[Treatment response and complications of older patients with ANCA(antineutrophil cytoplasmatic antibody)-associated vasculitis]. / Therapieansprechen und Komplikationen von älteren Patienten mit ANCA(antineutrophile cytoplasmatische Antikörper)-assoziierten Vaskulitiden.

BACKGROUND: ANCA (antineutrophil cytoplasmatic antibody)-associated vasculitis (AAV) mainly affects elderley people but adjusted therapy concepts for this patient group are lacking. AIM: The aim of this study was therefore to analyze differences in course and outcome of patients with AAV with respect to age. MATERIALS AND METHODS: 62 patients were analyzed for treatment response, of whom 53 (85%) experienced adverse events (AE and SAE) that could be evaluated. Older (> 65 yrs.) versus younger (< 65 yrs.) patients were compared. Treatment response was assessed at 6 months, complications were assessed over 18 months. RESULTS: Treatment response was not seen to differ by age groups. In multiple logistic regression, pulmonary involvement (OR = 6,9; CI = 1,7-27,8, p < 0,01) and ΔGFR [ml/min] (OR = 0,93; CI = 0,89-0,97, p < 0,01) were predictors of SAE. 14 patients had more than 1 SAE. Again, pulmonary involvement (28,2% vs. 78,6%, p < 0,01) was a risk factor and older patients (78,6% vs. 43,6%, p = 0,025) were more frequently affected. Patients with multiple SAEs received glucocorticoids of more than 5 mg/d for longer periods of time (171 ± 65 days vs. 120 ± 70 days, p = 0,03). DISCUSSION: No differences were found between older and younger patients with regard to treatment response. Multiple SAEs occurred more frequently in elderly patients. There was a correlation between pulmonary manifestation and duration of glucocorticoid therapy with a complicated course. The most frequent SAEs were infections requiring hospitalisation. CONCLUSION: Therapy for elderly patients should be individualized with the goal of a fast reduction of glucocorticoids. Special monitoring is indicated for elderly patients, especially those with pulmonary involvement.

Survey among nephrologists in Germany: current practice and management of pregnant women on dialysis
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BACKGROUND: To assess the experience and practice patterns of nephrologists in Germany with regard to the care of pregnant women on dialysis. METHODS: The 26-item internet survey sent by email asked for demographic information, subjective proficiency, maternal and fetal complications, treatment approaches and goals. RESULTS: Of the 2,015 surveys sent out, 200 (10%) were available for evaluation. 38% of respondents never provided care, whereas 62% treated at least one pregnant patient on dialysis. In 306 total reported cases of pregnant women on dialysis, 58% became pregnant while on maintenance dialysis, and 42% developed dialysis-dependent renal failure in the course of pregnancy. For women on peritoneal dialysis (PD), only 22% of the nephrologists would continue PD until delivery, while 78% would convert to hemodialysis either immediately or shortly before delivery. 40% of the respondents reported complications in either mother or child. 45% of the respondents routinely provided prenatal counseling, and 2/3 of the nephrologists did not routinely perform fetal monitoring. While we found a significant difference in self-reported proficiency between nephrologists having and those not having treated pregnant women on dialysis, only 40% of all physicians felt confident in treating pregnant women on dialysis. CONCLUSIONS: Our survey demonstrates that the practice of nephrologists in treating pregnant women on dialysis differs significantly. These findings highlight the need for European guidelines to standardize the care of pregnant dialysis patients.
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Subclinical and clinical hypothyroidism and non-alcoholic fatty liver disease: a cross-sectional study of a random population sample aged 18 to 65 years.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most common disorders of the liver worldwide. Recently, a correlation between thyroid dysfunction and NAFLD has been discussed. Objective of the present study was to investigate the association between thyroid dysfunction and hepatic steatosis. METHODS: Data from 2,445 subjects (51.7% females) aged 18 to 65 years participating in a population-based cross-sectional study were assessed based on a standardized questionnaire and documentation of physical, biochemical and ultrasonographic findings. After application of exclusion criteria, a total of 1,276 subjects were included in the study collective. The influence of potential factors on the development of hepatic steatosis was assessed using multivariate logistic regression. RESULTS: The prevalence of hepatic steatosis in the study collective was 27.4% (n = 349). The serum thyroxin (TT4) concentration in subjects with hepatic steatosis was reduced (p =0.0004). Adjusting for age, or BMI, there was an increased prevalence of hepatic steatosis in subjects with reduced TT4 concentrations (p = 0.0143; p = < .0001). CONCLUSIONS: The findings of the present study confirm an association between both subclinical and clinical hypothyroidism and hepatic steatosis.

Effect of low-osmolar contrast medium iopromide and iso-osmolar iodixanol on DNA fragmentation in renal tubular cell culture.

BACKGROUND: Intravascular administration of iodinated contrast media continues to be a common cause of hospital-acquired acute kidney injury. Accumulating evidence suggests that radiocontrast agent-induced nephrotoxicity is associated with increased oxidative stress, which leads to renal tissue damage with DNA fragmentation. We therefore tested whether an iso-osmolar contrast medium (iodixanol) causes less oxidative DNA damage to renal tubular cells than a low-osmolar contrast medium (iopromide). METHODS: HK-2 cells (human proximal renal tubular cell line) were incubated at different time points (10 min-2 h) with increasing concentrations (20-120 mg/ml iodine) of iodixanol or of iopromide. Oxidative DNA damage to renal tubular cells was measured by alkaline comet assay (single-cell gel electrophoresis). RESULTS: Both iso- and low-osmolar contrast agents induced time- and concentration-dependent DNA fragmentation. DNA fragmentation was maximal at 2 h with 120 mg/ml iodine for iopromide (32 ± 27 tail moments) and iodixanol (46 ± 41 tail moments); both were significantly different from the control value with 3.15 ± 1.6 tail moments (Student's t test; p < 0.001). After 1 and 2 h and for all concentrations, iodixanol produced significantly higher DNA fragmentation than iopromide (ANOVA for 1 h p = 0.039 and 2 h p = 0.025, respectively). CONCLUSION: We were able to demonstrate for the first time that an iso-osmolar contrast medium induced even greater oxidative stress and DNA damage than a low-osmolar agent in HK-2 cells. This could provide an explanation for the nephrotoxicity that also is observed with iodixanol in clinical practice.

Enemy or friend: the personal and the factual patient-physician relationship.

Physicians are expected to place the patient's interests above their own. Such prioritization has worldwide consent. It constitutes the difference between medicine and other professions. The present conceptual opinion paper summarizes the authors' clinical experience with patient care and student teaching during the last 45 years. The authors comment on their own conception by referring to present debates and prominent statements from the past. Fundamental changes in medicine have taken place over the last five decades. New diseases have emerged while diagnostic and therapeutic options for patients have grown steadily - along with healthcare costs. At the same time, economic and legal constraints for physicians have increased, as has moral pressure. The interaction of physicians with patients has gradually shifted from a personal to a factual relationship. In the factual, more formal relationship, the patient and physician represent equal partners of a legal contract, which jeopardizes the prioritization of the patient's interests. The formal relationship implies defensiveness. By contrast, in the personal relationship, the physician adopts an existentialist commitment while simultaneously enabling and respecting the patient's autonomous decision-making. The authors argue for the personal relationship. However, the patient and physician are no friends. Consequently, the physician in effect competes with the patient from a knowledge-based but opposite position. Both need to make efforts to consent and maintain the relationship even when they dissent. This implies that the physician does not simply comply with the patient's wishes.

Eculizumab in chemotherapy-induced thrombotic microangiopathy.

Thrombotic microangiopathy (TMA) is a rare but severe complication of tumors and their chemotherapeutic treatment. We report on two patients with chemotherapy-induced TMA who were successfully treated with a short course of the terminal complement inhibitor eculizumab. Both patients quickly achieved remission of microangiopathic hemolytic anemia and recovery of renal function. After withdrawal of eculizumab, remission was stable over an observation period of 47 months and 15 months, respectively. Our data show that eculizumab is effective in treating chemotherapy-induced TMA. Discontinuation of eculizumab is feasible once the complement-activating condition is controlled and the trigger is eliminated. Additional studies need to determine the optimal duration of complement-directed therapies and validate effective monitoring strategies after discontinuation of such therapy.

Pharmacokinetic and pharmacodynamic considerations of antimicrobial drug therapy in cancer patients with kidney dysfunction.

Patients with cancer have a high inherent risk of infectious complications. In addition, the incidence of acute and chronic kidney dysfunction rises in this population. Anti-infective drugs often require dosing modifications based on an estimate of kidney function, usually the glomerular filtration rate (GFR). However, there is still no preferential GFR formula to be used, and in acute kidney injury there is always a considerable time delay between true kidney function and estimated GFR. In most cases, the anti-infective therapy should start with an immediate and high loading dose. Pharmacokinetic as well as pharmacodynamic principles must be applied for further dose adjustment. Anti-infective drugs with time-dependent action should be given with the target of high trough concentrations (e.g., beta lactam antibiotics, penems, vancomycin, antiviral drugs). Anti-infective drugs with concentration-dependent action should be given with the target of high peak concentrations (e.g., aminoglycosides, daptomycin, colistin, quinolones). Our group created a pharmacokinetic database, called NEPharm, hat serves as a reference to obtain reliable dosing regimens of anti-infective drugs in kidney dysfunction as well as renal replacement therapy. To avoid the risk of either too low or too infrequent peak concentrations, we prefer the eliminated fraction rule for dose adjustment calculations.

Pharmacokinetic and pharmacodynamic considerations on the erythropoietin effect and adverse events of darbepoetin.

INTRODUCTION: In the TREAT and RED-HF trials, patients who received a high darbepoetin dose had an increased risk of adverse events. To find an explanation, the published literature was analyzed on the pharmacokinetics and pharmacodynamics of darbepoetin. AREAS COVERED: Based on the sigmoid Emax model, the concentration producing 50% of the maximum erythropoietin effect is reported as CE50 = 0.41 ng/ml and the Hill coefficient as H = 3.0 for darbepoetin. Accordingly, a pharmacodynamics-based threshold concentration can be estimated with CE05 = 0.153 ng/ml producing 5% of Emax and a ceiling concentration with CE95 = 1.098 ng/ml producing 95% of Emax, respectively. EXPERT OPINION: Darbepoetin trough levels should not be less than the threshold concentration but peak levels above the ceiling concentration could be associated with an increased risk of adverse events. The time span associated with the concentration fluctuation between the ceiling and the threshold concentration is estimated with 236 h (= 2.84 times elimination half-life of 83 h) and shorter than the 336 h when dosing every other week. According to such time-dependent pharmacodynamics, a weekly dosing regimen might be more effective and associated with less adverse events than higher doses every other week in patients with suboptimal response to a normal darbepoetin dose.

Prophylaxis of contrast-induced nephrotoxicity.

Contrast-induced nephrotoxicity (CIN) is a form of acute kidney injury that follows intravascular contrast media exposure. CIN may be preventable because its risk factors are well established and the timing of renal insult is commonly known in advance. However, contrast-induced nephrotoxicity is still the third leading cause of iatrogenic renal failure. This important complication accounts up to 10% of acute renal failure cases in hospitalized patients and it is associated with increased short- and long-term morbidity and mortality. Prolonged hospitalization follows and overall increases healthcare resource utilization. This paper will discuss the various prophylactic procedures tested in clinical trials.