International journal of molecular sciences, Apr 4, 2024
Renin-angiotensin-aldosterone system (RAAS) inhibitors are standard care in patients with hyperte... more Renin-angiotensin-aldosterone system (RAAS) inhibitors are standard care in patients with hypertension, heart failure or chronic kidney disease (CKD). Although we have studied the RAAS for decades, there are still circumstances that remain unclear. In this review, we describe the evolution of the RAAS and pose the question of whether this survival trait is still necessary to humankind in the present age. We elucidate the benefits on cardiovascular health and kidney disease of RAAS inhibition and present promising novel medications. Furthermore, we address why more studies are needed to establish a new standard of care away from generally prescribing ACEi or ARB toward an improved approach to combine drugs tailored to the needs of individual patients.
Fibrinogen-like 2 (FGL2) was recently found to be associated with fibrosis in a mouse model of ki... more 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.
The burden of disease associated with FSGS has not been well characterized, especially with regar... more The burden of disease associated with FSGS has not been well characterized, especially with regard to health care resource utilization (HCRU) and related costs. The aim of this study was to evaluate all-cause HCRU and estimate associated costs in patients with FSGS compared with a matched non-FSGS cohort; a secondary aim was to evaluate the impact of nephrotic range proteinuria on these outcomes. METHOD: Data were from the Optum ClinformaticsV R Data Mart Database. Patients with 1 claim (1 st claim = index event) for FSGS between April 2016 and December 2018 were identified based on ICD-10-CM codes and matched 1:2 (FSGS:controls) on index date, age, sex, and race to non-FSGS controls; continuous enrollment 6 months pre-and 12 months post-index was required. FSGS nephrotic range (either UPCR >3000 mg/g or ACR >2000 mg/g) and non-nephrotic subpopulations were also identified. Quan-Charlson Comorbidity Index (CCI) and individual comorbidities at baseline, and 12-month post-index all-cause HCRU and associated costs (per patient per year [PPPY]) as well as medication prescriptions related to FSGS treatment were compared between the matched cohorts and between the FSGS subpopulations; t-tests were used for continuous variables and chi-square tests for categorical variables. RESULTS: 844 patients with FSGS were matched with 1688 non-FSGS controls; 57.4% male, 56.9% white, mean (SD) age 54.7 (18.4) years. Mean (SD) CCI was higher in the FSGS cohort relative to matched controls (2.72 [2.12] vs 0.55 [1.29]; P < .0001), with prevalence of most individual comorbidities higher in the FSGS cohort. Only 308 FSGS patients (36.5%) had UPCR or ACR tests with available results during the review period; 112 (36.4%) were in the nephrotic range and 196 were non-nephrotic (63.6%). The FSGS cohort was characterized by higher rates of all-cause HCRU across resource categories (all P < .0001) (Table ); outpatient visits was the most frequently used category (99.1% vs 69.0%), followed by prescription medications. Among patients who used these resources, units of use were significantly higher in FSGS vs matched controls except for length of stay (Table ). Readmission rates following 1st post-index hospitalization were higher in the FSGS cohort vs matched controls at 30 days (16.1% vs 6.0%; P < .05) and 365 days (39.1% vs 22.9%; P < .05). Glucocorticoids were the most frequently prescribed FSGS-related medication in both cohorts, with a higher rate in FSGS vs matched controls (50.6% vs 23.3%; P < .0001); other FSGS-related medications were infrequently prescribed (< 14%). Inpatient, outpatient, and prescription costs were higher in the FSGS cohort vs matched controls (all P < .0001) resulting in mean total annual medical costs of $59,753 vs $8,431 PPPY (P < .0001) that were driven by outpatient costs (Fig. ). Nephrotic range proteinuria was associated with higher all-cause inpatient, outpatient, and prescription costs vs nonnephrotic patients (all P < .0001; Fig. ), resulting in higher total costs ($70,481 vs $36,099 PPPY; P < .0001). A higher proportion of nephrotic range patients were prescribed FSGS-modifying medications (73.2% vs 54.1%; P = 0.001), with glucocorticoids the most frequent medication. However, 26.8% of nephrotic range patients were not prescribed any FSGS-related medications. MO513 Figure : Annual all-cause medical costs per patient. A) FSGS and matched non-FSGS cohorts. B) Nephrotic range and non-nephrotic FSGS patients. CONCLUSION: FSGS is associated with significant clinical and economic burdens with total annual medical costs > 7-fold higher than matched controls that were driven by outpatient costs. The presence of nephrotic range proteinuria substantially and significantly increased the economic burden. New treatment modalities leading to lower rates of proteinuria may help improve patient outcomes while reducing HCRU and their associated costs.
Donor organ quality affects long term outcome after renal transplantation. A variety of prognosti... more Donor organ quality affects long term outcome after renal transplantation. A variety of prognostic molecular markers is available, yet their validity often remains undetermined. A network-based molecular model reflecting donor kidney status based on transcriptomics data and molecular features reported in scientific literature to be associated with chronic allograft nephropathy was created. Significantly enriched biological processes were identified and representative markers were selected. An independent kidney pre-implantation transcriptomics dataset of 76 organs was used to predict estimated glomerular filtration rate (eGFR) values twelve months after transplantation using available clinical data and marker expression values. The best-performing regression model solely based on the clinical parameters donor age, donor gender, and recipient gender explained 17% of variance in post-transplant eGFR values. The five molecular markers EGF, CD2BP2, RALBP1, SF3B1, and DDX19B representing key molecular processes of the constructed renal donor organ status molecular model in addition to the clinical parameters significantly improved model performance (p-value = 0.0007) explaining around 33% of the variability of eGFR values twelve months after transplantation. Collectively, molecular markers reflecting donor organ status significantly add to prediction of posttransplant renal function when added to the clinical parameters donor age and gender.
IMPORTANCE Type 2 diabetes increases the risk of progressive diabetic kidney disease, but reliabl... more IMPORTANCE Type 2 diabetes increases the risk of progressive diabetic kidney disease, but reliable prediction tools that can be used in clinical practice and aid in patients' understanding of disease progression are currently lacking. OBJECTIVE To develop and externally validate a model to predict future trajectories in estimated glomerular filtration rate (eGFR) in adults with type 2 diabetes and chronic kidney disease using data from 3 European multinational cohorts. This prognostic study used baseline and follow-up information collected between February 2010 and December 2019 from 3 prospective multinational cohort studies: PROVALID (Prospective Cohort Study in Patients with Type 2 Diabetes Mellitus for Validation of Biomarkers), GCKD (German Chronic Kidney Disease), and DIACORE (Diabetes Cohorte). A total of 4637 adult participants (aged 18-75 years) with type 2 diabetes and mildly to moderately impaired kidney function (baseline eGFR of Ն30 mL/min/1.73 m 2 ) were included. Data were analyzed between June 30, 2021, and January 31, 2023. MAIN OUTCOMES AND MEASURES Thirteen variables readily available from routine clinical care visits (age, sex, body mass index; smoking status; hemoglobin A 1c [mmol/mol and percentage]; hemoglobin, and serum cholesterol levels; mean arterial pressure, urinary albumin-creatinine ratio, and intake of glucose-lowering, blood-pressure lowering, or lipid-lowering medication) were selected as predictors. Repeated eGFR measurements at baseline and follow-up visits were used as the outcome. A linear mixed-effects model for repeated eGFR measurements at study entry up to the last recorded follow-up visit (up to 5 years after baseline) was fit and externally validated. RESULTS Among 4637 adults with type 2 diabetes and chronic kidney disease (mean [SD] age at baseline, 63.5 [9.1] years; 2680 men [57.8%]; all of White race), 3323 participants from the PROVALID and GCKD studies (mean [SD] age at baseline, 63.2 [9.3] years; 1864 men [56.1%]) were included in the model development cohort, and 1314 participants from the DIACORE study (mean [SD] age at baseline, 64.5 [8.3] years; 816 men [62.1%]) were included in the external validation cohort, with a mean (SD) follow-up of 5.0 (0.6) years. Updating the random coefficient estimates with baseline eGFR values yielded improved predictive performance, which was particularly evident in the visual inspection of the calibration curve (calibration slope at 5 years: 1.09; 95% CI, 1.04-1.15). The prediction model had good discrimination in the validation cohort, with the lowest C statistic at 5 years after baseline (0.79; 95% CI, 0.77-0.80). The model also had predictive accuracy, with an R 2 ranging from 0.70 (95% CI, 0.63-0.76) at year 1 to 0.58 (95% CI, 0.53-0.63) at year 5. In this prognostic study, a reliable prediction model was developed and externally validated; the robust model was well calibrated and capable of predicting (continued) Key Points Question Can routinely available data from primary care visits be used to develop and externally validate a prediction model that reliably predicts estimated glomerular filtration rate (eGFR) for upcoming follow-up visits? Findings In this prognostic study involving 4637 adults with type 2 diabetes and chronic kidney disease, a prediction model including 13 routinely collected baseline variables based on data from 3 prospective multinational cohort studies was developed and externally validated. The model was robust, well calibrated, and capable of predicting decreases in eGFR up to 5 years after baseline. Meaning These findings suggest that the prediction model, which is publicly available in a web-based application, may be used to improve prediction of individual eGFR trajectories and kidney function decline.
International Journal of Molecular Sciences, Nov 1, 2020
SGLT2 inhibitors (SGLT2i) slow the progression of chronic kidney disease; however, evidence for t... more SGLT2 inhibitors (SGLT2i) slow the progression of chronic kidney disease; however, evidence for the underlying molecular mechanisms is scarce. We investigated SGLT2i-mediated effects on differential gene expression in two independent human proximal tubular cell (HPTC) lines (HK-2 and RPTEC/TERT1) at the mRNA and protein levels under normoglycemic conditions, utilizing IL-1β as a pro-inflammatory mediator. Microarray hybridization identified 259 genes that were uniformly upregulated by IL-1β (10 mg/mL) and downregulated by empagliflozin (Empa) (500 nM) after 24 h of stimulation in two independent HPTC lines (n = 2, each). The functional annotation of these genes identified eight pathway clusters. Among 12 genes annotated to the highest ranked cluster (enrichment score, 3.51), monocyte chemoattractant protein-1/CC-chemokine ligand 2 (MCP-1/CCL2) and endothelin-1 (ET-1) were selected for verification at mRNA and protein levels based on their established involvement in the early pathogenesis of chronic kidney disease: IL-1β upregulated basal MCP-1/CCL2 (15-and 19-fold) and ET-1 (3-and 8-fold) mRNA expression, while Empa downregulated basal MCP-1/CCL2 (0.6-and 0.5-fold) and ET-1 (0.3-and 0.2-fold) mRNA expression as early as 1 h after stimulation and for at least 24 h in HK-2 and RPTEC/TERT1 cells, respectively. The co-administration of Empa inhibited IL-1β-mediated MCP-1/CCL2 (0.2-fold, each) and ET-1 (0.2-fold, each) mRNA expression as early as 1 h after ligand stimulation and for at least 24 h in both HPTC lines, respectively. This inhibitory effect of Empa on basal and IL-1β-mediated MCP-1/CCL2 and ET-1 mRNA expression was corroborated at the protein level. Our study presents novel evidence for the interference of SGLT2 inhibition with tubular inflammatory response mechanisms under normoglycemic conditions that might account for SGLT2i-mediated nephroprotection.
The pathophysiology of diabetic nephropathy (DN) is driven by a complex, multi-facetted interplay... more The pathophysiology of diabetic nephropathy (DN) is driven by a complex, multi-facetted interplay of numerous molecular processes (protective as well as damaging) and the balance between these, rather than the activity of a single pathway, determines clinical presentation and outcome. We present a concept for deriving a biomarker panel aimed to represent the relevant processes involved. Our approach rests on a hybrid gene/protein interaction network that holds ample information on molecular features (nodes) and their relations (edges), as a result providing a basic structure to navigate in molecular content and context being identified as relevant in DN. Extensive literature search on omics studies in DN provided a molecular feature list mapping to a total of 2175 unique protein-coding genes [13 from single nucleotide polymorphisms (SNPs), 12 as targets from relevant miRNAs, 1583 from transcriptomics, 5 from proteomics and 53 from metabolomics via linking to enzymes; 509 features were identified from multiple sources]. Two hundred and eighty-seven further human protein-coding genes associated with DN were derived from searching NCBI Pubmed (utilizing MeSH and gene-topubmed). Text mining of patents and clinical trial descriptors in the context of DN further added about 1 000 features. These data were used to label the respective nodes in the interaction network, as a result obtaining a DN-specific subgraph. Application of a segmentation algorithm on this subgraph allowed the identification of DN-specific molecular units, each characterizing a cluster of genes/proteins with a high internal functional association. We interpret each such unit as a functionally relevant molecular process contributing to the presentation of DN, and the total set of such units as a molecular model of DN. We propose that selecting appropriate biomarkers from each unit might allow the description of a patient's specific 'type' of DN, ultimately leading to a better stratification of patients regarding progression risk and optimal interventional approach.
International Journal of Molecular Sciences, Jun 26, 2021
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorde... more Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder leading to deterioration of kidney function and end stage kidney disease (ESKD). A number of molecular processes are dysregulated in ADPKD but the exact mechanism of disease progression is not fully understood. We measured protein biomarkers being linked to ADPKDassociated molecular processes via ELISA in urine and serum in a cohort of ADPKD patients as well as age, gender and eGFR matched CKD patients and healthy controls. ANOVA and t-tests were used to determine differences between cohorts. Spearman correlation coefficient analysis was performed to assess coregulation patterns of individual biomarkers and renal function. Urinary epidermal growth factor (EGF) and serum apelin (APLN) levels were significantly downregulated in ADPKD patients. Serum vascular endothelial growth factor alpha (VEGFA) and urinary angiotensinogen (AGT) were significantly upregulated in ADPKD patients as compared with healthy controls. Arginine vasopressin (AVP) was significantly upregulated in ADPKD patients as compared with CKD patients. Serum VEGFA and VIM concentrations were positively correlated and urinary EGF levels were negatively correlated with urinary AGT levels. Urinary EGF and AGT levels were furthermore significantly associated with estimated glomerular filtration rate (eGFR) in ADPKD patients. In summary, altered protein concentrations in body fluids of ADPKD patients were found for the mechanistic markers EGF, APLN, VEGFA, AGT, AVP, and VIM. In particular, the connection between EGF and AGT during progression of ADPKD warrants further investigation.
European Journal of Clinical Investigation, Oct 27, 2016
Background Primary focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndr... more Background Primary focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome. Aims The pathogenic steps leading to primary FSGS are still obscure, although evidence suggests that circulatory factor(s) are involved in the onset of disease. Recent technical advances allow the analysis of miRNA expression in tissues and body fluids, leading to reports of miRNAs involved in the molecular mechanisms of FSGS-aetiopathogenesis. Moreover, investigations have also highlighted miRNAs that might serve as biomarkers for primary FSGS. Discussion/Conclusions The aim of this review was to summarize reports showing a direct relation between miRNAs and primary FSGS. In addition, the impact of identified miRNAs on treatment response, prediction of the disease onset as well as the regulation in different disease activities is summarized.
Diabetic kidney disease (DKD) is a complex and multifactorial disorder associated with deregulati... more Diabetic kidney disease (DKD) is a complex and multifactorial disorder associated with deregulations in a large number of different biological pathways on the molecular level. Using the 2 established biomarkers, estimated glomerular filtration rate (eGFR) and albuminuria will not allow allocating patients to tailored therapy. Molecular multimarker panels as sensors for the deregulation of the various disease mechanisms combined with a better understanding of how investigational as well as approved drugs interfere with these disease processes forms the basis for platform trials in DKD. In these platform trials, patients with DKD are assigned to the most suitable treatment arm based on their molecular marker profile. Close monitoring of biomarkers after treatment initiation together with assessment of renal function and "offtarget" effects will allow identification of therapy responders, with nonresponders shifted to the next-best treatment arm based on their molecular profile. In this viewpoint article, we summarize evidence on the variation of DKD disease progression as well as the response to therapy and outline procedures to model disease pathophysiology supporting biomarker panel construction. Finally, the use of biomarkers in clinical trial setup is discussed.
Kidney transplantation is the preferred method for selected patients with kidney failure. Despite... more 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 noninterventional 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 m 2 at hospital discharge to 45.0 ± 14.5 mL/min/ 1.73 m 2 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.
International Journal of Molecular Sciences, May 11, 2021
SGLT2 inhibitor-related nephroprotection is-at least partially-mediated by anti-inflammatory drug... more SGLT2 inhibitor-related nephroprotection is-at least partially-mediated by anti-inflammatory drug effects, as previously demonstrated in diabetic animal and human studies, as well as hyperglycemic cell culture models. We recently presented first evidence for anti-inflammatory potential of empagliflozin (Empa) under normoglycemic conditions in human proximal tubular cells (HPTC) by demonstrating Empa-mediated inhibition of IL-1β-induced MCP-1/CCL2 and ET-1 expression on the mRNA and protein level. We now add corroborating evidence on a genome-wide level by demonstrating that Empa attenuates the expression of several inflammatory response genes in IL-1β-induced (10 ng/mL) normoglycemic HPTCs. Using microarray-hybridization analysis, 19 inflammatory response genes out of >30.000 human genes presented a consistent expression pattern, that is, inhibition of IL-1β (10 ng/mL)-stimulated gene expression by Empa (500 nM), in both HK-2 and RPTEC/TERT1 cells. Pathway enrichment analysis demonstrated statistically significant clustering of annotated pathways (enrichment score 3.64). Our transcriptomic approach reveals novel genes such as CXCL8/IL8, LOX, NOV, PTX3, and SGK1 that might be causally involved in glycemia-independent nephroprotection by SGLT2i.
Aims/hypothesis The sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin slows progress... more Aims/hypothesis The sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin slows progression of kidney function decline in type 2 diabetes. The aim of this study was to assess the effect of the SGLT2 inhibitor canagliflozin on biomarkers for progression of diabetic kidney disease (DKD). Methods A canagliflozin mechanism of action (MoA) network model was constructed based on an in vitro transcriptomics experiment in human proximal tubular cells and molecular features linked to SGLT2 inhibitors from scientific literature. This model was mapped onto an established DKD network model that describes molecular processes associated with DKD. Overlapping areas in both networks were subsequently used to select candidate biomarkers that change with canagliflozin therapy. These biomarkers were measured in 296 stored plasma samples from a previously reported 2 year clinical trial comparing canagliflozin with glimepiride. Results Forty-four proteins present in the canagliflozin MoA molecular model overlapped with proteins in the DKD network model. These proteins were considered candidates for monitoring impact of canagliflozin on DKD pathophysiology. For ten of these proteins, scientific evidence was available suggesting that they are involved in DKD progression. Of these, compared with glimepiride, canagliflozin 300 mg/day decreased plasma levels of TNF receptor 1 (TNFR1; 9.2%; p < 0.001), IL-6 (26.6%; p = 0.010), matrix metalloproteinase 7 (MMP7; 24.9%; p = 0.011) and fibronectin 1 (FN1; 14.9%; p = 0.055) during 2 years of follow-up. Conclusions/interpretation The observed reduction in TNFR1, IL-6, MMP7 and FN1 suggests that canagliflozin contributes to reversing molecular processes related to inflammation, extracellular matrix turnover and fibrosis. Trial registration ClinicalTrials.gov NCT00968812
K leitlinien für die praxis schaften für Nephrologie und Diabetologie werden die entsprechende Di... more K leitlinien für die praxis schaften für Nephrologie und Diabetologie werden die entsprechende Diagnostik und therapeutische Strategien bei diabetischer Nierenerkrankung vorgeschlagen. Schlüsselwörter Diabetes mellitus Typ 1 • Diabetes mellitus Typ 2 • Diabetische Nierenerkrankung • Chronische Nierenerkrankung • Dialyse Diabetic kidney disease (update 2023) Position paper of the Austrian Diabetes Association and the Austrian Society for Nephrology Summary Epidemiological investigations have shown that approximately 2-3% of all Austrians have diabetes mellitus with renal involvement, leaving 250,000 people in Austria affected. The risk of occurrence and progression of this disease can be attenuated by lifestyle interventions as well as optimization of blood pressure, blood glucose control and special drug classes. The present article represents the joint recommendations of the Austrian Diabetes Association and the Austrian Society of Nephrology for the diagnostic and treatment strategies of diabetic kidney disease. Keywords Type 1 diabetes • Type 2 diabetes • Diabetic kidney disease • Chronic kidney disease • Dialysis K Diabetische Nierenerkrankung (Update 2023) S183
Plasma exposure of the endothelin receptor antagonist atrasentan varies between individuals and i... more Plasma exposure of the endothelin receptor antagonist atrasentan varies between individuals and is associated with nephroprotective effects and the risk of heart failure. We examined the influence of genetic polymorphisms on atrasentan plasma exposure and pharmacodynamic effects. We performed a substudy of the Study of Diabetic Nephropathy With Atrasentan (SONAR) trial which enrolled adults with type 2 diabetes and chronic kidney disease (estimated glomerular filtration rate: 25–75 mL/min/1.73 m2, and a urine albumin‐to‐creatinine ratio of 300–5,000 mg/g). Single nucleotide polymorphisms (SNPs) were determined for prespecified membrane transporters, metabolizing enzymes, and the endothelin‐1 peptide. The associations among genotype, atrasentan plasma exposure, and the effect of atrasentan on the prespecified kidney and heart failure hospitalization (HHF) outcomes was assessed with Cox proportional hazards regression models. Of 3,668 patients randomized, 2,329 (63.5%) consented to ge...
memo - Magazine of European Medical Oncology, 2019
Immunosuppression (IS) is administered to kidney transplant recipients to prevent rejection episo... more Immunosuppression (IS) is administered to kidney transplant recipients to prevent rejection episodes and loss of the renal allograft. Most centers rely on a triple IS after induction with either interleukin-2 receptor antibodies or antithymocyte globulin. The most frequently used substances for maintenance IS are glucocorticoids, antimetabolites, mTOR inhibitors (mTORi), calcineurin inhibitors (CNI) and the costimulation blocker belatacept. Guidelines recommend a triple combination consisting of CNIs, antimetabolites and corticosteroids for the majority of patients. The long-term risk for malignancy in general is increased in solid organ recipients compared to the general population. Modification of IS may result in reduced risk for nonmelanoma skin cancers but results in higher graft rejection rates and in the case of mTORi, deaths. In the case of posttransplantation lymphoproliferative disorders (PTLD) treatment options are reduction of IS, rituximab, chemotherapy, radiation therapy or a combination of these. The optimal protocol has not yet been established and depends on patient age and status, tumor load, laboratory findings, organ functions (heart, kidney, liver) and PTLD subtype. Posttransplantation diabetes mellitus is a frequent complication after kidney transplantation. Tacrolimus more than cyclosporine A, sirolimus and corticosteroids are considered to be diabetogenic; however, tacrolimus remains the first choice as the mainstay of IS. In general, the IS regimen should be tailored for optimal kidney allograft survival rather than better diabetic
Diabetic kidney disease (DKD) is a complex and multifactorial disorder associated with deregulati... more Diabetic kidney disease (DKD) is a complex and multifactorial disorder associated with deregulations in a large number of different biological pathways on the molecular level. Using the 2 established biomarkers, estimated glomerular filtration rate (eGFR) and albuminuria will not allow allocating patients to tailored therapy. Molecular multimarker panels as sensors for the deregulation of the various disease mechanisms combined with a better understanding of how investigational as well as approved drugs interfere with these disease processes forms the basis for platform trials in DKD. In these platform trials, patients with DKD are assigned to the most suitable treatment arm based on their molecular marker profile. Close monitoring of biomarkers after treatment initiation together with assessment of renal function and "offtarget" effects will allow identification of therapy responders, with nonresponders shifted to the next-best treatment arm based on their molecular profile. In this viewpoint article, we summarize evidence on the variation of DKD disease progression as well as the response to therapy and outline procedures to model disease pathophysiology supporting biomarker panel construction. Finally, the use of biomarkers in clinical trial setup is discussed.
American Journal of Physiology-Renal Physiology, 2018
Large clinical trials demonstrated that SGLT2 inhibitors (SGLT2i) slow the progression of kidney ... more Large clinical trials demonstrated that SGLT2 inhibitors (SGLT2i) slow the progression of kidney function decline in type 2 diabetes. Because the underlying molecular mechanisms are largely unknown, we studied the effects of SGLT2i on gene expression in two human proximal tubular (PT) cell lines under normoglycemic conditions, utilizing two SGLT2i, namely empagliflocin and canagliflocin. Genome-wide expression analysis did not reveal substantial differences between these two SGLT2i. Microarray hybridization analysis identified 94 genes that were both upregulated by TGF-β1 and downregulated by either of the two SGLT2i in HK-2 and RPTEC/TERT1 (renal proximal tubular epithelial cells/telomerase reverse transcriptase 1) cells. Extracellular matrix organization showed the highest significance in pathway enrichment analysis. Differential gene expression of three annotated genes of interest within this pathway was verified on mRNA level in both cell lines. Whereas TGF-β1 induced mRNA expre...
In chronic kidney disease (CKD), the decline in the glomerular filtration rate is associated with... more In chronic kidney disease (CKD), the decline in the glomerular filtration rate is associated with increased morbidity and mortality and thus poses a major challenge for healthcare systems. While the contribution of tissue-derived miRNAs and mRNAs to CKD progression has been extensively studied, little is known about the role of urinary exosomes and their association with CKD. Exosomes are small, membrane-derived endocytic vesicles that contribute to cell-to-cell communication and are present in various body fluids, such as blood or urine. Next-generation sequencing approaches have revealed that exosomes are enriched in noncoding RNAs and thus exhibit great potential for sensitive nucleic acid biomarkers in various human diseases. Therefore, in this study we aimed to identify urinary exosomal ncRNAs as novel biomarkers for diagnosis of CKD. Since up to now most approaches have focused on the class of miRNAs, we extended our analysis to several other noncoding RNA classes, such as tRN...
Chronic kidney disease (CKD) is a global health burden, yet it is still underrepresented within p... more Chronic kidney disease (CKD) is a global health burden, yet it is still underrepresented within public health agendas in many countries. Studies focusing on the natural history of CKD are challenging to design and conduct, because of the long time-course of disease progression, a wide variation in etiologies, and a large amount of clinical variability among individuals with CKD. With the difference in health-related behaviors, healthcare delivery, genetics, and environmental exposures, this variability is greater across countries than within one locale and may not be captured effectively in a single study. Studies were invited to join the network. Prerequisites for membership included: 1) observational designs with a priori hypotheses and defined study objectives, patient-level information, prospective data acquisition and collection of bio-samples, all focused on predialysis CKD patients; 2) target sample sizes of 1,000 patients for adult cohorts and 300 for pediatric cohorts; and ...
International journal of molecular sciences, Apr 4, 2024
Renin-angiotensin-aldosterone system (RAAS) inhibitors are standard care in patients with hyperte... more Renin-angiotensin-aldosterone system (RAAS) inhibitors are standard care in patients with hypertension, heart failure or chronic kidney disease (CKD). Although we have studied the RAAS for decades, there are still circumstances that remain unclear. In this review, we describe the evolution of the RAAS and pose the question of whether this survival trait is still necessary to humankind in the present age. We elucidate the benefits on cardiovascular health and kidney disease of RAAS inhibition and present promising novel medications. Furthermore, we address why more studies are needed to establish a new standard of care away from generally prescribing ACEi or ARB toward an improved approach to combine drugs tailored to the needs of individual patients.
Fibrinogen-like 2 (FGL2) was recently found to be associated with fibrosis in a mouse model of ki... more 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.
The burden of disease associated with FSGS has not been well characterized, especially with regar... more The burden of disease associated with FSGS has not been well characterized, especially with regard to health care resource utilization (HCRU) and related costs. The aim of this study was to evaluate all-cause HCRU and estimate associated costs in patients with FSGS compared with a matched non-FSGS cohort; a secondary aim was to evaluate the impact of nephrotic range proteinuria on these outcomes. METHOD: Data were from the Optum ClinformaticsV R Data Mart Database. Patients with 1 claim (1 st claim = index event) for FSGS between April 2016 and December 2018 were identified based on ICD-10-CM codes and matched 1:2 (FSGS:controls) on index date, age, sex, and race to non-FSGS controls; continuous enrollment 6 months pre-and 12 months post-index was required. FSGS nephrotic range (either UPCR >3000 mg/g or ACR >2000 mg/g) and non-nephrotic subpopulations were also identified. Quan-Charlson Comorbidity Index (CCI) and individual comorbidities at baseline, and 12-month post-index all-cause HCRU and associated costs (per patient per year [PPPY]) as well as medication prescriptions related to FSGS treatment were compared between the matched cohorts and between the FSGS subpopulations; t-tests were used for continuous variables and chi-square tests for categorical variables. RESULTS: 844 patients with FSGS were matched with 1688 non-FSGS controls; 57.4% male, 56.9% white, mean (SD) age 54.7 (18.4) years. Mean (SD) CCI was higher in the FSGS cohort relative to matched controls (2.72 [2.12] vs 0.55 [1.29]; P < .0001), with prevalence of most individual comorbidities higher in the FSGS cohort. Only 308 FSGS patients (36.5%) had UPCR or ACR tests with available results during the review period; 112 (36.4%) were in the nephrotic range and 196 were non-nephrotic (63.6%). The FSGS cohort was characterized by higher rates of all-cause HCRU across resource categories (all P < .0001) (Table ); outpatient visits was the most frequently used category (99.1% vs 69.0%), followed by prescription medications. Among patients who used these resources, units of use were significantly higher in FSGS vs matched controls except for length of stay (Table ). Readmission rates following 1st post-index hospitalization were higher in the FSGS cohort vs matched controls at 30 days (16.1% vs 6.0%; P < .05) and 365 days (39.1% vs 22.9%; P < .05). Glucocorticoids were the most frequently prescribed FSGS-related medication in both cohorts, with a higher rate in FSGS vs matched controls (50.6% vs 23.3%; P < .0001); other FSGS-related medications were infrequently prescribed (< 14%). Inpatient, outpatient, and prescription costs were higher in the FSGS cohort vs matched controls (all P < .0001) resulting in mean total annual medical costs of $59,753 vs $8,431 PPPY (P < .0001) that were driven by outpatient costs (Fig. ). Nephrotic range proteinuria was associated with higher all-cause inpatient, outpatient, and prescription costs vs nonnephrotic patients (all P < .0001; Fig. ), resulting in higher total costs ($70,481 vs $36,099 PPPY; P < .0001). A higher proportion of nephrotic range patients were prescribed FSGS-modifying medications (73.2% vs 54.1%; P = 0.001), with glucocorticoids the most frequent medication. However, 26.8% of nephrotic range patients were not prescribed any FSGS-related medications. MO513 Figure : Annual all-cause medical costs per patient. A) FSGS and matched non-FSGS cohorts. B) Nephrotic range and non-nephrotic FSGS patients. CONCLUSION: FSGS is associated with significant clinical and economic burdens with total annual medical costs > 7-fold higher than matched controls that were driven by outpatient costs. The presence of nephrotic range proteinuria substantially and significantly increased the economic burden. New treatment modalities leading to lower rates of proteinuria may help improve patient outcomes while reducing HCRU and their associated costs.
Donor organ quality affects long term outcome after renal transplantation. A variety of prognosti... more Donor organ quality affects long term outcome after renal transplantation. A variety of prognostic molecular markers is available, yet their validity often remains undetermined. A network-based molecular model reflecting donor kidney status based on transcriptomics data and molecular features reported in scientific literature to be associated with chronic allograft nephropathy was created. Significantly enriched biological processes were identified and representative markers were selected. An independent kidney pre-implantation transcriptomics dataset of 76 organs was used to predict estimated glomerular filtration rate (eGFR) values twelve months after transplantation using available clinical data and marker expression values. The best-performing regression model solely based on the clinical parameters donor age, donor gender, and recipient gender explained 17% of variance in post-transplant eGFR values. The five molecular markers EGF, CD2BP2, RALBP1, SF3B1, and DDX19B representing key molecular processes of the constructed renal donor organ status molecular model in addition to the clinical parameters significantly improved model performance (p-value = 0.0007) explaining around 33% of the variability of eGFR values twelve months after transplantation. Collectively, molecular markers reflecting donor organ status significantly add to prediction of posttransplant renal function when added to the clinical parameters donor age and gender.
IMPORTANCE Type 2 diabetes increases the risk of progressive diabetic kidney disease, but reliabl... more IMPORTANCE Type 2 diabetes increases the risk of progressive diabetic kidney disease, but reliable prediction tools that can be used in clinical practice and aid in patients' understanding of disease progression are currently lacking. OBJECTIVE To develop and externally validate a model to predict future trajectories in estimated glomerular filtration rate (eGFR) in adults with type 2 diabetes and chronic kidney disease using data from 3 European multinational cohorts. This prognostic study used baseline and follow-up information collected between February 2010 and December 2019 from 3 prospective multinational cohort studies: PROVALID (Prospective Cohort Study in Patients with Type 2 Diabetes Mellitus for Validation of Biomarkers), GCKD (German Chronic Kidney Disease), and DIACORE (Diabetes Cohorte). A total of 4637 adult participants (aged 18-75 years) with type 2 diabetes and mildly to moderately impaired kidney function (baseline eGFR of Ն30 mL/min/1.73 m 2 ) were included. Data were analyzed between June 30, 2021, and January 31, 2023. MAIN OUTCOMES AND MEASURES Thirteen variables readily available from routine clinical care visits (age, sex, body mass index; smoking status; hemoglobin A 1c [mmol/mol and percentage]; hemoglobin, and serum cholesterol levels; mean arterial pressure, urinary albumin-creatinine ratio, and intake of glucose-lowering, blood-pressure lowering, or lipid-lowering medication) were selected as predictors. Repeated eGFR measurements at baseline and follow-up visits were used as the outcome. A linear mixed-effects model for repeated eGFR measurements at study entry up to the last recorded follow-up visit (up to 5 years after baseline) was fit and externally validated. RESULTS Among 4637 adults with type 2 diabetes and chronic kidney disease (mean [SD] age at baseline, 63.5 [9.1] years; 2680 men [57.8%]; all of White race), 3323 participants from the PROVALID and GCKD studies (mean [SD] age at baseline, 63.2 [9.3] years; 1864 men [56.1%]) were included in the model development cohort, and 1314 participants from the DIACORE study (mean [SD] age at baseline, 64.5 [8.3] years; 816 men [62.1%]) were included in the external validation cohort, with a mean (SD) follow-up of 5.0 (0.6) years. Updating the random coefficient estimates with baseline eGFR values yielded improved predictive performance, which was particularly evident in the visual inspection of the calibration curve (calibration slope at 5 years: 1.09; 95% CI, 1.04-1.15). The prediction model had good discrimination in the validation cohort, with the lowest C statistic at 5 years after baseline (0.79; 95% CI, 0.77-0.80). The model also had predictive accuracy, with an R 2 ranging from 0.70 (95% CI, 0.63-0.76) at year 1 to 0.58 (95% CI, 0.53-0.63) at year 5. In this prognostic study, a reliable prediction model was developed and externally validated; the robust model was well calibrated and capable of predicting (continued) Key Points Question Can routinely available data from primary care visits be used to develop and externally validate a prediction model that reliably predicts estimated glomerular filtration rate (eGFR) for upcoming follow-up visits? Findings In this prognostic study involving 4637 adults with type 2 diabetes and chronic kidney disease, a prediction model including 13 routinely collected baseline variables based on data from 3 prospective multinational cohort studies was developed and externally validated. The model was robust, well calibrated, and capable of predicting decreases in eGFR up to 5 years after baseline. Meaning These findings suggest that the prediction model, which is publicly available in a web-based application, may be used to improve prediction of individual eGFR trajectories and kidney function decline.
International Journal of Molecular Sciences, Nov 1, 2020
SGLT2 inhibitors (SGLT2i) slow the progression of chronic kidney disease; however, evidence for t... more SGLT2 inhibitors (SGLT2i) slow the progression of chronic kidney disease; however, evidence for the underlying molecular mechanisms is scarce. We investigated SGLT2i-mediated effects on differential gene expression in two independent human proximal tubular cell (HPTC) lines (HK-2 and RPTEC/TERT1) at the mRNA and protein levels under normoglycemic conditions, utilizing IL-1β as a pro-inflammatory mediator. Microarray hybridization identified 259 genes that were uniformly upregulated by IL-1β (10 mg/mL) and downregulated by empagliflozin (Empa) (500 nM) after 24 h of stimulation in two independent HPTC lines (n = 2, each). The functional annotation of these genes identified eight pathway clusters. Among 12 genes annotated to the highest ranked cluster (enrichment score, 3.51), monocyte chemoattractant protein-1/CC-chemokine ligand 2 (MCP-1/CCL2) and endothelin-1 (ET-1) were selected for verification at mRNA and protein levels based on their established involvement in the early pathogenesis of chronic kidney disease: IL-1β upregulated basal MCP-1/CCL2 (15-and 19-fold) and ET-1 (3-and 8-fold) mRNA expression, while Empa downregulated basal MCP-1/CCL2 (0.6-and 0.5-fold) and ET-1 (0.3-and 0.2-fold) mRNA expression as early as 1 h after stimulation and for at least 24 h in HK-2 and RPTEC/TERT1 cells, respectively. The co-administration of Empa inhibited IL-1β-mediated MCP-1/CCL2 (0.2-fold, each) and ET-1 (0.2-fold, each) mRNA expression as early as 1 h after ligand stimulation and for at least 24 h in both HPTC lines, respectively. This inhibitory effect of Empa on basal and IL-1β-mediated MCP-1/CCL2 and ET-1 mRNA expression was corroborated at the protein level. Our study presents novel evidence for the interference of SGLT2 inhibition with tubular inflammatory response mechanisms under normoglycemic conditions that might account for SGLT2i-mediated nephroprotection.
The pathophysiology of diabetic nephropathy (DN) is driven by a complex, multi-facetted interplay... more The pathophysiology of diabetic nephropathy (DN) is driven by a complex, multi-facetted interplay of numerous molecular processes (protective as well as damaging) and the balance between these, rather than the activity of a single pathway, determines clinical presentation and outcome. We present a concept for deriving a biomarker panel aimed to represent the relevant processes involved. Our approach rests on a hybrid gene/protein interaction network that holds ample information on molecular features (nodes) and their relations (edges), as a result providing a basic structure to navigate in molecular content and context being identified as relevant in DN. Extensive literature search on omics studies in DN provided a molecular feature list mapping to a total of 2175 unique protein-coding genes [13 from single nucleotide polymorphisms (SNPs), 12 as targets from relevant miRNAs, 1583 from transcriptomics, 5 from proteomics and 53 from metabolomics via linking to enzymes; 509 features were identified from multiple sources]. Two hundred and eighty-seven further human protein-coding genes associated with DN were derived from searching NCBI Pubmed (utilizing MeSH and gene-topubmed). Text mining of patents and clinical trial descriptors in the context of DN further added about 1 000 features. These data were used to label the respective nodes in the interaction network, as a result obtaining a DN-specific subgraph. Application of a segmentation algorithm on this subgraph allowed the identification of DN-specific molecular units, each characterizing a cluster of genes/proteins with a high internal functional association. We interpret each such unit as a functionally relevant molecular process contributing to the presentation of DN, and the total set of such units as a molecular model of DN. We propose that selecting appropriate biomarkers from each unit might allow the description of a patient's specific 'type' of DN, ultimately leading to a better stratification of patients regarding progression risk and optimal interventional approach.
International Journal of Molecular Sciences, Jun 26, 2021
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorde... more Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder leading to deterioration of kidney function and end stage kidney disease (ESKD). A number of molecular processes are dysregulated in ADPKD but the exact mechanism of disease progression is not fully understood. We measured protein biomarkers being linked to ADPKDassociated molecular processes via ELISA in urine and serum in a cohort of ADPKD patients as well as age, gender and eGFR matched CKD patients and healthy controls. ANOVA and t-tests were used to determine differences between cohorts. Spearman correlation coefficient analysis was performed to assess coregulation patterns of individual biomarkers and renal function. Urinary epidermal growth factor (EGF) and serum apelin (APLN) levels were significantly downregulated in ADPKD patients. Serum vascular endothelial growth factor alpha (VEGFA) and urinary angiotensinogen (AGT) were significantly upregulated in ADPKD patients as compared with healthy controls. Arginine vasopressin (AVP) was significantly upregulated in ADPKD patients as compared with CKD patients. Serum VEGFA and VIM concentrations were positively correlated and urinary EGF levels were negatively correlated with urinary AGT levels. Urinary EGF and AGT levels were furthermore significantly associated with estimated glomerular filtration rate (eGFR) in ADPKD patients. In summary, altered protein concentrations in body fluids of ADPKD patients were found for the mechanistic markers EGF, APLN, VEGFA, AGT, AVP, and VIM. In particular, the connection between EGF and AGT during progression of ADPKD warrants further investigation.
European Journal of Clinical Investigation, Oct 27, 2016
Background Primary focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndr... more Background Primary focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome. Aims The pathogenic steps leading to primary FSGS are still obscure, although evidence suggests that circulatory factor(s) are involved in the onset of disease. Recent technical advances allow the analysis of miRNA expression in tissues and body fluids, leading to reports of miRNAs involved in the molecular mechanisms of FSGS-aetiopathogenesis. Moreover, investigations have also highlighted miRNAs that might serve as biomarkers for primary FSGS. Discussion/Conclusions The aim of this review was to summarize reports showing a direct relation between miRNAs and primary FSGS. In addition, the impact of identified miRNAs on treatment response, prediction of the disease onset as well as the regulation in different disease activities is summarized.
Diabetic kidney disease (DKD) is a complex and multifactorial disorder associated with deregulati... more Diabetic kidney disease (DKD) is a complex and multifactorial disorder associated with deregulations in a large number of different biological pathways on the molecular level. Using the 2 established biomarkers, estimated glomerular filtration rate (eGFR) and albuminuria will not allow allocating patients to tailored therapy. Molecular multimarker panels as sensors for the deregulation of the various disease mechanisms combined with a better understanding of how investigational as well as approved drugs interfere with these disease processes forms the basis for platform trials in DKD. In these platform trials, patients with DKD are assigned to the most suitable treatment arm based on their molecular marker profile. Close monitoring of biomarkers after treatment initiation together with assessment of renal function and "offtarget" effects will allow identification of therapy responders, with nonresponders shifted to the next-best treatment arm based on their molecular profile. In this viewpoint article, we summarize evidence on the variation of DKD disease progression as well as the response to therapy and outline procedures to model disease pathophysiology supporting biomarker panel construction. Finally, the use of biomarkers in clinical trial setup is discussed.
Kidney transplantation is the preferred method for selected patients with kidney failure. Despite... more 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 noninterventional 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 m 2 at hospital discharge to 45.0 ± 14.5 mL/min/ 1.73 m 2 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.
International Journal of Molecular Sciences, May 11, 2021
SGLT2 inhibitor-related nephroprotection is-at least partially-mediated by anti-inflammatory drug... more SGLT2 inhibitor-related nephroprotection is-at least partially-mediated by anti-inflammatory drug effects, as previously demonstrated in diabetic animal and human studies, as well as hyperglycemic cell culture models. We recently presented first evidence for anti-inflammatory potential of empagliflozin (Empa) under normoglycemic conditions in human proximal tubular cells (HPTC) by demonstrating Empa-mediated inhibition of IL-1β-induced MCP-1/CCL2 and ET-1 expression on the mRNA and protein level. We now add corroborating evidence on a genome-wide level by demonstrating that Empa attenuates the expression of several inflammatory response genes in IL-1β-induced (10 ng/mL) normoglycemic HPTCs. Using microarray-hybridization analysis, 19 inflammatory response genes out of >30.000 human genes presented a consistent expression pattern, that is, inhibition of IL-1β (10 ng/mL)-stimulated gene expression by Empa (500 nM), in both HK-2 and RPTEC/TERT1 cells. Pathway enrichment analysis demonstrated statistically significant clustering of annotated pathways (enrichment score 3.64). Our transcriptomic approach reveals novel genes such as CXCL8/IL8, LOX, NOV, PTX3, and SGK1 that might be causally involved in glycemia-independent nephroprotection by SGLT2i.
Aims/hypothesis The sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin slows progress... more Aims/hypothesis The sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin slows progression of kidney function decline in type 2 diabetes. The aim of this study was to assess the effect of the SGLT2 inhibitor canagliflozin on biomarkers for progression of diabetic kidney disease (DKD). Methods A canagliflozin mechanism of action (MoA) network model was constructed based on an in vitro transcriptomics experiment in human proximal tubular cells and molecular features linked to SGLT2 inhibitors from scientific literature. This model was mapped onto an established DKD network model that describes molecular processes associated with DKD. Overlapping areas in both networks were subsequently used to select candidate biomarkers that change with canagliflozin therapy. These biomarkers were measured in 296 stored plasma samples from a previously reported 2 year clinical trial comparing canagliflozin with glimepiride. Results Forty-four proteins present in the canagliflozin MoA molecular model overlapped with proteins in the DKD network model. These proteins were considered candidates for monitoring impact of canagliflozin on DKD pathophysiology. For ten of these proteins, scientific evidence was available suggesting that they are involved in DKD progression. Of these, compared with glimepiride, canagliflozin 300 mg/day decreased plasma levels of TNF receptor 1 (TNFR1; 9.2%; p < 0.001), IL-6 (26.6%; p = 0.010), matrix metalloproteinase 7 (MMP7; 24.9%; p = 0.011) and fibronectin 1 (FN1; 14.9%; p = 0.055) during 2 years of follow-up. Conclusions/interpretation The observed reduction in TNFR1, IL-6, MMP7 and FN1 suggests that canagliflozin contributes to reversing molecular processes related to inflammation, extracellular matrix turnover and fibrosis. Trial registration ClinicalTrials.gov NCT00968812
K leitlinien für die praxis schaften für Nephrologie und Diabetologie werden die entsprechende Di... more K leitlinien für die praxis schaften für Nephrologie und Diabetologie werden die entsprechende Diagnostik und therapeutische Strategien bei diabetischer Nierenerkrankung vorgeschlagen. Schlüsselwörter Diabetes mellitus Typ 1 • Diabetes mellitus Typ 2 • Diabetische Nierenerkrankung • Chronische Nierenerkrankung • Dialyse Diabetic kidney disease (update 2023) Position paper of the Austrian Diabetes Association and the Austrian Society for Nephrology Summary Epidemiological investigations have shown that approximately 2-3% of all Austrians have diabetes mellitus with renal involvement, leaving 250,000 people in Austria affected. The risk of occurrence and progression of this disease can be attenuated by lifestyle interventions as well as optimization of blood pressure, blood glucose control and special drug classes. The present article represents the joint recommendations of the Austrian Diabetes Association and the Austrian Society of Nephrology for the diagnostic and treatment strategies of diabetic kidney disease. Keywords Type 1 diabetes • Type 2 diabetes • Diabetic kidney disease • Chronic kidney disease • Dialysis K Diabetische Nierenerkrankung (Update 2023) S183
Plasma exposure of the endothelin receptor antagonist atrasentan varies between individuals and i... more Plasma exposure of the endothelin receptor antagonist atrasentan varies between individuals and is associated with nephroprotective effects and the risk of heart failure. We examined the influence of genetic polymorphisms on atrasentan plasma exposure and pharmacodynamic effects. We performed a substudy of the Study of Diabetic Nephropathy With Atrasentan (SONAR) trial which enrolled adults with type 2 diabetes and chronic kidney disease (estimated glomerular filtration rate: 25–75 mL/min/1.73 m2, and a urine albumin‐to‐creatinine ratio of 300–5,000 mg/g). Single nucleotide polymorphisms (SNPs) were determined for prespecified membrane transporters, metabolizing enzymes, and the endothelin‐1 peptide. The associations among genotype, atrasentan plasma exposure, and the effect of atrasentan on the prespecified kidney and heart failure hospitalization (HHF) outcomes was assessed with Cox proportional hazards regression models. Of 3,668 patients randomized, 2,329 (63.5%) consented to ge...
memo - Magazine of European Medical Oncology, 2019
Immunosuppression (IS) is administered to kidney transplant recipients to prevent rejection episo... more Immunosuppression (IS) is administered to kidney transplant recipients to prevent rejection episodes and loss of the renal allograft. Most centers rely on a triple IS after induction with either interleukin-2 receptor antibodies or antithymocyte globulin. The most frequently used substances for maintenance IS are glucocorticoids, antimetabolites, mTOR inhibitors (mTORi), calcineurin inhibitors (CNI) and the costimulation blocker belatacept. Guidelines recommend a triple combination consisting of CNIs, antimetabolites and corticosteroids for the majority of patients. The long-term risk for malignancy in general is increased in solid organ recipients compared to the general population. Modification of IS may result in reduced risk for nonmelanoma skin cancers but results in higher graft rejection rates and in the case of mTORi, deaths. In the case of posttransplantation lymphoproliferative disorders (PTLD) treatment options are reduction of IS, rituximab, chemotherapy, radiation therapy or a combination of these. The optimal protocol has not yet been established and depends on patient age and status, tumor load, laboratory findings, organ functions (heart, kidney, liver) and PTLD subtype. Posttransplantation diabetes mellitus is a frequent complication after kidney transplantation. Tacrolimus more than cyclosporine A, sirolimus and corticosteroids are considered to be diabetogenic; however, tacrolimus remains the first choice as the mainstay of IS. In general, the IS regimen should be tailored for optimal kidney allograft survival rather than better diabetic
Diabetic kidney disease (DKD) is a complex and multifactorial disorder associated with deregulati... more Diabetic kidney disease (DKD) is a complex and multifactorial disorder associated with deregulations in a large number of different biological pathways on the molecular level. Using the 2 established biomarkers, estimated glomerular filtration rate (eGFR) and albuminuria will not allow allocating patients to tailored therapy. Molecular multimarker panels as sensors for the deregulation of the various disease mechanisms combined with a better understanding of how investigational as well as approved drugs interfere with these disease processes forms the basis for platform trials in DKD. In these platform trials, patients with DKD are assigned to the most suitable treatment arm based on their molecular marker profile. Close monitoring of biomarkers after treatment initiation together with assessment of renal function and "offtarget" effects will allow identification of therapy responders, with nonresponders shifted to the next-best treatment arm based on their molecular profile. In this viewpoint article, we summarize evidence on the variation of DKD disease progression as well as the response to therapy and outline procedures to model disease pathophysiology supporting biomarker panel construction. Finally, the use of biomarkers in clinical trial setup is discussed.
American Journal of Physiology-Renal Physiology, 2018
Large clinical trials demonstrated that SGLT2 inhibitors (SGLT2i) slow the progression of kidney ... more Large clinical trials demonstrated that SGLT2 inhibitors (SGLT2i) slow the progression of kidney function decline in type 2 diabetes. Because the underlying molecular mechanisms are largely unknown, we studied the effects of SGLT2i on gene expression in two human proximal tubular (PT) cell lines under normoglycemic conditions, utilizing two SGLT2i, namely empagliflocin and canagliflocin. Genome-wide expression analysis did not reveal substantial differences between these two SGLT2i. Microarray hybridization analysis identified 94 genes that were both upregulated by TGF-β1 and downregulated by either of the two SGLT2i in HK-2 and RPTEC/TERT1 (renal proximal tubular epithelial cells/telomerase reverse transcriptase 1) cells. Extracellular matrix organization showed the highest significance in pathway enrichment analysis. Differential gene expression of three annotated genes of interest within this pathway was verified on mRNA level in both cell lines. Whereas TGF-β1 induced mRNA expre...
In chronic kidney disease (CKD), the decline in the glomerular filtration rate is associated with... more In chronic kidney disease (CKD), the decline in the glomerular filtration rate is associated with increased morbidity and mortality and thus poses a major challenge for healthcare systems. While the contribution of tissue-derived miRNAs and mRNAs to CKD progression has been extensively studied, little is known about the role of urinary exosomes and their association with CKD. Exosomes are small, membrane-derived endocytic vesicles that contribute to cell-to-cell communication and are present in various body fluids, such as blood or urine. Next-generation sequencing approaches have revealed that exosomes are enriched in noncoding RNAs and thus exhibit great potential for sensitive nucleic acid biomarkers in various human diseases. Therefore, in this study we aimed to identify urinary exosomal ncRNAs as novel biomarkers for diagnosis of CKD. Since up to now most approaches have focused on the class of miRNAs, we extended our analysis to several other noncoding RNA classes, such as tRN...
Chronic kidney disease (CKD) is a global health burden, yet it is still underrepresented within p... more Chronic kidney disease (CKD) is a global health burden, yet it is still underrepresented within public health agendas in many countries. Studies focusing on the natural history of CKD are challenging to design and conduct, because of the long time-course of disease progression, a wide variation in etiologies, and a large amount of clinical variability among individuals with CKD. With the difference in health-related behaviors, healthcare delivery, genetics, and environmental exposures, this variability is greater across countries than within one locale and may not be captured effectively in a single study. Studies were invited to join the network. Prerequisites for membership included: 1) observational designs with a priori hypotheses and defined study objectives, patient-level information, prospective data acquisition and collection of bio-samples, all focused on predialysis CKD patients; 2) target sample sizes of 1,000 patients for adult cohorts and 300 for pediatric cohorts; and ...
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Papers by Gert Mayer