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Acute kidney injury (AKI) is a frequent complication of cardiac surgery and usually occurs in patients with preexisting chronic kidney disease (CKD). Remote ischemic preconditioning (RIPC) may mitigate the renal ischemia-reperfusion injury associated with cardiac surgery and may be a preventive strategy for postsurgical AKI. We undertook a randomized controlled trial of RIPC to prevent AKI in 86 patients with CKD (estimated glomerular filtration rate under 60 ml/min per 1.73 m(2)) undergoing coronary artery bypass graft (CABG) surgery. Forty-three patients each were randomized to receive standard care with or without RIPC consisting of three 5-minute cycles of forearm ischemia followed by reperfusion. The primary end point was the development of AKI defined as an increase in serum creatinine concentration over 0.3 mg/dl within 48 h of surgery. Secondary end points included a comparison between the study and control groups of several serum biomarkers of renal injury including cystatin-C, neutrophil gelatinase-associated lipocalin (NGAL), and interleukin-18 (IL-18), and urinary biomarkers including NGAL, IL-18, and kidney injury molecule-1 measured at 6, 12, and 24 h after CABG, and the 72-h serum troponin T concentration area under the curve as a marker of myocardial injury. Clinical and operative characteristics were similar between the preconditioned and control groups. AKI developed in 12 patients in both groups within 48 h of CABG. There were no significant differences between the two groups in the concentrations of any of the serum or urinary biomarkers of renal or cardiac injury after CABG. Thus, RIPC induced by forearm ischemia-reperfusion had no effect on the frequency of AKI after CABG in patients with CKD.

Insidious Mycobacterium tuberculosis infection causing tubulointerstitial nephritis is a rare disorder. Here we report on a single-center case series of patients with tubulointerstitial nephritis due to tuberculosis, addressing clinicopathologic features and treatment outcome. Twenty-five adult patients with clinical evidence of tuberculosis and significant renal disease were assessed, 17 of whom had a kidney biopsy and were subsequently diagnosed with chronic granulomatous tubulointerstitial nephritis as the primary lesion. All patients were given standard antitubercular treatment, with some receiving corticosteroids, and showed a good response in clinical symptoms and inflammatory markers. Nine of the 25 patients, however, started renal replacement therapy within 6 months of presentation. Of the remaining 16, renal function improved for up to a year after presentation but subsequently declined through a median follow-up of 36 months. This case series supports that chronic tubulointerstitial nephritis is the most frequent kidney biopsy finding in patients with renal involvement from tuberculosis. Thus, a kidney biopsy should be considered in the clinical evaluation of kidney dysfunction with tuberculosis since tubulointerstitial nephritis presents late with advanced disease. A low threshold of suspicion in high-risk populations might lead to earlier diagnosis and treatment, preserving renal function and delaying initiation of renal replacement therapy.

Increased nitrotyrosine staining in kidneys from patients with diabetic nephropathy. Background Proximal tubular cells produce nitric oxide (NO · ). We have shown that under hyperglycemic conditions, cultured proximal tubular cells express cytochrome P450 2E 1 , which is capable of producing superoxide (O 2 · ). NO · and O 2 · react to form peroxynitrite (ONOO · ), a powerful oxidant. ONOO · nitrosylates tyrosine moieties on proteins causing tissue damage. Our hypothesis is that ONOO · plays a role in early diabetic tubular damage and perhaps disease progression. Methods Renal biopsies from patients with diabetic nephropathy (DM), acute allograft rejection (AAR), acute allograft tubular necrosis (ATN), and glomerulonephritis (GN) were obtained. Normal kidney specimens were taken from nephrectomy samples ( N = 10 for each group). The tissues were examined for the presence of nitrotyrosine using an immunoperoxidase technique with a polyclonal antibody. Samples were then arbitrarily scored, and the results analyzed (analysis of variance and Student's t -test for unpaired data). The number of apoptotic cells in a sample of tubules in each biopsy was also assessed. Results The DM biopsies showed increased staining for nitrotyrosine in proximal tubules ( P = 0.0001) and in the thin limb of the loop of Henle ( P = 0.0006) compared with all other groups. There was increased staining in the ascending and distal tubules in GN as compared to DM and ATN ( P = 0.01). Nitrotyrosine was also found in all distal tubules and collecting ducts, including normals. There was no difference in the number of apoptotic tubular cells in diabetics compared with controls. Conclusion To our knowledge, these data provide the first evidence for the presence of nitrotyrosine in both normal and diseased kidneys. The significance of the findings in normals is unclear, but could be due to activation of constitutive NOS. However, the study clearly demonstrates increased production of ONOO · in proximal tubules of patients with DM, and suggests that oxidant injury of the proximal tubules plays an important part in the pathogenesis of DM.

Modulation of hypoxia-induced calpain activity in rat renal proximal tubules. The effect of the newly developed, nonpeptide, calpain inhibitor, PD 150606, on hypoxia and ionomycin-induced increases in calpain activity in rat proximal tubules (PT) was determined. PD 150606 inhibited both hypoxia and ionomycin-induced calpain activity as determined by the fluorescent substrate N-succinyl-Leu-Leu-Val-Tyr-7-amido-4-methyl coumarin (N-succinyl-Leu-Leu-Val-Tyr-AMC). This decrease in calpain activity was accompanied by dose-dependent cytoprotection against hypoxia and ionomycin-induced cell membrane damage. PD150606 had no effect on cathepsin B and L activity in PT as measured by the fluorescent substrate, benzyloxycarbonyl-L-phenylalanyl-L-arginine-7-amido-4-methyl coumarin (Z-Phe-Arg-AMC). The effects of low intracellular pH (pH i ) or low free cytosolic calcium [Ca 2+ ] i on this hypoxia-induced calpain activity were also determined. Both low pH i and low [Ca 2+ ] i attenuated the hypoxia-induced increase in calpain activity. This attenuation of calpain activity was observed early before hypoxia-induced membrane damage and was associated with marked reduction in the typical pattern of hypoxia-induced cell membrane damage observed in this model. To identify the isoform of calpain activated in rat proximal tubules, normoxic, hypoxic and ionomycin treated tubules were fractionated by MONO-Q anion exchange chromatography and the fractions were assayed for calpain activity. A single peak of calpain activity characteristic of μ-calpain was found. The calcium dependency of the calpain activity was in the nanomolar range, further confirming that the activity was the low Ca 2+ -sensitive μ-calpain. The present study suggests that in rat proximal tubules: (1) PD 150606 is a specific inhibitor of calpain and not cathepsins B and L; (2) the cytoprotective effects of low pH i and low [Ca 2+ ] i are mediated, at least in part, by inhibition of calpain activity; and (3) the predominant active form of calpain is the isoenzyme μ -calpain.

Arachidonic acid protects against hypoxic injury in rat proximal tubules. Free fatty acids (FFA) and lysophospholipids accumulate during hypoxia (H) in rat proximal tubular epithelial cells partly as a result of increased phospholipase A 2 (PLA 2 ) activity. The role of FFA in mediating hypoxic injury and modulating PLA 2 activity is not clear. In the present study, the effect of several FFA including arachidonic acid (AA, 20:4) on hypoxia-induced injury and PLA 2 activity was assessed in freshly isolated rat proximal tubules. Hypoxia (H) was induced in the presence of either an unsaturated free fatty acid (uFFA) [AA or linoleic acid (LA, 18:2)] or a saturated FFA (sFFA) [palmitic (PA, 16:0) or myristic acid (MA, 14:0)]. Cell membrane injury was assessed by measuring lactate dehydrogenase release (LDH). AA markedly reduced LDH release during hypoxia in a dose dependent manner, while sFFA had no protective effect. LA showed similar protection to that observed with AA. AA did not affect buffer calcium concentration, buffer pH, intracellular pH or intracellular calcium concentration. Neither inhibiting the cyclooxygenase pathway with indomethacin, nor the lipoxygenase pathway with nordihydroguaiaretic acid (NDGA) had any effect on the AA observed cytoprotection. In vitro PLA 2 activity in the control tubular extracts was compared to that following addition of AA or PA. PLA 2 activity decreased significantly with AA but not with PA in a dose dependent manner. These data suggest that: (1) AA protects against hypoxic injury in rat proximal tubules. (2) This cytoprotection is not specific for AA and other uFFA have a similar effect. (3) AA significantly inhibits PLA 2 activity. (4) AA induced cytoprotection may be related to a negative feedback inhibition of PLA 2 activity.

Residual kidney function is important for patient and technique survival in peritoneal dialysis (PD). Biocompatible dialysis solutions are thought to improve function and viability of peritoneal mesothelial cells and to preserve residual renal function (RRF). We conducted a randomized controlled study comparing use of biocompatible (B) with standard (S) solutions in 93 incident PD patients during a 1-year period. The demographics, comorbidities, and RRF of both groups were similar. At 3 and 12 months, 24-h urine samples were collected to measure volume and the mean of urea and creatinine clearance normalized to body surface area. Surrogate markers of fluid status, diuretic usage, C-reactive protein concentration, peritonitis episodes, survival data, and peritoneal equilibrium tests were also collected. Changes in the normalized mean urea and creatinine clearance were the same for both groups, with no significant differences in secondary end points. Despite non-randomized studies suggesting benefits of these newer biocompatible solutions, we could not detect any clinically significant advantages. Additional studies are needed to determine if advantages are seen with longer term use.

A 46-year-old woman with known epilepsy, on long-term phenobarbitone therapy, developed end-stage renal failure. She had been on maintenance hemodialysis for 2 years when she became noncompliant with oral α-calcidiol therapy. She subsequently developed bulging of the malar bones and widening of the nares and interdontal space (Figure 1). Her intact parathyroid hormone was 230 pmol per liter, and a skeletal survey was consistent with renal osteodystrophy. A radiograph (Figure 2) and a computed tomographic scan of the skull (Figure 3) showed hyperostosis of facial and cranial bones (Figure 2, arrows) and ground-glass expansion of the maxilla, mandible, and skull vault with a 7 × 2.5 cm brown tumor arising from the maxilla (Figure 3, arrows). Th ese fi ndings are characteristic of uremic leontiasis ossea. Parenteral vitamin D was commenced for the patient, and she is awaiting parathyroidectomy. It is important to recognize features of uremic leontiasis ossea, as it may result in life-threatening upper airway obstruction and compressive cranial neuropathy. Figure 2 | Plain radiograph of the skull, revealing hyperostosis of the facial and calvarial bones (arrows).

The selective PPARγ antagonist GW9662 reverses the protection of LPS in a model of renal ischemia-reperfusion. Background We have recently reported that pretreatment of rats with endotoxin (lipopolysaccharide, LPS) and selective agonists of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) protect the kidney against ischemia/reperfusion (I/R) injury. Here we investigate the hypothesis that the renoprotective effects of LPS may be due to an enhanced formation of endogenous ligands of PPARγ, rather than an up-regulation of PPARγ expression. Methods Rats were pretreated with LPS (1mg/kg, IP, 24 hours prior to ischemia) in the absence (control) or presence of the selective PPARγ antagonist GW9662 (1mg/kg, IP, 24 and 12 hours prior to ischemia). Twenty-four hours after injection of LPS, rats were subjected to 60 minutes of bilateral renal ischemia, followed by 6 hours of reperfusion. Serum and urinary indicators of renal injury and dysfunction were measured, specifically serum creatinine, aspartate aminotransferase, and γ-glutamyl-transferase, creatinine clearance, urine flow, and fractional excretion of sodium. Kidney PPARγ1 mRNA levels were determined by reverse transcriptase-polymerase chain reaction. Results Pretreatment with LPS significantly attenuated all markers of renal injury and dysfunction caused by I/R. Most notably, GW9662 abolished the protective effects of LPS. Additionally, I/R caused an up-regulation of kidney PPARγ1 mRNA levels compared to sham animals, which were unchanged in rats pretreated with LPS. Conclusion We document here for the first time that endogenous ligands of PPARγ may contribute to the protection against renal I/R injury afforded by LPS pretreatment in the rat.

Structural remodeling of resistance arteries in uremic hypertension. Background Structural remodeling of the resistance vasculature is present in many forms of human and experimental hypertension. In particular, an increase in the ratio of wall thickness to lumen diameter develops, and might in itself maintain hypertension by increasing vascular resistance. Because uremia is associated with raised peripheral resistance, hypertension, and histologic changes suggestive of vascular remodeling, we sought to formally examine the structural and mechanical (elastic) properties of isolated pressurized resistance arteries in uremic hypertension. Methods Cremaster, cerebral and mesenteric arteries from subtotally nephrectomised Wistar-Kyoto rats, normotensive control Wistar-Kyoto rats, and spontaneously hypertensive rats were mounted on a pressure myograph and relaxed in calcium-free buffer. Wall thickness and lumen diameter were measured at increasing lumen pressures from 10 to 200mm Hg, and from this wall:lumen ratio, wall cross-sectional area, and an index of elasticity were derived. Results In uremic hypertensive animals increased wall:lumen ratio and decreased lumen diameter was seen in cremaster and mesenteric arteries, although no significant changes were observed in cerebral arteries, compared to normotensive controls. In spontaneously hypertensive animals increased wall thickness and wall:lumen ratio was seen in cerebral and mesenteric arteries, decreased lumen diameter in cremaster and mesenteric arteries, and increased wall cross-sectional area in cerebral arteries, compared to normotensive controls. Elasticity of the arterial wall in uremic and spontaneously hypertensive animals did not differ from normotensive controls. Conclusion Cremaster and mesenteric resistance arteries undergo predominantly eutrophic inward remodeling in uremic hypertension, broadly similar to that seen in spontaneous hypertension.

A 59-year-old man with end-stage renal failure secondary to autosomal dominant polycystic kidney disease received a renal transplant in 1994. Between 2008 and 2010 he developed recurrent, microbiologically proven episodes of urosepsis associated with a ureteric stricture, which required balloon ureteroplasty, insertion of a JJ stent, and finally a doubleended Memokath. Despite this, graft function continued to decline with nephrotic-range proteinuria, and in 2011 he recommenced hemodialysis. Ongoing episodes of urosepsis necessitated graft nephrectomy. The septic episodes subsequently abated and inflammatory markers normalized. Histology of the kidney revealed scarring and an accumulation of eosinophilic material in the glomeruli and vessel walls, which stained positive for Congo red (Figure 1a and b). Immunohistochemisty for AA amyloid was positive. It appears that AA amyloid deposition resulting from chronic graft pyelonephritis was the cause of this patient’s nephrotic-range proteinuria and, ultimately, graft failure. There have been very few case reports of de novo AA amyloid in renal allografts, and in these cases it has occurred in patients with chronic infective or inflammatory conditions that were present before transplantation. To our knowledge, this is the first case of de novo AA amyloid in a transplanted kidney not associated with a pre-existing chronic inflammatory or immune disorder. http://www.kidney-international.org n e p h r o l o g y i m a g e

Nitric oxide kinetics during hypoxia in proximal tubules: effects of glycine and acidosis . In the present study, we directly monitored nitric oxide (NO) with an amperometric NO-sensor in suspensions of rat proximal tubules. Hypoxia-stimulated NO generation was characterized by an initial rise and a subsequent sustained increase which preceded cell membrane damage as assessed by lactic dehydrogenase (LDH) release. In contrast, the NO concentration remained unmeasurable in normoxic controls. Nitro-L-arginine-methyl ester (L-NAME) prevented the hypoxia-induced increase in NO in a dose dependent manner in parallel with incremental cytoprotection. The hypoxia-induced elevation in NO and the associated membrane injury were both markedly prevented by extracellular acidosis (pH 6.95). In vitro proximal tubular nitric oxide synthase (NOS) activity ( 3 H-arginine to 3 H-citrulline assay) was pH dependent with optimum activity at pH 8.0 and greatly reduced activity at acidic pH even in the presence of calcium and co-factors. However, glycine, a well recognized cytoprotective agent, did not attenuate the NO concentration during hypoxia. The present study therefore provides direct evidence that NO is generated by rat proximal tubules during hypoxia and demonstrates that the protective effect of low pH against hypoxic rat tubular injury is associated with an inhibition of this NO production.

Albumin stimulates cell growth, L-arginine transport, and metabolism to polyamines in human proximal tubular cells. Background Pure albumin stimulates proximal tubular epithelial cell (PTEC) proliferation, and may have a role in homeostasis in health, as well as in disrupted PTEC turnover in proteinuric nephropathies. We investigated a role for arginine and its metabolites, the polyamines, in this process, given the ability of polyamines to trigger proliferation in other mammalian cells. Methods [ 3 H]-L-arginine uptake was examined after incubation with 20 mg/mL recombinant human serum albumin (rHSA) in HK-2 PTEC monolayers. Nitric oxide synthase (NOS) and arginase activity was measured; NOS, arginase, and ornithine decarboxylase (ODC) expression was identified by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Polyamine synthesis and intracellular amino acid concentrations were compared using high-performance liquid chromatography, and cell growth measured by [ 3 H]-thymidine incorporation. Results In HK-2 PTEC exposed to 20 mg/mL rHSA for 24 hours, cell proliferation as determined by [ 3 H]-thymidine incorporation was increased. In parallel, L-arginine transport capacity was increased in a dose- and time-dependent manner. This effect was specific to rHSA, and was not seen with transferrin or immunoglobulin G. The intracellular concentration of L-arginine remained unchanged, although L-ornithine was increased with rHSA incubation. rHSA up-regulated type II arginase mRNA, and increased arginase activity, although no difference in nitric oxide synthase expression or activity was seen. ODC mRNA was increased, as were intracellular polyamine concentrations. α-Difluoromethylornithine (DFMO), an ODC inhibitor, reduced intracellular polyamine concentrations and rHSA-induced cell proliferation to control levels. Conclusion The arginine-ornithine-polyamine pathway appears enhanced in PTEC incubated with rHSA and is involved in cellular proliferation; this may offer novel approaches to understanding progressive proteinuric nephropathies.

GW274150, a potent and highly selective inhibitor of iNOS, reduces experimental renal ischemia/reperfusion injury. Background Generation of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) may contribute to renal ischemia/reperfusion (I/R) injury. The aim of this study was to investigate the effects of GW274150, a novel, highly selective, potent and long-acting inhibitor of iNOS activity in rat and mouse models of renal I/R. Methods Rats were administered GW274150 (5 mg/kg intravenous bolus administered 30 minutes prior to I/R) and subjected to bilateral renal ischemia (45 minutes) followed by reperfusion (6 hours). Serum and urinary indicators of renal dysfunction, tubular and reperfusion injury were measured, specifically, serum urea, creatinine, aspartate aminotransferase (AST) and N -acetyl-β-D-glucosaminidase (NAG) enzymuria. In addition, renal sections were used for histologic scoring of renal injury and for immunologic evidence of nitrotyrosine formation and poly [adenosine diphosphate (ADP)-ribose] (PAR). Nitrate levels were measured in rat plasma using the Griess assay. Mice (wild-type, administered 5 mg/kg GW274150, and iNOS-/-) were subjected to bilateral renal ischemia (30 minutes) followed by reperfusion (24 hours) after which renal dysfunction (serum urea, creatinine), renal myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels were measured. Results GW274150, administered prior to I/R, significantly reduced serum urea, serum creatinine, AST, and NAG indicating reduction of renal dysfunction and injury caused by I/R. GW274150 reduced histologic evidence of tubular injury and markedly reduced immunohistochemical evidence of nitrotyrosine and PAR formation, indicating reduced peroxynitrite formation and poly (ADP-ribose) polymerase (PARP) activation, respectively. GW274150 abolished the rise in the plasma levels of nitrate (indicating reduced NO production). GW274150 also reduced the renal dysfunction in wild-type mice to levels similar to that observed in iNOS-/- mice subjected to I/R. Renal MPO activity and MDA levels were significantly reduced in wild-type mice administered GW274150 and iNOS-/- mice subjected to renal I/R, indicating reduced polymorphonuclear leukocyte (PMN) infiltration and lipid peroxidation. Conclusions These results suggest that ( 1 ) an enhanced formation of NO by iNOS contributes to the pathophysiology of renal I/R injury and ( 2 ) GW274150 reduces I/R injury of the kidney. We propose that selective inhibitors of iNOS activity may be useful against renal dysfunction and injury associated with I/R of the kidney.

Calpain is a mediator of myocardial injury in experimental and sodium and water retention are thought to be impor- uremia: Is it activated by endogenous ouabain? tant factors. We thought it likely that calpain, a Ca 2 - Background. Incidence of cardiovascular disease is more requiring cysteine protease that is a known mediator of than 20-fold higher in patients with chronic renal failure than cell death, might also play a role. This is because long- in aged-matched individuals with normal renal function. Little term studies in our laboratory have revealed that Ca 2 is understood about the causes or the mechanism of uremia- induced cardiovascular injury, but the involvement of calpain homeostasis is altered in myocytes from uremic rats com- as a possible mediator has recently been under investigation. pared with pair-fed, sham-operated controls (3). There Mean calpain activity was found to be 3.4-fold higher in the is also evidence indicating that intracellular calcium hearts of uremic rats than in control or spontaneously hyperten- ((Ca 2 ) j) is increased in the hearts of uremic patients sive (SHR) rats. In addition, calpain activity was found to be stimulated in myoblasts (Girardi) treated with media enriched compared with healthy subjects (4). A likely outcome of with uremic serum compared with cells treated with serum raised (Ca 2 )j in the uremic myocardium is the activation from healthy volunteers. In this study, we assessed the impact of calpain, which may, in turn, lead to cell death. Calpain of calpain activation in uremia and explored the possibility that activation has been identified in numerous injurious calpain might be activated in uremia by endogenous ouabain. states in which (Ca 2 )j is known to be elevated, including Ouabain is known to be elevated in uremia and is strongly associated with left ventricular hypertrophy in essential hyper- traumatic brain injury, Alzheimer's disease, and ischemic tension. stroke (5). Methods. Calpain activity was measured in situ in human- Calpain has many protein substrates that are closely derived myoblasts treated with low doses of ouabain similar associated with the structural integrity of the cell. It is to those concentrations found in uremic patients. feasible that the activation of calpain may help facilitate Results. Low concentrations of ouabain (10 nmol/L) caused a highly significant increase in calpain activity, which could be the cellular structural remodeling that leads to the devel- completely inhibited by the simultaneous chelation of intracel- opment of LVH. Indeed, some evidence of a role for lular and extracellular Ca

Calpain is activated in experimental uremia: Is calpain a mediator of uremia-induced myocardial injury?BackgroundThe cysteine proteases calpain and caspase-3 are known mediators of cell death. The aim of this study was to assess their contribution to the tissue damage found in experimental uremia.MethodsCalpain and caspase-3 activities were measured in the hearts of rats that were sham-operated (control), sham-operated and spontaneously hypertensive (SHR), and those rendered uremic by 5/6 nephrectomy (uremic). In an in vitro study, heart myoblasts (Girardi) were incubated with human serum from healthy subjects (control serum conditioned media, CSCM) or uremic patients (uremic serum conditioned media, USCM), in the presence and absence of calpain and caspase-3 inhibitors. After 48 hours the activity of calpain and caspase-3 was measured, and cell injury determined by DNA fragmentation (ELISA) and lactate dehydrogenase (LDH) release. An in situ assay was designed to study how USCM affects calpain activity over time.ResultsIn the in vivo study, mean calpain activities were almost identical in the control and SHR groups, but calpain and caspase-3 activities were much elevated in the uremic group (P < 0.01 and 0.001 respectively vs. control). The SHR group had significantly higher mean arterial blood pressure (P < 0.001 vs. control, 0.01 vs. uremic). In the in vitro study calpain activity and DNA fragmentation were markedly higher in USCM treated cells compared to CSCM (both P

Sarcoidosis is a chronic relapsing multi-systemic disorder characterized by the development of non-caseating granulomas. Granulomatous tubulo-interstitial nephritis is an uncommon manifestation of this condition. We identified 39 patients with sarcoidosis and renal disease from a single center of whom 17 patients had biopsy-proven tubulo-interstitial nephritis. They were analyzed with respect to demographic and clinical features, including response to corticosteroids and length of follow-up. They all presented with significant renal impairment. At presentation the mean+/-s.d. estimated glomerular filtration rate (eGFR) was 26.8+/-14 ml/min by modification of diet in renal disease (MDRD) equation 7. With treatment there was a significant improvement in renal function with eGFR 49.6+/-5.2 ml/min (P0.01) at 1 year, and 47.9+/-6.8 ml/min (P0.05) at the last review. The median follow-up was 84 months (range 6-284 months). Patients with chronic kidney disease (CKD) 3, the mean eGFR was 38.30+/-2.4 ml/min at presentation and 60.2+/-7.4 ml/min at 1 year (P=0.02) and in CKD 4 it improved from 19+/-2 to 38+/-6.6 ml/min at 1 year (P0.05). After the 1st year, the change in eGFR was +0.8 ml/min/year for CKD 3 and -2 ml/min/year for CKD 4 (P0.05). Three patients ceased their therapy either due to complications or poor compliance and experienced a worsening of renal function which was then reversed on re-commencing corticosteroids. Corticosteroids are effective in advanced tubulo-interstitial nephritis due to sarcoidosis. Long-term treatment is necessary to preserve renal function and to delay the onset of end-stage renal disease.

Oxidative consumption of nitric oxide: A potential mediator of uremic vascular disease. Recent data has drawn our attention to the relationship between altered biomechanical properties of the vasculature and left ventricular hypertrophy (LVH) in uremia. We have been able to show that uremia causes functional changes in the conduit vessels of rats, predating structural changes and independent of blood pressure. As nitric oxide (NO) is a potent modulator of the cardiovascular system, we studied the NO pathway in uremia. The existing data are somewhat confusing, with some suggesting up-regulation of the NO system, and others the opposite. When examined critically, however, a pattern emerges, with studies examining NO release showing increased production, whereas those examining NO bioactivity show it to be attenuated. We hypothesized that there is increased NO release, but excess consumption in uremia. Our own data on NO metabolites (NOx) in the serum of healthy young male hemodialysis patients indicate higher concentrations both pre- and post-dialysis compared to controls. As the endothelium is a potential source of NO, we cultured endothelial cells in uremic plasma. These studies demonstrated increased basal NO release from cells cultured under uremic conditions compared to controls. Furthermore, alterations in arginine metabolism appear to play a role, as there is evidence for reduced arginase activity in these cells, thereby increasing arginine availability for the NO pathway. Given the in vivo data and clinical characteristics of the uremic syndrome suggesting reduced NO bioactivity, we examined the possibility that the excess NO generated is being consumed and rendered bio-inactive. Aortae from uremic and control rats were stained for the presence of nitrotyrosine. All uremic aortae stained positively, but nitrotyrosine was not present in any control aortae.

Cells exposed to high ambient glucose concentrations are subject to increases in intracellular calcium ([Ca(2+)](i)). We therefore considered it likely that the calcium-dependent cysteine protease calpain would play a role in the development of high glucose-induced cell injury. After 3 and 24 h, high glucose concentrations (25 mM D-glucose) produced almost identical increases in the degree of necrotic cell death in kidney proximal tubular epithelial cells (LLC-PK(1)) compared to cells treated with control glucose (5 mM D-glucose). Necrotic cell death could be restricted by inhibiting the activity of calpain. High glucose-treated LLC-PK(1) cells were found to have significantly elevated [Ca(2+)](i) concentrations within 1 h, and elevated calpain activity within 2 h compared to control treated cells. The DNA nick sensor poly(ADP-ribose) polymerase (PARP) has previously been shown to be an important driver of high glucose-induced cell death, but here we found that although PARP activity was increased after 24 h, it was unaltered after 3 h. Furthermore, PARP inhibition with PJ-34 did not restrict early high glucose-induced necrosis. Using a gene knockdown strategy with small interference RNA, we found that silencing calpain was effective in reducing the degree of early high glucose-induced necrosis. We conclude that high glucose concentrations evoke an early, calpain-mediated necrosis in cultured proximal tubular cells that is PARP-independent, and precedes the previously recognized activation of apoptosis.

There is a general perception that patients with polycystic kidney disease on peritoneal dialysis have poor long-term technique survival. In order to test this opinion, we performed a retrospective analysis comparing results of 56 consecutive patients with polycystic kidney disease to 56 non-diabetic patients with bilateral small kidneys. The patient groups were all initiated on peritoneal dialysis over a 12 year period and matched for age, gender and years of end stage renal failure. After a mean follow-up period of 37 months the two groups were statistically indistinguishable in terms of mortality, kidney transplantation-censored technique survival, median death-censored technique survival, the number of patients switched permanently to hemodialysis due to technique failure and the rate of peritonitis. On Cox regression (multivariate) analysis, only the baseline serum albumin level was a significant and independent risk factor of death-censored technique failure. Our study found no difference in long term outcome of peritoneal dialysis therapy in patients with polycystic kidney disease compared to a non-diabetic matched control group.

The myogenic response in uremic hypertension. Background The constriction of resistance arteries in response to an increase in transmural pressure, the myogenic response, is thought to be an important determinant of peripheral vascular resistance and therefore of arterial blood pressure. Since raised peripheral resistance is known to occur in uremic hypertension, abnormal myogenic constriction might be responsible. We sought to assess the myogenic response of resistance arteries from the subtotal nephrectomy rat model of uremic hypertension. Methods Uremic Wistar-Kyoto (WKYU) rats, and sham-operated normotensive (WKYC) and spontaneously hypertensive (SHRC) controls were studied in parallel. Skeletal muscle arteries were mounted on a pressure myograph and allowed to develop myogenic constriction. The active internal diameter was measured at increasing lumen pressures from 20 to 200 mm Hg. Vascular smooth muscle then was relaxed in a calcium free solution containing nitroprusside, and the passive internal diameter measured at the same pressure steps. The ratio of active to passive diameter at any given pressure was used to assess the myogenic response. Results Myogenic constriction was not increased in either WKYU or SHRC compared to WKYC at pressures up to 180 mm Hg. Conclusions Increased myogenic tone is not the cause of uremic hypertension.