A novel drug response score more accurately predicts renoprotective drug effects than existing renal risk scores.

BACKGROUND: Risk factor-based equations are used to predict risk of kidney disease progression in patients with type 2 diabetes order to guide treatment decisions. It is, however, unknown whether these models can also be used to predict the effects of drugs on clinical outcomes. METHODS: The previously developed Parameter Response Efficacy (PRE) score, which integrates multiple short-term drug effects, was first compared with the existing risk scores, Kidney Failure Risk Equation (KFRE) and The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) renal risk score, in its performance to predict end-stage renal disease (ESRD; KFRE) and doubling of serum creatinine or ESRD (ADVANCE). Second, changes in the risk scores were compared after 6 months' treatment to predict the long-term effects of losartan on these renal outcomes in patients with type 2 diabetes and chronic kidney disease. RESULTS: The KFRE, ADVANCE and PRE scores showed similarly good performance in predicting renal risk. However, for prediction of the effect of losartan, the KFRE risk score predicted a relative risk change in the occurrence of ESRD of 3.1% [95% confidence interval (CI) -5 to 12], whereas the observed risk change was -28.8% (95% CI -42.0 to -11.5). For the composite endpoint of doubling of serum creatinine or ESRD, the ADVANCE score predicted a risk change of -12.4% (95% CI -17 to -7), which underestimated the observed risk change -21.8% (95% CI -34 to -6). The PRE score predicted renal risk changes that were close to the observed risk changes with losartan treatment [-24.0% (95% CI -30 to -17) and -22.6% (95% CI -23 to -16) for ESRD and the composite renal outcome, respectively]. CONCLUSION: A drug response score such as the PRE score may assist in improving clinical decision making and implement precision medicine strategies.

An acute rise of plasma Na+ concentration associates with syndecan-1 shedding during hemodialysis.

Endothelial dysfunction (ED) contributes to the high incidence of cardiovascular events in patients undergoing hemodialysis. Syndecan-1 in the endothelial glycocalyx can be shed into the circulation, serving as a biomarker for ED. As Na+ is a trigger for glycocalyx shedding, we now tested whether hemodialysis, with higher dialysate Na+ concentrations, is associated with more syndecan-1 shedding compared with standard hemodialysis (SHD). In this crossover study in 29 patients, plasma syndecan-1 was repeatedly measured during SHD and during Hemocontrol hemodialysis (HHD), which is characterized by initially higher dialysate and plasma Na+ levels. Courses of syndecan-1 were compared with linear mixed models. Syndecan-1 shedding was assessed by area under the curve analysis. Plasma Na+ increased early after the start of SHD and HHD, with higher values during HHD (30 min: 142.3 vs. 139.9 mM, P < 0.001). Syndecan-1 increased significantly during both conditions, but the percent change was higher (42.9% vs. 19.5%) and occurred earlier (120 vs. 180 min) during HHD. Syndecan-1 levels were significantly higher at 120 min during HHD compared with SHD (P < 0.05). Overall, syndecan-1 shedding was higher during HHD compared with SHD (means: 40.4 vs. 19.0 arbitrary units, P = 0.06). Lower predialysis plasma Na+ and osmolality were associated with greater intradialytic increases in syndecan-1 levels (both groups, P = 0.001). The rise in plasma syndecan-1 levels was more pronounced and occurred earlier during hemodialysis with higher plasma Na+ levels. Although we cannot prove that the rise in plasma syndecan-1 originates from the endothelial glycocalyx, our findings are compatible with Na+-driven endothelial glycocalyx-derived syndecan-1 shedding.

Prediction and validation of exenatide risk marker effects on progression of renal disease: Insights from EXSCEL.

AIM: To assess whether the previously developed multivariable risk prediction framework (PRE score) could predict the renal effects observed in the EXSCEL cardiovascular outcomes trial using short-term changes in cardio-renal risk markers. MATERIALS AND METHODS: Changes from baseline to 6 months in HbA1c, systolic blood pressure (SBP), body mass index (BMI), haemoglobin, total cholesterol, and new micro- or macroalbuminuria were evaluated. The renal outcomes were defined as a composite of a sustained 30% or 40% decline in estimated glomerular filtration rate (eGFR) or end-stage renal disease (ESRD). Relationships between risk markers and long-term renal outcomes were determined in patients with type 2 diabetes from the ALTITUDE study using multivariable Cox regression analysis, and then applied to short-term changes in risk markers observed in EXSCEL to predict the exenatide-induced impact on renal outcomes. RESULTS: Compared with placebo, mean HbA1c, BMI, SBP and total cholesterol were lower at 6 months with exenatide, as was the incidence of new microalbuminuria. The PRE score predicted a relative risk reduction for the 30% eGFR decline + ESRD endpoint of 11.3% (HR 0.89; 95% CI 0.83-0.94), compared with 12.7% (HR 0.87; 0.77-0.99) observed risk reduction. For the 40% eGFR decline + ESRD endpoint, the predicted and observed risk reductions were 11.0% (HR 0.89; 0.82-0.97) and 13.7% (HR 0.86, 0.72-1.04), respectively. CONCLUSIONS: Integrating short-term risk marker changes into a multivariable risk score predicted the magnitude of renal risk reduction observed in EXSCEL.

Prediction of the effect of dapagliflozin on kidney and heart failure outcomes based on short-term changes in multiple risk markers.

BACKGROUND: Besides improving glucose control, sodium-glucose co-transporter 2 inhibition with dapagliflozin reduces blood pressure, body weight and urinary albumin:creatinine ratio (UACR) in patients with type 2 diabetes (T2DM). The parameter response efficacy (PRE) score was developed to predict how short-term drug effects on cardiovascular risk markers translate into long-term changes in clinical outcomes. We applied the PRE score to clinical trials of dapagliflozin to model the effect of the drug on kidney and heart failure (HF) outcomes in patients with T2DM and impaired kidney function. METHODS: The relationships between multiple risk markers and long-term outcome were determined in a background population of patients with T2DM with a multivariable Cox model. These relationships were then applied to short-term changes in risk markers observed in a pooled database of dapagliflozin trials (n = 7) that recruited patients with albuminuria to predict the drug-induced changes to kidney and HF outcomes. RESULTS: A total of 132 and 350 patients had UACR >200 mg/g and >30 mg/g at baseline, respectively, and were selected for analysis. The PRE score predicted a risk change for kidney events of -40.8% [95% confidence interval (CI) -51.7 to -29.4) and -40.4% (95% CI -48.4 to -31.1) with dapagliflozin 10 mg compared with placebo for the UACR >200 mg/g and >30 mg/g subgroups. The predicted change in risk for HF events was -27.3% (95% CI -47.7 to -5.1) and -21.2% (95% CI -35.0 to -7.8), respectively. Simulation analyses showed that even with a smaller albuminuria-lowering effect of dapagliflozin (10% instead of the observed 35% in both groups), the estimated kidney risk reduction was still 26.5 and 26.8%, respectively. CONCLUSIONS: The PRE score predicted clinically meaningful reductions in kidney and HF events associated with dapagliflozin therapy in patients with diabetic kidney disease. These results support a large long-term outcome trial in this population to confirm the benefits of the drug on these endpoints.

Proteinuria and cholesterol reduction are independently associated with less renal function decline in statin-treated patients; a post hoc analysis of the PLANET trials.

BACKGROUND: Statins have shown multiple effects on different renal risk factors such as lowering of total cholesterol (TC) and lowering of urine protein:creatinine ratio (UPCR). We assessed whether these effects of statins vary between individuals, the extent of discordance of treatment effects on both TC and UPCR within an individual, and the association of responses in TC and UPCR with estimated glomerular filtration rate (eGFR) decline. METHODS: The PLANET I and II (Renal effects of Rosuvastatin and Atorvastatin in Patients Who Have Progressive Renal Disease) trials examined effects of atorvastatin and rosuvastatin on proteinuria and renal function in patients with proteinuria. We post hoc analysed 471 therapy-adherent proteinuric patients from the two trials and assessed the individual variability in UPCR and TC response from 0 to 14 weeks and whether these responses were predictive of eGFR decline during the subsequent 9 months of follow-up. RESULTS: UPCR and TC response varied between individuals: mean UPCR response was -1.3% (5th-95th percentile -59.9 to 141.8) and mean TC response was -93.9 mg/dL (-169.1 to -26.9). Out of 471 patients, 123 (26.1%) showed a response in UPCR but not in TC, and 96 (20.4%) showed a response in TC but not in UPCR. eGFR (mL/min/1.73 m2) did not decrease significantly from baseline in both UPCR responders [0.4; 95% confidence interval (CI) -1.6 to 0.9; P = 0.54] and TC responders (0.3; 95% CI -1.8 to 1.1; P = 0.64), whereas UPCR and TC non-responders showed a significant decline in eGFR from baseline (1.8; 95% CI 0.6-3.0; P = 0.004 and 1.7; 95% CI 0.5-2.9; P = 0.007, respectively). A lack of response in both parameters resulted in the fastest rate of eGFR decline (2.1; 95% CI 0.5-3.7; P = 0.01). These findings were not different for rosuvastatin or atorvastatin. CONCLUSIONS: Statin-induced changes in cholesterol and proteinuria vary between individuals and do not run in parallel within an individual. The initial fall in cholesterol and proteinuria is independently associated with a reduction in eGFR decline. This highlights the importance of monitoring both cholesterol and proteinuria after initiating statin therapy.

Plasma syndecan-1 in hemodialysis patients associates with survival and lower markers of volume status.

Syndecan-1, a transmembrane heparan sulfate proteoglycan, associates with renal and cardiovascular functioning. We earlier reported syndecan-1 to be involved in renal tubular regeneration. We now examined plasma values of syndecan-1 in a hemodialysis cohort and its association with volume and inflammatory and endothelial markers in addition to outcome. Eighty-four prevalent hemodialysis patients were evaluated for their plasma syndecan-1 levels by ELISA before the start of hemodialysis, as well as 60, 180, and 240 min after start of dialysis. Patients were divided into sex-stratified tertiles based on predialysis plasma syndecan-1 levels. We studied the association between plasma levels of syndecan-1 and volume, inflammation, and endothelial markers and its association with cardiovascular events and all-cause mortality using Kaplan-Meier curves and Cox regression analyses with adjustments for gender, age, diabetes, and dialysis vintage. Predialysis syndecan-1 levels were twofold higher in men compared with women ( P = 0.0003). Patients in the highest predialysis plasma syndecan-1 tertile had a significantly higher ultrafiltration rate ( P = 0.034) and lower plasma values of BNP ( P = 0.019), pro-ANP ( P = 0.024), and endothelin ( P < 0.0001) compared with the two lower predialysis syndecan-1 tertiles. No significant associations with inflammatory markers were found. Cox regression analysis showed that patients in the highest syndecan-1 tertile had significantly less cardiovascular events and better survival compared with the lowest syndecan-1 tertile ( P = 0.02 and P = 0.005, respectively). In hemodialysis patients, higher plasma syndecan-1 levels were associated with lower concentrations of BNP, pro-ANP, and endothelin and with better patient survival. This may suggest that control of volume status in hemodialysis patients allows an adaptive tissue regenerative response as reflected by higher plasma syndecan-1 levels.

Personalized medicine in diabetic kidney disease: a novel approach to improve trial design and patient outcomes.

PURPOSE OF REVIEW: In the last decade many attempts have been made to reduce the high residual risk of end-stage kidney disease and cardiovascular disease in patients with diabetic kidney disease by targeting a variety of risk markers. Subsequent analyses revealed that the variation in individual drug response to the tested interventions partly explains why these trials did not result in additional kidney or cardiovascular protection. This review summarizes recent insights regarding individual variation in drug response. Additionally, we explore novel approaches to incorporate this drug response variability in the design of new clinical trials. RECENT FINDINGS: Recent studies suggest that a plausible explanation for individual therapy resistance emanates from intrinsic individual characteristics such as genetic make-up or volume status and is likely only partially explained by drug characteristics such as the dose or type of intervention. Biomarker-based enrichment strategies to identify high-risk individuals and/or those who are more likely to respond to interventions offer opportunities to tailor therapies to individual patients. SUMMARY: Individual drug response variability is a recognized phenomenon in clinical practice. It is time to implement novel approaches that take into account this response variability in the design of new trials in diabetic kidney disease in order to define optimal therapies for individual patients.

N-terminal pro-brain natriuretic peptide (NT-proBNP) predicts the cardio-renal response to aliskiren in patients with type 2 diabetes at high renal and cardiovascular risk.

Sodium retention and volume overload are the main determinants of poor response to renin-angiotensin-aldosterone system (RAAS) inhibition in patients with diabetes. As volume excess can exist without symptoms, biomarkers are needed to identify a priori which patients are volume overloaded and may experience less benefit from RAAS inhibition. N-terminal pro-brain natriuretic peptide (NT-proBNP) is released in the setting of increased cardiac wall stress and volume overload. We conducted a post hoc analysis among 5081 patients with type 2 diabetes mellitus participating in the ALTITUDE trial to investigate whether NTproBNP can predict the effects of additional therapy with aliskiren on cardio-renal endpoints. Aliskiren compared to placebo reduced the risk of the primary cardio-renal endpoint events by 20% (95% confidence interval [CI] 16 to 61) and 2% (95% CI -42 to 30) in the two lowest NT-proBNP tertiles, and it increased the risk by 25% (95% CI -4 to 96) in the highest NT-proBNP tertile (P value for trend = 0.009). Similar trends were observed for the cardiovascular and end-stage renal disease endpoints. Effects of aliskiren compared to placebo on safety outcomes (hyperkalaemia and hospitalization for acute kidney injury) were independent of NT-proBNP. In conclusion, baseline NT-proBNP may be used as a marker to predict the response to aliskiren with regard to cardio-renal outcomes when added to standard therapy with RAAS inhibition.