[Kidney function in contrast media-enhanced imaging]. / Nierenfunktion bei kontrastmittelverstärkter Bildgebung.

BACKGROUND: The potential adverse reactions to contrast media-enhanced imaging regularly offer challenges in decision-making for nephrologists and radiologists. OBJECTIVE: The clinical pictures of contrast media-induced acute kidney injury (CI-AKI) and nephrogenic systemic fibrosis (NSF) were evaluated, which are both caused by contrast media and closely linked to the kidney function. MATERIAL AND METHODS: The literature in PubMed and Medline was searched for the terms "kidney function" and "contrast media" and complemented by our own experiences. RESULTS: While there is an ongoing re-evaluation of the clinical relevance of CI-AKI, no new cases of NSF have recently been reported under consideration of certain preventive interventions and very restricted use of gadolinium-based contrast agents. CONCLUSION: Considering the results of the latest clinical research, the potential risk of CI-AKI has been overestimated for a long time and should no longer outweigh the diagnostic benefit of contrast media-enhanced imaging. Nevertheless, the most effective prophylaxis for CI-AKI is the avoidance of unnecessary administration of contrast media.

Autophagy activation in circulating proangiogenic cells aggravates AKI in type I diabetes mellitus.

Acute kidney injury (AKI) occurs frequently in hospitals worldwide, but the therapeutic options are limited. Diabetes mellitus (DM) affects more and more people around the globe. The disease worsens the prognosis of AKI even further. In recent years, cell-based therapies have increasingly been applied in experimental AKI. The aim of the study was to utilize two established autophagy inducers for pharmacological preconditioning of so-called proangiogenic cells (PACs) in PAC treatment of diabetic AKI. Insulin-dependent DM was induced in male C57/Bl6N mice by intraperitoneal injections of streptozotocine. Six weeks later, animals underwent bilateral renal ischemia for 45 min, followed by intravenous injections of either native or zVAD (benzyloxycarbonyl-Val-Ala-Asp-fluoro-methylketone)- or Z-Leu-Leu-Leu-al (MG132)-pretreated syngeneic murine PACs. Mice were analyzed 48 h (short term) and 6 wk (long term) later, respectively. DM worsened postischemic AKI, and PAC preconditioning with zVAD and MG132 resulted in a further decline of excretory kidney function. Injection of native PACs reduced fibrosis in nondiabetic mice, but cell preconditioning promoted interstitial matrix accumulation significantly. Both substances aggravated endothelial-to-mesenchymal transition (EndoMT) under diabetic conditions; these effects occurred either exclusively in the short (zVAD) or in the short and long term (MG132). Preconditioned cells stimulated the autophagocytic flux in intrarenal endothelial cells, and all experimental groups displayed increased endothelial abundances of senescence-associated ß-galactosidase, a marker of premature cell senescence. Pharmacological autophagy activation may not serve as an effective strategy for improving PAC competence in diabetic AKI in general. On the contrary, several outcome parameters (excretory function, fibrosis, EndoMT) may even be worsened.

Postischemic microvasculopathy and endothelial progenitor cell-based therapy in ischemic AKI: update and perspectives.

Acute kidney injury (AKI) dramatically increases mortality of hospitalized patients. Incidences have been increased in recent years. The most frequent cause is transient renal hypoperfusion or ischemia which induces significant tubular cell dysfunction/damage. In addition, two further events take place: interstitial inflammation and microvasculopathy (MV). The latter evolves within minutes to hours postischemia and may result in permanent deterioration of the peritubular capillary network, ultimately increasing the risk for chronic kidney disease (CKD) in the long term. In recent years, our understanding of the molecular/cellular processes responsible for acute and sustained microvasculopathy has increasingly been expanded. The methodical approaches for visualizing impaired peritubular blood flow and increased vascular permeability have been optimized, even allowing the depiction of tissue abnormalities in a three-dimensional manner. In addition, endothelial dysfunction, a hallmark of MV, has increasingly been recognized as an inductor of both vascular malfunction and interstitial inflammation. In this regard, so-called regulated necrosis of the endothelium could potentially play a role in postischemic inflammation. Endothelial progenitor cells (EPCs), represented by at least two major subpopulations, have been shown to promote vascular repair in experimental AKI, not only in the short but also in the long term. The discussion about the true biology of the cells continues. It has been proposed that early EPCs are most likely myelomonocytic in nature, and thus they may simply be termed proangiogenic cells (PACs). Nevertheless, they reliably protect certain types of tissues/organs from ischemia-induced damage, mostly by modulating the perivascular microenvironment in an indirect manner. The aim of the present review is to summarize the current knowledge on postischemic MV and EPC-mediated renal repair.

Decreased IL-10(+) regulatory B cells (Bregs) in lupus nephritis patients.

OBJECTIVES: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell-dependent autoantibody production. Recently, a new B-cell subset was discovered that has a regulatory capacity. The aim of this study was to analyse regulatory B cells (Bregs) in SLE patients. METHOD: Peripheral mononuclear blood cells (PBMCs) of 34 SLE patients fulfilling the American College of Rheumatology (ACR) criteria for SLE and 21 healthy controls (HC) were included. PBMCs were stained for CD19, CD24, and CD38 and analysed by flow cytometry. In vitro stimulated PBMCs with CpG and restimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin were investigated for IL-10(+) Bregs . RESULTS: The percentages of circulating CD19(+)CD24(hi)CD38(hi) cells in HC were not different those in from SLE patients. The percentages of IL-10(+) Bregs were significantly decreased in SLE patients, in particular those with lupus nephritis (LN), compared to HC. The proportion was independent of disease activity. CONCLUSIONS: This is the first study to demonstrate a decrease in IL-10-producing B cells in LN patients compared to HC, reflecting an impaired regulatory function.

[Acute kidney injury : A clinical syndrome]. / Akutes Nierenversagen : Ein klinisches Syndrom.

Acute kidney injury (AKI) is a clinical syndrome occurring in the context of multiple and diverse disease entities. Although the term AKI implies renal damage as well as functional impairment or a combination of both, diagnosis is solely based on the functional parameters serum creatinine and urine output. Independent of the underlying disease and even assuming full recovery of renal function, AKI is associated with increased morbidity and mortality not only during the acute situation, but also long term. Awareness of the individual risk profile of each patient and the variety of causes and clinical manifestations of AKI is pivotal for prophylaxis, diagnosis, and therapy. The complexity of the clinical syndrome in the context of sepsis, solid organ transplantation, malignancy, and autoimmune diseases requires differentiated diagnostic and therapeutic approaches and interdisciplinary care.

Increased percentages of PD-1 on CD4+ T cells is associated with higher INF-γ production and altered IL-17 production in patients with systemic lupus erythematosus.

OBJECTIVES: Programmed death (PD)-1 is a cell death receptor that, upon stimulation, leads to apoptosis. Previous studies have shown alteration of PD-1 expression on T cells and PD-1 genes in patients with systemic lupus erythematosus (SLE). The aim of this study was to assess the expression of this receptor on effector T cells in patients with SLE. METHOD: In this study we enrolled 32 SLE patients and 31 healthy controls. T cells from peripheral blood were analysed by flow cytometry for the expression of PD-1. Interferon (IFN)-γ and interleukin (IL)-17-producing cells were investigated for the expression of this co-stimulatory marker. RESULTS: Percentages of CD4(+) T cells expressing PD-1 were significantly increased in patients with SLE compared to healthy controls. The percentage of PD-1 expression was correlated with the production of INF-γ (r = 0.83, p < 0.0001). We also investigated the production of IL-17 by PD-1(+) CD3(+) T cells. Inactive patients (3.2 ± 1.2% vs. 5.9 ± 3.5%, p = 0.002) and patients without lupus nephritis (LN) (3.2 ± 1.5% vs. 5.9 ± 3.5%, p = 0.005) showed lower levels of IL-17 compared to healthy controls. CONCLUSION: We have demonstrated increased expression of PD-1 on CD4(+) T cells in SLE patients and an association between PD-1 expression on CD4(+) T cells and IFN-γ expression on CD3(+) T cells. We have also shown that there is an altered subset of PD-1(+) T cells in inactive patients and patients without LN producing lower amounts of IL-17.

Cyclosporin but not everolimus inhibits chemokine receptor expression on CD4+ T cell subsets circulating in the peripheral blood of renal transplant recipients.

The peripheral chemokine receptors chemokine receptor 3 (CXCR3) and CC chemokine receptor 5 (CCR5) have been reported to be associated with allograft rejection. The impact of the expression of immunosuppressive drugs on peripherally circulating CD4(+) T cell subsets after renal transplantation is unknown. Expression of CXCR3 and CCR5 was investigated by flow cytometry in 20 renal allograft recipients participating in a prospective, randomized trial (NCT00514514). Initial immunosuppression consisted of basiliximab, cyclosporin A (CsA), mycophenolate sodium and corticosteroids. After 3 months, patients were treated either with CsA, mycophenolate sodium (MPA) plus corticosteroids (n = 6), CsA and everolimus plus corticosteroids (n =8) or CsA-free (CsA(free)) receiving everolimus, MPA and corticosteroids (n = 6). After initial reduction of CD4(+) forkhead box protein 3 (FoxP3)(+) and CD4(+) CD25(hi) FoxP3(+) regulatory T cells (T(regs)) (P < 0.05; P < 0.01), 3-month post-transplant percentages of T(regs) were reconstituted in CsA(free) and CsA(lo) arms compared to CsA(reg) 12 months post transplant. Expression of CCR5 and CXCR3 on CD4(+) FoxP3(+) and CD4(+) FoxP3(-) T cells 12 months post transplant was increased in CsA(free) versus CsA(reg). Increase in CCR5(+) CXCR3(+) co-expressing CD4(+) FoxP3(-) cells between 3 and 12 months correlated negatively with the glomerular filtration rate (GFR) slope/year [modification of diet in renal disease (MDRD); r = -0.59, P < 0.01]. CsA, but not everolimus, inhibits both T(reg) development and expression of CXCR3 and CCR5 on CD4(+) T cell subsets. Increase in CCR5(+) CXCR3(+) co-expressing CD4(+) FoxP3(-) T cells is associated with early loss in allograft function.

Peripherally circulating CD4⁺ FOXP3⁺ CXCR3⁺ T regulatory cells correlate with renal allograft function.

Peripheral immunoregulation depends on T regulatory cell trafficking into the allograft to modulate the local alloresponse. Little is known about the relevance of trafficking receptors for Tregs after solid organ transplantation in humans. In this study, expression of the peripheral chemokine receptors CXCR3 and CCR5 on CD4⁺ FOXP3⁺ Treg cells was analysed and correlated with allograft function in renal transplant recipients. Flow cytometry analysis of peripheral blood mononuclear cells of 54 renal transplant recipients receiving a calcineurin inhibitor-based immunosuppression was performed for CD4, CD25, FOXP3, CXCR3 and CCR5 within the first 18 months post-transplantation. Correlation analysis of chemokine receptor expression and glomerular filtration rate as calculated by MDRD (eGFR) was performed. Expression of the peripheral homing receptors CXCR3 (r = 0.44, P < 0.05) and CCR5 (r = 0.45, P < 0.05) on FOXP3⁺ Tregs correlated with renal allograft function (eGFR) in patients receiving tacrolimus (n = 28), but not cyclosporine A (CsA) (n = 26). CsA but not tacrolimus reduced surface expression of CXCR3 on FOXP3⁺ Tregs in renal transplant recipients as correlated to trough levels (r = -0.42, P < 0.05). In contrast to CD4⁺ CXCR3⁺ CD25(lo) T cells, flow-sorted CD4⁺ CXCR3⁺ CD25(hi) Tregs isolated from healthy individuals did not produce IFNγ or IL-17 ex vivo and expressed high levels of GARP mRNA both at baseline as well as after TCR activation indicating functional regulatory activity. Expression of the peripheral trafficking receptors CXCR3 and CCR5 on FOXP3⁺ Tregs is associated with renal allograft function. These results suggest that Treg trafficking may also depend on the interaction of CXCR3 or CCR5 and their respective ligands.

[Mobile applications and management of hypertension: possibilities, problems and perspectives]. / Mobilapplikationen und Management der Hypertonie: Möglichkeiten, Probleme und Perspektiven.

Via the internet smartphones allow the download of applications ("Apps") that can address various requirements of daily life. These technical advances create new opportunities to better meet needs of patients suffering from hypertension. This may apply particularly for medication adherence, blood pressure control and lifestyle-changing activities. At the moment younger users in particular are interested in such technology. From other clinical contexts it is known that text messages via cell phones improve medication adherence. A combination of a smartphone and a blood pressure measurement device with the possibility to electronically collect data is promising as the quality of data may improve. Technology interventions by mobile applications that are supported by education or an additional intervention demonstrate a beneficial impact for the reduction of physical inactivity and/or overweight and obesity. However, it is not clear what parts of the technology or interventions are effective. For future developments it will be important to reduce costs and better meet hardware and software requirements of elderly users.

Impact of renal failure on metabolic bone parameters in a vitamin D-deficient patient cohort.

INTRODUCTION: Chronic renal failure is associated with major changes in bone metabolism, but studies evaluating bone metabolism with mild or moderate renal failure are rare. Moreover, the study populations were often heterogenous and/or patients were pretreated with calcium and vitamin-D preparations. Therefore, we prospectively evaluated metabolic bone parameters in patients with renal insufficiency (Stage 1 - 4) on their first visit to outpatient nephrologists. PATIENTS AND METHODS: 285 patients were prospectively evaluated regarding renal function, serum phosphorous, plasma parathyroid hormone (PTH), serum 25-OH-vitamin-D and serum bone specific alkaline phosphatase (BAP) concentrations. Patients were subdivided according to the stages of chronic kidney disease. RESULTS: Hypocalcemia occurred in only 10% of patients in Stage 4, whereas serum phosphorous was elevated at the same stage in 40% of the patients. PTH increased from Stage 1 to 4 continually with a high prevalence of elevated PTH levels (> 65 pg/ml) in Stage 1: 44%; Stage 4: 84%. Serum 25-OH-vitamin-D levels were very low irrespective of renal function: < 15 ng/dl, i.e., 37.5 nmol/l in 70% of all patients. 25-OH-D was negatively correlated with PTH (r = 0.3, p < 0.0002). BAP was within the normal range in all stages but with a high prevalence of BAP values < 7.5 ng/ml in up to 25% in Stage 4. Only 6.5% of patients had features of classical renal hyperparathyroidism. Nearly 20% had low BAP levels in the presence of normal (9.5%) or increased (9.6%) PTH levels. CONCLUSION: This study demonstrates a high prevalence of hyperphosphatemia in patients with moderate renal failure. Hyperparathyroidism was present even in earlier stages and was aggravated by a high prevalence of vitamin D deficiency. However, also in the presence of elevated PTH levels, there is indication of low bone turnover as evidenced by low BAP levels, suggesting adynamic bone disease.

The German registry for nephrogenic systemic fibrosis: findings from 23 patients.

BACKGROUND AND AIM: Nephrogenic systemic fibrosis (NSF) is a highly debilitating disorder primarily affecting the skin, but also other organ compartments. So far, it has only occurred in patients suffering from acute or chronic renal failure, with almost all of them having been exposed to gadolinium-based contrast agents (GBCA). The NSF registry was initiated on behalf of the German Society of Nephrology. The aim was to analyze the development, risk factors and clinical course of patients suffering from NSF. PATIENTS AND METHODS: Between July 2007 and July 2009, 23 patients were registered (12/23 (52,2%) male and 11/23 (47,8%) female). Onset of NSF symptoms was between 2002 and 2008, with a maximum of 8 cases in 2005. Since January 2008 no patient with a new onset of NSF has been reported. On all patients nuclear magnetic resonance procedures were performed between 1 day and 3 years (median 30 days) before the onset of symptoms ("index procedure"). At the time of the index procedure 21/23 (91,3%) patients required dialysis, 15/22 patients (68,2%) showed signs and symptoms of atherosclerosis and 17/20 (76,5%) of inflammation. 22/23 patients remained in chronic kidney disease stage 5D. Upper and lower extremities were affected in 18/23 (78,3%) patients; 20/23 (87%) developed joint contractures. RESULTS: Our data confirm previous observations that NSF is associated with impaired renal function and the application of GBCA. In individual cases the interval between the index procedure and the onset of symptoms lasted years. CONCLUSION: The incidence of NSF has decreased rapidly within the past 4 years. This could be due to general awareness within the medical community and the application of macrocyclic chelates.

Pulse wave velocity predicts mortality in renal transplant patients.

BACKGROUND: measuring arterial stiffness using pulse wave velocity (PWV) has become an important tool to assess vascular function and cardiovascular mortality. For subject with hypertension, end-stage renal disease and diabetes, PWV has been shown to predict cardiovascular and all-cause mortality. We hypothesize that PWV would also predict mortality in subjects who have undergone kidney transplantation. METHODS: a cohort of 330 patients with renal transplantation was studied with a mean age at entry 51.4 ± 0.75 years. Mean follow-up was 3.8 years (± 0.7 years); 16 deaths occurred during follow-up. At entry, together with standard clinical and biochemical parameters, PWV was determined from pressure tracing over carotid and femoral arteries. RESULTS: with increasing PWV, there was a significant increase in age, systolic blood pressure and pulse pressure. In addition, subjects with higher PWV also exhibited more frequently the presence of coronary heart disease. On the basis of Cox analyses, PWV and systolic blood pressure emerged as predictors of all-cause mortality. CONCLUSION: these results provide evidence that PWV is a strong predictor of all-cause mortality in the population of renal transplant recipients.

How does late nephrological co-management impact chronic kidney disease? - an observational study.

AIMS: To assess the impact of late referral (LR) for nephrological co-management compared with early referral (ER) on morbidity and mortality in chronic kidney disease (CKD) and to identify individual factors associated with higher mortality in LR, correcting for lead-time and immortal time bias. PATIENTS AND METHODS: Retrospective observational study comparing 46 LR patients with 103 ER patients. The quality of CKD management was assessed by measures to prevent CKD progression and to modify CKD complications and cardiovascular risk factors according to current guidelines. One-year mortality of LR and ER was compared and factors associated with mortality were identified. Analysis was performed with equivalent GFR (glomerular filtration rate) of ER and LR at baseline to correct for lead-time and immortal time bias. RESULTS: Late referral was associated with inferior control of most risk factors for CKD progression, CKD complications and cardiovascular risk factors. In particular, glycaemic control, the use of angiotensin converting enzyme inhibitors and angiotensin-2-receptor blockers in diabetic nephropathy or proteinuria, the control of nutritional and volume status were inferior in LR. One-year mortality was significantly higher in LR (RR 5.9 (95% CI 1.5-19.6); p < 0.01). Inadequate control of blood pressure, anaemia, volume status, malnutrition and emergency initial dialysis, but not LR itself were independently associated with mortality. CONCLUSIONS: Late referral was associated with a substantially lower survival after correction for lead-time and immortal time bias and with inferior control of most risk factors for CKD progression, complications and cardiovascular risk factors. CKD patients may particularly profit from adequate control of blood pressure, anaemia, nutritional and volume status, and avoidance of emergency initial dialysis as these factors may predominately contribute to survival.

Lack of de novo hepatitis C virus infections and absence of nosocomial transmissions of GB virus C in a large cohort of German haemodialysis patients.

To determine the prevalence and incidence of hepatitis C virus (HCV) infections among haemodialysis patients, a large prospective multicentre trial was conducted in the German Federal State of North Rhine-Westphalia. Sera obtained from the recruited patients in two separate sampling rounds run 1 year apart were analysed for both anti-HCV antibodies and HCV RNA. HCV RNA positive samples were also genotyped by direct sequencing of an HCV core fragment. In the first and second rounds, 150 (5.2%) of 2909 and 114 (5.4%) of 2100 patients were anti-HCV positive, respectively, and 4% of individuals were viraemic. Evaluation of potential risk factors in a case-control study indicated that the factors 'foreign country of birth', 'blood transfusions given before 1991' and 'duration of treatment on haemodialysis' were associated with the risk of HCV infection. Among the 2100 patients of whom 'paired' serum samples from both rounds were available for testing, not a single 'de novo' HCV infection could be recorded. The fact that in a subset of about 20% of these patients no nosocomial GB virus C (GBV-C) transmission occurred during the observational period suggests that the lack of HCV seroconversions was not only attributable to the isolation of HCV-infected patients but also to the strict adherence to so-called universal hygienic precautions for infection control maintained in the participating dialysis centres.

Gliquidone therapy of new-onset diabetes mellitus after kidney transplantation.

BACKGROUND: New-onset diabetes mellitus (NODM) in renal transplant recipients is a complication associated with an increased long-term morbidity and mortality. However, classic sulphonylureas have not been studied in transplanted patients to date. The purpose of this study was to investigate the use of gliquidone in NODM after renal transplantation. METHODS: 47 Caucasian patients with NODM received gliquidone therapy (dose range 15 - 105 mg/d) and were followed for at least 6 months. Controls receiving rosiglitazone (n = 28) were chosen for comparison. Successful treatment was defined as a significant improvement of fasting blood glucose (FBG) concentrations, and HbA1c < 7% in the absence of glucosuria, and without the need for further antidiabetic agents. RESULTS: 29 of the 47 patients were successfully treated with gliquidone. Mean FBG improved from 154 +/- 62 mg/dl to 120 +/- 30 mg/dl (p = 0.002). The success rate was similar in both groups (62 vs. 71%, p = 0.39). In 4 patients the initial daily dose of gliquidone had to be decreased due to symptoms of hypoglycemia. Pretreatment with other oral antidiabetics could be identified as a negative prognostic factor. CONCLUSIONS: The data of our retrospective database study suggest that gliquidone is a safe and effective treatment option for NODM. In comparison to rosiglitazone, gliquidone has shown similar efficacy.

Contrast media induced nephropathy: definition, incidence, outcome, pathophysiology, risk factors and prevention.

Iodanated contrast media related nephrotoxicity is a common phenomenon, which has been known for over five decades now and is widely termed contrast media induced nephropathy (CIN). CIN is one of the most common reasons for hospital-acquired acute kidney injury. The incidence of CIN varies widely, depending on the diagnostic criteria and on the individual risk factors for CIN. CIN is associated with a significant increase in mortality. The clinical features and the histological morphology of CIN are well characterized, whereas the precise mechanisms of renal injury during CIN are not clear. Most likely a combination of different pathomechanisms is involved: contrast media induced reduction of renal perfusion, reduction of tubular flow and direct tubular toxicity leading to a decrease of glomerular filtration rate. Several risk factors for the development of CIN exist, which can be divided into patient related and non-patient related risk factors as well as in modifiable and non-modifiable risk factors. Among them pre-existing renal failure is the most critical parameter. There is no effective treatment for CIN, however, because the development of CIN is predictable, preventional strategies for CIN have been developed. They can be divided into four different categories: volume expansion before, during and after contrast media administration, pharmacological strategies to prevent reduction of renal perfusion, reduction of tubular flow and direct tubular toxicity, renal replacement therapy, and selection of contrast media. Among them, volume expansion is the most critical measure for reducing CIN and should be used in all patients undergoing contrast media procedures.

Effect of ABO incompatibility on T-cell flow cytometry cross-match results prior to living donor kidney transplantation.

BACKGROUND: Due to its high sensitivity, the flow cytometry cross-match (FCXM) has been described as valuable tool for identifying an optimal donor. We here focused on the impact of ABO incompatibility on FCXM results. METHODS: We analyzed 29 ABO incompatible and 89 ABO compatible donor-recipient pairs (73 and 175 datasets, respectively) prior to living donor kidney transplantation. In all patients, lymphocytotoxic cross-matches for B and T cells were negative. RESULTS: Recipients with blood group O (A to O and B to O) displayed significantly (P < 0.05) higher T-FCXM results than those with blood group A and B (A to B, B to A and AB to A), respectively. Donor-specific T-FCXM responses (ΔMFI values) were significantly higher (P < 0.05) in ABO incompatible vs. compatible pairs (ABO incompatible recipients with blood group O: 32 ± 6; with blood group A: 19 ± 7; with blood group B: 7 ± 4; recipients with ABO compatibility: 3 ± 2, respectively, data represent mean ± SEM). Consistent with the T-FCXM results donor-specific isohemagglutinins (IgG titers) were significantly higher in recipients with blood group O vs. A, both prior to rituximab treatment and plasmapheresis/immune adsorption (P = 0.004) and immediately prior to transplantation, i.e., after rituximab and antibody-depleting therapies (P = 0.04). CONCLUSIONS: ABO incompatibility was associated with higher T-FCXM responses, especially in recipients with blood group O. This finding has major impact on the interpretation of flow cross-match results. Current cut-off values need to be reassessed in the ABO incompatible setting. © 2016 International Clinical Cytometry Society.

Evidence for role of cytosolic free calcium in hypoxia-induced proximal tubule injury.

The role of cytosolic free Ca2+ ([Ca2+]i) in hypoxic injury was investigated in rat proximal tubules. [Ca2+]i was measured using fura-2 and cell injury was estimated with propidium iodide (PI) in individual tubules using video imaging fluorescence microscopy. [Ca2+]i increased from approximately 170 to approximately 390 nM during 5 min of hypoxia. This increase preceded detectable cell injury as assessed by PI and was reversible with reoxygenation. 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA; 100 microM) reduced [Ca2+]i under basal conditions (approximately 80 nM) and during hypoxia (approximately 120 nM) and significantly attenuated hypoxic injury. When [Ca2+]i and hypoxic cell injury were studied concurrently in the same individual tubules, the 10 min [Ca2+]i rise correlated significantly with subsequent cell damage observed at 20 min. 2 mM glycine did not block the rise in [Ca2+]i, yet protected the tubules from hypoxic injury. These results indicate that in rat proximal tubules, hypoxia induces an increase of [Ca2+]i which occurs before cell damage. The protective effect of BAPTA supports a role for [Ca2+]i in the initiation of hypoxic proximal tubule injury. The glycine results, however, implicate calcium-independent mechanisms of injury and/or blockade of calcium-mediated processes of injury such as activation of phospholipases or proteases.

The influence of continuous venovenous haemodialysis on the pharmacokinetics of multiple oral moxifloxacin administration to patients with severe renal dysfunction.

AIM: We investigated single dose and steady-state pharmacokinetics of moxifloxacin in eight venovenous haemodialysis patients. METHODS: Plasma, dialysate and urine pharmacokinetic parameters for moxifloxacin and its main metabolites were calculated after single and multiple (7 days) dosing with 400 mg day(-1). RESULTS: Moxifloxacin pharmacokinetics after a single dose and at steady state (multidose day 7) were comparable in patients with impaired renal function and healthy subjects (geometric mean/%CV AUC mg l(-1) h single dose 37.0/24.3 in haemodialysis patients vs. 29.8/22.6 in healthy subjects, 95% CI for ratio of haemodialysis patients to healthy subjects 99.34%, 154.60%; steady state 40.4/29.1 haemodialysis patients vs. 33.9/20.1 in healthy subjects, 95% CI for ratio of haemodialysis patients to healthy subjects 90/39%, 156.93%). In haemodialysis patients plasma concentrations of moxifloxacin at steady-state were elevated compared with those after a single 400 mg dose (AUC mg l(-1) h, geometric mean/%CV, 40.4/29.1) compared with 37.0/24.3; 95% CI for ratio of steady-state to single dose 87.29%, 136.52%, as were concentrations of metabolite M1 3.21/34.6 compared with 2.02/45.3, 95% CI for ratio of steady state to single dose 14.21%, 175.07%. Haemodialysis cleared about 9% of the dose as unchanged moxifloxacin. CONCLUSIONS: No dose adjustments are required for venovenous haemodialysis patients on oral moxifloxacin therapy.