Sara Denicolò

Accurate prediction of diabetic kidney disease progression is challenging, but mandatory. Urinary Dickkopf-3 (uDKK3), a tubular, epithelial-derived glycoprotein and marker of tubular injury, is a promising biomarker for kidney function decline. We explored the clinical utility of uDKK3 to predict kidney function decline and adverse cardiovascular events in patients with type 2 diabetes mellitus (T2DM) in a primary health care setting. In this cohort study, 3,232 patients with T2DM were analyzed. The primary end point was a composite of a sustained estimated glomerular filtration rate (eGFR) decline ≥40%; a sustained increase in albuminuria of at least 30%, including a transition in albuminuria class; progression to end-stage kidney disease; and death from kidney failure. After adjustment for confounding variables, uDKK3 values >200 pg/mg creatinine were associated with a higher risk of the composite kidney end point during a median follow-up of 4.26 years. Furthermore, uDKK3 improved the prediction of the 1-year eGFR decline on top of albuminuria. Individuals with high uDKK3 levels also had an increased risk for adverse cardiovascular events and all-cause mortality. uDKK3 identifies patients with T2DM at high risk for kidney function decline on top of established biomarkers (albuminuria and eGFR). In primary care, uDKK3 may help to identify high-risk patients who might benefit from intensified treatment and/or referrals to specialists. Article Highlights: Prediction of kidney function decline is challenging in patients with type 2 diabetes mellitus (T2DM). Urinary Dickkopf-3 (uDKK3), a profibrotic tubular protein, is a promising biomarker for detecting tubular injury and predicting the progression of chronic kidney disease. This study assessed whether uDKK3 measurements improve risk prediction in patients with T2DM treated at the primary care level. Elevated uDKK3 levels were associated with kidney function decline, on top of established biomarkers (estimated glomerular filtration rate and albuminuria). uDKK3 also identified patients at increased risk for cardiovascular events. uDKK3 may help identify high-risk patients in primary care who could benefit from intensified treatment and/or referrals to specialists.

Background/Objectives: Anemia is a frequent multifactorial co-morbidity in end-stage kidney disease (ESKD) associated with morbidity and poor QoL. Apart from insufficient erythropoietin formation, iron deficiency (ID) contributes to anemia development. Identifying patients in need of iron supplementation with current ID definitions is difficult since no good biomarker is available to detect actual iron needs. Therefore, new diagnostic tools to guide therapy are needed. Methods: We performed a prospective cohort study analyzing tissue iron content with MRI-based R2*-relaxometry in 20 anemic ESKD patients and linked it with iron biomarkers in comparison to 20 otherwise healthy individuals. Results: ESKD patients had significantly higher liver (90.1 s⁻¹ vs. 36.1 s⁻¹, p < 0.001) and spleen R2* values (119.8 s⁻¹ vs. 19.3 s⁻¹, p < 0.001) compared to otherwise healthy individuals, while their pancreas and heart R2* values did not significantly differ. Out of the 20 ESKD patients, 17 had elevated spleen and 12 had elevated liver R2* values. KDIGO guidelines (focusing on serum iron parameters) would recommend iron supplementation in seven patients with elevated spleen and four patients with elevated liver R2* values. Conclusions: These findings highlight that liver and especially spleen iron concentrations are significantly higher in ESKD patients compared to controls. Tissue iron overload diverged from classical iron parameters suggesting need of iron supplementation. Measurement of MRI-guided tissue iron distribution might help guide treatment of anemic ESKD patients.

Introduction: Diabetic kidney disease (DKD) is a common cause of chronic kidney disease with around 25–40% of patients with diabetes being affected. The course of DKD is variable, and estimated glomerular filtration rate (eGFR) and albuminuria, the currently used clinical markers, are not able to accurately predict the individual disease trajectory, in particular in early stages of the disease. The aim of this study was to assess the association of urine levels of selected protein biomarkers with the progression of DKD at an early stage of disease. Methods: We measured 22 protein biomarkers using the Mesoscale Discovery platform in 461 urine samples of the PROVALID cohort, an observational study of patients with type 2 diabetes mellitus followed at the primary health care level for a minimum of 4 years. Odds ratios (ORs) were estimated for the effect of marker values above median on fast progression using unadjusted and adjusted logistic regression models. RNA expression at the single-cell level in kidney biopsy samples obtained from a cohort of young persons with type 2 diabetes mellitus was in addition determined for markers showing significant associations with disease progression. Results: Increased urinary levels of epidermal growth factor (EGF) were linked to lower odds of fast progression (defined as annual eGFR decline greater than 2.58 mL/min per 1.73 m2) with an OR of 0.60 (95% CI: 0.46, 0.78). The association with outcome was even stronger when adjusting for a set of 14 baseline clinical parameters including age, biological sex, eGFR, body mass index, albuminuria, and HbA1c. Elevated urinary levels of fatty acid-binding protein 3 (FABP3) and vascular cell adhesion molecule 1 (VCAM1) were each significantly associated with fast progression with an OR of 1.44 (95% CI: 1.11, 1.87) and an OR of 1.41 (95% CI: 1.08, 1.83), respectively. Enriched expression of EGF and FABP3 was observed in distal convoluted tubular cells and VCAM1 in parietal epithelial cells at single-cell level from biopsies of patients with early DKD. Conclusion: In summary, we show that lower urinary levels of EGF and higher urinary levels of FABP3 and VCAM1 are significantly associated with DKD progression in early-stage disease.

Aims/hypothesis: Non-adherence to medication is a frequent barrier in the treatment of patients with type 2 diabetes mellitus, potentially limiting the effectiveness of evidence-based treatments. Previous studies have mostly relied on indirect adherence measures to analyse outcomes based on adherence. The aim of this study was to use LC-MS/MS in urine—a non-invasive, direct and objective measure—to assess non-adherence to cardiometabolic drugs and analyse its association with kidney and cardiovascular outcomes. Methods: This cohort study includes 1125 participants from the PROVALID study, which follows patients with type 2 diabetes mellitus at the primary care level. Baseline urine samples were tested for 79 cardiometabolic drugs and metabolites thereof via LC-MS/MS. An individual was classified as totally adherent if markers for all drugs were detected, partially non-adherent when at least one marker for one drug was detected, and totally non-adherent if no markers for any drugs were detected. Non-adherence was then analysed in the context of cardiovascular (composite of myocardial infarction, stroke and cardiovascular death) and kidney (composite of sustained 40% decline in eGFR, sustained progression of albuminuria, kidney replacement therapy and death from kidney failure) outcomes. Results: Of the participants, 56.3% were totally adherent, 42.0% were partially non-adherent, and 1.7% were totally non-adherent to screened cardiometabolic drugs. Adherence was highest to antiplatelet and glucose-lowering agents and lowest to lipid-lowering agents. Over a median (IQR) follow-up time of 5.10 (4.12–6.12) years, worse cardiovascular outcomes were observed with non-adherence to antiplatelet drugs (HR 10.13 [95% CI 3.06, 33.56]) and worse kidney outcomes were observed with non-adherence to antihypertensive drugs (HR 1.98 [95% CI 1.37, 2.86]). Conclusions/interpretation: This analysis shows that non-adherence to cardiometabolic drug regimens is common in type 2 diabetes mellitus and negatively affects kidney and cardiovascular outcomes. Graphical

Fibrinogen-like 2 (FGL2) was recently found to be associated with fibrosis in a mouse model of kidney damage and was proposed as a potential therapeutic target in chronic kidney disease (CKD). We assessed the association of renal FGL2 mRNA expression with the disease outcome in two independent CKD cohorts (NEPTUNE and Innsbruck CKD cohort) using Kaplan Meier survival analysis. The regulation of FGL2 in kidney biopsies of CKD patients as compared to healthy controls was further assessed in 13 human CKD transcriptomics datasets. The FGL2 protein expression in human renal tissue sections was determined via immunohistochemistry. The regulators of FGL2 mRNA expression in renal tissue were identified in the co-expression and upstream regulator analysis of FGL2-positive renal cells via the use of single-cell RNA sequencing data from the kidney precision medicine project (KPMP). Higher renal FGL2 mRNA expression was positively associated with kidney fibrosis and negatively associated with eGFR. Renal FGL2 mRNA expression was upregulated in CKD as compared with healthy controls and associated with CKD progression in the Innsbruck CKD cohort (p-value = 0.0036) and NEPTUNE cohort (p-value = 0.0048). The highest abundance of FGL2 protein in renal tissue was detected in the thick ascending limb of the loop of Henle and macula densa, proximal tubular cells, as well as in glomerular endothelial cells. The upstream regulator analysis identified TNF, IL1B, IFNG, NFKB1, and SP1 as factors potentially inducing FGL2-co-expressed genes, whereas factors counterbalancing FGL2-co-expressed genes included GLI1, HNF1B, or PPARGC1A. In conclusion, renal FGL2 mRNA expression is elevated in human CKD, and higher FGL2 levels are associated with fibrosis and worse outcomes.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disorder which affects small- and, to a lesser degree, medium-sized vessels. ANCA-associated vasculitis encompasses three disease phenotypes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). This classification is largely based on clinical presentations and has several limitations. Recent research provided evidence that genetic background, risk of relapse, prognosis, and co-morbidities are more closely related to the ANCA serotype, proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA, compared to the disease phenotypes GPA or MPA. This finding has been extended to the investigation of biomarkers predicting disease activity, which again more closely relate to the ANCA serotype. Discoveries related to the immunopathogenesis translated into clinical practice as targeted therapies are on the rise. This review will summarize the current understanding of the immunopathogenesis of ANCA-associated vasculitis and the interplay between ANCA serotype and proposed disease biomarkers and illustrate how the extending knowledge of the immunopathogenesis will likely translate into development of a personalized medicine approach in the management of ANCA-associated vasculitis.

Background and objectives: Renal transplantation is the preferred form of renal replacement therapy for the majority of patients with end stage renal disease (ESRD). The Internet is a key tool for people seeking healthcare-related information. This current work explored the interest in kidney transplantation based on Internet search queries using Google Trends^TM. Design, setting, participants, and measurements: We performed a Google Trends^TM search with the search term “kidney transplantation” between 2004 (year of inception) and 2018. We retrieved and analyzed data on the worldwide trend as well as data from the United Network for Organ Sharing (UNOS), the Organización Nacional de Trasplantes (ONT), the Eurotransplant area, and the National Health Service (NHS) Transplant Register. Google Trends^TM indices were investigated and compared to the numbers of performed kidney transplants, which were extracted from the respective official websites of UNOS, ONT, Eurotransplant, and the NHS. Results: During an investigational period of 15 years, there was a significant decrease of the worldwide Google Trends^TM index from 76.3 to 25.4, corresponding to an absolute reduction of −50.9% and a relative reduction by −66.7%. The trend was even more pronounced for the UNOS area (−75.2%), while in the same time period the number of transplanted kidneys in the UNOS area increased by 21.9%. Events of public interest had an impact on the search queries in the year of occurrence, as shown by an increase in the Google Trends^TM index by 39.2% in the year 2005 in Austria when a person of public interest received his second live donor kidney transplant. Conclusions: This study indicates a decreased public interest in kidney transplantation. There is a clear need to raise public awareness, since transplantation represents the best form of renal replacement therapy for patients with ESRD. Information should be provided on social media, with a special focus on readability and equitable access, as well as on web pages.