Urinary peptide analysis to predict the response to blood pressure medication.

BACKGROUND AND HYPOTHESIS: The risk of Diabetic Kidney Disease (DKD) progression is significant despite renin-angiotensin system (RAS) blocking agents treatment. Current clinical tools cannot predict whether or not patients will respond to the treatment with RAS-inhibitors (RASi). We aimed to investigate if proteome analysis could identify urinary peptides as biomarkers that could predict the response to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARBs) treatment to avoid DKD progression. Furthermore, we investigated the comparability of the estimated glomerular filtration rate (eGFR), calculated using four different GFR-equations, for DKD progression. METHODS: We evaluated urine samples from a discovery cohort of 199 diabetic patients treated with RASi. DKD progression was defined based on eGFR percentage slope results between visits (∼1 year) and for the entire period (∼3 year) based on the eGFR values of each GFR-equation. Urine samples were analysed using capillary electrophoresis coupled mass spectrometry. Statistical analysis was performed between the uncontrolled (patients who did not respond to RASi treatment) and controlled kidney function groups (patients who responded to the RASi treatment). Peptides were combined in a support vector machine-based model. The area under the receiver operating characteristic curve (AUC) was used to evaluate the risk prediction models in two independent validation cohorts treated with RASi. RESULTS: The classification of patients into uncontrolled and controlled kidney function varies depending on the GFR-equation used, despite the same sample set. We identified 227 peptides showing nominal significant difference and consistent fold changes between uncontrolled and controlled patients in at least three methods of eGFR calculation. These included fragments of collagens, alpha-1-antitrypsin, antithrombin-III, CD99 antigen, and uromodulin. A model based on 189 of 227 peptides (DKDp189) showed a significant prediction of non-response to the treatment/DKD progression in two independent cohorts. CONCLUSIONS: The DKDp189 model demonstrates potential as a predictive tool for guiding treatment with RASi in diabetic patients.

International Variability of Renal and Cardiovascular Outcomes and Mortality in Patients with Type 2 Diabetes Mellitus in Europe.

INTRODUCTION: Type 2 diabetes and its complications represent a huge burden to public health. With this prospective, observational cohort study, we aimed to estimate and to compare the incidence rate (IR) of renal and cardiovascular outcomes and all-cause mortality in patients with type 2 diabetes in different European countries. METHODS: The renal endpoint was a composite of a sustained decline in estimated GFR of at least 40%, a sustained increase in albuminuria of at least 30% including a transition in albuminuria class, progression to kidney failure with replacement therapy, or death from renal causes. The cardiovascular endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: 3,131 participants from four European countries (Austria, Hungary, The Netherlands, and Scotland) with a median follow-up time of 4.4 years were included. IRs were adjusted for several risk factors including sex, age, estimated GFR, albuminuria, HbA1c, blood pressure, and duration of type 2 diabetes. Across countries, the adjusted IR for the renal endpoint was significantly higher in Hungary and Austria, and the adjusted IR for the cardiovascular endpoint was significantly higher in Scotland and Austria. All-cause mortality was significantly higher in Scotland compared to all other countries. CONCLUSION: Our findings show how the longitudinal outcome of patients with type 2 diabetes varies significantly across European countries even after accounting for the distribution of underlying risk factors.

Virus-Subtype-Specific Cellular and Humoral Immune Response to a COVID-19 mRNA Vaccine in Chronic Kidney Disease Patients and Renal Transplant Recipients.

Patients with chronic kidney disease (CKD) or immunosuppression are at increased risk of severe SARS-CoV-2 infection. The vaccination of CKD patients has resulted in lower antibody concentrations and possibly reduced protection. However, little information is available on how T-cell-mediated immune response is affected in those patients and how vaccine-induced immune responses can neutralise different SARS-CoV-2 variants. Herein, we studied virus-specific humoral and cellular immune responses after two doses of mRNA-1273 (Moderna) vaccine in 42 patients suffering from CKD, small vessel vasculitis (maintenance phase), or kidney transplant recipients (KT). Serum and PBMCs from baseline and at three months after vaccination were used to determine SARS-CoV-2 S1-specific antibodies, neutralisation titers against SARS-CoV-2 WT, B1.617.2 (delta), and BA.1 (omicron) variants as well as virus-specific T-cells via IFNγ ELISpot assays. We observed a significant increase in quantitative and neutralising antibody titers against SARS-CoV-2 and significantly increased T-cell responses to SARS-CoV-2 S1 antigen after vaccination only in the CKD patients. In patients with vasculitis, neither humoral nor cellular responses were detected. In KT recipients, antibodies and virus neutralisation against WT and delta, but not against omicron BA.1, was assured. Importantly, we found no specific SARS-CoV-2 T-cell response in vasculitis and KT subjects, although unspecific T-cell activation was evident in most patients even before vaccination. While pre-dialysis CKD patients appear to mount an effective immune response for in vitro neutralisation of SARS-CoV-2, KT and vasculitis patients under immunosuppressive therapy were insufficiently protected from SARS-CoV-2 two months after the second dose of an mRNA vaccine.

Biological variation and reference change value of the estimated glomerular filtration rate in humans: A systematic review and meta-analysis.

Background: Knowledge of the biological variation of serum or plasma creatinine (Cr) and the estimated glomerular filtration rate (eGFR) is important for understanding disease dynamics in Chronic Kidney Disease (CKD). The aim of our study was to determine the magnitude of random fluctuation of eGFR by determining its reference change value (RCV). Methods: We performed a systematic review and meta-analysis of studies on biological variation of Cr. Relevant studies were identified by systematic literature search on PubMed. Additional studies were retrieved from the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Biological Variation Database. Random-effects meta-analysis was conducted to derive an overall estimate of intra-individual variation of creatinine (CVICr). Based on our estimate of CVICr and RCV for Cr, the RCV for the eGFR was determined. Results: Among identified studies, 37 met our inclusion criteria. Meta-analysis of all studies yielded a CVICr of 5.2% (95% confidence interval [CI] 4.6-5.8%), however high between-study heterogeneity (I 2 = 82.3%) was found. Exclusion of outliers led to a significant reduction of heterogeneity while still including 85% of all studies and resulted in a slightly lower CVICr of 5.0% (95% CI 4.7-5.4%). Assuming an analytical variation of CVA 1.1%, we found an overall RCV for eGFR of ±16.5%. After exclusion of outlier studies, we found a minimum conservative RCV for eGFR of ±12.5%. Conclusion: The RCV of the eGFR represents a valuable tool for clinicians to discern true changes in kidney function from random fluctuation.

Humoral Immune Response to a Timely Booster mRNA Vaccination in Non-Responders to a Standard Vaccination Schedule against COVID-19 in Kidney Transplant Recipients.

Kidney transplant recipients who are at increased risk for COVID-19 infection and associated morbidity and mortality have been shown to be prone to an impaired humoral immune response to a standard vaccination schedule against COVID-19 with two doses of SARS-CoV-2 mRNA vaccines. In this study, response rate of 94 kidney transplant recipients without detectable seroconversion after two doses of a mRNA vaccine who were offered a timely third mRNA vaccine after completion of the standard vaccination schedule was retrospectively analyzed. After a median of 28 days, antibody titers against the S1 spike protein showed a non-response rate of 53%. No significant risk factors for non-response could be identified. The responders showed a high variation in antibody titers (median 73.9 BAU/mL, IQR 221.5). In conclusion, a third booster mRNA vaccine in non-responding kidney transplant recipients leads to a detectable humoral immune response in approximately half of the patients. In the seroconversion group, antibody titers were highly variable, indicating that even non-responders to the standard vaccination schedule might develop a significant humoral immune response after a timely booster vaccine.

Population Characteristics and Clinical Outcomes from the Renal Transplant Outcome Prediction Validation Study (TOPVAS).

Kidney transplantation is the preferred method for selected patients with kidney failure. Despite major improvements over the last decades, a significant proportion of organs are still lost every year. Causes of graft loss and impaired graft function are incompletely understood and prognostic tools are lacking. Here, we describe baseline characteristics and outcomes of the non-interventional Transplant Outcome Prediction Validation Study (TOPVAS). A total of 241 patients receiving a non-living kidney transplant were recruited in three Austrian transplantation centres and treated according to local practices. Clinical information as well as blood and urine samples were obtained at baseline and consecutive follow-ups up to 24 months. Out of the overall 16 graft losses, 11 occurred in the first year. The patient survival rate was 96.7% (95% CI: 94.3-99.1%) in the first year and 94.3% (95% CI: 91.1-97.7%) in the second year. Estimated glomerular filtration rate (eGFR) improved from 37.1 ± 14.0 mL/min/1.73 m2 at hospital discharge to 45.0 ± 14.5 mL/min/1.73 m2 at 24 months. The TOPVAS study provides information on current kidney graft and patient survival, eGFR trajectories, and rejection rates, as well as infectious and surgical complication rates under different immunosuppressive drug regimens. More importantly, it provides an extensive and well-characterized biobank for the future discovery and validation of prognostic methods.

Antibody Response to mRNA Vaccines against SARS-CoV-2 with Chronic Kidney Disease, Hemodialysis, and after Kidney Transplantation.

Most trials on mRNA vaccines against SARS-CoV-2 did not include patients with chronic kidney disease (CKD), hemodialysis (HD) patients, or kidney transplant recipients (KTR). However, those patients have a higher risk for a severe course of COVID-19 disease and mortality. Available literature has demonstrated a reduced efficacy of mRNA vaccines in HD patients and KTR, while data on CKD patients is scarce. Additionally, factors associated with non-response are poorly understood and not well characterized. We assessed antibody (AB) response (n = 582, 160 CKD patients, 206 patients on HD, 216 KTR) after the administration of two doses of a mRNA-vaccine with either BNT162b2 or mRNA-1273. AB measurements were carried out after a median of 91 days after first vaccinations, demonstrating non-response in 12.5% of CKD patients, 12.1% of HD patients, and 50% of KTR. AB titers were significantly higher in CKD patients than in HD patients or KTR. Factors associated with non-response were treated with rituximab in CKD patients, the use of calcineurin inhibitors in HD patients and older age, and the use of BNT162b2, mycophenolic acid, or glucocorticoids and lower hemoglobin levels in KTR. This study contributes to the understanding of the extent and conditions that predispose for non-response in patients with impaired kidney function.