Increased interleukin-26 in the peripheral joints of patients with axial spondyloarthritis and psoriatic arthritis, co-localizing with CD68-positive synoviocytes

Objectives: IL26 levels are elevated in the blood and synovial fluid of patients with inflammatory arthritis. IL26 can be produced by Th17 cells and locally within joints by tissue-resident cells. IL26 induces osteoblast mineralization in vitro. As osteoproliferation and Th17 cells are important factors in the pathogenesis of axial spondyloarthritis (axSpA), we aimed to clarify the cellular sources of IL26 in spondyloarthritis. Methods: Serum, peripheral blood mononuclear cells (n = 15–35) and synovial tissue (n = 3–9) of adult patients with axSpA, psoriatic arthritis (PsA) and rheumatoid arthritis (RA) and healthy controls (HCs, n = 5) were evaluated by ELISA, flow cytometry including PrimeFlow assay, immunohistochemistry and immunofluorescence and quantitative PCR. Results: Synovial tissue of axSpA patients shows significantly more IL26-positive cells than that of HCs (p < 0.01), but numbers are also elevated in PsA and RA patients. Immunofluorescence shows co-localization of IL26 with CD68, but not with CD3, SMA, CD163, cadherin-11, or CD90. IL26 is elevated in the serum of RA and PsA (but not axSpA) patients compared with HCs (p < 0.001 and p < 0.01). However, peripheral blood CD4+ T cells from axSpA and PsA patients show higher positivity for IL26 in the PrimeFlow assay compared with HCs. CD4+ memory T cells from axSpA patients produce more IL26 under Th17-favoring conditions (IL-1β and IL-23) than cells from PsA and RA patients or HCs. Conclusion: IL26 production is increased in the synovial tissue of SpA and can be localized to CD68+ macrophage-like synoviocytes, whereas circulating IL26+ Th17 cells are only modestly enriched. Considering the osteoproliferative properties of IL26, this offers new therapeutic options independent of Th17 pathways

Renal and Skeletal Anomalies in a Cohort of Individuals With Clinically Presumed Hereditary Nephropathy Analyzed by Molecular Genetic Testing

Background: Chronic kidney disease (CKD) in childhood and adolescence occurs with a median incidence of 9 per million of the age-related population. Over 70% of CKD cases under the age of 25 years can be attributed to a hereditary kidney disease. Among these are hereditary podocytopathies, ciliopathies and (monogenic) congenital anomalies of the kidney and urinary tract (CAKUT). These disease entities can present with a vast variety of extrarenal manifestations. So far, skeletal anomalies (SA) have been infrequently described as extrarenal manifestation in these entities. The aim of this study was to retrospectively investigate a cohort of individuals with hereditary podocytopathies, ciliopathies or CAKUT, in which molecular genetic testing had been performed, for the extrarenal manifestation of SA. Material and Methods: A cohort of 65 unrelated individuals with a clinically presumed hereditary podocytopathy (focal segmental glomerulosclerosis, steroid resistant nephrotic syndrome), ciliopathy (nephronophthisis, Bardet-Biedl syndrome, autosomal recessive/dominant polycystic kidney disease), or CAKUT was screened for SA. Data was acquired using a standardized questionnaire and medical reports. 57/65 (88%) of the index cases were analyzed using exome sequencing (ES). Results: 8/65 (12%) index individuals presented with a hereditary podocytopathy, ciliopathy, or CAKUT and an additional skeletal phenotype. In 5/8 families (63%), pathogenic variants in known disease-associated genes (1x BBS1, 1x MAFB, 2x PBX1, 1x SIX2) could be identified. Conclusions: This study highlights the genetic heterogeneity and clinical variability of hereditary nephropathies in respect of skeletal anomalies as extrarenal manifestation

IFN regulatory factor 4 controls post-ischemic inflammation and prevents chronic kidney disease

Ischemia reperfusion injury (IRI) of the kidney results in interferon regulatory factor 4 (IRF4)–mediated counter-regulation of the acute inflammatory response. Beyond that, IRF4 exerts important functions in controlling the cytokine milieu, T-cell differentiation, and macrophage polarization. The latter has been implicated in tissue remodeling. It therefore remains elusive what the role of IRF4 is in terms of long-term outcome following IRI. We hypothesized that an inability to resolve chronic inflammation in Irf4−/− mice would promote chronic kidney disease (CKD) progression. To evaluate the effects of IRF4 in chronic upon acute injury in vivo, a mouse model of chronic injury following acute IRI was employed. The expression of Irf4 increased within 10 days after IRI in renal tissue. Both mRNA and protein levels remained high up to 5 weeks upon IRI, suggesting a regulatory function in the chronic phase. Mice deficient in IRF4 display increased tubular cell loss and defective clearance of infiltrating macrophages. These phenomena were associated with increased expression of pro-inflammatory macrophage markers together with reduced expression of alternatively activated macrophage markers. In addition, IRF4-deficient mice showed defective development of alternatively activated macrophages. Hints of a residual M1 macrophage signature were further observed in human biopsy specimens of patients with hypertensive nephropathy vs. living donor specimens. Thus, IRF4 restricts CKD progression and kidney fibrosis following IRI, potentially by enabling M2 macrophage polarization and restricting a Th1 cytokine response. Deteriorated alternative macrophage subpopulations in Irf4−/− mice provoke chronic intrarenal inflammation, tubular epithelial cell loss, and renal fibrosis in the long course after IRI in mice. The clinical significance of these finding for human CKD remains uncertain at present and warrants further studies

Worsening calcification propensity precedes all-cause and cardiovascular mortality in haemodialyzed patients

A novel in-vitro test (T-50-test) assesses ex-vivo serum calcification propensity which predicts mortality in HD patients. The association of longitudinal changes of T-50 with all-cause and cardiovascular mortality has not been investigated. We assessed T-50 in paired sera collected at baseline and at 24 months in 188 prevalent European HD patients from the ISAR cohort, most of whom were Caucasians. Patients were followed for another 19 [interquartile range: 11-37] months. Serum T-50 exhibited a significant decline between baseline and 24 months (246 +/- 64 to 190 +/- 68 minutes;p < 0.001). With serum Delta-phosphate showing the strongest independent association with declining T-50 (r = -0.39;p < 0.001) in multivariable linear regression. The rate of decline of T-50 over 24 months was a significant predictor of all-cause (HR = 1.51 per 1SD decline, 95% CI: 1.04 to 2.2;p = 0.03) and cardiovascular mortality (HR = 2.15;95% CI: 1.15 to 3.97;p = 0.02) in Kaplan Meier and multivariable Cox-regression analysis, while cross-sectional T-50 at inclusion and 24 months were not. Worsening serum calcification propensity was an independent predictor of mortality in this small cohort of prevalent HD patients. Prospective larger scaled studies are needed to assess the value of calcification propensity as a longitudinal parameter for risk stratification and monitoring of therapeutic interventions

The Kidney Donor Profile Index (KDPI) Correlates With Histopathologic Findings in Post-reperfusion Baseline Biopsies and Predicts Kidney Transplant Outcome

Background The increasing organ shortage in kidney transplantation leads to the necessity to use kidneys previously considered unsuitable for transplantation. Numerous studies illustrate the need for a better decision guidance rather than only the classification into kidneys from standard or expanded criteria donors referred to as SCD/ECD-classification. The kidney donor profile index (KDPI) exhibits a score utilizing a much higher number of donor characteristics. Moreover, graft biopsies provide an opportunity to assess organ quality. Methods In a single center analysis 383 kidney transplantations (277 after deceased and 106 after living donation) performed between January 1st, 2006, and December 31st, 2016, retrospectively underwent SCD/ECD and KDPI scoring. Thereby, the quality of deceased donor kidneys was assessed by using the KDPI and the living donor kidneys by using the living KDPI, in the further analysis merged as (L)KDPI. Baseline biopsies taken 10 min after the onset of reperfusion were reviewed for chronic and acute lesions. Survival analyses were performed using Kaplan-Meier analysis and Cox proportional hazards analysis within a 5-year follow-up. Results The (L)KDPI correlated with glomerulosclerosis (r = 0.30, p 85%, respectively. Conclusion With a higher granularity compared to the SCD/ECD-classification the (L)KDPI is a promising tool to judge graft quality. The correlation with chronic and acute histological lesions in post-reperfusion kidney biopsies underlines the descriptive value of the (L)KDPI. However, its prognostic value is limited and underlines the urgent need for a more precise prognostic tool adopted to European kidney transplant conditions

Extracorporeal light-chain elimination in myeloma with simple medium cutoff membrane hemodialysis: a retrospective cohort study

Background We determined the efficacy of free light chain (FLC) removal by regular dialysis equipment (high-flux filtration) with medium cutoff (MCO) membrane hemodialysis (HD) as an adjuvant treatment to standard chemotherapy for patients with acute kidney injury complicating multiple myeloma (MM) and its impact on further dialysis dependency. Methods Sixty patients with acute dialysis-dependent renal failure secondary to MM were treated with MCO-HD (55 patients) or HCO (high cutoff)-HD (5 patients) as a control. FLC serum concentration, total protein, immunoglobulins, and LDH were measured throughout the dialysis therapy. The kidney function of the patients was followed up for 1 year. Results The median age was 69 years; 25 female and 35 male patients were enrolled. HD significantly reduced FLC kappa levels in the MCO/HCO group by 58%/84% (MCO/HCO group; p &lt; 0.05) and FLC lambda by 39%/33% (MCO/HCO group; p &lt; 0.05). Single HD data (MCO) showed a relative reduction of 70% in kappa and 37% in lambda FLC concentration, as expected by the different sizes of the light chains. Renal function improved significantly and continuously from starting creatinine 5.7/3.8 mg/dl (MCO/HCO group) before HD to 1.4/2.0 mg/dl (MCO/HCO group; p &lt; 0.001) after 1 year. No significant alteration of total protein, immunoglobulins, and LDH concentrations by HD (HCO and MCO group) was observed. After 1 year, 37 of 60 patients were alive and 34 of them were off dialysis. Conclusion FLC elimination with MCO-HD is effective, technically easy, and less cost-intensive as compared with HCO-HD. Kidney function recovery in MM patients is achievable. </sec

Heterozygous COL4A3 Variants in Histologically Diagnosed Focal Segmental Glomerulosclerosis

Introduction: Steroid-resistant nephrotic syndrome (SRNS) is one of the most frequent causes for chronic kidney disease in childhood. In ~30% of these cases a genetic cause can be identified. The histological finding in SRNS is often focal segmental glomerulosclerosis (FSGS). In rare cases, however, pathogenic variants in genes associated with Alport syndrome can be identified in patients with the histological finding of FSGS. Materials and Methods: Clinical information was collected out of clinical reports and medical history. Focused molecular genetic analysis included sequencing of COL4A5 and COL4A3 in the index patient. Segregation analysis of identified variants was performed in the parents and children of the index patient. Results: The female index patient developed mild proteinuria and microscopic hematuria in childhood (12 years of age). The histological examination of the kidney biopsies performed at the age of 21, 28, and 32 years showed findings partly compatible with FSGS. However, immunosuppressive treatment of the index patient did not lead to a sufficient reduction of in part nephrotic-range proteinuria. After the patient developed hearing impairment at the age of 34 years and her daughter was diagnosed with microscopic hematuria at the age of 6 years, re-examination of the index's kidney biopsies by electron microscopy revealed textural changes of glomerular basement membrane compatible with Alport syndrome. Molecular genetic analysis identified two missense variants in COL4A3 in a compound heterozygous state with maternal and paternal inheritance. One of them is a novel variant that was also found in the 6 year old daughter of the index patient who presented with microscopic hematuria. Discussion: We were able to show that a novel variant combined with a previously described variant in compound heterozygous state resulted in a phenotype that was histologically associated with FSGS. Molecular genetic analysis therefore can be essential to solve difficult cases that show an unusual appearance and therefore improve diagnostic accuracy. Additionally, unnecessary and inefficient treatment with multiple side effects can be avoided

Pretransplant Serum Uromodulin and Its Association with Delayed Graft Function Following Kidney Transplantation—A Prospective Cohort Study

Delayed graft function (DGF) following kidney transplantation is associated with increased risk of graft failure, but biomarkers to predict DGF are scarce. We evaluated serum uromodulin (sUMOD), a potential marker for tubular integrity with immunomodulatory capacities, in kidney transplant recipients and its association with DGF. We included 239 kidney transplant recipients and measured sUMOD pretransplant and on postoperative Day 1 (POD1) as independent variables. The primary outcome was DGF, defined as need for dialysis within one week after transplantation. In total, 64 patients (27%) experienced DGF. In multivariable logistic regression analysis adjusting for recipient, donor and transplant associated risk factors each 10 ng/mL higher pretransplant sUMOD was associated with 47% lower odds for DGF (odds ratio (OR) 0.53, 95% confidence interval (95%-CI) 0.30–0.82). When categorizing pretransplant sUMOD into quartiles, the quartile with the lowest values had 4.4-fold higher odds for DGF compared to the highest quartile (OR 4.41, 95%-CI 1.54–13.93). Adding pretransplant sUMOD to a model containing established risk factors for DGF in multivariable receiver-operating-characteristics (ROC) curve analysis, the area-under-the-curve improved from 0.786 [95%-CI 0.723–0.848] to 0.813 [95%-CI 0.755–0.871, p = 0.05]. SUMOD on POD1 was not associated with DGF. In conclusion, higher pretransplant sUMOD was independently associated with lower odds for DGF, potentially serving as a non-invasive marker to stratify patients according to their risk for developing DGF early in the setting of kidney transplantation

Cardiovascular Mortality Can Be Predicted by Heart Rate Turbulence in Hemodialysis Patients

Background: Excess mortality in hemodialysis patients is mostly of cardiovascular origin. We examined the association of heart rate turbulence (HRT), a marker of baroreflex sensitivity, with cardiovascular mortality in hemodialysis patients. Methods: A population of 290 prevalent hemodialysis patients was followed up for a median of 3 years. HRT categories 0 (both turbulence onset [TO] and slope [TS] normal), 1 (TO or TS abnormal), and 2 (both TO and TS abnormal) were obtained from 24 h Holter recordings. The primary end-point was cardiovascular mortality. Associations of HRT categories with the endpoints were analyzed by multivariable Cox regression models including HRT, age, albumin, and the improved Charlson Comorbidity Index for hemodialysis patients. Multivariable linear regression analysis identified factors associated with TO and TS. Results: During the follow-up period, 20 patients died from cardiovascular causes. In patients with HRT categories 0, 1 and 2, cardiovascular mortality was 1, 10, and 22%, respectively. HRT category 2 showed the strongest independent association with cardiovascular mortality with a hazard ratio of 19.3 (95% confidence interval: 3.69-92.03;P < 0.001). Age, calcium phosphate product, and smoking status were associated with TO and TS. Diabetes mellitus and diastolic blood pressure were only associated with TS. Conclusion: Independent of known risk factors, HRT assessment allows identification of hemodialysis patients with low, intermediate, and high risk of cardiovascular mortality. Future prospective studies are needed to translate risk prediction into risk reduction in hemodialysis patients