no differences between normal (n = 5) and renal failure (n = 8) groups (median survival: 70.5 vs 74.5 h; p = 0.331) in terms of survival, indicating that the grafts prolonged rat survival, even under renal failure conditions. Furosemide (n = 9) significantly increased urine volume compared with saline-treated controls (n = 7; p < 0.05), confirming that the grafts were functional. We also demonstrated the possibilities of an in vivo imaging system for determining the viability of transplanted embryonic kidney with bladder. CONCLUSION: The results of this study demonstrate that transplanted embryonic kidney and bladder can grow and function effectively, even under uremic conditions.

Increased upper and lower tract urothelial carcinoma in patients with end-stage renal disease: a nationwide cohort study in Taiwan during 1997-2008.

BACKGROUND: Urothelial cancer (UC) is the leading cancer of patients with end-stage renal disease (ESRD) in Taiwan. The aims of this study were to explore the time trends of UC incidences and propose possible etiologic factors. METHODS: Abstracting from the National Health Insurance Research Database (NHIRD), there were 90,477 newly diagnosed cases of ESRD between 1997 and 2008 covering the patients aged 40-85. Among them, 2,708 had developed UC after diagnosis of ESRD. The CIR40-85 (cumulative incidence rate) of upper tract UC (UTUC) and lower tract UC (LTUC) were calculated for ESRD patients and general population, as well as SIR40-85 (standardized incidence ratio) for comparison. RESULTS: Female ESRD patients were found to have 9-18 times of elevated risks of UC, while those of males were increased up to 4-14 times. The time trends of CIR40-84 and SIR40-84 of UTUC in females appear to decline after calendar year 2000. These trends may be related to AA associated herbal products after 1998. CONCLUSIONS: Patients with ESRD are at increased risks for both LTUC and UTUC in Taiwan. We hypothesize that the time trends associate with the consumption of aristolochic acid in Chinese herbal products (female predominant).

Prenatal programming of kidney disease.

PURPOSE OF REVIEW: To introduce the concept of prenatal programming; to discuss the emerging evidence that adverse prenatal environment programs increased risk of chronic kidney disease in the offspring in later life; to review the mechanism involved; and to present potential intervention strategies. RECENT FINDINGS: New observational studies in humans and studies in animal models have strengthened the association between low birth weight and chronic kidney disease in adulthood. The consequences of low birth weight are less obvious in children and young animals. A likely mechanism is that adverse intrauterine environment results in decreased final number of nephrons. The existing fewer glomeruli compensate by hyperfiltrating, which may accelerate the normal gradual age-related loss of nephrons throughout one's lifespan. Beginning life with a low nephron count may not cause morbidity during childhood because of the large functional reserve kidneys have, but as the count later falls below a critical level, chronic kidney disease may become manifest. Early life dietary factors may modify the risk. SUMMARY: The charge for pediatricians is to identify children at risk, to counsel families to minimize any further renal risk factors such as smoking, obesity, and hypertension, and, in some cases together with a nephrologist, to institute pharmacologic therapy.

The long-term outcome of prenatally detected posterior urethral valves: a 10 to 23-year follow-up study.

OBJECTIVE: To document the functional outcome of patients with prenatally detected posterior urethral valves (PUV) in the second decade of life, and to evaluate the possible impact of prenatal diagnosis on the long-term outcome of this condition. PATIENTS AND METHODS: We analysed the functional outcome of 25 patients with prenatally detected PUV born between 1984 and 1996, whose mean (range) age at follow-up was 17.7 (10-23) years. The findings were compared with those in 17 patients (mean age 16.1 years) who had presented clinically to our unit during the same period. The duration of follow-up in both groups was >or=10 years. Late outcomes were also compared with published data for PUV. Outcome measures included; death, incidence of end-stage renal failure (ESRF), age at transplantation and the most the recently available plasma creatinine level in untransplanted patients. We also examined any possible association between functional outcome and early predictors, including nadir plasma creatinine level at <1 year and vesico-ureteric reflux (VUR). RESULTS: Three patients died (12%), two as neonates and one aged 3 years. Of five patients who had been shunted in utero, four died or developed early-onset renal failure. In the 23 prenatally detected patients who survived the neonatal period, four (17%) had a renal transplant at a mean (range) age of 6.5 (3.0-12.0) years. Of 19 patients with prenatally detected PUV who had not been transplanted in the first 12 years of life, only one (5%) developed new-onset ESRF at 10.0-23.4 years whilst 11 (58%) of these patients had normal creatinine values. In the untransplanted patients there was a statistically significant correlation between age and plasma creatinine level, but no correlation between late functional outcome and nadir creatinine in the first year of life, or bilateral VUR. CONCLUSIONS: Prenatal diagnosis had little impact on mortality or ESRF in the first decade of life. This appears to be largely predetermined by renal dysplasia and the severity of intrauterine obstruction. However, the functional outcome of patients with prenatally detected PUV aged 10-23 years was considerably better than published long-term data and the outcome of clinically presenting patients in our study. These findings suggest that the long-term prognosis of PUV of intermediate severity might be improved by prenatal diagnosis.

Dietary soya protein during pregnancy and lactation in rats with hereditary kidney disease attenuates disease progression in offspring.

Dietary soya protein substitution for casein initiated at weaning slows disease progression in animal models of chronic renal disease. As there is increasing evidence that fetal programming can have a significant impact on kidney physiology and function in offspring, the objective of the current study was to determine whether exposure to soya protein in the diet earlier than weaning would have further benefits. Han:SPRD-cy (cy/+) breeder rats were fed a casein-based or soya protein-based diet 2 weeks prior to mating, throughout pregnancy and during lactation. Following this maternal period, 3-week-old pups were given either the same or the alternate diet for a 7-week weaning period. Dietary soya protein compared with casein in the maternal or weaning period both independently resulted in less renal inflammation (macrophage infiltration lower by 24% (P=0.0003) and 32% (P<0.001), respectively). When soya protein was given in both feeding periods, the effect was additive. Soya protein substitution for casein resulted in less oxidative damages as indicated by 28% lower oxidized-LDL staining (P=0.013) when present in the maternal period, or in the weaning period (by 56%, P<0.0001). Renal cell proliferation was reduced by 29-33% (P<0.05) in rats given soya protein whether the exposure was during the maternal or weaning period. Soya protein compared with casein in the maternal period also resulted in 33% (P=0.0013) less proteinuria, indicating superior renal function. Dietary soya protein during pregnancy and lactation represents a potential preventative approach in treating for those with congenital kidney diseases.

Microalbuminuria and lower glomerular filtration rate at young adult age in subjects born very premature and after intrauterine growth retardation.

This prospective follow-up study of 422 19-yr-old subjects born very preterm in The Netherlands was performed to determine whether intrauterine growth retardation (IUGR) predisposes to abnormal GFR and microalbuminuria in adolescents. GFR (ml/min per 1.73 m2) was estimated using the Cockcroft-Gault equation, and albumin-creatinine ratio (mg/mmol) was calculated in a cohort of 19-yr-old subjects born very preterm (gestational age <32 wk) in 1983. Birth weights were adjusted for gestational age and expressed as standard deviation scores (sds) as a measure of IUGR. All subjects had normal renal function. Birth weight (sds) was associated negatively with serum creatinine concentration (micromol/L) (beta = -1.0 micromol/L, 95% confidence interval [CI]: -1.9 to -0.2), positively with GFR (beta = 3.0, 95% CI: 1.7 to 4.2), and negatively with the logarithm of albumin-creatinine ratio (beta = -0.05, 95% CI: -0.09 to -0.01) in young adults born very preterm. IUGR is associated with unfavorable renal functions at young adult age in subjects born very premature. These data suggest that intrauterine growth-retarded subjects born very premature have an increased risk to develop progressive renal failure in later life.

Fetal cells in mother rats contribute to the remodeling of liver and kidney after injury.

Fetal microchimerism indicates a mixture of cells of maternal and fetal origin seen in maternal tissues during and after pregnancy. Controversy exists about whether persistent fetal microchimerism is related with some autoimmune disorders occurring during and after pregnancy. In the current experiment, an animal model in which EGFP positive cells were taken as fetal-origin cells was designed to detect the fetal microchimerism in various maternal organs. Ethanol drinking and gentamicin injection were adopted to induce liver and kidney injury simultaneously. EGFP positive cells were engrafted not only in the maternal circulation and bone marrow, but also in the liver and kidney as hepatocytes and tubular cells, respectively. These results indicate that fetal cells are engrafted to maternal hematopoietic system without apparent injury and they also contribute to the repairing process of maternal liver and kidney.

Effects of in utero bladder outflow obstruction on fetal sheep detrusor contractility, compliance and innervation.

PURPOSE: Congenital bladder outflow obstruction caused by posterior urethral valves is a common cause of end stage renal failure in boys. We hypothesized that fetal bladder outflow obstruction perturbs detrusor contractility and innervation and bladder storage volume-pressure relationships. MATERIALS AND METHODS: Severe bladder outflow obstruction was induced in male fetal sheep by placing a urethral ring and urachal ligation midway through gestation at 75 days. Fetuses were examined 30 days after surgery, when urinary tract dilatation, enlarged bladders and histologically abnormal kidneys were documented. Isolated strips of bladder detrusor from sham operated and obstructed fetuses were subjected to electrical field stimulation, carbachol, KCl and alpha-beta methylene-adenosine triphosphate. Whole bladder storage characteristics were determined by filling cystometry and bladder innervation was investigated by immunohistochemistry and Western blot. RESULTS: Tension-frequency contractility studies showed that obstructed fetal bladder strips were significantly hypocontractile versus sham operated controls in response to electrical field stimulation and the specific agonists carbachol, KCl and alpha-beta methylene-adenosine triphosphate. Hypocontractility was greater with nerve mediated stimulation than with carbachol, suggesting relative denervation. Reduced innervation was confirmed by S100 and protein gene product 9.5 immunohistochemistry and by measuring a significant reduction in protein gene product 9.5 protein expression using Western blot. Filling cystometry showed that obstructed fetal bladders appeared more compliant (Delta V/Delta P, where Delta V is the change in volume and Delta P is the change in pressure) with larger capacity, more flaccidity and yet retained stress relaxation. CONCLUSIONS: In response to severe experimental fetal bladder outflow obstruction the bladder becomes large and hypocontractile, and has aberrant innervation.

How they begin and how they end: classic and new theories for the development and deterioration of congenital anomalies of the kidney and urinary tract, CAKUT.

CAKUT are problems that often require surgical intervention or, in the worst case, lead to renal failure and the need for dialysis and/or renal transplantation. It is believed that these anomalies share a common genetic cause and to date there has been no good animal model with which to study these abnormalities. Although the abnormal interaction between the ureteral bud and metanephric blastema leads to renal hypodysplasia, vesicoureteral reflux, and ectopic ureters to name a few, the genetic and biochemical modulation of urinary tract development is not understood. Studies using the mouse strain mutant for angiotensin type 2 (AT2) receptors have given new insight into this mystery. The animals show defective apoptosis of undifferentiated mesenchymal cells in the area surrounding the developing kidney and urinary tract. This abnormal apoptosis may well interfere with the normal interaction between the ureteral bud and metanephric blastema resulting in CAKUT. This abnormal interaction would theoretically lead to preexisting intrinsic abnormalities of the kidney, which are programmed and take effect early in embryonic development. In the worst cases, the renal abnormalities would lead to progressive deterioration of renal function. Undoubtedly, there are more genes and biochemical modulators involved in this process other than the RAS and AT2 receptors. Our current animal model gives new and unique possibilities with which to study development of the kidney and urinary tract and ultimately seek ways of preventing an often debilitating disease process.

[The growth of children and thyroid function in differentiation disorders of renal tissue]. / Rost detei i funktsiia shchitovidnoi zhelezy pri narusheniiakh differentsirovki pochechnoi tkani.

The growth of children and thyroid function were examined in abnormal differentiation of renal tissue. Forty-four children with different varieties of renal dysembryogenesis were examined. Seventy-three children with acquired renal pathology made up a reference group. Children with congenital nephropathies manifested a higher incidence of delayed growth. The majority of patients with renal dysembryogenesis showed the laboratory signs of both primary and secondary hypothyrosis. The role of thyroid hormones in the genesis of delayed growth and development of children afflicted with renal diseases is under discussion.