[Acute kidney injury]. / Die akute Nierenschädigung.

Acute kidney injury plays a pivotal role in intensive care medicine and exerts crucial adverse effects on the course of the disease and overall prognosis of the critically ill patient. Intensive renal support, including initiation of earlier dialysis or maximal uremic toxin removal by higher dosage and frequency of renal replacement therapy, and individualized selection of modality were not able to decrease excessive mortality in this population. Systemic acute inflammation, mediated, at least in part, by cytokines, and not secondary uremic side effects, seems to have a major impact on nonrenal organ damage. Assessment of short-term outcome in critically ill patients who develop acute kidney injury may underestimate the true burden of disease. The overall survival at 5 years in patients discharged alive after severe acute kidney injury necessitating renal replacement therapy is only 20-30%, comparable to cancer patients. In addition, acute renal damage was identified as an independent risk factor for progression of chronic renal insufficiency. Current research focuses on strategies for the prevention of acute kidney injury and on the establishment of effective biomarkers for the early recognition and accurate diagnosis of subclinical renal damage.

Nasal carriage of meticillin resistant Staphylococcus aureus: the prevalence, patients at risk and the effect of elimination on outcomes among outclinic haemodialysis patients.

OBJECTIVE: Haemodialysis (HD) patients with meticillin-resistant Staphylococcus aureus (MRSA) infections face high morbidity and mortality. Nasal carriage of Staphylococcus aureus is known to play an important role as an endogenous source for HD-access-related infections that contribute significantly to morbidity, mortality and cost of end-stage renal disease (ESRD) management. This prospective investigation in regular out-clinic haemodialysis patients was undertaken to estimate the prevalence of S.aureus nasal carriage, to define patient groups at risk and to evaluate the effect of elimination on outcomes among outclinic haemodialysis patients. METHODS: 136 HD patients without signs of overt clinical infection (48 women, 88 men, age 22-88 years) were screened at least twice for the nasal carriage for meticillin-susceptible SA (MSSA) or meticillin-resistant SA (MRSA). Nasal carriage of S. aureus was related to demographic (age, gender, duration on HD), comorbidity (diabetes, malignancy) and exposure to health care (dialysis staff, hospitalisation). Nasal carriers for MRSA received standardized mupirocin therapy and were followed up for elimination and infections for 1 year. RESULTS: The prevalence of nasal carriage for staphylococcus aureus was 53 % (41 % MSSA, 12 % MRSA). Compared with patients showing no colonization or with MSSA carriers, the 16 patients with nasal carriage for MRSA were older and more likely to have acquired the bacteria while hospitalised. Genotyping of MRSA isolates revealed different strains in patients and care-providers. Mupirocin eliminated MRSA in all patients, none of these patients experienced an infection caused by staphylococcus aureus, confirming the known value of MRSA elimination from other studies. CONCLUSIONS: Elderly patients hospitalised for surgery constitute a high risk group for nasal carriage for MRSA. Early diagnosis may help prevent clinically relevant infection. Elimination of colonization by mupirocin appears to be an attractive preventive strategy.

Ultrapure dialysis fluid lowers the cardiovascular morbidity in patients on maintenance hemodialysis by reducing continuous microinflammation.

The aims of our prospective 3-year investigation were (1) to clarify whether high C-reactive protein (CRP) levels are an intermittent or a continuous phenomenon in individual hemodialysis patients and (2) to evaluate a possible relationship between ultrapure dialysis fluid associated CRP levels and an increased prevalence of atherosclerosis in a group of 60 hemodialysis patients treated either with conventional (n = 38) or on-line-produced ultrapure dialysis fluid (n = 22). Primary end points of the study were angiographically confirmed cerebrovascular, cardiovascular, or peripheral vascular events. Measurements of the CRP levels were done every 3 months using a highly sensitive assay. The CRP levels were normal (<0.5 mg/dl) in 45 patients and raised in 15 patients at the time of recruitment. In 87% of the patients with normal CRP levels, ultrapure dialysis fluid was used. The CRP levels measured at recruitment and at various time points thereafter did not differ significantly within patient groups. However, patients with increased CRP concentrations experienced significantly more vascular events as compared with patients with normal CRP levels (11 events vs. 1 event; p < 0.001). The data indicate that continuous induction of acute-phase proteins represents a nontraditional vascular risk factor contributing to the development and progression of atherosclerosis in dialysis patients. Ultrapure dialysis fluid lowers cardiovascular morbidity by preventing/reducing chronic microinflammation.

Reversible MRI changes in a patient with uremic encephalopathy.

A 19-year-old patient on chronic ambulatory peritoneal dialysis experienced severe neurologic disturbances caused by uremia. Increased signal intensity was seen bilaterally in the cortical and subcortical areas of the occipital and parietal lobe on cranial magnetic resonance imaging (MRI). Insufficient peritoneal dialysis efficacy was documented and the patient was switched from peritoneal to hemodialysis. Cranial MRI indicated a marked regression of the lesions to nearly normal, confirming the diagnosis of uremic encephalopathy.

Effect of high glucose concentration on the synthesis of monocyte chemoattractant protein-1 in human peritoneal mesothelial cells: involvement of protein kinase C.

Human peritoneal mesothelial cells (HMC) contribute to the activation and control of inflammatory processes in the peritoneum by their potential to produce various inflammatory mediators. The present study was designed to assess the effect of glucose, the osmotic active compound in most commercially available peritoneal dialysis fluids, on the synthesis of the C-C chemokine monocyte chemoattractant protein-1 (MCP-1) in cultured HMC. The MCP-1 concentration in the cell supernatants was determined by enzyme-linked immunosorbent assay and the MCP-1 mRNA expression was examined using Northern blot analysis. Incubation of HMC with glucose (30-120 mM) resulted in a time- and concentration-dependent increase in MCP-1 protein secretion and mRNA expression. After 24 h the MCP-1 synthesis was increased from 2.8 +/- 0.46 to 4.2 +/- 0.32 ng/10(5) cells (n = 5, p < 0.05) in HMC treated with 60 mM glucose. In contrast, osmotic control media containing either the metabolically inert monosaccharide mannitol or NaCl did not influence MCP-1 production. The stimulating effect of high glucose on MCP-1 expression in HMC was mimicked by activation of protein kinase C (PKC) with the phorbol ester PMA (20 nM). Coincubation of the cells with glucose and the specific PKC inhibitor Ro 31-8220 completely blunted glucose-mediated MCP-1 expression. In summary, our results indicate that glucose induces MCP-1 synthesis by a PKC-dependent pathway. Since osmotic control media did not increase MCP-1 release, it is suggested that the effect of glucose is mainly related to metabolism and not to hyperosmolarity. These data may in part explain elevated steady-state levels of MCP-1 found in the dialysis effluent of continuous ambulatory peritoneal dialysis patients.

Heat-killed microorganisms induce PAI-1 expression in human peritoneal mesothelial cells: role of interleukin-1alpha.

Human peritoneal mesothelial cells (HMCs) have a critical role in maintaining the intraperitoneal balance between fibrinolysis and coagulation by expressing the fibrinolytic enzyme, tissue-type plasminogen activator (tPA), as well as a specific plasminogen activator inhibitor (type 1; PAI-1). During bacterial peritonitis, the balance between intraperitoneal generation and degradation of fibrin is disturbed. As a consequence, severe peritoneal damage occurs, which is one of the leading causes of patient dropout from continuous ambulatory peritoneal dialysis (CAPD) therapy. Cultured HMCs isolated from omental biopsy specimens were used to study the effect of heat-killed strains (2 x 10(8)/mL) of Staphylococcus aureus, Staphylococcus epidermidis, and Escherichia coli on the synthesis of tPA and PAI-1. Conditioned media were obtained by incubating cells with the different bacterial strains. tPA and PAI-1 antigen concentrations were measured in the cell supernatants by enzyme-linked immunosorbent assay. Each of the three heat-killed microorganisms induced a time-dependent increase in PAI-1 synthesis. After a 48-hour incubation period, the strongest effect was seen in the presence of S aureus (3.5-fold versus control), followed by S epidermidis (2.5-fold versus control) and E coli (1.5-fold versus control). Under the same conditions, tPA antigen levels did not change after exposure to S aureus or E coli, whereas the addition of S epidermidis resulted in enhanced tPA antigen production (2-fold versus control). The increase in PAI-1 synthesis in the presence of the heat-killed microorganisms was preceded by similar changes in interleukin-1alpha (IL-1alpha) levels. Inhibiting the activity of IL-1alpha with a neutralizing antibody significantly reduced bacterial-induced PAI-1 production. Our results indicate that the fibrinolytic imbalance during bacterial peritonitis depends on the bacterial species. The increase in PAI-1 synthesis, not the decrease in the production of tPA, alters mesothelial fibrinolytic activity. Because the increase in PAI-1 expression is significantly quenched by blocking the activity of IL-1alpha, the mesothelial release of this cytokine is involved in bacterial-induced changes in the fibrinolytic system.

Impact of humoral alloreactivity early after transplantation on the long-term survival of renal allografts.

BACKGROUND: The contribution of humoral alloreactivity to the rejection of renal allografts is not well defined because humoral antigraft reactions are not easily detectable in transplant biopsies, and serial measurements of circulating allo-antibodies in the post-transplantation period are not routinely performed. We have developed diagnostic techniques that improve the assessment of humoral alloreactivity in vivo and in vitro. METHODS: Humoral alloreactivity in transplant biopsies derived from 218 single kidney grafts was detected by assessing the deposition of complement fragment C4d in interstitial capillaries. Circulating alloantibodies were determined in corresponding serum samples by flow cytometry using lymphoblastoid cell lines of donor DR-type as target cells and by a conventional microcytotoxicity test. The impact of capillary C4d and other selected variables on renal graft survival was calculated by univariate and multivariate analysis. RESULTS: Capillary C4d, present in 46% of biopsies from first grafts and 72% of regrafts, is related to circulating alloantibodies. Grafts with capillary C4d have a markedly shorter survival than grafts without capillary C4d (50% graft survival, 4 vs. 8 years, P = 0.0001). Among several risk factors, capillary C4d is the strongest predictor of subsequent graft loss in a multivariate analysis (relative risk, 2.1, 95% CI, 1.4 to 3.1). Humoral alloreactivity detectable within six months after transplantation has a much stronger impact on graft survival than alloreactivity detected beyond this period. CONCLUSIONS: Humoral alloreactivity, manifested by the capillary deposition of complement C4d in about 50% of biopsied renal grafts, exerts a strong impact on graft survival when it operates within six months after transplantation.

Early renal graft dysfunction. The role of preformed antibodies to DR-typed lymphoblastoid cell lines.

Diverse pathogenetic factors may lead to the complex syndrome of early graft dysfunction, an important determinant of later renal graft outcome. That humoral factors could play a prominent role in the development of the syndrome was suggested by the capillary deposition of complement fragment C4d in about 50% of graft biopsies. This study investigates whether the presumed classical activation of complement is derived from preformed antibodies that would possibly react against endothelial HLA-class II molecules. Such antibodies were detectable by flow cytometry using a representative collection of 11 DR-typed lymphoblastoid cell lines (LCL) as targets. Simultaneous discrimination between complement-activating and -nonactivating antibodies was achieved by two-color FACS analysis. Using this method, 44 out of 86 pretransplant serum samples from recipients with early dysfunction showed reactivity against LCL (18 complement-activating, 14 nonactivating, 12 complement-activating non-IgG). Conventional panel-reactivity was observed in 20 sera only (14 also LCL-reactive). Evaluation of corresponding graft biopsies revealed that capillary C4d was associated with LCL (P = 0.018) and panel reactivity (P = 0.015) alone and in combination (P = 0.001; Pearson's chi-square test). Thirteen subsequent graft losses within one year were observed in the LCL-reactive group as compared with seven losses in the nonreactive group (panel-reactive: 7; nonreactive: 13). Thus, measurement of LCL-reactive antibodies in prospective transplant recipients improves the assessment of an individual immunological risk. The results further demonstrate that performed antibodies do not simply reflect the enhanced overall immune reactivity of certain recipients but rather act locally in vivo, thus emphasizing the role of humoral factors in the development of early graft dysfunction.