Background: Cystatin C has recently been proposed as an ideal marker for glomerular filtration rate (GFR). In this study, cystatin C serum levels were evaluated in comparison to serum creatinine concentrations and inulin clearances in patients with normal kidney function receiving cisplatin-based chemotherapy to assess the validity of cystatin C as an alternative endogenous marker of GFR. Methods: Blood samples for the assessment of cystatin C, creatinine and inulin clearances were collected in patients before and after application of cisplatin in a clinical trial. Overall, 41 patients were included in the study, 35 of them were eligible receiving cisplatin in two different cisplatin-based chemotherapy schedules. Results: A 21% increase of cystatin C serum levels was demonstrated in the placebo group after application of cisplatin. Analysis of inulin clearances revealed a 23% loss of inulin clearance in patients of the placebo arm. In contrast, significant changes could not be detected by analysis of serum creatinine levels. Conclusions: Cystatin C represents a more sensitive clinical marker than serum creatinine for the early assessment of GFR damage caused by cisplatin. Changes in cystatin C serum concentrations correlate well to GFR decrease as measured by inulin clearance.

Genetic polymorphisms in ERCC1 may be valuable predictors of cisplatin-induced nephrotoxicity.

Summary Background : Glucocorticoids (GC) play a major role in the attenuation of inflammation. Glucocorticoid receptor (GR) expression is an important determinant of steroid sensitivity. Aims : To investigate whether GR mRNA expression is altered in inflammatory bowel disease, and whether GR mRNA expression correlates with disease activity and may predict response to GC therapy. Methods : Mucosal biopsies were taken from 33 patients with ulcerative colitis, 21 with Crohn's disease and 11 controls. Peripheral blood mononuclear cells were isolated from 24 ulcerative colitis and 18 Crohn's disease patients and 11 controls. GR mRNA was measured by quantitative reverse transcriptase polymerase chain reaction (RT‐PCR), and correlated to endoscopic findings, clinical activity and outcome of GC therapy. In a subset of subjects GR localisation was shown by immunohistochemistry. Results : In patients with inflammatory bowel disease GR expression was not different from controls. However, GR was decreased in biopsies from ulcerative colitis patients with impaired GC response. The inhibitory subtype GRβ was expressed 100–1000 times lower than GRα. GR immunoreactivity was identified in immune and epithelial cells except for colonic crypts. Conclusion : In inflammatory bowel disease systemic and mucosal GR mRNA expression is not altered. However, in ulcerative colitis patients, low mucosal GR expression may predict the outcome of GC therapy. The low expression of GRβ challenges its role in steroid refractoriness in inflammatory bowel disease.

Renin, the key element of the renin-angiotensin-aldosterone system, is mainly produced by and stored in the juxtaglomerular cells in the kidney. These cells are situated in the media of the afferent arteriole close to the vessel pole and can transform into smooth muscle cells and vice versa. In this study, the electrophysiological properties and the molecular identity of the K + channels responsible for the resting membrane potential (∼ −60 mV) of the juxtaglomerular cells were examined. In order to increase the number of juxtaglomerular cells, afferent arterioles from NaCl-depleted rats were used, and > 90% of the afferent arterioles were renin positive at the distal end of the arteriole. Whole-cell and cell-attached single-channel patch-clamp experiments showed that juxtaglomerular cells are endowed with a strongly inwardly rectifying K + channel (Kir). The channel was highly sensitive to inhibition by Ba 2+ (inhibition constant 37 µM at 0 mV), but relatively insensitive to Cs + and, with 142 mM K + in the pipette, had a single-channel conductance of 31.5 pS. Immunocytochemical studies showed the presence of Kir2.1 but no signal for Kir2.2 in the media of the afferent arteriole. In PCR analyses using isolated juxtaglomerular cells, the mRNA for Kir2.1 and Kir2.2 was detected. Collectively, the results show that Kir2.1 is the dominant component of the channel. The current carried by these channels plays a decisive role in setting the membrane potential of juxtaglomerular cells.

Background. Adenosine is a vasoactive metabolite of ATP hydrolysis that is involved in the regulation of renal haemodynamics, tubular reabsorption and renin release. Elevated tissue levels are found under conditions of increased metabolic load, ischaemia or renal injury. Urinary adenosine excretion (E ADO ) may therefore provide a sensitive marker of renal functional impairment in allograft rejection and kidney disease. To provide a basis for evaluation of E ADO in clinical settings, we investigated, in an intra-individual, crossover clinical trial the physiological variability and regulation of E ADO in response to altered sodium and fluid balance. Methods. Twelve healthy volunteers were randomized to normal (ad libitum), low (<5 g/day) or high (supplementation of 100 mg/kg/day) sodium chloride diets for 8 days prior to assessment of renal haemodynamics and tubular function in standard clearance investigations. Following baseline periods, fluid homeostasis was altered independently by acute oral water load. E ADO was determined in 24 h urine collections and during clearance investigations. Results. Mean E ADO in humans was 3.2±0.2 mmol/ 24 h during euvolaemia and normal sodium intake. A weak correlation was found between sodium load and E ADO . In clearance experiments, variation in E ADO was <1.3-fold, despite profound alterations in sodium intake. E ADO was independent of urinary flow rate. Renal haemodynamics were not significantly altered by dietary regimen or by acute volume load. Conclusion. In summary, the physiological variability of E ADO is remarkably small in humans. We demonstrate that even profound alterations in sodium and fluid homeostasis do not significantly affect E ADO . These data provide a basis for evaluation of elevated E ADO as a marker of renal injury in various clinical settings.