Ischemic acute renal failure (ARF) is a common clinical syndrome, associated with high morbidity and mortality, for which there is no specific therapy. Polymorphonuclear neutrophils (PMN) recruited during reperfusion have been implicated as mediators of renal parenchymal injury in ischemic ARF. Leukocyte adhesion molecules appear to facilitate PMN recruitment in this setting. Complementary studies using monoclonal antibodies, antisense oligonucleotides and gene "knock-out" indicate that blockade of CD11/CD18 integrins and intercellular adhesion molecule-1 (ICAM-1) attenuates ARF in some experimental models of renal ischemia. These exciting observations may herald the development of novel anti-adhesion strategies for use in human disease.

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OBJECTIVEGremlin (grem1) is an antagonist of the bone morphogenetic protein family that plays a key role in limb bud development and kidney formation. There is a growing appreciation that altered grem1 expression may regulate the homeostatic constraints on damage responses in diseases such as diabetic nephropathy.RESEARCH DESIGN AND METHODSHere we explored whether knockout mice heterozygous for grem1 gene deletion (grem1+/−) exhibit protection from the progression of diabetic kidney disease in a streptozotocin-induced model of type 1 diabetes.RESULTSA marked elevation in grem1 expression was detected in the kidneys and particularly in kidney tubules of diabetic wild-type mice compared with those of littermate controls. In contrast, diabetic grem1+/− mice displayed a significant attenuation in grem1 expression at 6 months of diabetes compared with that in age- and sex-matched wild-type controls. Whereas the onset and induction of diabetes were similar between grem1+/− and wild-type mice, several indicators of diabetes-associated kidney damage such as increased glomerular basement membrane thickening and microalbuminuria were attenuated in grem1+/− mice compared with those in wild-type controls. Markers of renal damage such as fibronectin and connective tissue growth factor were elevated in diabetic wild-type but not in grem1+/− kidneys. Levels of pSmad1/5/8 decreased in wild-type but not in grem1+/− diabetic kidneys, suggesting that bone morphogenetic protein signaling may be maintained in the absence of grem1.CONCLUSIONSThese data identify grem1 as a potential modifier of renal injury in the context of diabetic kidney disease.

There was no evidence to suggest that there were significant differences in health status between males and females, or between this Irish sample and the published norms for the US population.

Subtle but significant deficits in subjective and objective physical function existed even in this select group of dialysis patients. These findings define in more detail the underlying neuromuscular impairments and support the early implementation of active targeted rehabilitation programmes. The subjective and objective measures used here offer a useful panel of tests for clinical use in high-functioning dialysis patients.

A retrospective study of the clinical records and biopsy specimens of all transplants performed between 1974 and 1987 was carried out. Recurrent glomerulonephritis was diagnosed only in those patients who had precise histological classification of their original disease. Of a total of 737 transplants performed in 633 recipients. 603 were from cadaveric and 134 from living related donors. Of 295 patients who were clinically classed as having chronic glomerulonephritis, histological confirmation was available in 156 (54%) as follows: membranoproliferative glomerulonephritis 34%, diffuse proliferative glomerulonephritis 27%, crescentic glomerulonephritis 13% IgA neuropathy 10%, focal sclerosing glomerulonephritis 10%, and membranous nephropathy 7%. There were 24 cases of recurrence in 23 recipients. Of these, 16 occurred in living-related and 8 in cadaveric grafts. Membranoproliferative glomerulonephritis recurred in 14 (8 type I and 6 type II), focal sclerosing glomerulonephritis in 5, IgA neuropathy in 3, crescentic glomerulonephritis in 1 and membranous nephropathy in 1. Graft failure occurred in 13 patients (54%) and was directly attributable to recurrent disease in 12. Membranoproliferative glomerulonephritis caused 8 graft losses, focal sclerosing glomerulonephritis 2, IgA 1 and crescentic glomerulonephritis 1. Recurrence caused graft loss in 50% of cases in which it occurred. The overall incidence of recurrence was 18%. In contrast to other series, a significantly higher incidence of recurrence was seen in our living-related group.

Hepatocyte death is an important contributing factor in a number of diseases of the liver. PHD1 confers hypoxic sensitivity upon transcription factors including the hypoxia inducible factor (HIF) and nuclear factor-kappaB (NF-κB). Reduced PHD1 activity is linked to decreased apoptosis. Here, we investigated the underlying mechanism(s) in hepatocytes. Basal NF-κB activity was elevated in PHD1(-/-) hepatocytes compared to wild type controls. ChIP-seq analysis confirmed enhanced binding of NF-κB to chromatin in regions proximal to the promoters of genes involved in the regulation of apoptosis. Inhibition of NF-κB (but not knock-out of HIF-1 or HIF-2) reversed the anti-apoptotic effects of pharmacologic hydroxylase inhibition. We hypothesize that PHD1 inhibition leads to altered expression of NF-κB-dependent genes resulting in reduced apoptosis. This study provides new information relating to the possible mechanism of therapeutic action of hydroxylase inhibitors that has been reported in pre-clinical models of intestinal and hepatic disease.

Background and purpose The prevalence of chronic kidney disease (estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m for ≥3 months, chronic kidney disease (CKD)) in ischemic stroke and transient ischemic attack (TIA) is unknown, as estimates have been based on single-point estimates of renal function. Studies investigating the effect of renal dysfunction (eGFR < 60 mL/min per 1.73 m, renal dysfunction) on post-stroke outcomes are limited to hospitalized cohorts and have provided conflicting results. Methods We investigated rates, determinants and outcomes of renal dysfunction in ischemic stroke and TIA in the North Dublin Population Stroke Study. We also investigate the persistence of renal dysfunction in 90-day survivors to determine the prevalence of CKD. Ascertainment included hot and cold pursuit using multiple overlapping sources. Survival analysis was performed using Kaplan-Meier survival curves and Cox proportional hazards modeling. Results In 547 patients (ischemic stroke in 76.4%, TIA in 23.6%), the mean eGFR at presentation was 63.7 mL/min/1.73 m (SD 22.1). Renal dysfunction was observed in 44.6% (244/547). Among 90-day survivors, 31.2% (139/446) met criteria for CKD. After adjusting for age and stroke severity, eGFR < 45 mL/min/1.73 m (hazard ratio 2.53, p = 0.01) independently predicted 28-day fatality but not at two years. Poor post-stroke functional outcome (Modified Rankin Scale 3-5) at two years was more common in those with renal dysfunction (52.5% vs. 20.6%, p < 0.001). After adjusting for age, stroke severity and pre-stroke disability, renal dysfunction (OR 2.17, p = 0.04) predicted poor functional outcome. Conclusion Renal dysfunction and CKD are common in ischemic stroke and TIA. Renal dysfunction is associated with considerable post-stroke morbidity and mortality. Further studies are needed to investigate if modifiable mechanisms underlie these associations.