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Vascular calcification is highly prevalent in end-stage renal diseases and is predictive of cardiovascular events and mortality. Poly(ADP-ribose) polymerase 1 (PARP1) inhibition or deletion is vasoprotective in several disease models. Here we show that PARP activity is increased in radial artery samples from patients with chronic renal failure, in arteries from uraemic rats, and in calcified vascular smooth muscle cells (VSMCs) in vitro. PARP1 deficiency blocks, whereas PARP1 overexpression exacerbates, the transdifferentiation of VSMCs from a contractile to an osteogenic phenotype, the expression of mineralization-regulating proteins, and calcium deposition. PARP1 promotes Runx2 expression, and Runx2 deficiency offsets the pro-calcifying effects of PARP1. Activated PARP1 suppresses miRNA-204 expression via the IL-6/STAT3 pathway and thus relieves the repression of its target, Runx2, resulting in increased Runx2 protein. Together, these results suggest that PARP1 counteracts vascular calcification and that therapeutic agents that influence PARP1 activity may be of benefit to treat vascular calcification.

Growth retardation is a major manifestation of chronic kidney disease (CKD) in pediatric patients. The involvement of the various pathogenic factors is difficult to evaluate in clinical studies. Here, we present an experimental model of adenine-induced CKD for the study of growth failure. Three groups (n = 10) of weaning female rats were studied: normal diet (control), 0.5% adenine diet (AD), and normal diet pair fed with AD (PF). After 21 days, serum urea nitrogen, creatinine, parathyroid hormone (PTH), weight and length gains, femur osseous front advance as an index of longitudinal growth rate, growth plate histomorphometry, chondrocyte proliferative activity, bone structure, aorta calcifications, and kidney histology were analyzed. Results are means ± SE. AD rats developed renal failure (serum urea nitrogen: 70 ± 6 mg/dl and creatinine: 0.6 ± 0.1 mg/dl) and secondary hyperparathyroidism (PTH: 480 ± 31 pg/ml). Growth retardation of AD rats was demonstrated by lower weight (AD rats: 63.3 ± 4.8 g, control rats: 112.6 ± 4.7 g, and PF rats: 60.0 ± 3.8 g) and length (AD rats: 7.2 ± 0.2 cm, control rats: 11.1 ± 0.3 cm, and PF rats: 8.1 ± 0.3 cm) gains as well as lower osseous front advances (AD rats: 141 ± 13 μm/day, control rats: 293 ± 16 μm/day, and PF rats: 251 ± 10 μm/day). The processes of chondrocyte maturation and proliferation were impaired in AD rats, as shown by lower growth plate terminal chondrocyte height (21.7 ± 2.3 vs. 26.2 ± 1.9 and 23.9 ± 1.3 μm in control and PF rats) and proliferative activity index (AD rats: 30 ± 2%, control rats: 38 ± 2%, and PF rats: 42 ± 3%). The bone primary spongiosa structure of AD rats was markedly disorganized. In conclusion, adenine-induced CKD in young rats is associated with growth retardation and disturbed endochondral ossification. This animal protocol may be a useful new experimental model to study growth in CKD., (Copyright © 2015 the American Physiological Society.)

Objective: Many Chinese herbs contain aristolochic acids (ALAs) which are nephrotoxic and carcinogenic. The objective of this study was to identify whether exposure to herbs containing ALAs increased the risk of kidney disease among Chinese herbalists., Methods: A nested case-control study was carried out on 6538 Chinese herbalists registered between 1985 and 1998. All incident cases of chronic renal failure reported to the Database of Catastrophic Illness of the National Health Insurance Bureau between 1995 and 2000 were defined as the case group. Up to four controls without renal failure were randomly matched to each case by sex and year of birth. A structured questionnaire survey was administered between November and December 2002. The Mantel-Haenszel method and conditional logistic regression were used to estimate the risks., Results: 40 cases and 98 matched controls were included in the final analysis. After adjusting for age, frequent analgesic use, and habitual consumption of alcohol, fermented or smoked food, we found manufacturing and selling Chinese herbal medicine (OR 3.43, 95% CI 1.16 to 10.19), processing, selling or dispensing herbal medicines containing Fangji (OR 4.17, 95% CI 1.36 to 12.81), living in the workplace (OR 3.14, 95% CI 1.11 to 8.84) and a history of taking of herbal medicines containing Fangji (frequently or occasionally) (OR 5.42, 95% CI 1.18 to 24.96) were significantly associated with renal failure., Conclusion: Occupational exposure to and consumption of herbs containing ALAs increases the risk of renal failure in Chinese herbalists.

Objective: Oxalic acid (OA) is thought to be a uremic toxin that participates in the pathogenesis of uremic syndrome. The objectives of this study were to: (1) evaluate the plasma levels of OA in patients with chronic renal disease with various levels of glomerular filtration rate and after renal transplantation; (2) investigate the salivary secretion of OA and ascorbic acid in healthy subjects and in patients with chronic renal failure (CRF); (3) examine the influence of water and sodium diuresis and furosemide administration on the urinary excretion of OA and ascorbic acid in healthy subjects and in CRF patients without dialysis treatment; and (4) evaluate the influence of renal replacement therapy (RRT) on secondary hyperoxalemia in hemodialysis patients., Design and Setting: This study was conducted at the Nephrological Department of P.J. Safárik University. Sixty-one patients with chronic renal disease, 64 CRF patients, 32 continuous ambulatory peritoneal dialysis (CAPD) patients, 15 hemodialysis patients, 21 patients after renal transplantation, and 15 healthy subjects were examined. Maximal water diuresis, diets with low (2 g/day) and high (15 g/day) sodium intake, administration of intravenous furosemide (20 mg), and renal replacement therapy (CAPD, hemodialysis, hemofiltration, and postdilution hemodiafiltration) were utilized in the study., Results: In patients with chronic renal disease and those after renal transplantation, direct relationships between plasma OA and serum creatinine were found (r = 0.904 and 0.9431, respectively, P < .01). Despite a high level of plasma OA in uremic patients (23.1 +/- 10 micromol/L), there was no significant difference in salivary OA between control subjects (128 +/- 19 micromol/L) and CRF patients (135 +/- 24 micromol/L). The urinary excretion of OA during maximal water diuresis (from 37.5 to 110.3 micromol/4 hours) and after intravenous furosemide (from 34.5 to 66.7 micromol/3 hours) increased significantly, but was not affected by high intake of NaCl. The most significant decrease of plasma OA was observed during postdilution hemodiafiltration (63.3%)., Conclusion: Our study indicates that renal replacement therapy is not effective for a permanent reduction of elevated plasma levels of OA.

High levels of homocysteine have been implicated as a cardiovascular risk factor in the general population and in patients with chronic renal failure, and particularly patients on hemodialysis. To classify a risk factor as causally related to a certain disease, both strong epidemiologic data and sound basic-science studies establishing a mechanism are needed. Among the latter, the hypomethylation of proteins and DNA, and protein homocysteinylation, have been investigated in uremia, providing for an array of toxic effects in this disease.

Toxic substances, known as uremic toxins, accumulate in body fluids during the course of progressive, chronic kidney disease. This article will briefly summarize current views on the definition, physico-chemical characteristics, pathobiological mechanisms for generation and retention, and cellular pathophysiology of uremic toxins. In addition, this article will attempt to integrate these disparate phenomena into a systems biology approach as to how such toxins lead to the diverse clinical manifestations so characteristic of the uremic state.

Background: A relatively high level of serum parathyroid hormone (PTH) is required to maintain normal bone turnover in patients with chronic kidney disease (CKD). 'Uraemic toxins' could cause an impaired response to PTH in bone and result in low turnover bone disease. Since phenylacetic acid (PAA) has been identified as one of the uraemic toxins in patients with CKD and has an inhibiting property of monocyte function, we examined if PAA might inhibit osteoblastic functions in vitro., Methods: Using mouse osteoblastic MC3T3-E1 cells, we performed BrdU incorporation, real-time PCR, Western blot and stainings to see the effect of PAA., Results: PAA significantly inhibited proliferation in a dose-dependent manner ranging between 0.5 and 5 mM. PAA reduced osteocalcin mRNA level, alkaline phosphatase activity and osteoblastic mineralization. PAA pre-treatment also decreased both PTH-induced cAMP production and extracellular signal-regulated kinase (ERK) phosphorylation., Conclusion: PAA, a newly identified uraemic toxin, affects osteoblastic functions such as proliferation, differentiation, mineralization and responsiveness to PTH, indicating that this molecule could play an important role in the pathogenesis of low turnover bone in CKD.

Background: We previously demonstrated that erythropoietin (Epo) expression increases in five-sixths nephrectomized rats, after muscle-targeted gene transfer by in vivo electroporation, using plasmid DNA expressing rat Epo (pCAGGS-Epo). Here, we apply this method to a rat model with severe anemia associated with chronic renal failure; these rats have hematocrit levels in the 30-35% range, similar to those in humans with end-stage renal disease., Methods: Wistar rats were treated to produce adenine-induced uremia. The uremic rats were then treated with muscle-targeted gene transfer using pCAGGS-Epo. Some uremic rats died from chronic renal failure; one of these was dissected, and the kidneys were histologically examined. For the remaining rats, we measured body weight and blood pressure, and obtained blood samples regularly., Results: The uremic rats showed severe anemia, with hematocrit levels at 32.6 +/- 3.3%. Epo-gene transfer increased Epo expression and serum Epo levels, and also increased the hematocrit levels to 64.5 +/- 4.8%. The dose of pCAGGS-Epo used in this study did not induce severe hypertension., Conclusions: Continuous Epo-gene expression improves the anemia associated with chronic renal failure, and without severe side effects. Our results support the potential use of gene electrotransfer for human gene therapy applications., (Copyright 2003 S. Karger AG, Basel)

Poisoning with flecainide acetate is rare and associated with a high mortality. This usually occurs after massive ingestion but can also be observed during therapeutic overdose in patients with renal failure or with amiodarone therapy. The prognostic depends on the haemodynamic and rhythmic effects of the overdose one sign of which is widening of the QRS complexes. Major sodium bicarbonate or lactate infusion is the generally prescribed treatment. The authors report one case of a patient with renal failure on amiodarone who survived a severe flecainide acetate overdose.

Background: A positive correlation between successful kidney transplantation, few rejection episodes, greater susceptibility to infection and morbidity in patients with high tissue levels of aluminium (Al) indicate that the metal may play a role in the immune response. The aim of this study was to determine if experimental aluminium intoxication could result in significant changes in lymphocyte activity in uraemic and nonuraemic rats., Methods: Lewis rats were divided into four groups: normals (N), nephrectomized control (U), and Al-treated (N + Al) and nephrectomized Al-treated (U + Al), which received a cumulative dose of 30 mg Al over a 4-week period. Al quantification, histology, histochemical analysis and immunological assays were performed after Al intoxication., Results: High tissue levels of Al and positive histochemical staining in bones were seen in Al-treated rats. Bone histology revealed osteomalacia in U + Al rats. No statistical differences were observed in mixed lymphocyte cultures from controls and Al-treated rats, whereas U and Al-treated rats showed a decrease in lymphoproliferative response to mitogen and natural killer cell cytotoxic activity. A decreased helper T lymphocyte: cytotoxic T lymphocyte cell ratio and a reduction in interleukin-2 production were observed only in the U + Al group. A reduced number of total T lymphocytes was detected in the spleens of all Al-treated rats., Conclusions: These findings suggest that aluminium toxicity may contribute to immunological impairment in chronic renal failure.

Heroin-associated nephropathy (HAN), a complication of intravenous heroin abuse, was initially recognized at Kings County Hospital in Brooklyn, NY, in the early 1970s. Our recent experience indicates that after a steady incidence of new cases of HAN throughout the mid-1980s, a sharp decrease in incidence of new cases occurred starting in 1989. We sought to explore possible explanations for what amounts to disappearance of a previously prevalent disease. By means of retrospective analysis of a hospital-specific registry of new cases of end-stage renal disease (ESRD) at Kings County Hospital in Brooklyn, incidence curves from 1981 through 1993 for new cases of HAN, diabetes-induced renal disease, and human immunodeficiency virus-associated nephropathy were constructed. From hospital computer records, the number of admissions directly related to opioid abuse were extracted and charted. Unpublished surveillance records of the New York State Office of Alcoholism and Substance Abuse Services as well as reports from the New York City Department of Health, Office of AIDS Surveillance and the US Department of Justice Drug Enforcement Administration were used to determine the pattern of change in the prevalence of heroin abuse. Additionally, we used analysis of "street" heroin by the Drug Enforcement Administration to draw curves detailing drug cost and purity in New York City. There were no new cases of ESRD due to HAN for the years 1991 through 1993. The rates for new cases of ESRD due to diabetes and hypertension remained relatively constant throughout this interval.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic renal failure was induced in Wistar rats by administration of a LiCl-containing (40 mmol/kg) diet from birth until an age of 55-65 weeks. The 55 weeks mortality was 51% in Li-uraemic rats versus 6% in control rats. In surviving rats the mean plasma Li levels were 0.6-0.7 mmol/l after 16 weeks and 1.0-1.1 mmol/l after 48 weeks. The mean plasma urea level was 14 mmol/l after 16 weeks and 22 mmol/l after 48 weeks of treatment compared with 8 mmol/l in the controls rats. In 55 weeks old Li-uraemic rats inulin clearance was reduced by 62% and Li clearance by 39%. Thus, fractional Li excretion was increased (from 20 to 34%) in rats with chronic Li-uraemia. Li-uraemic rats also had polyuria and failed to concentrate their urine in response to exogenous vasopressin. Systolic and mean arterial blood pressures were not significantly changed in rats with Li-uraemia. Morphological examinations of the kidneys showed large cortical cysts formed by dilated distal tubules and collecting ducts and widespread interstitial fibrosis. Proximal tubular mass was reduced by 50% and glomerular volume was also significantly reduced. The results indicate that in rats with Li-induced uraemia renal function and morphology deteriorate during Li-exposure up to an age of one year, associated with increased mortality.

Eight men with chronic renal disease in the stage of compensated retention were given high doses of the androgen fluoxymesterone (40 mg/m2/day) for erythropoietin stimulation for 4 weeks. Seven of them showed a transient significant average rise in the serum creatinine level of 3.8 to 6.1 mg% which partly regressed only 8 to 12 weeks after stopping the medication. The rise in serum creatinine which appears under fluoxymesterone is attributable to a transient increase in the renal excretory function disturbance and/or a raised catabolism. Warning should be given against the further use of this drug in the treatment of renal anemia.

Three groups of new-born rats were studied: Group Li/Li treated with Li for 16 weeks, group Li/C treated for 8 weeks followed by 8 weeks without Li, and Group C/C 16 weeks old controls. Both Li-treated groups showed severe reduction of renal function, particularly group Li/Li, where the mean GFR was reduced by 80%. Plasma urea, creatinine, and osmolality were increased, blood hemoglobin and hematocrit were reduced, whereas plasma Na, K, and standard bicarbonate were unchanged. Na clearance was maintained and fractional Na excretion thus increased. Fractional Li excretion was also increased, indicating inhibition of proximal tubular salt and water reabsorption. Renal concentrating ability was markedly reduced. When Li was withdrawn, plasma urea levels remained unchanged or continued to rise, and the concentrating defect persisted. The results demonstrate that Li administration to new-born rats causes irreversible chronic renal failure which may progress even in the absence of Li. This model of chronic renal failure has several characteristics in common with chronic renal failure in humans.