The extracellular matrix protein fibronectin promotes metanephric kidney development.

Complex interactions of the branching ureteric bud (UB) and surrounding mesenchymal cells during metanephric kidney development determine the final number of nephrons. Impaired nephron endowment predisposes to arterial hypertension and chronic kidney disease. In the kidney, extracellular matrix (ECM) proteins are usually regarded as acellular scaffolds or as the common histological end-point of chronic kidney diseases. Since only little is known about their physiological role in kidney development, we aimed for analyzing the expression and role of fibronectin. In mouse, fibronectin was expressed during all stages of kidney development with significant changes over time. At embryonic day (E) 12.5 and E13.5, fibronectin lined the UB epithelium, which became less pronounced at E16.5 and then switched to a glomerular expression in the postnatal and adult kidneys. Similar results were obtained in human kidneys. Deletion of fibronectin at E13.5 in cultured metanephric mouse kidneys resulted in reduced kidney sizes and impaired glomerulogenesis following reduced cell proliferation and branching of the UB epithelium. Fibronectin colocalized with alpha 8 integrin and fibronectin loss caused a reduction in alpha 8 integrin expression, release of glial-derived neurotrophic factor and expression of Wnt11, both of which are promoters of UB branching. In conclusion, the ECM protein fibronectin acts as a regulator of kidney development and is a determinant of the final nephron number.

Oxysterol-binding protein-like 7 deficiency leads to ER stress-mediated apoptosis in podocytes and proteinuria.

Chronic kidney disease (CKD) is associated with renal lipid dysmetabolism among a variety of other pathways. We recently demonstrated that oxysterol-binding protein-like 7 (OSBPL7) modulates the expression and function of ATP-binding cassette subfamily A member 1 (ABCA1) in podocytes, a specialized type of cell essential for kidney filtration. Drugs that target OSBPL7 lead to improved renal outcomes in several experimental models of CKD. However, the role of OSBPL7 in podocyte injury remains unclear. Using mouse models and cellular assays, we investigated the influence of OSBPL7 deficiency on podocytes. We demonstrated that reduced renal OSBPL7 levels as observed in two different models of experimental CKD are linked to increased podocyte apoptosis, primarily mediated by heightened endoplasmic reticulum (ER) stress. Although as expected, the absence of OSBPL7 also resulted in lipid dysregulation (increased lipid droplets and triglycerides content), OSBPL7 deficiency-related lipid dysmetabolism did not contribute to podocyte injury. Similarly, we demonstrated that the decreased autophagic flux we observed in OSBPL7-deficient podocytes was not the mechanistic link between OSBPL7 deficiency and apoptosis. In a complementary zebrafish model, osbpl7 knockdown was sufficient to induce proteinuria and morphological damage to the glomerulus, underscoring its physiological relevance. Our study sheds new light on the mechanistic link between OSBPL7 deficiency and podocyte injury in glomerular diseases associated with CKD, and it strengthens the role of OSBPL7 as a novel therapeutic target.NEW & NOTEWORTHY OSBPL7 and ER stress comprise a central mechanism in glomerular injury. This study highlights a crucial link between OSBPL7 deficiency and ER stress in CKD. OSBPL7 deficiency causes ER stress, leading to podocyte apoptosis. There is a selective effect on lipid homeostasis in that OSBPL7 deficiency affects lipid homeostasis, altering cellular triglyceride but not cholesterol content. The interaction of ER stress and apoptosis supports that ER stress, not reduced autophagy, is the main driver of apoptosis in OSBPL7-deficient podocytes.

Pancreas transplantation as rescue therapy in a patient with type 1 diabetes and concurrent subcutaneous insulin resistance.

Patients with type 1 diabetes and concurrent subcutaneous insulin resistance present unique diagnostic and therapeutic challenges for clinicians. The standard therapeutic approach is the administration of intravenous insulin. Pancreatic transplantation should be considered at an appropriate time, particularly in the event of life-threatening ketoacidosis, hyperglycemia, hypoglycemia, catheter-associated thrombosis, and infections. We present the case of a 24-year-old woman with type 1 diabetes since early childhood and increasingly uncontrollable subcutaneous and intramuscular insulin resistance. Furthermore, we present the diagnostic pathway and therapeutic interventions performed, culminating in pancreatic transplantation as a curative approach. Immediate graft function resulted in optimal glycemic control.

Is GFR decline induced by SGLT2 inhibitor of clinical importance?

BACKGROUND: Use of sodium-glucose-cotransporter-2 (SGLT2) inhibitors often causes an initial decline in glomerular filtration rate (GFR). This study addresses the question whether the initial decline of renal function with SGLT2 inhibitor treatment is related to vascular changes in the systemic circulation. METHODS: We measured GFR (mGFR) and estimated GFR (eGFR) in 65 patients with type 2 diabetes (T2D) at baseline and after 12 weeks of treatment randomized either to a combination of empagliflozin and linagliptin (SGLT2 inhibitor based treatment group) (n = 34) or metformin and insulin (non-SGLT2 inhibitor based treatment group) (n = 31). mGFR was measured using the gold standard clearance technique by constant infusion of inulin. In addition to blood pressure (BP), we measured pulse wave velocity (PWV) under standardized conditions reflecting vascular compliance of large arteries, as PWV is considered to be one of the most reliable vascular parameter of cardiovascular (CV) prognosis. RESULTS: Both mGFR and eGFR decreased significantly after initiating treatment, but no correlation was found between change in mGFR and change in eGFR in either treatment group (SGLT2 inhibitor based treatment group: r=-0.148, p = 0.404; non-SGLT2 inhibitor based treatment group: r = 0.138, p = 0.460). Noticeably, change in mGFR correlated with change in PWV (r = 0.476, p = 0.005) in the SGLT2 inhibitor based treatment group only and remained significant after adjustment for the change in systolic BP and the change in heart rate (r = 0.422, p = 0.018). No such correlation was observed between the change in eGFR and the change in PWV in either treatment group. CONCLUSIONS: Our main finding is that after initiating a SGLT2 inhibitor based therapy an exaggerated decline in mGFR was related with improved vascular compliance of large arteries reflecting the pharmacologic effects of SGLT2 inhibitor in the renal and systemic vascular bed. Second, in a single patient with T2D, eGFR may not be an appropriate parameter to assess the true change of renal function after receiving SGLT2 inhibitor based therapy. TRIAL REGISTRATION: clinicaltrials.gov (NCT02752113).

Spot urinary sodium in CKD patients: correlation with 24h-excretion and evaluation of commonly used prediction equations.

BACKGROUND: Salt intake in CKD patients can affect cardiovascular risk and kidney disease progression. Twenty-four hour (24h) urine collections are often used to investigate salt metabolism but are cumbersome to perform. We assessed urinary sodium (U-Na) concentration in spot urine samples and investigated the correlation with 24h U-Na excretion and concentration in CKD patients under nephrological care. Further, we studied the role of CKD stage and diuretics and evaluated the performance of commonly used formulas for the prediction of 24h U-Na excretion from spot urine samples. METHODS: One hundred eight patients of the German Chronic Kidney Disease (GCKD) study were included. Each participant collected a 24h urine and two spot urine samples within the same period. The first spot urine sample (AM) was part of the second morning urine. The second urine sample was collected before dinner (PM). Patients were advised to take their medication as usual without changing dietary habits. U-Na concentrations in the two spot urine samples and their average ((AM + PM)/2) were correlated with U-Na concentration and total Na excretion in the 24h urine collections. Correlations were subsequently studied after stratification by CKD stage and diuretic intake. The usefulness of three commonly applied equations to estimate 24h U-Na excretion from spot urine samples (Kawasaki, Tanaka and Intersalt) was determined using Bland-Altman plots, analyses of sensitivity, specificity, as well as positive (PPV) and negative predictive values (NPV). RESULTS: Participants (42 women, 66 men) were on average (± SD) 62.2 (± 11.9) years old, with a mean serum creatinine of 1.6 (± 0.5) mg/dl. 95% had arterial hypertension, 37% diabetes mellitus and 55% were on diuretics. The best correlation with 24h U-Na total excretion was found for the PM spot U-Na sample. We also found strong correlations when comparing spot and 24h urine U-Na concentration. Correction of spot U-Na for U-creatinine did not improve strength of correlations. Neither CKD stage, nor intake of diuretics had significant impact on these correlations. All examined formulas revealed a significant mean bias. The lowest mean bias and the strongest correlation between estimated and measured U-Na excretion in 24h were obtained using the Tanaka-formula. Also, application of the Tanaka-formula with PM U-Na provided best sensitivity, specificity, PPV and NPV to estimate U-Na excretion > 4g/d corresponding to a salt consumption > 10g/d. CONCLUSION: U-Na concentration of spot urine samples correlated with 24h U-Na excretion especially when PM spot U-Na was used. However, correlation coefficients were relatively low. Neither CKD stage nor intake of diuretics appeared to have an influence on these correlations. There was a significant bias for all tested formulas with the Tanaka-formula providing the strongest correlation with measured 24h U-Na excretion. In summary, using spot urine samples together with the Tanaka-formula in epidemiological studies appears feasible to determine associations between approximate salt intake and outcomes in CKD patients. However, the usefulness of spot-urine samples to guide and monitor salt consumption in individual patients remains limited.

[Comprehensive care for kidney transplantation-optimization of interdisciplinary support before and after kidney transplantation]. / Rundumversorgung Nierentransplantation ­ Optimierung der interdisziplinären Betreuung vor und nach Nierentransplantation.

Due to the divergence between the number of potential organ recipients and organ availability, transplant survival is of particular importance. In order to create the best possible conditions, it is not only important to address the risk factors for loss of organ functionality after transplantation, but also to focus on the time before transplantation. During this period, which lasts several years on average, the patient can create the conditions for risk reduction before and after transplantation with support. The optimization of physical health plays an important role here in order to maintain transplantability, on the one hand, and to counteract the general loss of physical performance due to dialysis, on the other. Therefore, the focus must be placed on "exercise" and "nutrition", which represent an increased risk of declining physical health in dialysis patients. After transplantation, the focus should again be on physical health. Through support, patients learn how to improve their cardiovascular risk profile and increase their physical performance. Psychosocial support is also important to combat psychological comorbidities and prevent risks such as nonadherence. In addition to improved physical and mental health, the focus here is also on the long-term survival of the patient and the transplant.

Distinct Changes in Gut Microbiota of Patients With Kidney Graft Rejection.

Background: Kidney graft rejection still represents the major cause of graft loss in kidney transplant recipients. Of growing interest is the bidirectional relationship between gut microbiome and immune system suggesting that gut microbiota can affect allograft outcome. Methods: In this cross-sectional case-control study, we characterized the gut microbial profile of adult renal transplant recipients with and without graft rejection to define a cohort-specific microbial fingerprint through 16S ribosomal RNA gene sequencing. We used very strict inclusion and exclusion criteria to address confounder of microbiota composition. Results: Different relative abundances in several gut microbial taxa were detectable in control patients compared with patients with kidney allograft rejection. Alpha diversity was lower in the rejection group and beta diversity revealed dissimilarity between patients with and without kidney graft rejection (P < 0.01). When the rejection group was stratified according to different types of allograft rejection, major changes were identified between patients with chronic T-cellular-mediated rejection and controls. Changes in alpha diversity within the gut microbiome were related to the probability of chronic T-cellular-mediated rejection (P < 0.05). Kidney transplant patients without rejection showed significant enrichment of rather anti-inflammatory taxa whereas in the rejection group bacteria well known for their role in chronic inflammation were increased. For example, amplicon sequence variant (ASV) 362 belonging to the genus Bacteroides and ASV 312 belonging to Tannerellaceae were enriched in no rejection (P < 0.001 and P < 0.01), whereas ASV 365 was enriched in patients with allograft rejection (P = 0.04). Looking at metagenomic functions, a higher abundance of genes coding for enzymes involved in bacterial multidrug resistance and processing of short-chain fatty acids was found in patients without rejection but an increase in enzymes involved in nicotinamide adenine dinucleotide phosphate production was seen in patients with allograft rejection. Conclusions: A distinct microbial fingerprint of patients with allograft rejection might serve as noninvasive biomarker in the future.

Long-Term Outcomes with Prolonged-Release Tacrolimus in Kidney Transplantation: A Retrospective Real-World Data Analysis.

BACKGROUND Long-term real-world outcomes data for kidney transplant recipients (KTRs) converting from immediate-release tacrolimus (IRT) to prolonged-release tacrolimus (PRT) are limited. MATERIAL AND METHODS A retrospective, non-interventional review of adult KTRs treated with PRT for ≥1 month was conducted in Germany. Data were extracted from time of transplant (2008-2014) to 2018. Primary composite endpoints (graft loss, biopsy-confirmed acute rejection, graft dysfunction) and secondary endpoints (all-cause mortality, kidney function course, and tacrolimus dose/trough levels) were analyzed for sub-cohorts: de novo PRT, early conversion from IRT (within 6 months post-transplant), and late conversion (7 months to 3 years). RESULTS Analysis included 163 patients (101 de novo, 12 early converters, and 50 late converters). The overall Kaplan-Meier estimate of freedom from efficacy failure through 5 years was 0.537, (95% confidence interval (CI) 0.455-0.612) (de novo: 0.512 [0.407-0.608]; early converters: 0.500 [0.208-0.736]; late converters: 0.594 [0.443-0.717]). The overall survival rate was 0.925 (95% CI 0.872-0.957) (de novo: 0.900 [0.823-0.945]; early converters: 0.917 [0.539-0.988]; late converters: 0.977 [0.846-0.997]). During follow-up, there was a gradual reduction in tacrolimus dose and trough levels; kidney function remained stable in all cohorts. Multivariable analysis found re-transplantation, organ donor quality, best estimated glomerular filtration rate 8-12 weeks after transplant, and treatment center (between-center differences in age, sex, donor status/quality) were significantly associated with efficacy failure. CONCLUSIONS There was no difference in long-term survival profiles between KTRs who received PRT de novo vs those who converted from IRT, with 5-year survival remaining high in both groups.

Blood pressure reduction after renal denervation in patients with or without chronic kidney disease.

Background: Renal denervation (RDN) has emerged as an adjacent option for the treatment of hypertension. This analysis of the Erlanger registry aimed to compare the blood pressure (BP)-lowering effects and safety of RDN in patients with and without chronic kidney disease (CKD). Methods: In this single-center retrospective analysis, 47 patients with and 127 without CKD underwent radiofrequency-, ultrasound- or alcohol-infusion-based RDN. Office and 24-h ambulatory BP and estimated glomerular filtration rate (eGFR) were measured at baseline, and after 6 and 12 months. Results: A total of 174 patients with a mean age of 59.0 ± 10 years were followed up for 12 months. At baseline, mean eGFR was 55.8 ± 21 mL/min/1.73 m2 in patients with CKD and 87.3 ± 13 mL/min/1.73 m2 in patients without CKD. There was no significant eGFR decline in either of the groups during 12 months of follow-up. In patients without CKD, office systolic and diastolic BP were reduced by -15.3 ± 17.5/-7.9 ± 10.8 mmHg 6 months after RDN and by -16.1 ± 18.2/-7.7 ± 9.6 mmHg 12 months after RDN. In patients with CKD, office systolic and diastolic BP were reduced by -10.7 ± 24.0/-5.8 ± 13.2 mmHg 6 months after RDN and by -15.1 ± 24.9/-5.9 ± 12.9 mmHg 12 months after RDN. Accordingly, in patients without CKD, 24-h ambulatory systolic and diastolic BP were reduced by -7.2 ± 15.8/-4.9 ± 8.8 mmHg 6 months after RDN and by -9.0 ± 17.0/-6.2 ± 9.8 mmHg 12 months after RDN. In patients with CKD, 24-h systolic and diastolic BP were reduced by -7.4 ± 12.9/-4.2 ± 9.9 mmHg 6 months after RDN and by -8.0 ± 14.0/-3.6 ± 9.6 mmHg 12 months after RDN. There was no difference in the reduction of office and 24-h ambulatory BP between the two groups at any time point (all P > .2). Similar results have been found for the 6 months data. With exception of rare local adverse events, we did not observe any safety signals. Conclusion: According to our single-center experience, we observed a similar reduction in 24-h, day and night-time ambulatory BP as well as in-office BP in patients with and without CKD at any time point up to 12 months. We conclude that RDN is an effective and safe treatment option for patients with hypertension and CKD.

Modification of Dialysate Na+ Concentration but not Ultrafiltration or Dialysis Treatment Time Affects Tissue Na+ Deposition in Patients on Hemodialysis.

Introduction: Tissue Na+ overload is present in patients receiving hemodialysis (HD) and is associated with cardiovascular mortality. Strategies to actively modify tissue Na+ amount in these patients by adjusting the HD regimen have not been evaluated. Methods: In several substudies, including cross-sectional analyses (n = 75 patients on HD), a cohort study and a cross-over interventional study (n = 10 patients each), we assessed the impact of ultrafiltration (UF) volume, prolongation of dialysis treatment time, and modification of dialysate Na+ concentration on tissue Na+ content using 23Na magnetic resonance imaging (23Na-MRI). Results: In the cross-sectional analysis of our patients on HD, differences in dialysate sodium concentration ([Na+]) were associated with changes in tissue Na+ content, whereas neither UF volume nor HD treatment time affected tissue Na+ amount. Skin Na+ content was lower in 17 patients on HD, with dialysate [Na+] of <138 mmol/l compared to 58 patients dialyzing at ≥138 mmol/l (20.7 ± 7.3 vs. 26.0 ± 8.8 arbitrary units [a.u.], P < 0.05). In the cohort study, intraindividual prolongation of HD treatment time was not associated with a reduction in tissue Na+ content. Corresponding to the observational data, intraindividual modification of dialysate [Na+] from 138 to 142 to 135 mmol/l resulted in concordant changes in skin Na+ (24.3 ± 7.6 vs. 26.3 ± 8.0 vs. 20.8 ± 5.6 a.u, P < 0.05 each), whereas no significant change in muscle Na+ occurred. Conclusion: Solely adjustment of dialysate [Na+] had a reproducible impact on tissue Na+ content. 23Na-MRI could be utilized to monitor the effectiveness of dialysate [Na+] modifications in randomized-controlled outcome trials.

Long-term outcomes of adults with FSGS in the German Chronic Kidney Disease cohort.

Background: Focal segmental glomerulosclerosis (FSGS) can lead to kidney failure in adults. This study examines the progression of FSGS in the German Chronic Kidney Disease (GCKD) cohort. Methods: The GCKD study (N = 5217), a prospective cohort, included 159 patients with biopsy-confirmed FSGS recruited from 2010 to 2012. Baseline was defined as the first study visit. Adjudicated endpoints included a composite kidney endpoint (CKE), including an estimated glomerular filtration rate (eGFR) decrease >40%, eGFR <15 ml/min/1.73 m2 or initiation of kidney replacement therapy and combined major adverse cardiovascular events (MACE), including non-fatal myocardial infarction or stroke and all-cause mortality. Associations between baseline demographics, laboratory data, comorbidity and CKE and MACE were analysed using the Cox proportional hazards regression model. Results: The mean age at baseline was 52.1 ± 13.6 years, with a disease duration of 4.72 years (quartile 1: 1; quartile 3: 6) before joining the study. The median urinary albumin:creatinine ratio (UACR) at baseline was 0.7 g/g (IQR 0.1;1.8), while mean eGFR was 55.8 ± 23 ml/min/1.73 m2. Based on clinical and pathological features, 69 (43.4%) patients were categorized as primary FSGS, 55 (34.6%) as secondary FSGS and 35 (22%) as indeterminate. Over a follow-up of 6.5 years, 44 patients reached the composite kidney endpoint and 16 individuals had at least one MACE. UACR ≥0.7 g/g was strongly associated with both the composite kidney endpoint {hazard ratio [HR] 5.27 [95% confidence interval (CI) 2.4-11.5]} and MACE [HR 3.37 (95% CI 1.05-10.82)] compared with <0.7 g/g, whereas a higher eGFR at baseline (per 10 ml/min) was protective for both endpoints [HR 0.8 (95% CI 0.68-0.95) and HR 0.63 (95% CI 0.46-0.88), respectively]. Patients with secondary FSGS experienced a greater rate of eGFR decline than patients with primary FSGS. Conclusions: Lower eGFR and higher albuminuria are key risk factors for kidney disease progression and cardiovascular events in patients with FSGS.

Differentiating primary and secondary FSGS using non-invasive urine biomarkers.

Background: Focal segmental glomerulosclerosis (FSGS) is divided into genetic, primary (p), uncertain cause, and secondary (s) forms. The subclasses differ in management and prognosis with differentiation often being challenging. We aimed to identify specific urine proteins/peptides discriminating between clinical and biopsy-proven pFSGS and sFSGS. Methods: Sixty-three urine samples were collected in two different centers (19 pFSGS and 44 sFSGS) prior to biopsy. Samples were analysed using capillary electrophoresis-coupled mass spectrometry. For biomarker definition, datasets of age-/sex-matched normal controls (NC, n = 98) and patients with other chronic kidney diseases (CKDs, n = 100) were extracted from the urinary proteome database. Independent specificity assessment was performed in additional data of NC (n = 110) and CKD (n = 170). Results: Proteomics data from patients with pFSGS were first compared to NC (n = 98). This resulted in 1179 biomarker (P < 0.05) candidates. Then, the pFSGS group was compared to sFSGS, and in a third step, pFSGS data were compared to data from different CKD etiologies (n = 100). Finally, 93 biomarkers were identified and combined in a classifier, pFSGS93. Total cross-validation of this classifier resulted in an area under the receiving operating curve of 0.95. The specificity investigated in an independent set of NC and CKD of other etiologies was 99.1% for NC and 94.7% for CKD, respectively. The defined biomarkers are largely fragments of different collagens (49%). Conclusion: A urine peptide-based classifier that selectively detects pFSGS could be developed. Specificity of 95%-99% could be assessed in independent samples. Sensitivity must be confirmed in independent cohorts before routine clinical application.

Pharmacodynamic Effect of mTOR Inhibition-based Immunosuppressive Therapy on T- and B-cell Subsets After Renal Transplantation.

Background: The mammalian target of rapamycin inhibitor (mTORi) therapy after kidney transplantation is solely monitored pharmacokinetically, not necessarily reflecting PI3K-Akt-mTOR pathway blockade efficacy leading to potential under-or overimmunosuppression. Methods: In this cross-sectional study, phosphoflow cytometry was used to determine the efficacy of mTOR inhibition in peripheral T- and B-lymphocyte subsets by assessing p70S6 kinase (p70S6K) phosphorylation in renal transplant recipients upon treatment with a combination of either mTORi and calcineurin inhibitors (n = 18), or mTORi with mycophenolic acid (n = 9). Nine dialysis patients with end-stage renal disease and 17 healthy age-matched volunteers served as controls. Results: mTORi treatment reduced p70S6K phosphorylation in CD4+, CD8+ T, and CD19+ B cells compared with healthy controls (HCs). Subpopulation analysis of CD4+ T cells and CD19+ B cells revealed a significant reduction of p70S6K phosphorylation in CD4+CD45RA-CD25- Th cells (P < 0.05), CD24hiCD38hi transitional B cells (P < 0.001), CD24+CD38- memory B cells (P < 0.001), and CD24intCD38int-naive B cells (P < 0.05) upon mTORi treatment, whereas CD4+CD45RA-CD25++CD127- regulatory T cells and CD24-CD38hi plasmablasts were not affected. Compared with mTORi + mycophenolic acid therapy, mTORi + calcineurin inhibitor treatment exhibited an even stronger inhibition of p70S6K phosphorylation in CD4+CD45RA-CD25- Th cells and CD8+ T cells. However, trough levels of mTORi did not correlate with p70S6K phosphorylation. Conclusions: mTORi selectively inhibited p70S6K phosphorylation in select lymphocyte subtypes. Assessing p70S6K phosphorylation by phosphoflow cytometry may serve as an approach to understand cell subset specific effects of mTORi providing detailed pharmacodynamic information for individualizing immunosuppression.

Long-term outcomes of patients with IgA nephropathy in the German CKD cohort.

Background: The importance of albuminuria as opposed to proteinuria in predicting kidney outcomes in primary immunoglobulin A nephropathy (IgAN) is not well established. Methods: From 2010 to 2012, 421 patients with biopsy-proven IgAN have been enrolled into the German Chronic Kidney Disease (GCKD) cohort, a prospective observational cohort study (N = 5217). Adjudicated endpoints include a composite kidney endpoint (CKE) consisting of eGFR decline >40%, eGFR <15 ml/min/1.73 m2 and initiation of kidney replacement therapy; the individual components of the CKE; and combined major adverse cardiac events (MACE), including non-fatal myocardial infarction, non-fatal stroke and all-cause mortality. The associations between the incidence of CKE and baseline factors, including demographics, laboratory values and comorbidities were analysed using the Cox proportional hazards regression model. Results: The mean age of IgAN patients at baseline was 51.6 years (± 13.6) and 67% were male. The patient-reported duration of disease at baseline was 5.9 ± 8.1 years. Baseline median urine albumin:creatinine ratio (UACR) was 0.4 g/g [interquartile range (IQR) 0.1-0.8] and mean eGFR was 52.5 ± 22.4 ml/min/1.73 m2. Over a follow-up of 6.5 years, 64 (15.2%) patients experienced a >40% eGFR decline, 3 (0.7%) reached eGFR <15 ml/min/1.73 m2, 53 (12.6%) initiated kidney replacement therapy and 28% of the patients experienced the CKE. Albuminuria, with reference to <0.1 g/g, was most associated with CKE. Hazard ratios (HRs) at UACRs of 0.1-0.6 g/g, 0.6-1.4 g/g, 1.4-2.2 g/g and >2.2 g/g were 2.03 [95% confidence interval (CI) 1.02-4.05], 3.8 (95% CI 1.92-7.5), 5.64 (95% CI 2.58-12.33) and 5.02 (95% CI 2.29-11-03), respectively. Regarding MACE, the presence of diabetes [HR 2.53 (95% CI 1.11-5.78)] was the most strongly associated factor, whereas UACR and eGFR did not show significant associations. Conclusion: In the GCKD IgAN subcohort, more than every fourth patient experienced a CKE event within 6.5 years. Our findings support the use of albuminuria as a surrogate to assess the risk of poor kidney outcomes.

A multimodal aftercare intervention improves the outcome after kidney transplantation - results of the KTx360° aftercare program using claims data.

Background: The after-care treatment project KTx360° aimed to reduce graft failure and mortality after kidney transplantation (KTx). Methods: The study was conducted in the study centers Hannover, Erlangen and Hannoversch Muenden from May 2017 to October 2020 under the trial registration ISRCTN29416382. The program provided a multimodal aftercare program including specialized case management, telemedicine support, psychological and exercise assessments, and interventions. For the analysis of graft failure, which was defined as death, re-transplantation or start of long-term dialysis, we used longitudinal claims data from participating statutory health insurances (SHI) which enabled us to compare participants with controls. To balance covariate distributions between these nonrandomized groups we used propensity score methodology, in particular the inverse probability of treatment weighting (IPTW) approach. Findings: In total, 930 adult participants were recruited at three different transplant centres in Germany, of whom 320 were incident (enrolled within the first year after KTx) and 610 prevalent (enrolled >1 year after KTx) patients. Due to differences in the availability of the claims data, the claims data of 411 participants and 418 controls could be used for the analyses. In the prevalent group we detected a significantly lower risk for graft failure in the study participants compared to the matched controls (HR = 0.13, 95% CI = 0.04-0.39, p = 0.005, n = 389 observations), whereas this difference could not be detected in the incident group (HR = 0.92, 95% CI = 0.54-1.56, p = 0.837, n = 440 observations). Interpretation: Our findings suggest that a multimodal and multidisciplinary aftercare intervention can significantly improve outcome after KTx, specifically in patients later after KTx. For evaluation of effects on these outcome parameters in patients enrolled within the first year after transplantation longer observation times are necessary. Funding: The study was funded by the Global Innovation fund of the Joint Federal Committee of the Federal Republic of Germany, grant number 01NVF16009.

Progressive Kidney Failure by Angiotensinogen Inactivation in the Germline.

BACKGROUND: Autosomal recessive renal tubular dysgenesis is a rare, usually fatal inherited disorder of the renin-angiotensis system (RAS). Herein, we report an adolescent individual experiencing an unknown chronic kidney disease and aim to provide novel insights into disease mechanisms. METHODS: Exome sequencing for a gene panel associated with renal disease was performed. The RAS was assessed by comprehensive biochemical analysis in blood. Renin expression was determined in primary tubular cells by quantitative polymerase chain reaction and in situ hybridization on kidney biopsy samples. Allele frequencies of heterozygous and biallelic deleterious variants were determined by analysis of the Genomics England 100,000 Genomes Project. RESULTS: The patient was delivered prematurely after oligohydramnios was detected during pregnancy. Postnatally, he recovered from third-degree acute kidney injury but developed chronic kidney disease stage G3b over time. Exome sequencing revealed a previously reported pathogenic homozygous missense variant, p.(Arg375Gln), in the AGT (angiotensinogen) gene. Blood AGT concentrations were low, but plasma renin concentration and gene expression in kidney biopsy, vascular, and tubular cells revealed strong upregulation of renin. Angiotensin II and aldosterone in blood were not abnormally elevated. CONCLUSIONS: Renal tubular dysgenesis may present as chronic kidney disease with a variable phenotype, necessitating broad genetic analysis for diagnosis. Functional analysis of the RAS in a patient with AGT mutation revealed novel insights regarding compensatory upregulation of renin in vascular and tubular cells of the kidney and in plasma in response to depletion of AGT substrate as a source of Ang II (similarly observed with hepatic AGT silencing for the treatment of hypertension).