Time-dependent lipid profile inversely associates with mortality in hemodialysis patients - independent of inflammation/malnutrition.

BACKGROUND: Patients with end-stage kidney disease have an extremely high cardiovascular mortality rate, but there is a paradoxical relationship between lipid profile and survival in haemodialysis patients. To investigate whether inflammation/malnutrition confounds the associations between lipids and mortality, we studied a full lipid profile comprising of five clinically well-established lipid parameters and its associations with mortality in a large, multinational European cohort with a median follow-up >3 years. METHODS: The association between quartiles of total, high-density lipoprotein (HDL), non-HDL, low-density lipoprotein (LDL) cholesterol, as well as triglyceride, levels and the end-points of all-cause, cardiovascular and non-cardiovascular mortality was assessed in a cohort of 5,382 incident, adult haemodialysis patients from >250 Fresenius Medical Care dialysis centres out of 14 participating countries using baseline and time-dependent Cox models. Analyses were fully adjusted and stratified for inflammation/malnutrition status and other patient-level variables. RESULTS: Time-dependent quartiles of total, HDL, non-HDL and LDL cholesterol were inversely associated with the hazard for all-cause, cardiovascular and non-cardiovascular mortality. Compared with the lowest quartile of the respective lipid parameter, hazard ratios of other quartiles were <0.86. Similar, albeit weaker, associations were found with baseline lipid profile and mortality. Neither time-dependent nor baseline associations between lipid profile and mortality were affected by inflammation/malnutrition, statin use or geography. CONCLUSIONS: Baseline and time-dependent lipid profile are inversely associated with mortality in a large, multicentre cohort of incident haemodialysis patients. Inflammation/malnutrition is not a confounder nor effect modificator of the associations between lipid profile and mortality in European haemodialysis patients.

Heart failure in advanced chronic kidney disease: treatment rationale.

Patients with chronic kidney disease (CKD) exhibit an increased risk to develop heart failure and the presence of heart failure in patients with CKD leads to a worse prognosis. The following overview article summarizes the current standard of medical heart failure therapy and discusses the treatment characteristics in patients with CKD.

[Immunoglobulin A nephropathy]. / Immunglobulin-A-Nephropathie.

Immunoglobulin A nephropathy (IgAN) is the most prevalent primary form of glomerulopathy in the western world. The pathogenetic relevance of autoimmune mechanisms, genetics and environmental or nutritional factors is not fully established. The majority of IgAN patients present with mild symptoms; however, the exact prognosis of the individual IgAN course is often difficult to predict. In approximately one third of the patients the disease remains on a stable benign course, whereas approximately 30% may develop end-stage renal disease. Risk factors for disease progression are a persistent microhematuria and proteinuria >1 g/day, arterial hypertension and the extent of tubulointerstitial fibrosis at the time of diagnosis. Recent genome-wide association studies (GWAS) identified numerous risk alleles, which can contribute to the pathophysiology of IgAN. The so-called gut-kidney axis as well as the complement system and genes that are linked to mucosal immunity appear to be important for the manifestation of the disease. Intensive supportive care should be initiated as first-line treatment and only rare cases with progressive features require treatment with corticosteroids. Other immunosuppressive treatment strategies have currently no indications for IgAN. Future approaches might be the use of local budesonide or the inhibition of lymphocyte activation.

[What is certain in the treatment of glomerulonephritis?] / Was ist gesichert in der Therapie der Glomerulonephritis?

Glomerulonephritides essentially all belong to the rare diseases; however, they are the most common cause of end-stage renal disease in young adults. Besides obtaining a specific diagnosis via a renal biopsy, assessing the prognosis constitutes the other essential step in the work-up, since this enables a decision to be made on whether supportive care with relatively few adverse effects is sufficient or whether additional immunosuppressive therapy is required. The latter is discussed focusing on the most common European types of glomerulonephritis: immunoglobulin A nephropathy, membranous glomerulonephritis, minimal change nephropathy and focal segmental glomerulosclerosis.

[Choosing wisely recommendations in nephrology]. / Klug-entscheiden-Empfehlungen in der Nephrologie.

The German Society of Internal Medicine ("Deutsche Gesellschaft für Innere Medizin", DGIM) founded the Choosing wisely initiative in order to address diagnostic and therapeutic procedures that are frequently inappropriately applied, whether this be in terms of over-, under-, or misuse of health services. The German Society of Nephrology ("Deutsche Gesellschaft für Nephrologie," DGfN) strongly supports the initiative and has contributed five positive and five negative recommendations. These ten recommendations are discussed in the current publication. The positive recommendations reflect the importance of early recognition of renal disease via simple blood and urine tests, the use of radiocontrast media in cases of impaired renal function, as well as the problems associated with low vaccination rates. Three of the negative recommendations are focused on hydration and diuretics. The remaining two negative recommendations concern angioplasty in cases of renal artery stenosis and the unconsidered use of nonsteroidal anti-inflammatory drugs.

[Anticoagulation in patients with chronic kidney disease : Recommendations from the working group "Heart-Kidney" of the German Cardiac Society and the German Society of Nephrology]. / Antikoagulation bei Patienten mit chronischer Niereninsuffizienz : Empfehlungen der Arbeitsgemeinschaft "Herz ­ Niere" der Deutschen Gesellschaft für Kardiologie ­ Herz- und Kreislaufforschung und der Deutschen Gesellschaft für Nephrologie.

Indications for anticoagulation are thromboembolic events, prosthetic heart valves, and atrial fibrillation with a corresponding risk score. Clinical trials have excluded patients with advanced chronic kidney disease and these data cannot be always generalized to patients with chronic kidney disease. Non-vitamin K antagonist oral anticoagulants (NOACs) are mostly not recommended or are contraindicated in advanced stages of chronic kidney disease. Observational studies have shown that dialysis patients with atrial fibrillation do not profit from coumarin anticoagulants; prospective studies are lacking.

Renal allograft fibrosis: biology and therapeutic targets.

Renal tubulointerstitial fibrosis is the final common pathway of progressive renal diseases. In allografts, it is assessed with tubular atrophy as interstitial fibrosis/tubular atrophy (IF/TA). IF/TA occurs in about 40% of kidney allografts at 3-6 months after transplantation, increasing to 65% at 2 years. The origin of renal fibrosis in the allograft is complex and includes donor-related factors, in particular in case of expanded criteria donors, ischemia-reperfusion injury, immune-mediated damage, recurrence of underlying diseases, hypertensive damage, nephrotoxicity of immunosuppressants, recurrent graft infections, postrenal obstruction, etc. Based largely on studies in the non-transplant setting, there is a large body of literature on the role of different cell types, be it intrinsic to the kidney or bone marrow derived, in mediating renal fibrosis, and the number of mediator systems contributing to fibrotic changes is growing steadily. Here we review the most important cellular processes and mediators involved in the progress of renal fibrosis, with a focus on the allograft situation, and discuss some of the challenges in translating experimental insights into clinical trials, in particular fibrosis biomarkers or imaging modalities.

[Glomerulonephritides]. / Glomerulonephritiden.

Many forms of glomerulonephritis, even the more common types belong to the so-called rare diseases; however, they are very important, for example with respect to health economics as they often affect young people. An example is immunoglobulin A (IgA) nephropathy, which is the most common cause of end stage renal disease in young adults. This review summarizes the current knowledge on the pathogenesis, clinical presentation and therapy of the most common European types of glomerulonephritis with a special focus on the most recently acquired knowledge on IgA nephropathy, membranous glomerulonephritis, minimal change nephropathy and focal segmental glomerulosclerosis (FSGS).

Long-term sustainability of hand hygiene improvements in the hemodialysis setting.

PURPOSE: In a previous observational intervention study, we achieved a more than 100 % increase in overall hand hygiene (HH) compliance in the hemodialysis setting by increasing the number of hand rubs (HR) performed and concomitantly optimizing HH standard operating procedures (SOPs). SOPs were mainly aimed at reducing the number of avoidable opportunities due to a less than perfect workflow. However, the long-term sustainability of this successful intervention was not evaluated. The present study was carried out to evaluate the long-term effects of our previous successful intervention. METHODS: We conducted a follow-up observational study 1 year after the first intervention study in the same hemodialysis unit to assess the sustainability. No HH-related interventions were performed in the 1 year between studies. The main outcome was HH compliance, and the secondary outcome was opportunities per hemodialysis procedure. RESULTS: A total of 1,574 opportunities for HH and 871 hand rubs (HR) were observed during the follow-up observational study. Overall, compliance was 55 %, which was significantly than that at the end of the first study (62 %; p < 0.0001), but significantly higher than that at the start and mid-term phases of the first study (37 and 49 %, p < 0.0001). Both the decrease in HH opportunities and the increase in HR were sustained over the course of this observational study. The number of avoidable opportunities in the present study was similar to that at the end of the previous study. Thus, in 320 opportunities (20 %), gloves were worn instead of HR performed, representing 46 % of all missed HR. CONCLUSIONS: Despite a decrease in HH compliance compared to the last postintervention period, a multifaceted intervention focusing on standardization and workflow optimization resulted in a sustained improvement in HH. We therefore propose that standardization of the hemodialysis workflow aimed at improving HH is a promising avenue for improving the quality of patient care and outcome.

[Calciphylaxis. A call for interdisciplinary cooperation]. / Kalziphylaxie. Eine nephrologisch-dermatologische Herausforderung.

Calciphylaxis is a rare, often very painful and potentially life-threatening disorder at the interface between nephrology and dermatology. It is characterized by skin lesions and ulcerations following calcification and occlusion of cutaneous arterioles. Most patients have chronic kidney disease or are on dialysis. A concert of various, still incompletely understood local and systemic risk factors is necessary to cause the development of calciphylaxis. Since randomized prospective trials are missing, interdisciplinary treatment is based on pathophysiological considerations as well as evidence derived from case reports or case series. Normalization of mineral metabolism, intensifying dialysis and avoidance of coumarins, as well as administration of calcimimetics, bisphosphonates and sodium thiosulfate and hyperbaric oxygen therapy are often used. Supportive measures include analgesics, antibiotics and local wound care. We have initiated an internet-based registry for patients with calciphylaxis in order to collect data for improved patient care (with support from Amgen) (www.calciphylaxie.de).

Inhibition of mesangial cell proliferation and matrix expansion in glomerulonephritis in the rat by antibody to platelet-derived growth factor.

Platelet-derived growth factor (PDGF), a potent mitogen for mesenchymal cells in culture, is expressed in vivo in a variety of inflammatory conditions associated with cell proliferation, including atherosclerosis, wound repair, pulmonary fibrosis, and glomerulonephritis. However, it is not known if PDGF mediates the fibroproliferative responses that characterize these inflammatory disorders. We administered neutralizing anti-PDGF IgG or control IgG to rats with mesangial proliferative nephritis. Inhibition of PDGF resulted in a significant reduction in mesangial cell proliferation, and largely prevented the increased deposition of extracellular matrix associated with the disease. This suggests that PDGF may have a central role in proliferative glomerular disease.

Modulation of peripheral chemoreflex by neurohumoral adaptations after kidney transplantation.

BACKGROUND: Peripheral chemoreceptors residing predominantly in the carotid body monitor changes in arterial blood oxygen and are mechanistically linked to the cardiorespiratory control by the autonomic nervous system. Enhanced sympathetic activation is common in end-stage renal disease and kidney transplantation has been shown to improve cardiorespiratory reflex measures of autonomic function. OBJECTIVE: The aim of the present study was to test whether improvement in renal function following kidney transplantation is related to an improvement in chemosensory function. METHODS AND RESULTS: We compared hyperoxic chemoreflex sensitivity (CHRS) in patients after renal transplantation (RTX) to that in patients on maintenance hemodialysis (HD), and that of age- and gender-matched healthy controls. In addition, we investigated the impact of common confounding factors including pharmacological neurohumoral modulation and diabetes mellitus. The difference in the R-R intervals divided by the difference in the oxygen pressures before and after deactivation of the chemoreceptors by 5-min inhalation of 7 L oxygen was calculated as the hyperoxic CHRS. Autonomic activity was characterized by 24-h time-domain heart rate variability (HRV) parameters. CHRS was improved in RTX patients as compared to HD patients being related to HRV. CHRS was related to the concomitant presence of diabetes and medication with cyclosporine. CONCLUSION: Our findings indicate that chemosensory activity following kidney transplantation is related to cardiac autonomic control, but functional testing might only be useful to characterize the time course and extent of sympathetic activation in selected patients due to existing co-morbidities and immunosuppressive medication in this population.

[When only the pathologist may help. Limitation and possibilities of biopsies in Internal Medicine]. / Wenn nur noch der Pathologe hilft. Grenzen und Möglichkeiten der Biopsie in der Inneren Medizin.

Histological evaluation after biopsy remains the gold standard for the diagnosis of numerous diseases in Internal Medicine. The gastrointestinal tract (e. g. esophagus, liver and large intestine), the kidneys or bone marrow are organs, where biopsy-driven diagnosis and evaluation of therapeutic regimens are of major relevance. Improvement in blood analysis, endoscopic techniques and radiology could significantly reduce the number of biopsies. Hence under certain circumstances, the risk of biopsy can be avoided and non-invasive markers can sufficiently substitute the histological evaluation. However, histological evaluation derived from biopsies remains the standard of diagnosis in many cases in Internal Medicine. In the present review the current standards and future developments of pathologic diagnosis through biopsy are illustrated.

Case series of idiopathic membranous nephropathy with long-term beneficial effects of ACTH peptide 1-24.

BACKGROUND: In patients with idiopathic membranous nephropathy (IMN), immunosuppressive therapy is usually considered when severe nephrotic syndrome or risk for progressive renal failure exist. Recently, several studies showing beneficial effects of synthetic adrenocorticotropic hormone (ACTH) under such circumstances have been published. The objective of the present case series was to evaluate long-term ACTH effects on proteinuria and renal function. METHODS: Four patients with biopsy-proven membranous nephropathy and nephrotic syndrome were enrolled (median age 50 years (range 38 - 61), median GFR 39.5 ml/min (range 20 - 62), median proteinuria 9.6 g/d (range 6.0 - 20.0). Prior immunosuppressive treatment regimens included steroids, cyclosporine A, cyclophosphamide, mycophenolate mofetil or azathioprine. The patients received a synthetic ACTH analogue intramuscularly for a median duration of 8 months (range 3 - 24). ACTH dosage was adjusted according to side effects between 0.25 and 2.25 mg/week. Follow-up lasted between 24 and 82 months after therapy initiation. RESULTS: All 4 patients exhibited partial (n = 2) or complete (n = 2) remissions of their nephrotic syndrome within the first year. After discontinuation of ACTH therapy, proteinuria remained low in 3 of 4 cases, whereas 1 patient exhibited undulating proteinuria. Glomerular function (as assessed by glomerular filtration rate, GFR) was maintained in all patients. Side effects were minor and included weight gain, elevated blood pressure and hyperglycemia. CONCLUSION: In all 4 cases with IMN, ACTH treatment induced a lasting disease remission with relatively few side effects.

Rat glomerular mesangial cells synthesize basic fibroblast growth factor. Release, upregulated synthesis, and mitogenicity in mesangial proliferative glomerulonephritis.

Mesangial injury and cell proliferation are frequent findings in various glomerular diseases in man. Previous studies have demonstrated that basic fibroblast growth factor (bFGF) is a potent mesangial cell mitogen in vitro. To further elucidate the role of bFGF in rat mesangial cell (RMC) proliferation, we examined whether RMC synthesize bFGF in vitro and whether bFGF is involved in mesangial proliferation in vivo. Cultured RMC expressed bFGF protein (23, 21.5, and 18 kD forms) and bFGF mRNA, and released biologically active bFGF into the culture medium after antibody- and complement-mediated injury. Normal rat glomeruli in vivo contained no detectable bFGF mRNA, but bFGF protein (23 and 21.5 kD) could be demonstrated, which immunolocalized to the mesangium. Glomerular bFGF decreased markedly during the acute phase of glomerulonephritis induced by anti-Thy 1.1 antibody, compatible with mesangial bFGF release after complement-mediated mesangiolysis. During the subsequent mesangial proliferative phase, glomerular bFGF protein and mRNA increased above normal. Intrarenal infusion of heparin did not affect the bFGF immunostaining of glomeruli at this stage, indicating a predominantly intracellular localization of the bFGF. The capability of bFGF to mediate proliferation in the anti-Thy 1.1 model was further supported by experiments in which intravenous bFGF given 24 h after a subnephritogenic dose of anti-Thy 1.1 antibody led to a 4.9- to 5.1-fold increase in glomerular cell proliferation (with > 60% of the cells identified as mesangial cells by double immunolabeling). No such increase was observed in normal rats injected with bFGF. These data show that mesangial cells produce and release bFGF after injury and that bFGF is mitogenic for injured mesangial cells in vivo. Release of mesangial cell bFGF thus may be an important mechanism involved in the initiation of mesangial cell proliferation in vivo.

Basic fibroblast growth factor augments podocyte injury and induces glomerulosclerosis in rats with experimental membranous nephropathy.

Podocyte injury is believed to contribute to glomerulosclerosis in membranous nephropathy. To identify the factors involved, we investigated the effects of basic fibroblast growth factor (bFGF), a cytokine produced by podocytes, on rats with membranous nephropathy (passive Heymann nephritis [PHN]). All rats received a daily i.v. bolus of 10 microg bFGF or vehicle from days 3-8 after PHN induction. In proteinuric PHN rats on day 8, bFGF injections further increased proteinuria. Podocytes of bFGF-injected PHN rats showed dramatic increases in mitoses, pseudocyst formation, foot process retraction, focal detachment from the glomerular basement membrane, and desmin expression. bFGF injections in PHN rats did not alter antibody or complement deposition or glomerular leukocyte influx. bFGF-injected PHN rats developed increased glomerulosclerosis when compared with control PHN rats. Also, bFGF induced proteinuria and podocyte damage in rats injected with 10% of the regular PHN-serum dose. None of these changes occurred in bFGF-injected normal rats, complement-depleted PHN rats or rats injected with 5% of the regular PHN serum dose. These divergent bFGF effects were explained in part by upregulated glomerular bFGF receptor expression, induced by PHN serum. Thus, bFGF can augment podocyte damage, resulting in increased glomerular protein permeability and accelerated glomerulosclerosis. This bFGF action is confined to previously injured podocytes. Release of bFGF from glomerular sources (including podocytes themselves) during injury may represent an important mechanism by which podocyte damage is enhanced or becomes self sustained.

VEGF(165) mediates glomerular endothelial repair.

VEGF(165), the most abundant isoform in man, is an angiogenic cytokine that also regulates vascular permeability. Its function in the renal glomerulus, where it is expressed in visceral epithelial and mesangial cells, is unknown. To assess the role of VEGF(165) in glomerular disease, we administered a novel antagonist - a high-affinity, nuclease-resistant RNA aptamer coupled to 40-kDa polyethylene glycol (PEG) - to normal rats and to rats with mesangioproliferative nephritis, passive Heymann nephritis (PHN), or puromycin aminonucleoside nephrosis (PAN). In normal rats, antagonism of VEGF(165) for 21 days failed to induce glomerular pathology or proteinuria. In rats with mesangioproliferative nephritis, the VEGF(165) aptamer (but not a sequence-scrambled control RNA or PEG alone) led to a reduction of glomerular endothelial regeneration and an increase in endothelial cell death, provoking an 8-fold increase in the frequency of glomerular microaneurysms by day 6. In contrast, early leukocyte influx and the proliferation, activation, and matrix accumulation of mesangial cells were not affected in these rats. In rats with PHN or PAN, administration of the VEGF(165) aptamer did not influence the course of proteinuria using various dosages and administration routes. These data identify VEGF(165) as a factor of central importance for endothelial cell survival and repair in glomerular disease, and point to a potentially novel way to influence the course of glomerular diseases characterized by endothelial cell damage, such as various glomerulonephritides, thrombotic microangiopathies, or renal transplant rejection.

Infusion of platelet-derived growth factor or basic fibroblast growth factor induces selective glomerular mesangial cell proliferation and matrix accumulation in rats.

Mesangial cell (MC) proliferation and extracellular matrix expansion are involved in the pathogenesis of glomerulosclerosis and renal failure. In vitro, PDGF and basic fibroblast growth factor (bFGF) regulate MC proliferation and/or matrix production. To elucidate the role of PDGF and bFGF in vivo, equimolar concentrations of recombinant PDGF-BB or bFGF or vehicle were infused intravenously into rats over a 7-d period. Rats were either nonmanipulated ("normals") or had received a subnephritogenic dose of anti-MC antibody ("anti-Thy 1.1 rats") before the infusion period. Glomerular cell proliferation (anti-proliferating cell nuclear antigen immunostaining) on days 2, 4, and 7 was unchanged in vehicle-infused normals or anti-Thy 1.1 rats. PDGF infusion increased glomerular cell proliferation 32-fold in anti-Thy 1.1 rats and an 11-fold in normals on day 2. bFGF increased glomerular cell proliferation fourfold in anti-Thy 1.1 rats but was ineffective in normals. Induction of cell proliferation in all kidneys was limited to the glomerulus. The majority of proliferating cells were identified as MC by double immunolabeling. No significant proteinuria, glomerular leukocyte, or platelet influx developed in any group. Glomerular matrix expansion with increased deposition of type IV collagen, laminin, and fibronectin, as well as upregulated laminin and collagen IV mRNA expression was confined to PDGF-infused anti-Thy 1.1 rats. These results show that PDGF and, to a lesser degree, bFGF are selective MC mitogens in vivo and that previous subclinical injury can enhance this MC response. The data thereby support a role of these cytokines in the pathogenesis of glomerulosclerosis.

PDGF-B gene single-nucleotide polymorphisms are not predictive for disease onset or progression of IgA nephropathy.

BACKGROUND: Few genetic factors have been identified that determine susceptibility to and progression of IgA-nephropathy (IgAN). Given that IgAN is usually characterized by mesangioproliferative glomerulonephritis and that PDGF-B is of central pathophysiological relevance in this process, we analyzed four single-nucleotide polymorphisms (SNPs) of the PDGF-B gene to evaluate a possible association of these SNPs with disease onset and progression, histological grading and responses to ACE inhibitor (ACEi) therapy. METHODS: The total study population consisted of 195 IgAN patients (127 from southern Italy and 68 from northern Germany) and 200 healthy controls (100 from each region). All four SNPs were in Hardy-Weinberg equilibrium and genotype distributions did not differ between patients and controls in either region. RESULTS: SNP distribution in Italian patients reaching end-stage renal disease (n=45) also was not significantly different from patients maintaining a serum creatinine below 1.2 mg/dl (n=60) during 5.6 +/- 5.5 years of follow-up. Furthermore, we failed to detect significant effects of any SNP on the slope of 1/serum creatinine, proteinuria level or the antiproteinuric response to ACEi. Additionally, particular PDGF-B genotypes did not correlate with histological grading using the Lee classification. CONCLUSION: We conclude that none of the four PDGF-B SNPs is related to the onset of IgAN in two different populations and that none of them has a major influence on the course of IgAN.

The effects of cinacalcet on blood pressure, mortality and cardiovascular endpoints in the EVOLVE trial.

Patients with end-stage renal disease often have derangements in calcium and phosphorus homeostasis and resultant secondary hyperparathyroidism (sHPT), which may contribute to the high prevalence of arterial stiffness and hypertension. We conducted a secondary analysis of the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial, in which patients receiving hemodialysis with sHPT were randomly assigned to receive cinacalcet or placebo. We sought to examine whether the effect of cinacalcet on death and major cardiovascular events was modified by baseline pulse pressure as a marker of arterial stiffness, and whether cinacalcet yielded any effects on blood pressure. As reported previously, an unadjusted intention-to-treat analysis failed to conclude that randomization to cinacalcet reduces the risk of the primary composite end point (all-cause mortality or non-fatal myocardial infarction, heart failure, hospitalization for unstable angina or peripheral vascular event). However, after prespecified adjustment for baseline characteristics, patients randomized to cinacalcet experienced a nominally significant 13% lower adjusted risk (95% confidence limit 4-20%) of the primary composite end point. The effect of cinacalcet was not modified by baseline pulse pressure (Pinteraction=0.44). In adjusted models, at 20 weeks cinacalcet resulted in a 2.2 mm Hg larger average decrease in systolic blood pressure (P=0.002) and a 1.3 mm Hg larger average decrease in diastolic blood pressure (P=0.002) compared with placebo. In summary, in the EVOLVE trial, the effect of cinacalcet on death and major cardiovascular events was independent of baseline pulse pressure.