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[Background:] Tertiary lymphoid tissues (TLTs) are ectopic lymphoid tissues found in chronically inflamed organs. Although studies have documented TLT formation in transplanted kidneys, the clinical relevance of these TLTs remains controversial. We examined the impacts of TLTs on future graft function using our histological TLT maturity stages and the association between TLTs and Banff pathologic scores. We also analyzed the risk factors for the development of TLTs. [Methods:] Serial protocol biopsy samples (0-hour, 1-, 6-, and 12-months) without rejection were retrospectively analyzed from 214 patients who underwent living donor kidney transplantation. TLTs were defined as lymphocyte aggregates with signs of proliferation and their stages were determined by the absence (stage I) or presence (stage II) of follicular dendritic cells. [Results:] Only 4% of patients exhibited TLTs at the 0-hour biopsy. Prevalence increased to almost 50% at the 1-month biopsy and then slightly further for 12 months. The proportion of advanced stage II TLTs increased gradually, reaching 19% at the 12-month biopsy. Presence of stage II TLTs was associated with higher risk of renal function decline after transplantation compared to patients with no TLT or stage I TLTs. Stage II TLTs were associated with more severe tubulitis and interstitial fibrosis/tubular atrophy at 12 months and predicted poorer graft function independently from the degree of interstitial inflammation. Pre-transplantation rituximab treatment dramatically attenuated the development of stage II TLTs. [Conclusions:] TLTs are commonly found in clinically stable transplanted kidneys. Advanced stage II TLTs are associated with progressive graft dysfunction, independent of interstitial inflammation., 移植腎の三次リンパ組織は腎予後と関連することを解明. 京都大学プレスリリース. 2021-11-02.

Cells : open access journal 10(8), 2097 (2021). doi:10.3390/cells10082097 special issue: "Special Issue "Research on Vascular Calcification in Cardiovascular Disease" / Special Issue Editors: Prof. Dr. Leon Schurgers, Guest Editor; Dr. Peter Stenvinkel, Guest Editor", Published by MDPI, Basel

Die Immunglobulin-A-Nephropathie (IgAN) ist die haufigste primare Glomerulonephritisform in der westlichen Welt. Die pathogenetische Bedeutung von autoimmunen Mechanismen, Genetik und Umwelt- bzw. Ernahrungsfaktoren ist nicht abschliesend geklart. Ein masgeblicher Anteil der Patienten prasentiert sich mit milden Symptomen, jedoch ist die individuelle Prognose einer IgAN oftmals schwer vorhersagbar. Bei etwa einem Drittel der Patienten nimmt die Erkrankung einen stabilen, benignen Verlauf, wohingegen sich bei etwa 30 % eine chronische Niereninsuffizienz mit drohender Dialysepflicht entwickelt. Als Risikofaktoren fur die Progression der Erkrankung gelten eine persistierende Mikrohamaturie und Proteinurie uber 1 g/Tag, das Vorliegen einer arteriellen Hypertonie und das Ausmas der tubulointerstitiellen Fibrose bei Diagnosestellung. In neueren genomweiten Assoziationsstudien konnten zahlreiche Risikoallele identifiziert werden, die zur Pathophysiologie der IgAN beitragen. Dabei ruckt die sogenannte Darm-Nieren-Achse, aber auch das Komplementsystem zunehmend in den Fokus. Neben intensivierten supportiven Therapiemasnahmen spielt die Steroidtherapie in seltenen Fallen weiterhin eine Rolle, wohingegen andere immunsuppressive Strategien uberwiegend verlassen wurden. Zudem werden neue Therapieansatze verfolgt, von verkapseltem Budesonid bis hin zur Hemmung der Lymphozytenaktivierung.

Kidney international 101(3), 574-584 (2022). doi:10.1016/j.kint.2021.10.018, Published by Elsevier, New York, NY

In COVID-19, guidelines recommend a urinalysis on hospital admission as SARS-CoV-2 renal tropism, post-mortem, was associated with disease severity and mortality. Following the hypothesis from our pilot study, we now validate an algorithm harnessing urinalysis to predict the outcome and the need for ICU resources on admission to hospital. Patients were screened for urinalysis, serum albumin (SA) and antithrombin III activity (AT-III) obtained prospectively on admission. The risk for an unfavorable course was categorized as (1) “low”, (2) “intermediate” or (3) “high”, depending on (1) normal urinalysis, (2) abnormal urinalysis with SA ≥ 2 g/dL and AT-III ≥ 70%, or (3) abnormal urinalysis with SA or AT-III abnormality. Time to ICU admission or death served as the primary endpoint. Among 223 screened patients, 145 were eligible for enrollment, 43 falling into the low, 84 intermediate, and 18 into high-risk categories. An abnormal urinalysis significantly elevated the risk for ICU admission or death (63.7% vs. 27.9%, HR 2.6, 95%-CI 1.4 to 4.9, p = 0.0020) and was 100% in the high-risk group. Having an abnormal urinalysis was associated with mortality, a need for mechanical ventilation, extra-corporeal membrane oxygenation or renal replacement therapy. In conclusion, our data confirm that COVID-19-associated urine abnormalities on admission predict disease aggravation and the need for ICU (ClinicalTrials.gov number NCT04347824).

Introduction: Patients with chronic kidney disease (CKD) and non-valvular atrial fibrillation (NVAF) are at increased risk for both ischemic stroke and hemorrhage. In addition, treatment with vitamin K antagonists (VKA) has been associated with worsening of renal function compared to direct oral anticoagulants (DOACs). XARENO (Factor XA -inhibition in RENal patients with non-valvular atrial fibrillation Observational registry) is an ongoing prospective, non-interventional, observational study conducted in Europe. XARENO evaluates the effectiveness of rivaroxaban in preserving renal function and preventing thromboembolic events as compared to VKA in NVAF patients with CKD in clinical practice. Methods: XARENO included male and female NVAF patients ≥18 years old with an estimated glomerular filtration rate (eGFR) between 15 and 49 mL/min per 1.73 m 2 and an indication for anticoagulation. Enrolment took place from April 2016 until January 2020. Patients treated with either rivaroxaban or VKA were included, while patients in whom physicians were withholding any anticoagulation could be also enrolled. Minimal planned follow-up is one year. Primary observational outcomes include efficacy and safety outcomes (progression of CKD, stroke, other thromboembolic events, major cardiovascular events, major bleeding, and all-cause mortality). First results on outcomes in the full cohort are expected in 2021. Results: In this analysis of a first set of 1485 patients (56.1% males), 731 and 666 patients received rivaroxaban and VKA, while 88 patients did not receive any anticoagulation. Mean age at baseline was 77.3 years (67.5% older than 75 years) with a mean eGFR of 38.9 mL/min per 1.73 m 2 . Overall 74.7% of patients had eGFR values below 45 mL/min per 1.73 m 2 and 28.0% below 30 mL/min per 1.73 m 2 . In the latter group, use of a VKA was about twofold more frequent compared to rivaroxaban. Conclusions: This first analysis of XARENO patients reveals the very high age of NVAF patients with concomitant non-dialysis dependent advanced CKD and a preferential use of VKA in stage 4 CKD. XARENO aims to provide important information on the real-world effectiveness and safety of rivaroxaban compared with VKA for this vulnerable patient group.

International journal of molecular sciences 21(18), 6547 (2020). doi:10.3390/ijms21186547 special issue: "Special Issue "The Role of Non-coding RNAs in Kidney Diseases" / Special Issue Editors: Prof. Dr. Laurent Metzinger, Guest Editor; Dr. Juan Antonio Moreno, Guest Editor; Dr. Valérie Metzinger-Le Meuth, Guest Editor", Published by Molecular Diversity Preservation International, Basel

Glomerulonephritiden stellen praktisch ausnahmslos seltene Erkrankungen dar, sind aber unter anderem der haufigste Grund, warum junge Erwachsene dialysepflichtig werden. Neben der bioptischen, spezifischen Diagnosesicherung stellt die Abschatzung der Prognose einen entscheidenden Schritt dar, da nur so beurteilt werden kann, ob eine vergleichsweise nebenwirkungsarme, aber hocheffektive „supportive“ Therapie ausreichend ist oder ob zusatzlich eine immunsuppressive Behandlung notwendig wird. Letzteres wird hier fur die haufigsten europaischen Glomerulonephritisformen diskutiert: Immunglobulin-A-Nephropathie, membranose Glomerulonephritis, Minimal-change-Nephropathie und fokal-segmentale Glomerulosklerose.

Nicht-Vitamin-K-abhangige orale Antikoagulanzien (NOAK) werden zur Schlaganfallprophylaxe bei Vorhofflimmern mit entsprechendem Risikoscore sowie zur Therapie venoser thromboembolischer Ereignisse (wie tiefe Beinvenenthrombose und Lungenembolie) und deren Prophylaxe bei rezidivierenden Ereignissen eingesetzt. Die in Studien uberwiegend an nierengesunden Patienten erhobenen Daten sind jedoch nicht immer auf Patienten mit chronischer Niereninsuffizienz ubertragbar. NOAK sind bei hohergradiger Niereninsuffizienz nicht empfohlen bzw. kontraindiziert.

Despite advancements in lowering blood pressure, the best approach to lower it remains controversial because of the lack of information on the molecular basis of hypertension. We, therefore, performed plasma proteomics of plasma from patients with hypertension to identify molecular determinants detectable in these subjects but not in controls and vice versa. Plasma samples from hypertensive subjects (cases; n=118) and controls (n=85) from the InGenious HyperCare cohort were used for this study and performed mass spectrometric analysis. Using biostatistical methods, plasma peptides specific for hypertension were identified, and a model was developed using least absolute shrinkage and selection operator logistic regression. The underlying peptides were identified and sequenced off-line using matrix-assisted laser desorption ionization orbitrap mass spectrometry. By comparison of the molecular composition of the plasma samples, 27 molecular determinants were identified differently expressed in cases from controls. Seventy percent of the molecular determinants selected were found to occur less likely in hypertensive patients. In cross-validation, the overall R 2 was 0.434, and the area under the curve was 0.891 with 95% confidence interval 0.8482 to 0.9349, P P

The German Society of Internal Medicine ("Deutsche Gesellschaft fur 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 fur 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.

Progressive renal diseases are associated with rarefaction of peritubular capillaries, but the ultrastructural and functional alterations of the microvasculature are not well described. To study this, we analyzed different time points during progressive kidney damage and fibrosis in 3 murine models of different disease etiologies. These models were unilateral ureteral obstruction, unilateral ischemia-reperfusion injury, and Col4a3 -deficient mice, we analyzed ultrastructural alterations in patient biopsy specimens. Compared with kidneys of healthy mice, we found a significant and progressive reduction of peritubular capillaries in all models analyzed. Ultrastructurally, compared with the kidneys of control mice, focal widening of the subendothelial space and higher numbers of endothelial vacuoles and caveolae were found in fibrotic kidneys. Quantitative analysis showed that peritubular capillary endothelial cells in fibrotic kidneys had significantly and progressively reduced numbers of fenestrations and increased thickness of the cell soma and lamina densa of the capillary basement membrane. Similar ultrastructural changes were also observed in patient's kidney biopsy specimens. Compared with healthy murine kidneys, fibrotic kidneys had significantly increased extravasation of Evans blue dye in all 3 models. The extravasation could be visualized using 2-photon microscopy in real time in living animals and was mainly localized to capillary branching points. Finally, fibrotic kidneys in all models exhibited a significantly greater degree of interstitial deposition of fibrinogen. Thus, peritubular capillaries undergo significant ultrastructural and functional alterations during experimental progressive renal diseases, independent of the underlying injury. Analyses of these alterations could provide read-outs for the evaluation of therapeutic approaches targeting the renal microvasculature.

ObjectiveCalcifications can disrupt organ function in the cardiovascular system and the kidney, and are particularly common in patients with chronic kidney disease (CKD). Fetuin-A deficient mice maintained against the genetic background DBA/2 exhibit particularly severe soft tissue calcifications, while fetuin-A deficient C57BL/6 mice remain healthy. We employed molecular genetic analysis to identify risk factors of calcification in fetuin-A deficient mice. We sought to identify pharmaceutical therapeutic target that could be influenced by dietary of parenteral supplementation.Approach and ResultsWe studied the progeny of an intercross of fetuin-A deficient DBA/2 and C57BL/6 mice to identify candidate risk genes involved in calcification. We determined that a hypomorphic mutation of the Abcc6 gene, a liver ATP transporter supplying systemic pyrophosphate, and failure to regulate the TRPM6 magnesium transporter in kidney were associated with severity of calcification. Calcification prone fetuin-A deficient mice were alternatively treated with dietary phosphate restriction, magnesium supplementation, or by parenteral administration of fetuin-A or pyrophosphate. All treatments markedly reduced soft tissue calcification, demonstrated by computed tomography, histology and tissue calcium measurement.ConclusionsWe show that pathological ectopic calcification in fetuin-A deficient DBA/2 mice is caused by a compound deficiency of three major extracellular and systemic inhibitors of calcification, namely fetuin-A, pyrophosphate, and magnesium. All three of these are individually known to contribute to stabilize protein-mineral complexes and thus inhibit mineral precipitation from extracellular fluid. We show for the first time a compound triple deficiency that can be treated by simple dietary or parenteral supplementation. This is of special importance in patients with advanced CKD, who commonly exhibit reduced serum fetuin-A, pyrophosphate and magnesium levels.Subject CodesAnimal Models of Human Disease, Fibrosis, Inflammation, Proteomics, Peripheral Vascular Disease

Die IgA-Nephropathie (IgAN) ist die haufigste primare Glomerulonephritis in der westlichen Welt. Ganz uberwiegend manifestiert sie sich oligosymptomatisch mit minimalen Urinbefunden im jungeren Erwachsenenalter. Die meisten Patienten nehmen einen unkomplizierten Verlauf, jedoch entwickeln etwa 20–30 % ein terminales Nierenversagen. Zu den Risikofaktoren fur einen progredienten Verlauf zahlen eine ausgepragte Proteinurie, eine eingeschrankte Nierenfunktion, das Vorliegen einer arteriellen Hypertonie sowie der Nachweis einer ausgepragten tubulointerstitiellen Fibrose zum Zeitpunkt der Diagnose. In den letzten Jahren konnten genetische und immunologische Mechanismen aufgedeckt werden, denen zufolge die IgAN zunehmend als autoimmun (mit)bedingte Erkrankung verstanden wird. Dennoch bleibt – gerade auch nach den neuesten Therapiestudien – der Stellenwert einer immunsuppressiven Therapie hochst fragwurdig. Vielmehr zeigt sich, dass forcierte Supportivmasnahmen im therapeutischen Mittelpunkt stehen sollten.

Background Systemic lupus erythematosus (SLE) is a chronic inflammatory disease that affects the kidneys in about 50% of patients. Lupus nephritis (LN) is a major risk factor for overall morbidity and mortality in SLE patients. Notch signaling constitutes an evolutionarily conserved pathway that determines major decisions in cell proliferation, survival, and differentiation. Objectives To address the role of Notch-3 signalling in the disease development of SLE and particularly LN. Methods We measured renal expression of Notch-3 in kidneys of both, LN patients and lupus-prone MRL.lpr mice. Notch-3-/- and B6. Faslpr/lpr mice were crossbred to generate a B6. Faslpr/lpr Notch-3-/- genotype and we analyzed the spontaneous disease manifestations in 40 week-old mice. Furthermore, we administered antisense oligodeoxynucleotides (ODNs) targeting Notch-3 or scrambled controls in the more aggressive lupus-prone mice strain (MRL. Faslpr/lp) mice starting at week 12 for 3 weeks and analyzed these mice at the age of 16 weeks. Results In 20-week old MRL.lpr mice, receptor Notch-3 and its target gene Hes2 were significantly up-regulated in kidneys in comparison to 8 and 12 week-old littermates. De novo renal Notch-3 expression in lupus mice and SLE patients was especially pronounced in the glomerular compartment. B6. Faslpr/lpr Notch-3-/- mice exhibited an aggravated lupus phenotype with earlier mortality, increased lymph nodes/spleen size, enhanced glomerular collagen IV deposition and increased immune cell infiltration in the kidneys. In line with this, application of anti-sense Notch-3 ODNs in MRL.lpr mice at the time of the transition from clinically inapparent to a manifested disease state (starting at week 12), resulted in accelerated disease progression as evidenced by enhanced lymphadenopathy, splenomegaly and an increase of inflammatory markers Conclusions Overall, these results demonstrate that Notch-3 exerts protective effects in the course of SLE, and its deficiency or inhibition accelerates the development of SLE manifestations. Disclosure of Interest None declared

To develop efficient therapies and identify novel early biomarkers for chronic kidney disease an understanding of the molecular mechanisms orchestrating it is essential. We here set out to understand how differences in CKD origin are reflected in gene expression. To this end, we integrated publicly available human glomerular microarray gene expression data for nine kidney disease entities that account for a majority of CKD worldwide. We included data from five distinct studies and compared glomerular gene expression profiles to that of non-tumor parts of kidney cancer nephrectomy tissues. A major challenge was the integration of the data from different sources, platforms and conditions, that we mitigated with a bespoke stringent procedure. This allowed us to perform a global transcriptome-based delineation of different kidney disease entities, obtaining a landscape of their similarities and differences based on the genes that acquire a consistent differential expression between each kidney disease entity and nephrectomy tissue. Furthermore, we derived functional insights by inferring activity of signaling pathways and transcription factors from the collected gene expression data, and identified potential drug candidates based on expression signature matching. We validated representative findings by immunostaining in human kidney biopsies indicating e.g. that the transcription factor FOXM1 is significantly and specifically expressed in parietal epithelial cells in RPGN whereas not expressed in control kidney tissue. These results provide a foundation to comprehend the specific molecular mechanisms underlying different kidney disease entities, that can pave the way to identify biomarkers and potential therapeutic targets. To facilitate this, we provide our results as a free interactive web application: https://saezlab.shinyapps.io/ckd_landscape/.Translational StatementChronic kidney disease is a combination of entities with different etiologies. We integrate and analyse transcriptomics analysis of glomerular from different entities to dissect their different pathophysiology, what might help to identify novel entity-specific therapeutic targets.

Background/Aims: Vascular calcifications are frequently found among dialysis patients, and the calcification process may influence the patient's outcome. The aim of the present study was to determine the role that vascular calcifications may have on autologous arteriovenous fistula (AVF) survival. Methods: This study included 90 patients (49 males, mean age 62 ± 11) with a native AVF treated by chronic hemodialysis (HD) for more than one year. The overall vascular calcification scores ranged from 0-11 (Adragao score + vascular access calcification score); patients were categorized into mild (score 0-3; n = 36), moderate (score 4-7; n = 24) and severe (score 8-11; n = 30) calcification groups. AVF survival was then followed for 5 years after calcification measurement or until the patient's death/transplantation. Results: Patients with more pronounced vascular calcifications were more frequently diabetic and male. Multiple linear regression analysis showed a significant relationship between calcification score and male gender, diabetes mellitus, previous duration of AVF, low dialysis flow rate and intact parathormone (iPTH) values. After multivariate adjustment for basal differences, Cox proportional analysis revealed a graded impact of calcification scores on AVF failure: moderate scores (were associated with a hazard rate (HR) of 3.82 (95% confidence interval (CI) 1.10-13.23) and severe scores with an HR of 4.65 (CI 0.97-22.38). Conclusion: Vascular calcifications are associated with worse survival of native arteriovenous hemodialysis fistulas.

Hintergrund Die Behandlung von erwachsenen Patienten mit Glomerulonephritiden (GN) stellt eine zentrale Aufgabe, allerdings oftmals auch eine grose Herausforderung fur den klinisch tatigen Nephrologen dar. Die Diagnose einer GN wird zumeist durch eine Nierenbiopsie gestellt, wobei das Erkrankungsspektrum eine Vielzahl sehr unterschiedlicher Krankheitsentitaten umfasst, beispielsweise die IgA-Nephropathie (als die haufigste primare GN), die „Minimal Change“-Glomerulopathie, die primare fokal-segmentale Glomerulosklerose oder die membranose GN.

Background: Patients on haemodialysis (HD) exhibit increased cardiovascular mortality associated with accelerated vascular calcification (VC). VC is influenced by inhibitors such as matrix Gla protein (MGP), a protein activated in the presence of vitamin K. HD patients exhibit marked vitamin K deficiency, and supplementation with vitamin K reduces inactive MGP levels in these patients. The VitaVasK trial analyses whether vitamin K1 supplementation affects the progression of coronary and aortic calcification in HD patients. Methods: VitaVasK is a prospective, randomized, parallel group, multicentre trial (EudraCT No.: 2010-021264-14) that will include 348 HD patients in an open-label, two-arm design. After baseline multi-slice computed tomography (MSCT) of the heart and thoracic aorta, patients with a coronary calcification volume score of at least 100 will be randomized to continue on standard care or to receive additional supplementation with 5 mg vitamin K1 orally thrice weekly. Treatment duration will be 18 months, and MSCT scans will be repeated after 12 and 18 months. Primary end points are the progression of thoracic aortic and coronary artery calcification (calculated as absolute changes in the volume scores at the 18-month MSCT versus the baseline MSCT). Secondary end points comprise changes in Agatston score, mitral and aortic valve calcification as well as major adverse cardiovascular events (MACE) and all-cause mortality. VitaVask also aims to record MACE and all-cause mortality in the follow-up period at 3 and 5 years after treatment initiation. This trial may lead to the identification of an inexpensive and safe treatment or prophylaxis of VC in HD patients.

Background and objectives Patients receiving hemodialysis are at risk of cardiovascular events. A novel blood test ( T 50 test) determines the individual calcification propensity of blood. Design, setting, participants, & measurements T 50 was determined in 2785 baseline serum samples of patients receiving hemodialysis enrolled in the Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE) trial and the T 50 results were related to patient outcomes. Results Serum albumin, bicarbonate, HDL cholesterol, and creatinine were the main factors positively/directly and phosphate was the main factor negatively/inversely associated with T 50 . The primary composite end point (all-cause mortality, myocardial infarction [MI], hospitalization for unstable angina, heart failure, or peripheral vascular event [PVE]) was reached in 1350 patients after a median follow-up time of 619 days. After adjustments for confounding, a lower T 50 was independently associated with a higher risk of the primary composite end point as a continuous measure (hazard ratio [HR] per 1 SD lower T 50 , 1.15; 95% confidence interval [95% CI], 1.08 to 1.22; P T 50 was associated with a higher risk in all-cause mortality (HR per 1 SD lower T 50 , 1.10; 95% CI, 1.02 to 1.17; P =0.001), MI (HR per 1 SD lower T 50 , 1.38; 95% CI, 1.19 to 1.60; P T 50 , 1.22; 95% CI, 1.05 to 1.42; P =0.01). T 50 improved risk prediction (integrated discrimination improvement and net reclassification improvement, P P =0.001) of the primary composite end point. Conclusions Blood calcification propensity was independently associated with the primary composite end point, all-cause mortality, MI, and PVE in the EVOLVE study and improved risk prediction. Prospective trials should clarify whether T 50 -guided therapies improve outcomes.

Calciprotein particle maturation time (T-50) in serum is a novel measure of individual blood calcification propensity. To determine the clinical relevance of T-50 in renal transplantation, baseline serum T-50 was measured in a longitudinal cohort of 699 stable renal transplant recipients and the associations of T-50 with mortality and graft failure were analyzed over a median follow-up of 3.1 years. Predictive value of T-50 was assessed for patient survival with reference to traditional (Framingham) risk factors and the calcium-phosphate product. Serum magnesium, bicarbonate, albumin, and phosphate levels were the main determinants of T-50, which was independent of renal function and dialysis vintage before transplant. During follow-up, 81(12%) patients died, of which 38 (47%) died from cardiovascular causes. Furthermore, 45(6%) patients developed graft failure. In fully adjusted models, lower T-50 values were independently associated with increased all-cause mortality (hazard ratio, 1.43; 95% confidence interval, 1.11 to 1.85; P=0.006 per SD decrease) and increased cardiovascular mortality (hazard ratio, 1.55; 95% confidence interval, 1.04 to 2.29; P=0.03 per SD decrease). In addition to age, sex, and eGFR, T-50 improved prognostication for all-cause mortality, whereas traditional risk factors or calcium-phosphate product did not. Lower T-50 was also associated with increased graft failure risk. The associations of T-50 with mortality and graft failure were confirmed in an independent replication cohort. In conclusion, reduced serum T-50 was associated with increased risk of all-cause mortality, cardiovascular mortality, and graft failure and, of all tested parameters, displayed the strongest association with all-cause mortality in these transplant recipients.

Cardiovascular calcification is both a risk factor and contributor to morbidity and mortality. Patients with chronic kidney disease (and/or diabetes) exhibit accelerated calcification of the intima, media, heart valves and likely the myocardium as well as the rare condition of calcific uraemic arteriolopathy (calciphylaxis). Pathomechanistically, an imbalance of promoters (e.g. calcium and phosphate) and inhibitors (e.g. fetuin-A and matrix Gla protein) is central in the development of calcification. Next to biochemical and proteinacous alterations, cellular processes are also involved in the pathogenesis. Vascular smooth muscle cells undergo osteochondrogenesis, excrete vesicles and show signs of senescence. Therapeutically, measures to prevent the initiation of calcification by correcting the imbalance of promoters and inhibitors appear to be essential. In contrast to prevention, therapeutic regression of cardiovascular calcification in humans has been rarely reported. Measures to enhance secondary prevention in patients with established cardiovascular calcifications are currently being tested in clinical trials.

BackgroundThe ADVANCE study assessed the progression of vascular and cardiac valve calcification in 360 hemodialysis patients with secondary hyperparathyroidism (sHPT) assigned randomly to treatment either with cinacalcet plus low-dose vitamin D (≤6 μg/week of intravenous paricalcitol equivalent) or with varying doses of vitamin D alone for 52 weeks. The primary efficacy endpoint was progression of coronary artery calcification (CAC).MethodsIn this post-hoc analysis, we compared CAC progression among 70 protocol-adherent subjects given cinacalcet and low doses of vitamin D (CPA) as specified in the study protocol and 120 control subjects given vitamin D sterols. Results Baseline patient characteristics did not differ between CPA and control subjects. The mean (standard error of the mean, SEM) doses of vitamin D at week 2 were 4.7 (0.3) and 12.8 (1.0) μg/week in CPA and control subjects, respectively, and the corresponding mean cumulative doses of vitamin D over 52 weeks in each group were 225 (22) and 671 (47) μg. The median change in Agatston CAC score after 52 weeks was less in CPA subjects than in controls (17.8% versus 31.3%, P = 0.02). The median increase in calcification scores in the aortic valve also was less in CPA subjects than in controls (6.0% versus 51.5% P = 0.02). Reductions in serum parathyroid hormone, calcium and phosphorus levels were significantly greater in CPA subjects than in controls (P < 0.05).ConclusionsThe progression of cardiovascular calcification was attenuated among cinacalcet-treated subjects with sHPT given low doses of vitamin D per protocol compared with control subjects in whom sHPT was treated with higher doses of vitamin D sterols alone.

Background: Vascular calcification is a predictor of cardiovascular morbidity and mortality. Hemodialysis patients experience severe vascular calcifications. Matrix Gla protein (MGP) is a central calcification inhibitor of the arterial wall; its activity depends on vitamin K-dependent gamma-glutamate carboxylation. Uncarboxylated MGP, formed as a result of vitamin K deficiency, is associated with cardiovascular disease. Recent studies suggest poor vitamin K status in hemodialysis patients. We therefore aimed to investigate whether daily vitamin K supplementation improves the bioactivity of vitamin K-dependent proteins in hemodialysis patients, assessed by circulating dephosphorylated-uncarboxylated MGP, uncarboxylated osteocalcin, and uncarboxylated prothrombin (PIVKA-II [protein induced by vitamin K absence II]). Study Design: Interventional randomized non-placebo-controlled trial with 3 parallel groups. Setting & Participants: 53 long-term hemodialysis patients in stable conditions, 18 years or older. 50 healthy age-matched individuals served as controls. Interventions: Menaquinone-7 (vitamin K-2) treatment at 45, 135, or 360 mu g/d for 6 weeks. Outcomes: Plasma levels of dephosphorylated-uncarboxylated MGP, uncarboxylated osteocalcin, and PIVKA-II. Measurements: Plasma levels were assessed using enzyme-linked immunosorbent assays. Results: At baseline, hemodialysis patients had 4.5-fold higher dephosphorylated-uncarboxylated MGP and 8.4-fold higher uncarboxylated osteocalcin levels compared with controls. PIVKA-II levels were elevated in 49 hemodialysis patients. Vitamin K-2 supplementation induced a dose- and time-dependent decrease in circulating dephosphorylated-uncarboxylated MGP, uncarboxylated osteocalcin, and PIVKA-II levels. Response rates in the reduction in dephosphorylated-uncarboxylated MGP levels were 77% and 93% in the groups receiving 135 mu g and 360 mu g of menaquinone-7, respectively. Limitations: Small sample size. Conclusions: This study confirms that most hemodialysis patients have a functional vitamin K deficiency. More importantly, it is the first study showing that inactive MGP levels can be decreased markedly by daily vitamin K-2 supplementation. Our study provides the rationale for intervention trials aimed at decreasing vascular calcification in hemodialysis patients by vitamin K supplementation. Am J Kidney Dis. 59(2):186-195.

Calcific uraemic arteriolopathy (CUA), or calciphylaxis, is a rare disease predominantly occurring in comorbidity with dialysis. Due to the very low frequency of CUA, prospective studies on its management are lacking and even anecdotal reports on treatment remain scarce. Therefore, calciphylaxis is still a challenging disease with dismal prognosis urgently requiring adequate strategies for diagnosis and treatment.In an attempt to fill some of the current gaps in evidence on various, highly debated and controversial aspects of dialysis-associated calciphylaxis, 13 international experts joined the 1st Consensus Conference on CUA, held in Leuven, Belgium on 21 September 2015. The conference was supported by the European Calciphylaxis Network (EuCalNet), which is a task force of the ERA-EDTA scientific working group on Chronic Kidney Disease-Mineral and Bone Disorders (CKD-MBD). After an intense discussion, a 9-point Likert scale questionnaire regarding 20 items on calciphylaxis was anonymously answered by each participant. These 20 items addressed unsolved issues in terms of diagnosis and management of calciphylaxis. On the one hand, the analysis of the expert opinions identified areas of general consensus, which might be a valuable aid for physicians treating such a disease with less experience in the field. On the other hand, some topics such as the pertinence of skin biopsy and administration of certain treatments revealed divergent opinions. The aim of the present summary report is to provide some guidance for clinicians who face patients with calciphylaxis in the current setting of absence of evidence-based medicine.? The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

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).

Cognitive impairment is a common and largely undiagnosed finding in a significant number of dialysis patients. These alterations may result from concomitant cerebrovascular disease, hemodynamic instability, the uremic milieu, or changes induced by the dialysis process. In order to gain further insight into this, we recruited 12 stable chronic hemodialysis patients (without clinical neurological disease) and an age- and gender-matched cohort of 12 control individuals (without renal or neurological problems) in a prospective, single-center study. In order to disentangle the influence of dialysis itself on memory function, each dialysis patient was tested twice: once immediately before dialysis following a long weekend (t1) and again the day after this dialysis (t2). The control individuals were tested in the same time frame. Neuropsychological testing found that the control individuals performed significantly better in verbal learning, motor speed, task switching, verbal comprehension, word fluency, spatial visualization, spatial perception, and reasoning; all independent of the time point. Functional magnetic resonance imaging of the whole brain in seven hemodialysis patients found significantly more bilateral activation of the hippocampus during the verbal working memory task at t2 relative to t1 compared with their seven matched control counterparts. Thus, our study found differential and task-specific activation of memory-relevant brain areas during a dialysis cycle.

Die histologische Diagnosesicherung mittels Biopsie spielt in vielen Fallen eine wesentliche Rolle bei der Diagnostik internistischer Erkrankungen. Der Gastrointestinaltrakt (z. B. Osophagus, Leber und Kolon), die Nieren und das Knochenmark sind exemplarische Organ(system)e mit regelhafter biopsiebasierter Diagnostik und Therapieevaluierung. Verbesserte laborchemische, bildgebende und endoskopische Techniken haben die Moglichkeiten verbessert, eine Diagnose bereits makroskopisch bzw. nicht-invasiv zu sichern. Dadurch konnte die Biopsiefrequenz deutlich reduziert und die Biopsie in bestimmten Bereichen sogar ersetzt werden. Die histologische Beurteilung der Biopsie bleibt jedoch ein wesentlicher Standard der internistischen Diagnostik. Ziel dieser Ubersicht ist, die aktuellen Standards und Moglichkeiten der pathologischen Diagnostik nach Biopsie und moderne Entwicklungen nicht-invasiver Methoden heute und in Zukunft darzustellen.

The increasing global prevalence of chronic kidney disease (CKD) and end-stage renal disease with the associated spiraling cost has profound public health and economic implications. This has made slowing the progression of CKD, a major health-care priority. CKD is invariably characterized by progressive kidney fibrosis and at present, treatment aiming to slow the progression of CKD is limited to aggressive blood pressure control, with few therapies targeting the fibrotic process itself. In this review, we explore the potential of experimental therapeutic strategies, based on preventing or reversing the pathophysiologic steps of kidney remodeling that lead to fibrosis.

Niedergelassene und im Krankenhaus tatige Internisten werden vor allem im Rahmen von Notfallen immer wieder mit Dialyse- oder nierentransplantierten Patienten konfrontiert. Bei Dialysepatienten ist zunachst die Art der Dialysetherapie zu ermitteln sowie der Dialysezugang zu sichern und die Indikation fur die nachste Dialysetherapie zu stellen. Hamodialysepatienten stellen sich haufig wegen Uberwasserung, hypo- oder hypertensiver Episoden, Elektrolytentgleisung, Fieber oder kardiovaskularer Notfalle vor. Patienten mit einer kontinuierlichen ambulanten Peritonealdialyse haben zusatzlich ein erhohtes Risiko fur eine Infektion des Katheters oder eine Peritonitis. Nierentransplantierte Patienten benotigen eine Uberwachung der Transplantatfunktion und eine gesicherte Fortfuhrung der Immunsuppression. Diese Patienten stellen sich haufig mit Infektionen vor. In solchen Fallen muss ggf. eine Reduktion der Immunsuppression erwogen werden. Schlieslich ist auf einen ausreichenden Impfschutz und auf das erhohte Risiko dieser Patienten fur Malignome zu achten.

Background. Sclerostin is a Wnt pathway antagonist regulating osteoblast activity and bone turnover, and it plays a role in cardiovascular calcification processes. Previous findings indicate that sclerostin regulation is disturbed in chronic kidney disease (CKD). The aim of this study was to assess the association of circulating sclerostin levels with mortality in dialysis patients.Methods. From a prospective cohort study of incident dialysis patients in the Netherlands, all patients with measured circulating sclerostin at 3 months after the start of dialysis (baseline) were included in the present analysis: n = 673, age 63 +/- 14 years, mean serum sclerostin (ELISA) 1.24 +/- 0.57 ng/mL. By Cox regression analyses, we assessed the association of sclerostin levels with cardiovascular and non-cardiovascular mortality both in the short (18 months) and long term (4-year follow-up).Results. Serum sclerostin levels in the entire cohort correlated with intact parathyroid hormone levels (r = -0.25, P Conclusions. High levels of serum sclerostin are associated with lower short-term cardiovascular mortality in dialysis patients. The exact mechanisms of this association, e. g. how sclerostin influences or reflects uraemic vascular calcification, need to be investigated in further studies.

Pathologic proliferation of mesangial and parietal epithelial cells (PECs) is a hallmark of various glomerulonephritides. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that mediates inflammation by engagement of a receptor complex involving the components CD74, CD44, CXCR2, and CXCR4. The proliferative effects of MIF may involve CD74 together with the coreceptor and PEC activation marker CD44. Herein, we analyzed the effects of local glomerular MIF/CD74/CD44 signaling in proliferative glomerulonephritides. MIF, CD74, and CD44 were upregulated in the glomeruli of patients and mice with proliferative glomerulonephritides. During disease, CD74 and CD44 were expressed de novo in PECs and colocalized in both PECs and mesangial cells. Stress stimuli induced MIF secretion from glomerular cells in vitro and in vivo, in particular from podocytes, and MIF stimulation induced proliferation of PECs and mesangial cells via CD74. In murine crescentic GN, Mif-deficient mice were almost completely protected from glomerular injury, the development of cellular crescents, and the activation and proliferation of PECs and mesangial cells, whereas wild-type mice were not. Bone marrow reconstitution studies showed that deficiency of both nonmyeloid and bone marrow-derived Mif reduced glomerular cell proliferation and injury. In contrast to wild-type mice, Cd74-deficient mice also were protected from glomerular injury and ensuing activation and proliferation of PECs and mesangial cells. Our data suggest a novel molecular mechanism and glomerular cell crosstalk by which local upregulation of MIF and its receptor complex CD74/CD44 mediate glomerular injury and pathologic proliferation in GN.

Platelet-derived growth factor (PDGF)-BB and PDGF-DD mediate mesangial cell proliferation in vitro and in vivo. While PDGF-BB is a ligand for the PDGF alpha- and beta-receptor chains, PDGF-DD binds more selectively to the beta-chain, suggesting potential differences in the biological activities. Signal transduction and regulation of gene expression induced by PDGF-BB and -DD were compared in primary human mesangial cells (HMCs), which expressed PDGF alpha- and beta-receptor subunits. The growth factor concentrations used were chosen based on their equipotency in inducing HMCs proliferation and binding to the betabeta-receptor. Both growth factors, albeit at different concentrations induced phosphorylation and activation of extracellular signal-regulated kinase 1 (ERK1) and ERK2. In addition, PDGFs led to the phosphorylation and activation of signal transducers and activators of transcription 1 (STAT1) and STAT3. HMCs proliferation induced by either PDGF-BB or -DD could be blocked by signal transduction inhibitors of the mitogen-activated protein kinase-, Janus kinase (JAK)/STAT-, or phosphatidyl-inositol 3-kinase pathways. Using a gene chip array and subsequent verification by real-time reverse transcriptase (RT)-polymerase chain reaction, we found that in HMC genes for matrix metalloproteinase 13 (MMP-13) and MMP-14 and, to a low extent, cytochrome B5 and cathepsin L were exclusively regulated by PDGF-BB, whereas no exclusive gene regulation was detected by PDGF-DD. However, at the protein level, both MMP-13 and -14 were equally induced by PDGF-BB and -DD. PDGF-BB and -DD effect similar biological responses in HMCs albeit at different potencies. Rare apparently differential gene regulation did not result in different protein expression, suggesting that in HMCs both PDGFs exert their biological activity almost exclusively via the PDGF beta-receptor.