Poor cell survival limits the beneficial impact of mesenchymal stem cell transplantation on acute kidney injury.

BACKGROUND: Although renal tubular epithelium has a great capacity for repair it has been suggested that the administration of mesenchymal stem cells may accelerate the recovery following severe ischemic injury. METHODS: Here we analyzed the survival rate and organ distribution of transplanted mesenchymal stem cells as well as their contribution to kidney regeneration after ischemic renal injury using functional tests, histological examination as well as quantitative real-time PCR. RESULTS: Intravenously injected stem cells were mainly trapped in lungs and liver. One hour after injection, less than 1% of the injected stem cells could be detected in the injured kidneys. These cells disappeared within the first few days and did not replace renal epithelial cells precluding substantial transdifferentiation. To clarify whether reinforced stem cell delivery might promote sustained survival or conversion to tubular epithelia, stem cells were directly injected into the injured kidneys. Although these grafted cells also did not show sustained survival or contribute to structural renal repair, stem cell injection was associated with a significant but transient initial decrease in serum creatinine. CONCLUSION: These data suggest that mesenchymal stem cells do not significantly contribute to epithelial renewal after ischemic injury, promoting the idea that the major impact of cell-based therapy for acute kidney injury may result from paracrine or endocrine effects unrelated to stem cell transdifferentiation.

Configural frequency analysis as a method of determining patients' preferred decision-making roles in dialysis.

BACKGROUND: Numerous studies examined factors in promoting a patient preference for active participation in treatment decision making with only modest success. The purpose of this study was to identify types of patients wishing to participate in treatment decisions as well as those wishing to play a completely active or passive role based on a Germany-wide survey of dialysis patients; using a prediction typal analysis method that defines types as configurations of categories belonging to different attributes and takes particularly higher order interactions between variables into account. METHODS: After randomly splitting the original patient sample into two halves, an exploratory prediction configural frequency analysis (CFA) was performed on one-half of the sample (n = 1969) and the identified types were considered as hypotheses for an inferential prediction CFA for the second half (n = 1914). 144 possible prediction types were tested by using five predictor variables and control preferences as criterion. An α-adjustment (0.05) for multiple testing was performed by the Holm procedure. RESULTS: 21 possible prediction types were identified as hypotheses in the exploratory prediction CFA; four patient types were confirmed in the confirmatory prediction CFA: patients preferring a passive role show low information seeking preference, above average trust in their physician, perceive their physician's participatory decision-making (PDM)-style positive, have a lower educational level, and are 56-75 years old (Type 1; p < 0.001) or > 76 years old (Type 2; p < 0.001). Patients preferring an active role show high information seeking preference, a higher educational level, and are < 55 years old. They have either below average trust, perceive the PDM-style negative (Type 3; p < 0.001) or above average trust and perceive the PDM-style positive (Type 4; p < 0.001). CONCLUSIONS: The method prediction configural frequency analysis was newly introduced to the research field of patient participation and could demonstrate how a particular control preference role is determined by an association of five variables.

Prevalence of anti-erythropoietin antibodies in hemodialysis patients without clinical signs of pure red cell aplasia. Comparison between hypo- and normoresponsive patients treated with epoetins for renal anemia.

BACKGROUND/AIMS: The prevalence of anti-erythropoietin antibodies in renal patients without clinical evidence of pure red cell aplasia (PRCA) who respond poorly to epoetin is unknown. This study tested for anti-erythropoietin antibodies in hemodialysis patients who were either hypo- or normoresponsive to epoetin treatment. METHODS: Epoetin hyporesponsiveness (hemoglobin < or =10.5 g/dl and epoetin > or =9,000 IU/week) and normoresponsiveness (hemoglobin >10.5 g/dl and epoetin <7,000 IU/week) were arbitrarily defined. Prevalence of anti-erythropoietin antibodies in hemodialysis patients without symptoms of PRCA was determined by screening sera of 536 patients from 35 German KfH dialysis units, using enzyme-linked immunosorbent assay (ELISA). Positive results were verified by radioimmunoprecipitation assay (RIP) and neutralizing activity was determined by bioassay. RESULTS: Anti-erythropoietin antibodies were detected in 3 hyporesponsive and 3 normoresponsive patients using ELISA. One patient per group was verified as borderline by RIP testing; the other 4 were negative. The bioassay was negative for 1 patient; the other died unrelated to PRCA before testing. Follow-up with RIP testing after 15 months under continuous epoetin treatment was negative (4 patients, 2 deceased). CONCLUSION: This survey did not identify anti-erythropoietin antibodies in hemodialysis patient's hyporesponsive to epoetin and does not support presumptive antibody screening as a routine work-up in these patients.

[Shared decision-making as a new quality indicator in nephrology: a nationwide survey in Germany]. / Partizipative Entscheidungsfindung als neuer Qualitätsindikator in der Nephrologie Eine bundesweite empirische Untersuchung.

BACKGROUND AND PURPOSE: Shared decision-making (SDM) as a model in physician-patient interaction is gaining relevance in the German health system. By applying this model, mid- and long-term improvements are expected especially in the outcomes of chronic diseases. Up to now, there has hardly been any empirical data available in German health services research regarding the state and development of SDM. This study establishes a baseline and provides actual data on this subject based on a German-wide survey of end-stage renal disease (ESRD) patients. METHODS: Standardized German-wide survey of 6,614 patients with ESRD. The questionnaire included an instrument to measure the patients' perceived involvement in care (PICS) which had been translated and validated before. RESULTS: 82% of the questioned patients feel their physicians facilitated involvement in decision making. 81% of the patients actively inform themselves concerning their disease and treatment options. 69% state that SDM has taken place. Age, years on dialysis and gender correlate with perceived involvement. CONCLUSION: This paper provides a valid baseline for the prospective research of SDM in ESRD. The results indicate that dialysis patients are willing to participate in the process of medical decision-making. Characteristics and preferences of the patients should be taken into account not only in everyday clinical interactions. They could be monitored systematically within the framework of quality management and used as potential for quality improvement.

Preferences of patients undergoing hemodialysis - results from a questionnaire-based study with 4,518 patients.

BACKGROUND: Chronic kidney disease is an increasing health problem worldwide and in its final stage (stage V) can only be treated by renal replacement therapy, mostly hemodialysis. Hemodialysis has a major influence on the everyday life of patients and many patients report dissatisfaction with treatment. Little is known about which aspects of treatment are considered important by hemodialysis patients. The objective of this study was to rate the relative importance of different outcomes for hemodialysis patients and to analyze whether the relative importance differed among subgroups of patients. PATIENTS AND METHODS: Within the framework of a yearly questionnaire which is distributed among patients receiving hemodialysis by the largest hemodialysis provider in Germany, we assessed the relative importance of 23 outcomes as rated on a discrete visual analog scale. Descriptive statistics were used to rank the outcomes. Subgroup analyses were performed using Mann-Whitney U or Kruskal-Wallis tests. RESULTS: Questionnaires of 4,518 hemodialysis patients were included in the analysis. The three most important outcomes were safety of treatment, health-related quality of life, and satisfaction with care. Further important outcomes were hospital stays, accompanying symptoms, hemodialysis duration, and the improvement or preservation of a good emotional state. Age, profession, and education had the strongest influence on relevant differences of preferences for outcomes; no relevant influence of sex or comorbidity was observed. CONCLUSION: Outcomes concerning the delivery or provision of care and aspects influencing quality of life are rated by patients to be at least as important as clinical outcomes. Many of the outcomes judged to be important by the patients are not regularly considered in research, evaluation studies, or quality programs.

Once-weekly compared with three-times-weekly subcutaneous epoetin beta: results from a randomized, multicenter, therapeutic-equivalence study.

BACKGROUND: The ability to reduce the administration frequency of subcutaneous (SC) epoetin could provide benefits. This multicenter open-label study investigated the therapeutic equivalence of SC epoetin beta once-weekly and thrice-weekly administration regimens in maintaining anemia correction in stable hemodialysis (HD) patients. METHODS: One hundred seventy-three patients were randomly assigned to either once-weekly epoetin beta (n = 84) or their original thrice-weekly regimen (n = 89) for 24 weeks. All patients were administered intravenous iron supplementation, as required. RESULTS: The per-protocol analysis included 134 patients (69 patients, once-weekly group; 65 patients, thrice-weekly group). Mean hematocrits in both groups remained stable throughout the study. The difference in mean time-adjusted area under the curve for hematocrits between the once-weekly and thrice-weekly groups (-0.54 vol%) and 90% confidence intervals (-1.27 to 0.19) were within the prespecified equivalence range (-2 to +2 vol%). There was no significant change in epoetin beta dose during the study. The ratio of mean weekly epoetin beta doses in the once-weekly and thrice-weekly groups (1.11) and 90% confidence interval (0.99 to 1.23) also remained within the prespecified range (0.8 to 1.25). Intention-to-treat analysis results were similar to per-protocol analysis results. Both regimens were well tolerated. CONCLUSION: Once-weekly and thrice-weekly SC epoetin beta administrations are statistically equivalent in terms of maintaining both stable hematocrits and epoetin beta dose requirements in HD patients. These findings may improve compliance among patients.

[Guideline-based medical quality management in dialysis. Motivation and structuring of a quality-management system and integration of earlier disease stages of chronic renal failure]. / Leitlinien-gestütztes medizinisches Qualitätsmanagement in der Dialyse. Motivation und Aufbau eines Qualitätsmanagement-Systems sowie Integration früherer Erkrankungsstadien der chronischen Niereninsuffizienz.

BACKGROUND AND PURPOSE: Health services are challenged by increasingly complex medical processes and economic restraints in an aging population. Under these circumstances, medical quality management is developed and increasingly applied to survey especially complex and expensive clinical processes in the sense of controlling. In this process, practicability and relevance are fundamental. METHODS: This paper presents the well-established quality management system QiN (quality in nephrology) in the context of dialysis in end-stage renal disease. RESULTS: A quality-management system is well applicable in the case of dialysis. It can positively influence relevant indicators of process and outcome quality, as demonstrated here by the example of dialysis quantity. CONCLUSIONS: Outcome and process quality in dialysis are quantifiable via defined indicators oriented on evidence-based medicine. The program based on benchmarking of basic clinical indicators leads to improved care of dialysis patients. A quality-management program of this type can represent an essential component of interdisciplinary, structured treatment programs, thereby influencing the whole treatment process.

Comparison of the therapeutic effects of epoetin zeta to epoetin alfa in the maintenance phase of renal anaemia treatment.

OBJECTIVE: To evaluate the therapeutic efficacy and safety of epoetin zeta, compared with epoetin alfa, in maintaining target haemoglobin (Hb) concentrations in patients with anaemia and chronic kidney disease (CKD) maintained on haemodialysis. METHODS: Patients received epoetin zeta or epoetin alfa intravenously, 1-3 times/week for 12 weeks, then the alternative treatment for 12 weeks, in this double-blind, crossover, phase III trial. Eligible patients were 18-75 years old with CKD stage 5 maintained on haemodialysis. Patients had received epoetin for > or = 3 months upon study entry and had achieved a target Hb level of 10.5-12.5 g/dL with a stable epoetin dose. MAIN OUTCOME MEASURES: Primary efficacy endpoints were intra-individual differences (test-reference) in mean Hb levels and mean weekly dose/kg of body weight. Safety endpoints included occurrence of neutralizing anti-erythro poietin antibodies, tolerability, and adverse events (AEs). RESULTS: In total, 313 patients were randomized to receive epoetin zeta (n = 155) or epoetin alfa (n = 158); 146 and 145 patients (respectively) switched treatment after 12 weeks. Mean (range) Hb levels were 11.35 (8.96-14.22) g/dL and 11.54 (8.74-13.84) g/dL for patients receiving epoetin zeta and epoetin alfa, respectively (95% confidence interval [CI] [test-reference]: 0.09-0.28 g/dL, within the predefined equivalence range of +/-0.6 g/dL). Mean (range) weekly doses were 92.68 (12.74-398.41) IU/kg/wk and 92.58 (10.53-393.07) IU/kg/wk for patients receiving epoetin zeta and epoetin alfa, respectively (95% CI [test-reference]: -4.67 and 4.29 IU/kg/wk, within the equivalence range of +/-45.00 IU/kg/wk). Patients underwent minor nominal dose adjustments during treatment crossover. AE profile was similar for both products; the most commonly reported AEs were infections and infestations (in 26.5% of patients receiving epoetin zeta and 23.6% receiving epoetin alfa). No patients developed neutralizing anti-erythropoietin antibodies. CONCLUSIONS: Epoetin zeta is therapeutically equivalent to epoetin alfa in the maintenance of target Hb levels in patients with renal anaemia. No unexpected AEs were seen.

Long-term safety and tolerability of epoetin zeta, administered intravenously, for maintenance treatment of renal anemia.

INTRODUCTION: The aim of this trial was to gather data on the long-term safety of a new erythropoietin preparation (epoetin zeta), focusing on the formation of anti-erythropoietin antibodies, when administered intravenously for maintenance of target hemoglobin concentration in anemic patients with end-stage renal failure receiving chronic hemodialysis. In addition, we aimed to provide information on the efficacy of epoetin zeta under open, noncontrolled conditions. METHODS: Patients received epoetin zeta intravenously, 1-3 times/week for 56 weeks (overall patient group, n=745) or 108 weeks (Bulgarian subgroup, n=164). The aim of treatment was to maintain hemoglobin values between 10.5 and 12.5 g/dL with constant epoetin dosage. Primary (safety) endpoints were the occurrence of anti-erythropoietin antibodies and the evaluation of adverse events (AEs). Secondary (efficacy) endpoints included the mean weekly dose of epoetin per kg of body weight and mean hemoglobin concentrations. RESULTS: No patients developed neutralizing anti-erythropoietin antibodies. The most commonly reported AEs were infections and infestations (34.1%); followed by injury, poisoning, and procedural complications (25.8%); and gastrointestinal disorders (21.9%); 37.3% of patients reported serious AEs. The hemoglobin values remained stable, with mean values after 56 weeks of 11.3-11.6 g/dL for the overall group and 11.1-11.6 g/dL for the Bulgarian subgroup. The dosage of epoetin zeta was stable throughout the course of the trial. No cases of lack of (or loss of ) efficacy were observed in the course of the trial. CONCLUSIONS: The evaluation of the primary endpoints provided data supporting the intravenous administration of epoetin zeta in patients with chronic renal failure. Neutralizing antibodies against erythropoietin were not detected, and there were no reports of patients with increasing erythropoietin resistance. Our results suggest that intravenous administration of epoetin zeta is effective regarding its ability to maintain stabilized hemoglobin levels within the target range of 10.5-12.5 g/dL.

Mutations of the Uromodulin gene in MCKD type 2 patients cluster in exon 4, which encodes three EGF-like domains.

BACKGROUND: Autosomal-dominant medullary cystic kidney disease type 2 (MCKD2) is a tubulointerstitial nephropathy that causes renal salt wasting, hyperuricemia, gout, and end-stage renal failure in the fifth decade of life. The chromosomal locus for MCKD2 was localized on chromosome 16p12. Within this chromosomal region, Uromodulin (UMOD) was located as a candidate gene. UMOD encodes the Tamm-Horsfall protein. By sequence analysis, one group formerly excluded UMOD as the disease-causing gene. In contrast, recently, another group described mutations in the UMOD gene as responsible for MCKD2 and familial juvenile hyperuricemic nephropathy (FJHN). METHODS: Haplotype analysis for linkage to MCKD2 was performed in 25 MCKD families. In the kindreds showing linkage to the MCKD2 locus on chromosome 16p12, mutational analysis of the UMOD gene was performed by exon polymerase chain reaction (PCR) and direct sequencing. RESULTS: In 19 families, haplotype analysis was compatible with linkage to the MCKD2 locus. All these kindreds were examined for mutations in the UMOD gene. In three different families, three novel heterozygous mutations in the UMOD gene were found and segregated with the phenotype in affected individuals. Mutations were found only in exon 4. CONCLUSION: We confirm the UMOD gene as the disease-causing gene for MCKD2. All three novel mutations were found in the fourth exon of UMOD, in which all mutations except one (this is located in the neighboring exon 5) published so far are located. These data point to a specific role of exon 4 encoded sequence of UMOD in the generation of the MCKD2 renal phenotype.