Faculty Bibliography

Background: The efficacy of an aggressive multiple risk factor intervention approach - optimal medical therapy (OMT) - to reduce major adverse cardiovascular events in patients with CKD has not been tested.
Objective(s): to examine OMT goal attainment in patients with CKD on dialysis (CKD-D) and non-dialysis CKD (CKD-ND) in the ISCHEMIA-CKD trial.
Method(s): OMT was recommended to all participants in ISCHEMIA-CKD. Longitudinal trajectories of individual OMT components (smoking cessation, systolic blood pressure (SBP) <140 mmHg, low density lipoprotein (LDL) cholesterol <70 mg/dL, high-intensity statin use, and aspirin use) were modeled over study follow-up. Covariateadjusted percentage point difference in each OMT goal achieved at 24 months between CKD-D and CKD-ND groups (% difference [95% credible interval (CrI)]) was estimated.
Result(s): There were 415 CKD-D and 362 CKD-ND patients at baseline. CKD-D were younger (61 v 67 yrs, p<0.001) and less often diabetic (53% v 62%, p=0.023). CKD-D patients were 7.9 % (0.7%, 14.8%) more likely than CKD-ND to attain the SBP goal at 24 months (Figure). CKD-D patients were 22.7% (-33.3%, -11.4%) less likely to receive high-intensity statins. There was a steady and similar increase in proportional achievement of OMT during follow up.
Conclusion(s): OMT improved over time in advanced CKD-ND and CKD-D. CKD-D achieved the SBP goal more than CKD-ND, yet CKD-D were less likely to be treated with high-intensity statin. Future studies should explore systemic and patient-related barriers to attainment of OMT in this high-risk cohort.(Figure Presented)

Background: People with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) are at very high risk of cardiovascular events and kidney failure. While canagliflozin reduces the risk of these outcomes, the consistency of this effect across all levels of estimated glomerular filtration rate (eGFR) and urinary albumin:creatinine ratio (UACR) remains uncertain.
Method(s): We pooled individual participant data from the CANVAS Program (n=10,142) and CREDENCE trial (n=4,401) to assess the effect of canagliflozin on a primary composite outcome of myocardial infarction, stroke, heart failure, doubling of serum creatinine, kidney failure, cardiovascular or kidney death. The effect of canagliflozin was assessed using Cox regression models with treatment by subgroup interaction terms stratified by trial.
Result(s): 2,051/14,543 (14%) participants experienced the primary outcome over a median follow-up of 2.5 years. Overall, canagliflozin reduced the risk of the primary outcome (HR 0.77, 95% 0.70-0.84; Figure). The magnitude of relative benefit increased as eGFR declined (P-trend=0.0067; Figure) with some evidence of greater relative benefit at higher UACR (P-trend=0.057; Figure). Lower eGFR and higher UACR levels were independently associated with cardio-renal risk. Consequently, absolute risk reductions increased more than 5-fold across lower eGFR categories and more than 9-fold across higher UACR categories (Figure).
Conclusion(s): Canagliflozin reduces the risk of cardio-renal outcomes in people with T2DM; the magnitude of relative and absolute protection varies by severity of CKD

Background: CANA slows progression of chronic kidney disease (CKD) in people with type 2 diabetes. CANA also induces a reversible acute decline in estimated glomerular filtration rate (eGFR), which is believed to be a hemodynamic effect. Predictors of the initial decline and its association with long-term eGFR trajectories and safety outcomes are unknown.
Method(s): This post hoc study of CREDENCE included 4289 patients with type 2 diabetes and CKD who had eGFR measured at both baseline and week 3. Participants were categorized by percentage decline in eGFR at week 3: greater than 10% decline; between 0 and 10% decline; and no decline. Baseline characteristics associated with acute eGFR drop >10% were evaluated using logistic regression. Long-term eGFR decline and safety outcomes were estimated in each eGFR decline category by linear mixed effects models and Cox regression after adjustment for laboratory measures and medication use.
Result(s): More participants in the CANA (956 [45%]) versus placebo (PBO) group (450 [21%]) had an acute eGFR decline >10% (p<0.001). A >30% decline occurred infrequently (89 [4%] with CANA and 39 [2%] with PBO; p<0.001). In the CANA but not in the PBO group, older age (OR CANA 1.17, 95% CI 1.05-1.31; per 10 years) and history of heart failure (OR CANA 0.77, 0.59-0.99) were associated with a higher and lower likelihood of an acute eGFR decline >10%, respectively (both p interaction<0.05). Following the initial eGFR change, long-term eGFR trajectories were similar across eGFR decline categories (all p>0.05). Safety profiles were also similar except when the drop unusually exceeded 30%, in which case adverse events and renal related adverse events occurred more frequently. Results were consistent in subgroup analysis by baseline eGFR (30-<45, 45-<60, and 60-<90 mL/min/1.73m²).
Conclusion(s): Although acute eGFR declines >10% occurred in nearly half of all patients following initiation of CANA, the benefit of CANA compared with PBO was observed regardless of the acute eGFR decline and safety profiles were similar

Background: Canagliflozin (CANA) reduces the risk of cardiovascular (CV) events and kidney failure in people with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Inherent in its mechanism of action is enhanced natriuresis and osmotic diuresis. It is unclear if the efficacy or safety of CANA is modified by concomitant diuretic use.
Method(s): CREDENCE randomized participants with T2DM and CKD to CANA or matching placebo. The primary outcome was a composite of end-stage kidney disease, doubling of serum creatinine, CV or renal death. We estimated effects on key efficacy and safety outcomes by baseline use of loop diuretics.
Result(s): Of 4401 CREDENCE participants, 955 (21.7%) received loop diuretics at baseline. These participants were older (mean age 63.5 vs 62.7 y; P=0.01), with a longer diabetes duration (17.0 vs 15.5 y), lower eGFR (49.7 vs 58.0 mL/min/1.73m²), and were more like to have a history of heart failure (27.6 vs 11.3%; all P<0.0001). Unadjusted event rates were higher in those using loop diuretics (Figure). Effects of CANA on the primary outcome and other CV and renal outcomes were consistent irrespective of loop diuretic use. The risk of renal-related adverse events, acute kidney injury, and volume depletion was not elevated by loop diuretic use (data not shown; all Pinteraction>0.05).
Conclusion(s): CANA reduces the risk of CV and renal outcomes in people with T2DM and CKD irrespective of baseline use of loop diuretics, without additional adverse effects. (Table Presented)

Background: Albuminuria is a risk factor for kidney disease progression and CV disease. We examined the relative and absolute effects of CANA by baseline albuminuria among CREDENCE participants.
Method(s): CREDENCE was a double-blind, randomized study of 4401 participants with eGFR 30-<90mL/min/1.73m2 and uACR >300-5000mg/g who demonstrated that CANA significantly reduced renal and CV outcomes, including the primary composite of end-stage kidney disease, doubling serum creatinine, or renal or CV death. We analyzed the effect of CANA on renal, CV, and safety outcomes by baseline uACR.
Result(s): At baseline, 2348 (53.4%), 1547 (35.2%), and 506 (11.5%) participants had uACR <=1000, >1000-<3000, >=3000mg/g. Higher uACR was associated with higher event rates (Figure). CANA reduced renal and CV endpoints, with no statistical variation by uACR (all p heterogeneity >0.17). CANA led to a greater absolute reduction in renal events in those with higher uACR (number needed to treat to prevent 1 episode of the primary composite: 22 and 8 for uACR >1000-<3000 and >=3000mg/g). Rates of renalrelated adverse events were lower with CANA, and the relative reduction was greater with higher uACR (p heterogeneity=0.003). CANA had no significant effect on acute kidney injury, volume depletion, hyperkalemia, urinary tract infections or hypoglycemia, with no differences by uACR (all p heterogeneity >0.12).
Conclusion(s): CANA safely reduces renal and CV events in people with type 2 diabetes and substantial albuminuria, with the greatest absolute renal benefit in those with uACR of 3000-5000mg/g

Background: There is a paucity of data examining electrolyte concentrations during and immediately after hemodialysis (HD) sessions. We describe these changes and provide predictive nomograms based on HD prescriptions and pre-HD electrolytes.
Method(s): We leveraged patient (n=66) and HD session-level pre- and post-HD laboratory data (n=1,713) from the Monitoring in Dialysis study and fit mixed effects regression models to analyze differences between pre-, 15-minutes post-, and 30-minutes post-HD levels (compared with immediately post-HD) of electrolytes, blood urea nitrogen, creatinine, and albumin as well as the association of post-HD values with dialysate prescriptions.
Result(s): Serum bicarbonate, calcium, and albumin increased (mean increase 4.9mEq/ L+/-0.3, 0.7mEq/L+/-0.1, and 0.4g/dL+/-0.03, respectively), and potassium, magnesium, and phosphorus decreased immediately post-HD (mean -1.2mEq/L+/-0.1, -0.3mEq/L+/-0.03, and -3.0mg/dL+/-0.2, respectively). Hypokalemia and hypophosphatemia were present in 34% and 67% of immediately post-HD samples, respectively. Changes were observed in electrolyte concentrations at 15- and 30-minutes post-HD compared to immediately post- HD (Fig. A: observed changes; Fig. B: predictive nomograms of post-HD electrolytes).
Conclusion(s): Contemporary HD results in marked changes in electrolyte concentrations during and after the treatment. We report a high frequency of post-HD hypokalemia and hypophosphatemia and present predictive nomograms relating post- HD changes to dialysate prescriptions. Whether the abnormalities observed in potassium and phosphorus post-HD predispose to adverse symptoms and arrhythmia is unclear and requires further research. (Figure Presented)

Background and aims: Canagliflozin (CANA) slows progression of chronic kidney disease (CKD) in people with type 2 diabetes. CANA also induces a reversible acute decline in estimated glomerular filtration rate (eGFR), which is believed to be a hemodynamic effect. Predictors of the initial decline and its associationwith long-term eGFRtrajectories and safety outcomes are unknown.
Material(s) and Method(s): This post hoc study of the CREDENCE trial included 4289 patientswith type 2 diabetes andCKDwho had eGFRmeasured at both baseline andweek 3. Participants were categorized by percentage decline in eGFR at week 3: >10%, <=10% to >0%, and <=0%. Baseline characteristics associatedwith acute eGFRdeclines >10%were evaluated using logistic regression. Long-term eGFR decline and safety outcomes were estimated in each eGFR decline category by linear mixed effects models and Cox regression after adjustment for laboratory measures and medication use.
Result(s): More participants in the CANA (956 [45%]) versus placebo (PBO) group (450 [21%]) had an acute eGFR decline >10% (p <0.001). A >30% decline occurred infrequently (89 [4%] with CANA and 39 [2%] with PBO; p <0.001). In the CANA but not in the PBO group, older age (OR CANA 1.17, 95% CI 1.05-1.31; per 10 years) and history of heart failure (OR CANA 0.77, 0.59-0.99) were associated with a higher and lower likelihood of an acute eGFR decline >10%, respectively (both p for interaction <0.05). Following the initial eGFR change, long-term eGFR trajectories as well as overall safety profiles were similar across eGFR decline categories (all p values >0.05). Results were consistent when other decline thresholds (>20%) were used and in subgroup analysis by baseline eGFR (30-<45, 45-<60, and 60-<90 mL/min/1.73 m2).
Conclusion(s): Although acute eGFR declines >10% occurred in nearly half of all patients following initiation of CANA, the benefit of CANA compared with placebo was observed regardless of the acute eGFR decline and safety profiles were similar

Background and aims: Individuals with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) are at high risk for hospitalized heart failure (HHF) and these events are reduced by canagliflozin (CANA). We investigated whether the effect of CANA on HHF or cardiovascular (CV) death differs by key participant characteristics.
Material(s) and Method(s): CREDENCE randomized participants with T2DM and CKD to CANA or matching placebo. In this analysis, we assessed the effect of CANA on the prespecified secondary outcome of HHF/CV death by baseline characteristics. Hazard ratios (HRs) and 95% CIs were estimated with Cox regression models, with subgroup by treatment interaction terms added to test for heterogeneity.
Result(s): Of 4401 trial participants, 432 experienced a HHF/CV death event over a median follow-up of 2.6 years. Participants at higher risk included those with a history of CV disease or HF, lower eGFR, higher UACR and baseline use of loop diuretics. CANA reduced the risk of HHF/CV death by 31% in the overall population (HR 0.69, 95% CI 0.57, 0.83), with consistent effect across a broad range of participant subgroups including those at high risk (all Pinteraction>0.246; Figure). The effect of CANA on HHF alone (HR 0.61, 95% CI 0.47-0.80) was also similar across most key participant subgroups (all Pinteraction>0.10).
Conclusion(s): CANA consistently reduces the risk of HHF/CV death and of HHF in T2DM and CKD across a broad range of participant subgroups, including those with and without prior HF

Renin angiotensin aldosterone system inhibitors (RAASi) and diuretics are among the most frequently prescribed anti-hypertensives. Individuals with chronic kidney disease (CKD) are particularly at risk for electrolyte disturbances and kidney injury but the appropriate use of lab monitoring following RAASi or diuretic initiation is uncertain in CKD.We describe the frequency and time interval of lab monitoring during initiation of RAASi and diuretics in CKD and assess whether close lab monitoring associates with one-year risk of emergency department (ED) visit or hospitalization.We evaluated an observational cohort of 8,217 individuals with stage 3-5 non-dialysis CKD newly prescribed a RAASi (52.3%) or diuretic (47.7%) from thirty-six primary care offices affiliated with Brigham and Women's Hospital and Massachusetts General Hospital between 2009 and 2011.Overall, 3306 (40.2%) individuals did not have pre-prescription labs done within 2 weeks, and 5957 (72.5%) did not have post-prescription labs done within 2 weeks which includes 524 (6.4%) individuals without post-prescription within 1 year. Close monitoring occurred in only 1547 (20.1%) and was more likely in individuals prescribed diuretics compared to RAASi (adjusted OR 1.39; 95%CI 1.20-1.62), with CKD stage 4,5 compared with stage 3 (adjusted OR 1.47; 95%CI 1.16-1.86) and with cardiovascular disease (adjusted OR 1.42; 95%CI 1.21-1.66). Close monitoring was not associated with decreased risk of ED visit or hospitalization.Close lab monitoring during initiation of RAASi or diuretics was more common in participants with cardiovascular disease and advanced CKD suggesting physicians selected high-risk individuals for close monitoring. As nearly 80% of individuals did not receive close lab monitoring there may be value in future research on electronic physician decision tools targeted at lab monitoring.

BACKGROUND:The effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors on kidney failure, particularly the need for dialysis or transplantation or death due to kidney disease, is uncertain. Additionally, previous studies have been underpowered to robustly assess heterogeneity of effects on kidney outcomes by different levels of estimated glomerular filtration rate (eGFR) and albuminuria. We aimed to do a systematic review and meta-analysis to assess the effects of SGLT2 inhibitors on major kidney outcomes in patients with type 2 diabetes and to determine the consistency of effect size across trials and different levels of eGFR and albuminuria. METHODS:We did a systematic review and meta-analysis of randomised, controlled, cardiovascular or kidney outcome trials of SGLT2 inhibitors that reported effects on major kidney outcomes in people with type 2 diabetes. We searched MEDLINE and Embase from database inception to June 14, 2019, to identify eligible trials. The primary outcome was a composite of dialysis, transplantation, or death due to kidney disease. We used random-effects models to obtain summary relative risks (RRs) with 95% CIs and random-effects meta-regression to explore effect modification by subgroups of baseline eGFR, albuminuria, and use of renin-angiotensin system (RAS) blockade. This review is registered with PROSPERO (CRD42019131774). FINDINGS/RESULTS:=0·31). INTERPRETATION/CONCLUSIONS:SGLT2 inhibitors reduced the risk of dialysis, transplantation, or death due to kidney disease in individuals with type 2 diabetes and provided protection against acute kidney injury. These data provide substantive evidence supporting the use of SGLT2 inhibitors to prevent major kidney outcomes in people with type 2 diabetes. FUNDING/BACKGROUND:None.