Factors Associated With Vaccine-Induced T-Cell Immune Responses Against Severe Acute Respiratory Syndrome Coronavirus 2 in Kidney Transplant Recipients.

Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important prophylactic measure in kidney transplant recipients (KTRs), but the immune response is often impaired. Here, we examined the T-cell immune response against SARS-CoV-2 in 148 KTRs after 3 or 4 vaccine doses, including 35 KTRs with subsequent SARS-CoV-2 infection. The frequency of spike-specific T cells was lower in KTRs than in immunocompetent controls and was correlated with the level of spike-specific antibodies. Positive predictors for detection of vaccine-induced T cells were detection of spike-specific antibodies, heterologous immunization with messenger RNA and a vector vaccine, and longer time after transplantation. In vaccinated KTRs with subsequent SARS-CoV-2 infection, the T-cell response was greatly enhanced and was significantly higher than in vaccinated KTRs without SARS-CoV-2 infection. Overall, the data show a correlation between impaired humoral and T-cell immunity to SARS-CoV-2 vaccination and provide evidence for greater robustness of hybrid immunity in KTRs.

A paired-kidney allocation study found superior survival with HLA-DR compatible kidney transplants in the Eurotransplant Senior Program.

The Eurotransplant Senior Program (ESP) has expedited the chance for elderly patients with kidney failure to receive a timely transplant. This current study evaluated survival parameters of kidneys donated after brain death with or without matching for HLA-DR antigens. This cohort study evaluated the period within ESP with paired allocation of 675 kidneys from donors 65 years and older to transplant candidates 65 years and older, the first kidney to 341 patients within the Eurotransplant Senior DR-compatible Program and 334 contralateral kidneys without (ESP) HLA-DR antigen matching. We used Kaplan-Meier estimates and competing risk analysis to assess all cause mortality and kidney graft failure, respectively. The log-rank test and Cox proportional hazards regression were used for comparisons. Within ESP, matching for HLA-DR antigens was associated with a significantly lower five-year risk of mortality (hazard ratio 0.71; 95% confidence interval 0.53-0.95) and significantly lower cause-specific hazards for kidney graft failure and return to dialysis at one year (0.55; 0.35-0.87) and five years (0.73; 0.53-0.99) post-transplant. Allocation based on HLA-DR matching resulted in longer cold ischemia (mean difference 1.00 hours; 95% confidence interval: 0.32-1.68) and kidney offers with a significantly shorter median dialysis vintage of 2.4 versus 4.1 yrs. in ESP without matching. Thus, our allocation based on HLA-DR matching improved five-year patient and kidney allograft survival. Hence, our paired allocation study suggests a superior outcome of HLA-DR matching in the context of old-for-old kidney transplantation.

Lithium Therapy in Old Age: Recommendations from a Delphi Survey.

INTRODUCTION: While lithium (Li) has been well established for the treatment of bipolar disorder, geriatric patients require special attention when it comes to issues of drug safety. Declining renal function, amongst other medical conditions, and polypharmacy may pose increased risks. Only a few previous studies have addressed the management of Li in geriatric patients. METHODS: Twenty-four German medical experts on geriatric medicine and Li treatment participated in a Delphi survey, consisting of two rounds of questionnaires and a final formulation of treatment recommendations. Three major issues of Li therapy were outlined: initiation of treatment, monitoring of ongoing therapy, and withdrawal due to medical reasons. Final recommendations were consented to at a threshold of at least 80% expert agreement. RESULTS: Final consensus was achieved on 21 clinical recommendations. The approved recommendations covered aspects of necessary laboratory checks, concomitant medication, and target Li serum concentration in geriatric patients. Concerning the termination of Li therapy, an agreement was reached on the appropriate time span for tapering and on potential alternatives to Li. No consensus was achieved on whether concomitant dementia or frailty should be considered contraindications for Li treatment and the appropriate threshold of the estimated glomerular function rate for withdrawing Li. CONCLUSION: According to the view of German experts, Li may be used in geriatric patients, but it should be monitored carefully. However, the lack of consent in several specific treatment situations underlines the need for research on specific issues of Li therapy.

Incidence and relative risk of renal replacement therapy in people with and without diabetes between 2002 and 2016 in a German region.

AIMS/HYPOTHESIS: Data on trends of end-stage renal disease among people with diabetes are lacking. We analysed the incidence of end-stage renal disease, defined as renal replacement therapy, among people with and without diabetes, and the corresponding relative risk. Moreover, we investigated time trends for the period 2002-2016. METHODS: In this retrospective population-based study we analysed data from one dialysis centre of a region in Germany covering a population of about 310,000 inhabitants. We estimated the age- and sex-standardised incidence rates for chronic renal replacement therapy among adults with and without diabetes and the corresponding relative risks. The time trend was analysed using Poisson regression models. RESULTS: Between 2002 and 2016, 1107 people (61.2% male; mean age 71.6 years; 48.7% with diabetes) had a first renal replacement therapy. During the study period, the incidence rate in the population with diabetes varied from 93.6 (95% CI 50.4, 136.7) in 2002 to 140.5 (95% CI 80.6, 200.4) in 2016 per 100,000 person-years. In the population without diabetes the incidence rate was substantially lower and reached 17.3 (95% CI 10.9, 23.6) in 2002 and 24.6 (95% CI 17.5, 31.7) in 2009. The relative risk comparing people with and without diabetes was 3.57 (95% CI 3.09, 4.13). No significant change in the incidence rates was found during the observation period, either in the population with or in the population without diabetes, and thus the relative risk also remained constant. CONCLUSIONS/INTERPRETATION: People with diabetes have a higher risk of needing renal replacement therapy than those without diabetes, a fact that remained constant over a time period of 15 years.

Short-Chain Fatty Acid Propionate Protects From Hypertensive Cardiovascular Damage.

BACKGROUND: Arterial hypertension and its organ sequelae show characteristics of T cell-mediated inflammatory diseases. Experimental anti-inflammatory therapies have been shown to ameliorate hypertensive end-organ damage. Recently, the CANTOS study (Canakinumab Antiinflammatory Thrombosis Outcome Study) targeting interleukin-1ß demonstrated that anti-inflammatory therapy reduces cardiovascular risk. The gut microbiome plays a pivotal role in immune homeostasis and cardiovascular health. Short-chain fatty acids (SCFAs) are produced from dietary fiber by gut bacteria and affect host immune homeostasis. Here, we investigated effects of the SCFA propionate in 2 different mouse models of hypertensive cardiovascular damage. METHODS: To investigate the effect of SCFAs on hypertensive cardiac damage and atherosclerosis, wild-type NMRI or apolipoprotein E knockout-deficient mice received propionate (200 mmol/L) or control in the drinking water. To induce hypertension, wild-type NMRI mice were infused with angiotensin II (1.44 mg·kg-1·d-1 subcutaneous) for 14 days. To accelerate the development of atherosclerosis, apolipoprotein E knockout mice were infused with angiotensin II (0.72 mg·kg-1·d-1 subcutaneous) for 28 days. Cardiac damage and atherosclerosis were assessed using histology, echocardiography, in vivo electrophysiology, immunofluorescence, and flow cytometry. Blood pressure was measured by radiotelemetry. Regulatory T cell depletion using PC61 antibody was used to examine the mode of action of propionate. RESULTS: Propionate significantly attenuated cardiac hypertrophy, fibrosis, vascular dysfunction, and hypertension in both models. Susceptibility to cardiac ventricular arrhythmias was significantly reduced in propionate-treated angiotensin II-infused wild-type NMRI mice. Aortic atherosclerotic lesion area was significantly decreased in propionate-treated apolipoprotein E knockout-deficient mice. Systemic inflammation was mitigated by propionate treatment, quantified as a reduction in splenic effector memory T cell frequencies and splenic T helper 17 cells in both models, and a decrease in local cardiac immune cell infiltration in wild-type NMRI mice. Cardioprotective effects of propionate were abrogated in regulatory T cell-depleted angiotensin II-infused mice, suggesting the effect is regulatory T cell-dependent. CONCLUSIONS: Our data emphasize an immune-modulatory role of SCFAs and their importance for cardiovascular health. The data suggest that lifestyle modifications leading to augmented SCFA production could be a beneficial nonpharmacological preventive strategy for patients with hypertensive cardiovascular disease.

Repeated kidney re-transplantation-the Eurotransplant experience: a retrospective multicenter outcome analysis.

In Eurotransplant kidney allocation system (ETKAS), candidates can be considered unlimitedly for repeated re-transplantation. Data on outcome and benefit are indeterminate. We performed a retrospective 15-year patient and graft outcome data analysis from 1464 recipients of a third or fourth or higher sequential deceased donor renal transplantation (DDRT) from 42 transplant centers. Repeated re-DDRT recipients were younger (mean 43.0 vs. 50.2 years) compared to first DDRT recipients. They received grafts with more favorable HLA matches (89.0% vs. 84.5%) but thereby no statistically significant improvement of patient and graft outcome was found as comparatively demonstrated in 1st DDRT. In the multivariate modeling accounting for confounding factors, mortality and graft loss after 3rd and ≥4th DDRT (P < 0.001 each) and death with functioning graft (DwFG) after 3rd DDRT (P = 0.001) were higher as compared to 1st DDRT. The incidence of primary nonfunction (PNF) was also significantly higher in re-DDRT (12.7%) than in 1st DDRT (7.1%; P < 0.001). Facing organ shortage, increasing waiting time, and considerable mortality on dialysis, we question the current policy of repeated re-DDRT. The data from this survey propose better HLA matching in first DDRT and second DDRT and careful selection of candidates, especially for ≥4th DDRT.

Mas receptor deficiency augments angiotensin II-induced atherosclerosis and aortic aneurysm ruptures in hypercholesterolemic male mice.

OBJECTIVE: Previous studies demonstrated that deficiency of angiotensin-converting enzyme 2 (ACE2) augmented angiotensin II (AngII)-induced atherosclerosis and abdominal aortic aneurysm (AAA) formation in hypercholesterolemic mice. Effects of ACE2 deficiency could arise from increased concentrations of its substrate, AngII, or decreased concentrations of its product, angiotensin-(1-7) [Ang-(1-7)]. Infusion of Ang-(1-7), a Mas receptor (MasR) ligand, to hypercholesterolemic male mice reduced AngII-induced atherosclerosis, suggesting a protective role of the Ang-(1-7)/MasR axis. However, it is unclear whether endogenous Ang-(1-7) acts at MasR to influence AngII-induced vascular diseases. The purpose of this study was to define the role of MasR deficiency in AngII-induced atherosclerosis and AAA formation and severity in hypercholesterolemic male mice. METHODS: MasR+/+ and MasR-/- male mice on a low-density lipoprotein receptor-deficient (Ldlr-/-) or apolipoprotein E-deficient (Apoe-/-) background were infused with AngII at either 600 or 1000 ng/kg/min by osmotic minipump for 28 days. Atherosclerosis was quantified at study end point as percentage lesion surface area of the aortic arch in Ldlr-/- mice. Abdominal aortic internal diameters were quantified by ultrasound, and maximal external AAA diameters were quantified at study end point. Blood pressure was quantified by radiotelemetry and a tail cuff-based technique. Serum cholesterol concentrations and vascular tissue characterization were examined at study end point. RESULTS: MasR deficiency did not influence body weight, systolic blood pressure at baseline and during AngII infusion, or serum cholesterol concentrations in either Apoe-/- or Ldlr-/- mice. MasR deficiency increased AngII-induced atherosclerosis in aortic arches of Ldlr-/- mice (P < .05), associated with increased oxidative stress and apoptosis in aortic root sections (P < .05). MasR deficiency also augmented internal and external AAA diameters and increased aortic ruptures of both Ldlr-/- and Apoe-/- mice (P < .05). These effects were associated with increased elastin breaks and T-lymphocyte and macrophage accumulation into abdominal aortas of AngII-infused MasR-deficient mice (P < .05). CONCLUSIONS: These results demonstrate that MasR deficiency augmented AngII-induced atherosclerosis and AAA rupture through mechanisms involving increased oxidative stress, inflammation, and apoptosis, suggesting that MasR activation may provide therapeutic efficacy against vascular diseases.

Angiotensin-(1-7)-induced Mas receptor activation attenuates atherosclerosis through a nitric oxide-dependent mechanism in apolipoproteinE-KO mice.

Angiotensin (Ang)-(1-7) ameliorates vascular injury by increasing nitric oxide (NO) bioavailability. Evidence that Ang-(1-7) attenuates the development of atherosclerosis through a NO-dependent mechanism is still missing. Moreover, it has been postulated that Ang-(1-7) may mediate its effects by other mechanisms than Mas receptor activation. To investigate Ang-(1-7)-dependent Mas receptor function, we treated apoE-KO and apoE/Mas-KO mice chronically with Ang-(1-7) (82 µg/kg per hour) or saline for 6 weeks. Flow-mediated dilation (FMD), a measure for NO-dependent vasodilation and the most accepted prognostic marker for the development of atherosclerosis, was measured in vivo. Chronic Ang-(1-7) treatment improved FMD and attenuated the development of atherosclerosis in apolipoproteinE (apoE)-KO but not in apoE/Mas-KO mice. These effects were accompanied by increased aortic nitrite and cGMP levels. To test whether Ang-(1-7) modulates atherosclerosis through a NO-dependent mechanism, apoE-KO mice were treated with the NO synthase inhibitor L-NAME (20 mg/kg/day) in the presence or absence of Ang-(1-7). L-NAME treatment reduced aortic nitrite content and increased blood pressure and exaggerated atherosclerosis compared to untreated apoE-KO mice. In L-NAME-treated apoE-KO mice, chronic Ang-(1-7) treatment did not increase aortic nitrite content and consequently showed no effect on blood pressure and the development of atherosclerosis. The present study proves that Ang-(1-7) mediates its protective vascular effects through Mas receptor activation. Moreover, Ang-(1-7)-mediated NO generation is essential for improving vascular function and prevents atherosclerosis in apoE-KO mice.

Impact of monocyte-macrophage inhibition by ibandronate on graft function and survival after kidney transplantation: a single-centre follow-up study over 15 years.

BACKGROUND: The aim of this study was to evaluate the effect of ibandronate administration on long-term graft function and graft survival after successful renal transplantation. METHODS: Seventy-two renal transplant recipients (36 patients each in the treatment and control group) were included and followed over a 15-year period. Data on graft function and death-censored transplant outcome were recorded at 1, 5, 10, and 15 years. RESULTS: Death-censored Kaplan-Meier analysis showed significantly improved graft survival of the treatment group (p = 0.026), whereas Cox regression analysis showed that ibandronate was positively associated with improved transplant survival (p = 0.028, hazard ratio 0.24, 95% confidence interval 0.07-0.86). Although general linear modelling did not indicate that ibandronate had a significant effect on transplant function (calculated using the estimated glomerular filtration rate according to Chronic Kidney Disease Epidemiology Collaboration equation) over the entire 15-year period (p = 0.650), there was a tendency towards improved graft function 1-year post-transplantion (p = 0.056). CONCLUSIONS: Ibandronate treatment within the first year of transplantation resulted in a trend towards better graft function within the first few year post-transplant, and was associated with increased transplant survival at long-term follow-up.

Impact of the NO-Sensitive Guanylyl Cyclase 1 and 2 on Renal Blood Flow and Systemic Blood Pressure in Mice.

Nitric oxide (NO) modulates renal blood flow (RBF) and kidney function and is involved in blood pressure (BP) regulation predominantly via stimulation of the NO-sensitive guanylyl cyclase (NO-GC), existing in two isoforms, NO-GC1 and NO-GC2. Here, we used isoform-specific knockout (KO) mice and investigated their contribution to renal hemodynamics under normotensive and angiotensin II-induced hypertensive conditions. Stimulation of the NO-GCs by S-nitrosoglutathione (GSNO) reduced BP in normotensive and hypertensive wildtype (WT) and NO-GC2-KO mice more efficiently than in NO-GC1-KO. NO-induced increase of RBF in normotensive mice did not differ between the genotypes, but the respective increase under hypertensive conditions was impaired in NO-GC1-KO. Similarly, inhibition of endogenous NO increased BP and reduced RBF to a lesser extent in NO-GC1-KO than in NO-GC2-KO. These findings indicate NO-GC1 as a target of NO to normalize RBF in hypertension. As these effects were not completely abolished in NO-GC1-KO and renal cyclic guanosine monophosphate (cGMP) levels were decreased in both NO-GC1-KO and NO-GC2-KO, the results suggest an additional contribution of NO-GC2. Hence, NO-GC1 plays a predominant role in the regulation of BP and RBF, especially in hypertension. However, renal NO-GC2 appears to compensate the loss of NO-GC1, and is able to regulate renal hemodynamics under physiological conditions.

Coronary artery stenosis: a new risk factor for chronic kidney injury?

Coronary artery stenosis induces renal inflammation and kidney injury in pigs even in the absence of myocardial infarction or clinically significant heart failure. This effect is aggravated by experimentally induced renovascular hypertension. Interestingly, oxidative stress originating from the ischemic myocardium was identified as a possible mediator of this new pathophysiological link between heart and kidney. Renin-angiotensin or sympathetic nervous system activation did not appear to play a role in the observed cardio-renal link.

Long-term graft outcome after renal arterial reconstruction during living related kidney transplantation.

BACKGROUND/OBJECTIVES: The aim of this retrospective study was to evaluate the repair of vascular variations/pathologies in living donor kidney transplantations in a single centre over a 15-year period. METHODS: Between 01/1997 and 05/2012, 338 living donor renal transplantations were performed in the Department for Endovascular and Vascular Surgery, University of Düsseldorf, Germany. Twenty-four of them showed disorders, like multiple renal arteries (MRA), atherosclerotic stenosis or fibromuscular dysplasia (FMD) needing vascular repair before transplantation. RESULTS: Mean age of donors was 51 ± 11.2, in recipient's 44 ± 13.9 years. In seven transplantations, renal artery (RA) repair was performed because of MRA. Atherosclerotic stenosis of the RA was apparent in 12 cases needing a repair with disobliteration. FMD was the reason in five transplantations for vascular repair. Complications like renal vessel thrombosis, lymphocele, heamorrhage, distal urinary leakage and ureteral obstruction was not significantly associated with RA reconstruction. Comparison of renal function in kidneys with reconstructed RA compared with kidneys without vascular repair showed no significant difference in primary function and serum creatinine up to the first year after transplantation. Mean follow-up was 75.6 ± 48.1 months. The 5-year graft survival rate for kidneys with RA repair was 88.5 vs. 93.4 % without reconstruction. CONCLUSIONS: We could show that RA pathologies, suitable repaired, are not a contraindication for transplantation with acceptable 5-year-graft-survival rates.

Subtype Identification of Surgically Curable Primary Aldosteronism During Treatment With Mineralocorticoid Receptor Blockade.

BACKGROUND: Current guidelines and consensus documents recommend withdrawal of mineralocorticoid receptor antagonists (MRAs) before primary aldosteronism (PA) subtyping by adrenal vein sampling (AVS), but this practice can cause severe hypokalemia and uncontrolled high blood pressure. Our aim was to investigate if unilateral PA can be identified by AVS during MRA treatment. METHODS: We compared the rate of unilateral PA identification between patients with and without MRA treatment in large data sets of patients submitted to AVS while off renin-angiotensin system blockers and ß-blockers. In sensitivity analyses, the between-group differences of lateralization index values after propensity score matching and the rate of unilateral PA identification in subgroups with undetectable (≤2 mUI/L), suppressed (<8.2 mUI/L), and unsuppressed (≥8.2 mUI/L) direct renin concentration levels were also evaluated. RESULTS: Plasma aldosterone concentration, direct renin concentration, and blood pressure values were similar in non-MRA-treated (n=779) and MRA-treated (n=61) patients with PA, but the latter required more antihypertensive agents (P=0.001) and showed a higher rate of adrenal nodules (82% versus 67%; P=0.022) and adrenalectomy (72% versus 54%; P=0.01). However, they exhibited no significant differences in commonly used AVS indices and the area under the receiving operating characteristic curve of lateralization index, both under unstimulated conditions and postcosyntropin. Several sensitivity analyses confirmed these results in propensity score matching adjusted models and in patients with undetectable, or suppressed or unsuppressed renin levels. CONCLUSIONS: At doses that controlled blood pressure and potassium levels, MRAs did not preclude the identification of unilateral PA at AVS. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01234220.

How acute renal failure led to the diagnosis of aortic coarctation.

The present case report focuses on a rare presentation of aortic coarctation. A 38-year-old man with well-controlled arterial hypertension, minimal change glomerulonephritis and colitis ulcerosa was suffering from recurrent acute renal failure episodes during viral gastroenteritis. No other symptoms at rest or during physical activity were present. The workup included renal duplex sonography, which unmasked tardus parvus profile in both kidneys without any acceleration of blood flow in the renal arteries. Further examination included CT angiography, which confirmed the diagnosis of aortic coarctation. The observed narrowing of the aorta measured 4 mm and was treated with percutaneous transluminal angioplasty and stent implantation (final diameter 12 mm). After the procedure, the patient had normal blood pressure values without the need of any medication; duplex sonography showed improved renal perfusion. The present case confirms the importance of evaluation for secondary hypertension and thorough workup of acute renal failure in young patients.

Contrast medium free selective adrenal vein sampling in the management of primary aldosteronism.

BACKGROUND: To analyze contrast free adrenal vein sampling (AVS) for differentiating unilateral from bilateral disease in patients diagnosed with hypertension due to primary aldosteronism (PA). METHODS: Consecutive patients with PA and subsequent contrast medium free AVS between April 2015 and March 2020 were retrospectively included. Cross-sectional imaging (CSI), AVS and clinical data were analyzed regarding diagnostic performance. In addition, patients with lateralisation receiving adrenalectomy were compared to a control group treated with mineralocorticoid antagonists. RESULTS: In total 186 patients with AVS were included. The success rate for bilateral catheterization was 88% (median effective dose 2.8 mSv). CSI had an accuracy of 60% (CI: 0.52-0.67) in the detection of lateralization compared to AVS. Patients with bilateral adrenal hyperplasia and those with aldosterone-producing adenoma did not differ in systolic blood pressure (sBP) (p = 0.63) or number of antihypertensive drugs (NAD) (p = 0.11). After adrenalectomy, 28 patients were cured (51%; sBP ≤130 mmHg, NAD = 0), 18 were improved (33%; decrease of sBP ≥20 mmHg and NAD), and 8 were unchanged (15%). Serum renin increased significantly after treatment (p < 0.01). CONCLUSION: Contrast medium free AVS is a reliable procedure in the diagnostic management of patients with PA with high technical success rate. The accordance between CSI and results from AVS was only moderate indicating the central role of AVS in the diagnostic work-up of patients with PA. Patients with predominant disease diagnosed with AVS had a high cure rate and/or significant improvement after adrenalectomy.

Unilaterally Selective Adrenal Vein Sampling for Identification of Surgically Curable Primary Aldosteronism.

BACKGROUND: Adrenal venous sampling is recommended for the identification of unilateral surgically curable primary aldosteronism but is often clinically useless, owing to failed bilateral adrenal vein cannulation. OBJECTIVES: To investigate if only unilaterally selective adrenal vein sampling studies can allow the identification of the responsible adrenal. METHODS: Among 1625 patients consecutively submitted to adrenal vein sampling in tertiary referral centers, we selected those with selective adrenal vein sampling results in at least one side; we used surgically cured unilateral primary aldosteronism as gold reference. The accuracy of different values of the relative aldosterone secretion index (RASI), which estimates the amount of aldosterone produced in each adrenal gland corrected for catheterization selectivity, was examined. RESULTS: We found prominent differences in RASI values distribution between patients with and without unilateral primary aldosteronism. The diagnostic accuracy of RASI values estimated by the area under receiver operating characteristic curves was 0.714 and 0.855, respectively, in the responsible and the contralateral side; RASI values >2.55 and ≤0.96 on the former and the latter side furnished the highest accuracy for detection of surgically cured unilateral primary aldosteronism. Moreover, in the patients without unilateral primary aldosteronism, only 20% and 16% had RASI values ≤0.96 and >2.55. CONCLUSIONS: With the strength of a large real-life data set and use of the gold reference entailing an unambiguous diagnosis of unilateral primary aldosteronism, these results indicate the feasibility of identifying unilateral primary aldosteronism using unilaterally selective adrenal vein sampling results. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01234220.

PKC alpha mediates beta-arrestin2-dependent nephrin endocytosis in hyperglycemia.

Nephrin, the key molecule of the glomerular slit diaphragm, is expressed on the surface of podocytes and is critical in preventing albuminuria. In diabetes, hyperglycemia leads to the loss of surface expression of nephrin and causes albuminuria. Here, we report a mechanism that can explain this phenomenon: hyperglycemia directly enhances the rate of nephrin endocytosis via regulation of the ß-arrestin2-nephrin interaction by PKCα. We identified PKCα and protein interacting with c kinase-1 (PICK1) as nephrin-binding proteins. Hyperglycemia induced up-regulation of PKCα and led to the formation of a complex of nephrin, PKCα, PICK1, and ß-arrestin2 in vitro and in vivo. Binding of ß-arrestin2 to the nephrin intracellular domain depended on phosphorylation of nephrin threonine residues 1120 and 1125 by PKCα. Further, cellular knockdown of PKCα and/or PICK1 attenuated the nephrin-ß-arrestin2 interaction and abrogated the amplifying effect of high blood glucose on nephrin endocytosis. In C57BL/6 mice, hyperglycemia over 24 h caused a significant increase in urinary albumin excretion, supporting the concept of the rapid impact of hyperglycemia on glomerular permselectivity. In summary, we have provided a molecular model of hyperglycemia-induced nephrin endocytosis and subsequent proteinuria and highlighted PKCα and PICK1 as promising therapeutic targets for diabetic nephropathy.

Comparable outcome of acute unplanned peritoneal dialysis and haemodialysis.

BACKGROUND: The impact of dialysis modality on outcome, especially on infection early in the course of dialysis, in unplanned acute dialysis initiation has not been well evaluated. The aim of the study was to compare the rates and causes of mortality and morbidity in incident dialysis patients started unplanned acute peritoneal dialysis (PD) or haemodialysis (HD). PATIENTS AND METHODS: In this observational cohort study, incident dialysis patients with initiation of unplanned and acute PD (n = 66) or HD (n = 57) at a single centre from March 2005 to June 2010 were included and followed up for 6 months (0-183 days, mean follow-up time 4.72 months). For PD, surgically placed Tenckhoff catheters were used. All HD patients were dialysed with a central venous catheter (non-tunnelled or tunnelled). There were no significant differences in terms of gender, age and prevalence of diabetes mellitus in either group. The prevalence of heart failure [New York Heart Association (NYHA) Stage III-IV] was significantly higher in the PD group (73 versus 46% in HD group, P < 0.01). The population was stratified to PD and HD comparing mortality, infection, bacteraemia and hospitalization. RESULTS: Of the 123 patients who commenced acute and unplanned dialysis, n = 44 (35.8%) died during the follow-up period of 0-183 days. There were no significant difference in half-year mortality in n = 20 PD patients (30.3%) versus n = 24 HD patients (42.1%) (P = 0.19). The cardiovascular mortality in PD and HD patients were 9.1 and 10.5%, respectively (P = 1.00). Overall mortality due to infection was higher in the HD (17.5%) versus in the PD group (9.1%), however, not significant (P = 0.19). HD patients had significantly higher probability of bacteraemia in the first 183 days compared to PD patients (21.1 versus 3.0%, P < 0.01). Group comparison by Poisson regression analyses showed that the relative risk of bacteraemia in the PD group versus HD group was 0.16 (95% confidence interval, 0.05-0.57, P = 0.005). The significant difference was not affected by the confounder's patient age at time of dialysis, male sex, heart failure (NYHA III-IV), diabetes, malignancy and peripheral arterial occlusive disease Stage IV. There were high proportions of hospitalization after the initiation of dialysis in both groups (PD 75.0% and HD 67.3%, P = 0.40). Univariate and multiple regression analyses revealed only age at initiation of dialysis to be significantly associated with overall mortality (P < 0.05). CONCLUSIONS: Dialysis modality (PD versus HD) in an acute unplanned dialysis setting showed, in our population, no significant influence on survival. HD patients had a significantly higher risk of bacteraemia, perhaps due to central venous dialysis catheter. PD seems to be a safe and efficient, at least comparable, alternative to HD in acute unplanned dialysis settings.

Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system.

Angiotensin II is the principle effector molecule of the renin angiotensin system (RAS). It exerts its various actions on the cardiovascular and renal system, mainly via interaction with the angiotensin II type-1 receptor (AT1R), which contributes to blood pressure regulation and development of hypertension but may also mediate effects on the immune system. Here we study the role of the RAS in myelin-oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE), a model mimicking many aspects of multiple sclerosis. Quantitative RT-PCR analyses showed an up-regulation of renin, angiotensin-converting enzyme, as well as AT1R in the inflamed spinal cord and the immune system, including antigen presenting cells (APC). Treatment with the renin inhibitor aliskiren, the angiotensin II converting-enzyme inhibitor enalapril, as well as preventive or therapeutic application of the AT1R antagonist losartan, resulted in a significantly ameliorated course of MOG-EAE. Blockade of AT1R did not directly impact on T-cell responses, but significantly reduced numbers of CD11b+ or CD11c+ APC in immune organs and in the inflamed spinal cord. Additionally, AT1R blockade impaired the expression of CCL2, CCL3, and CXCL10, and reduced CCL2-induced APC migration. Our findings suggest a pivotal role of the RAS in autoimmune inflammation of the central nervous system and identify RAS blockade as a potential new target for multiple sclerosis therapy.