Hypervolemia in Dialysis Patients Impairs STAT3 Signaling and Upregulates miR-142-3p: Effects on IL-10 and IL-6.

Fluid overload in hemodialysis patients (HD) has been proven to be associated with inflammation. Elevated levels of the pro-inflammatory cytokine interleukin-6 (IL-6) appear to be inadequately counterbalanced by the anti-inflammatory cytokine interleukin-10 (IL-10). We initiated a cross-sectional study enrolling 40 HD patients who were categorized by a bioimpedance measurement in normovolemic (N; 23) and hypervolemic (H; 17) groups to test whether IL-10- and IL-6-related signal transduction pathways (signal transducer of transcript 3: STAT3) and/or a post-transcriptional regulating mechanism (miR-142) are impaired by hypervolemia. IL-10/IL-6 transcript and protein production by PBMCs (peripheral blood mononuclear cells) were determined. Phospho-flow cytometry was used to detect the phosphorylated forms of STAT3 (pY705 and pS727). miR-142-3p/5p levels were detected by qPCR. Hypervolemic patients were older, more frequently had diabetes, and showed higher CRP levels. IL-10 transcripts were elevated in H patients but not IL-10 protein levels. In spite of the elevated mRNA expression of the suppressor of cytokine expression 3 (SOCS3), IL-6 mRNA and protein expression were increased in immune cells of H patients. The percentage of cells staining positive for STAT3 (pY705) were comparable in both groups; in STAT3 (pS727), however, the signal needed for full transactivation was decreased in H patients. miR-142-3p, a proven target of IL-10 and IL-6, was significantly elevated in H patients. Insufficient phosphorylation of STAT3 may impair inflammatory and anti-inflammatory cytokine signaling. How far degradative mechanisms induced by elevated miR-142-3p levels contribute to an inefficient anti-inflammatory IL-10 signaling remains elusive.

Pyroptosis: A Common Feature of Immune Cells of Haemodialysis Patients.

NLRP-3 inflammasome activation can result in interleukin-1ß (IL-1ß) release and inflammatory cell death (pyroptosis). Caspase-1 is able to trigger both processes. However, other caspases, caspase-4, -5 and -8, are believed to initiate pyroptosis without affecting IL-1 secretion. In this study, we evaluated two cardiovascular risk groups, haemodialysis patients (HD) and patients with intact kidney function but high blood pressure (BP), to analyse the mechanisms driving pyroptosis. Twenty HD were age-, gender- and diabetes-matched to BP. We found a common pyroptotic pattern in both patient groups, at which pyroptosis rates but not IL-1 ß levels were significantly higher in monocytes (HD vs. BP: p < 0.05), granulocytes (p < 0.01) and lymphocytes (p < 0.01) of HD patients. As uremic toxins are drivers of inflammation and regulated cell death, we applied a monocyte- and macrophage-like THP-1 model system to demonstrate that the protein-bound uremic toxin indoxyl sulfate (IS) is an inducer of pyroptotic cell death, particularly engaging caspase-4/caspase-5 and to a lesser extent caspase-8 and caspase-1. These data suggest that the uremic toxin IS can mediate pyroptosis in HD patients and the inflammatory caspase-4 and/or caspase-5 contribute to pyroptosis rates to a higher extent in comparison to caspase-1.

[Contrast media use in kidney disease - clinical practice recommendations]. / Kontrastmittelgabe bei Niereninsuffizienz ­ praktische Handlungsempfehlungen.

Contrast media use in patients with renal disease regularly ensures discussions in everyday clinical practice. Both X-ray and MRI contrast media are predominantly eliminated by the kidneys and therefore closely linked to kidney function. Risk stratification prior to contrast media use in patients with pre-existing renal dysfunction should be based on eGFR-determination. Patients with an eGFR ≥ 30 ml/min require an individual risk assessment. In patients with advanced renal insufficiency ensuring euvolemia is crucial. Currently, there is no evidence for any other preventive approach. Therefore, no further specific procedures preventing contrast-associated kidney injury are recommended. Timing of contrast media injection and dialysis sessions in patients with end stage renal disease is necessary only after MRI contrast media use. Independently, acute kidney injury requires a patient individual decision.

NLRP3 Inflammasome Activation in Hemodialysis and Hypertensive Patients with Intact Kidney Function.

Hypertension is not only an integrative characteristic of hemodialysis (HD) patients but is also very common in the general population. There is evidence that the inflammatory cytokine IL-ß, regulated by the NLRP3 inflammasome via caspase-1, contributes to the hypertensive setting. Therefore, we investigated in an observational pilot study whether IL-1ß secretion and inflammatory cell death (pyroptosis) are different in HD and hypertensive patients with intact kidney function. Twenty HD patients were age-, gender-, and diabetes-mellitus-matched to patients with hypertension and intact kidney function. Caspase-1 activity and pyroptosis rates were measured by flow cytometry. IL-1ß was determined by qPCR and the ELISA technique. The inflammatory status (CRP) did not differ between both groups; however, the body mass index, a classical cardiovascular risk factor, was significantly elevated in blood pressure (BP) patients. BP patients had a higher frequency of caspase-1-positive monocytes compared to HD (p < 0.001). IL1-ß protein secretion was significantly enhanced in BP, but ex vivo stimulation of blood cells resulted in higher pyroptosis rates in HD compared to BP patients (p < 0.01). Therefore, HD and BP patients differ in the extent of the NLRP3 inflammasome activation. The consequences of overweight, present in BP patients, may contribute to the significantly higher inflammasomal induction level. Whether low pyroptotic rates are equivalent to a dysfunctional immune response or a high pyroptotic output corresponds to over-activation remains to be clarified.

Real-world data confirm the effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare but life-threatening condition. In 2018, the nanobody caplacizumab was approved for the treatment of adults experiencing an acute episode of aTTP, in conjunction with plasma exchange (PEX) and immunosuppression for a minimum of 30 days after stopping daily PEX. We performed a retrospective, observational analysis on the use of caplacizumab in 60 patients from 29 medical centers in Germany during acute disease management. Caplacizumab led to a rapid normalization of the platelet count (median, 3 days; mean 3.78 days). One patient died after late treatment initiation due to aTTP-associated complications. In 2 patients with initial disease presentation and in 4 additional patients with laboratory signs of an exacerbation or relapse after the initial therapy, PEX-free treatment regimens could be established with overall favorable outcome. Caplacizumab is efficacious in the treatment of aTTP independent of timing and ancillary treatment modalities. Based on this real-world experience and published literature, we propose to administer caplacizumab immediately to all patients with an acute episode of aTTP. Treatment decisions regarding the use of PEX should be based on the severity of the clinical presentation and known risk factors. PEX might be dispensable in some patients.

ADAMTS13 and VWF activities guide individualized caplacizumab treatment in patients with aTTP.

Introduction of the nanobody caplacizumab was shown to be effective in the treatment of acquired thrombotic thrombocytopenic purpura (aTTP) in the acute setting. The official recommendations include plasma exchange (PEX), immunosuppression, and the use of caplacizumab for a minimum of 30 days after stopping daily PEX. This study was a retrospective, observational analysis of the use of caplacizumab in 60 patients from 29 medical centers in Germany. Immunosuppressive treatment led to a rapid normalization of ADAMTS13 activities (calculated median, 21 days). In 35 of 60 patients, ADAMTS13 activities started to normalize before day 30 after PEX; in 11 of 60 patients, the treatment was extended beyond day 30; and in 5 patients, it was extended even beyond day 58 due to persistent autoimmune activity. In 34 of 60 instances, caplacizumab was stopped before day 30 with a favorable outcome whenever ADAMTS13 activities were >10%. In contrast, 11 of 34 patients with ADAMTS13 activities <10% at the time of stopping caplacizumab treatment developed a nonfavorable outcome (disease exacerbation or relapse). In some cases, prolongation of the treatment interval to every other day was feasible and resulted in a sustained reduction of von Willebrand factor activity. ADAMTS13 activity measurements are central for a rapid diagnosis in the acute setting but also to tailor disease management. An ADAMTS13 activity-guided approach seems safe for identifying the individual time point when to stop caplacizumab to prevent overtreatment and undertreatment; this approach will result in significant cost savings without jeopardizing the well-being of patients. In addition, von Willebrand factor activity may serve as a biomarker for drug monitoring.

Minimally invasive robotic versus conventional open living donor kidney transplantation.

PURPOSE: First robotic-assisted kidney transplants (RAKT) were performed in Germany in 2016. To introduce and establish this method as a routine procedure for patients in transplantation medicine, our 2-year experiences are presented. METHODS: Non-randomized open-label cohort study to compare functional and operative results as well as complication rates between RAKT and standard open transplantation. Collected data are part of ERUS RAKT Group Registry. RESULTS: Since initiation of the RAKT program 21/27 transplantations after living kidney donations have been performed as RAKT. This represents the largest series of RAKT in Germany. Patient survival, transplant survival, and primary function rate are 100% (mean follow-up 12.9 ± 8.6 month). Mean incision to closure time was 306.1 ± 45.5, mean handling time 70.8 ± 13.1 min compared to 212.1 ± 40.6 min and 51.7 ± 9.9 min, respectively, in the standard group. Despite extended operating times using the robotic approach, comparable complication rates and graft function with significant reduction in median length of hospital stay (14 vs. 20 days) were observed. CONCLUSIONS: RAKT extends the options for recipients towards minimally invasive techniques. Compared to classic open surgery, RAKT appears to be safe in selected patients without influencing graft outcome or higher complication rates. However, RAKT till today is not suitable for all patients but seems to be one of the upcoming new standard techniques in kidney transplantation.

Influence of SPRINT Study Type Automated Office Blood Pressure Measurements on Hypertension Diagnosis in Kidney Transplant Patients.

BACKGROUND/AIMS: We compare conventional office blood pressure measurements with automated SPRINT-study type readings in kidney transplant recipients in order to determine the impact of the white coat effect in a prospective observational study. METHODS: Adult patients with a functional renal transplant not dependent on dialysis were eligible. Readings were taken in the office in presence of the physician with an oscillometric method. Afterwards, readings were repeated with the patients resting alone in a quiet examination room with an automated blood pressure monitor. After 5 minutes of rest, 3 readings were taken at 1 minute intervals, with an average of these 3 readings calculated by the monitor. RESULTS: 120 patients with an average age of 58.5±12.2 years were included. Mean time since transplantation was 7.95±6.48 years. Mean eGFR (CKD-EPI) was 48.5±18.3 ml/min. SPRINT-study type readings were significantly lower than office readings (139.01±18.45 vs. 149.00±21.02 mmHg systolic, p<0.001; 80.88±11.63 mmHg vs. 84.35±12.41 mmHg diastolic, p <0.001). Correlation analysis for many potentially influencing factors (diabetes mellitus, transplant vintage, proteinuria, age, immunosuppression, donor type) was not significant but obese women were significantly more prone to white coat hypertension. CONCLUSION: Automated office blood pressure measurements should be considered the method of choice in kidney transplant recipients.

Impact of the estimation equation for GFR on population-based prevalence estimates of kidney dysfunction.

BACKGROUND: Estimating equations are recommended by clinical guidelines as the preferred method for assessment of glomerular filtration rate (GFR). The aim of the study was to compare population-based prevalence estimates of decreased kidney function in Germany defined by an estimated GFR (eGFR) <60 ml/min/1.73m2 using different equations. METHODS: The study included 7001 participants of the German Health Interview and Examination Survey for Adults 2008-2011 (DEGS1) for whom GFR was estimated using the Modification of Diet in Renal Disease study equation (MDRD), the revised Lund-Malmö equation (LM), the Full Age Spectrum creatinine equation (FAScre), the Chronic Kidney Disease Epidemiology Collaboration equations with creatinine and cystatin C (CKD-EPIcrecys), with creatinine (CKD-EPIcre) and with cystatin C (CKD-EPIcys). Bland-Altman plots were used to evaluate the agreement between the equations. RESULTS: Prevalence estimates of decreased kidney function were: 2.1% (CKD-EPIcys), 2.3% (CKD-EPIcrecys), 3.8% (CKD-EPIcre), 5.0% (MDRD), 6.0% (LM) and 6.9% (FAScre). The systematic differences between the equations were smaller by comparing either equations that include serum cystatin C or equations that include serum creatinine alone and increased considerably by increasing eGFR. CONCLUSIONS: Prevalence estimates of decreased kidney function vary considerably according to the equation used for estimating GFR. Equations that include serum cystatin C provide lower prevalence estimates if compared with equations based on serum creatinine alone. However, the analysis of the agreement between the equations according to eGFR provides evidence that the equations may be used interchangeably among persons with pronounced decreased kidney function. The study illustrates the implications of the choice of the estimating equation in an epidemiological setting.

Clinical Course of Acute Kidney Injury in Elderly Individuals Above 80 Years.

BACKGROUND/AIMS: Aging is associated with renal function decline and elderly patients are more vulnerable to acute kidney injury (AKI). The causes and prognosis of AKI according to new KDIGO definition that broadened the diagnosis and included more patients without dialysis dependence have not yet been compared between younger and elderly patients. METHODS: In a retrospective analysis all patients with AKI admitted to a tertiary care Nephrology department (N=424) were included. Individuals were stratified by age (≤80 years, >80 years). Primary end-point was death or dialysis dependence at hospital discharge, secondary analyses addressed the need for dialysis, creatinine at discharge, mortality, and length of stay. RESULTS: The distribution of AKI causes was different between the age groups. Circulatory AKI was the most important cause in both groups; however, septic or toxic AKI contributed relevantly in younger patients. Nevertheless, the number of patients reaching the primary end-point was similar (younger, 20.4%; older, 18.0%; OR 1.17, 95%CI, 0.703-1.948). While mortality tended to be higher in the older population, none of the secondary analyses indicated worse outcome for the older patients. CONCLUSION: The prognosis of AKI in elderly patients is not necessarily worse than in middle aged individuals. Nevertheless, older patients may be particularly vulnerable to circulatory or ischemic insults of the kidneys.

The Prevalence of Renal Failure. Results from the German Health Interview and Examination Survey for Adults, 2008-2011 (DEGS1).

BACKGROUND: The prevalence of non-end stage renal failure among adults in Germany is unknown. Accurate figures would enable us to estimate the overall need for kidney replacement therapies and the unexploited potential for disease prevention. Renal failure is also an important cardiovascular risk factor. Until now, American prevalence figures have often been applied to Germany despite dissimilarities between the two populations. METHODS: We analyzed data on renal function from the nationwide German Health Interview and Examination Survey for Adults, 2008-2011 (DEGS1), which was carried out by the Robert Koch Institute. The glomerular filtration rate was estimated (eGFR) from the serum creatinine and cystatin C levels (CKD-EPI formula) and a semiquantitative measure of albuminuria. Relationships between renal failure and its possible determinants were quantified with adjusted prevalence ratios (PR) and 95% confidence intervals (95% CI). RESULTS: Roughly 2.3% (95% CI: [1.9; 2.6 ]) of persons aged 18-79 had an eGFR below 60 mL/min/1.73 m2. The prevalence rose with age. We extrapolated these figures conservatively to persons aged 80 and above, who were not included in the DEGS1, and arrived at a figure of at least 2 million persons in Germany with renal failure. 11.5% of the population have albuminuria of at least 30 mg/L. Diabetes mellitus (PR = 2.25, 95% CI: [1.59; 3.16]) and arterial hypertension (PR = 3.46, 95% CI: [1.95; 6.12]) are important determinants. CONCLUSION: This study provides the first representative estimate of the prevalence of renal failure in Germany. The condition is highly dependent on age but less prevalent than previously assumed on the basis of American prevalence figures.

Plasmapheresis leading to remission of refractory nephrotic syndrome due to fibrillary glomerulonephritis: a case report.

INTRODUCTION: Fibrillary glomerulonephritis (FibGN) is characterized by extracellular deposition of Congo red-negative microfibrils within the glomerular mesangium and leads to gross proteinuria or nephrotic syndrome. After diagnosis of FibGN, end-stage renal disease occurs within four years in 50% of patients. CASE PRESENTATION: A 36-year-old Caucasian woman with proteinuria and intermittent nephrotic syndrome due to FibGN intermittently received immunosuppressive therapies, including glucocorticoids, mycophenolate mofetil, and rituximab, for 10 years. However, disease remission was not achieved and progressive kidney injury developed. Ultimately, in stage IV of chronic kidney disease (Kidney Disease: Improving Global Outcomes), three cycles of plasmapheresis of five to seven sessions each were performed every three to four months, reducing steady-state proteinuria from 7 to less than 1 g/day. Here, plasmapheresis led to a remission of nephrotic syndrome associated with FibGN. CONCLUSIONS: Plasmapheresis therapy is proposed as a further option for immunosuppressant-refractory FibGN.

Vitamin D deficiency, mortality, and hospitalization in hemodialysis patients with or without protein-energy wasting.

BACKGROUND: Vitamin D deficiency and protein-energy wasting (PEW) are highly prevalent in hemodialysis (HD) patients. The goal of our study was to investigate if a lack of vitamin D influences mortality and hospitalization of HD patients with or without PEW. METHODS: In 81 chronic HD patients with different nutritional status assessed by the Malnutrition Inflammation Score (MIS), vitamin D deficiency (25-OH-vitamin D(3) levels ≤30 nmol/l or ≤12 ng/ml) was prospectively investigated for its prognostic impact on mortality and hospitalization. Over a 3-year follow-up, all-cause mortality and hospitalization were determined. The predictive value of low vitamin D levels and PEW as well as their combined effect were evaluated using a multivariate Cox regression model. RESULTS: Vitamin D deficiency was frequent in HD patients with and without PEW. It significantly increased mortality rate in HD patients (HR 2.76 (1.33-5.73), p < 0.01), which was aggravated by concomitant PEW (HR 5.88 (2.29-15.09), p < 0.001). The hospitalization rate, however, was not influenced independently by nutritional status. CONCLUSIONS: Low 25-OH-vitamin D(3) concentration is an independent predictor for survival, but not for hospitalization of HD patients. It is not merely a malnutrition-associated finding, although a MIS ≥8 further impaired survival prognosis.

Effect of immunoadsorption on refractory idiopathic focal and segmental glomerulosclerosis.

A case of a young adult with refractory nephrotic syndrome due to focal segmental glomerulosclerosis is reported. Several treatments had been used without success including steroids, cyclophosphamide, cyclosporine A, tacrolimus, and mycophenolate mofetil. Immunoadsorption was performed as a last resort to manage the nephrotic syndrome, which led to a drastic urinary protein reduction. We review the literature supporting immunoadsorption in primary focal segmental glomerulosclerosis.

Anemia and elevated systemic levels of vascular endothelial growth factor (VEGF).

BACKGROUND: Tissue hypoxia is a major stimulus for the up-regulation of vascular endothelial growth factor (VEGF). Anemia might theoretically impact on angiogenesis via impairment of tissue oxygenation. We have investigated this hypothesis in patients with solid cancers and benign diseases. PATIENTS AND METHODS: 49 patients with untreated locoregionally confined solid cancers of the head and neck, cervix, rectum and lung and 59 additional patients with non-malignant diseases (36 normemic patients without serious diseases and 23 patients with renal anemia) were enrolled and the impact of anemia on plasma VEGF levels were determined. VEGF was measured with a commercially available sandwich enzyme immunoassay technique. RESULTS: Plasma levels of VEGF were 16.2 +/- 12.7 pg/ml in 36 normemic patients without malignant disease, 49.2 +/- 34.5 pg/ml in 49 patients with cancers (p < 0.001), and 89.9 +/- 67.8 pg/ml in 23 patients with renal anemia (p = 0.001). VEGF levels in cancer patients were significantly correlated with hemoglobin (hb) levels and platelet counts (each p = 0.001), but not with type of tumor, stage, histology or age. Patients with cancers had higher plasma levels of VEGF than patients with non-malignant diseases in case of hb > or = 12 g/dl (33.1 +/- 17.5 vs 16.6 +/- 13.0 pg/ml, p < 0.001) and in case of hb between 11.0 and 11.9 g/dl (56.1 +/- 26.4 vs 18.5 +/- 14.5 pg/ml, p = 0.038). In case of a hb < 11 g/dl, plasma VEGF levels were significantly elevated in patients with and without cancers (67.0 +/- 47.5 vs 88.9 +/- 68.8 pg/ml, n.s.). In a multivariate model, a significant association between low hb levels and increased plasma levels of VEGF was confirmed. In 16 patients with renal anemia, changes in hb under erythropoietin treatment were inversely correlated with changes in plasma VEGF levels with decreasing VEGF after increase in hb (p = 0.01). CONCLUSIONS: Anemic patients have elevated levels of VEGF. The data suggest that anemia might impact on the progression of angiogenesis in malignant and benign diseases.