CHRONIC KIDNEY DISEASE
Variability in eGFR and Risk of Adverse Outcomes
Nephrology Dialysis Transplantation. 2019;34(12):2066-2078
There are few available data on the association between variability in first-year estimated glomerular filtration rate (eGFR) and longitudinal change scales concomitantly to the risk of developing end-stage renal disease (ESRD), acute coronary syndrome (ACS), and death following pre-ESRD program enrollment of patients with chronic kidney disease (CKD).
Ching-Wei Tsai, MD, and colleagues conducted a prospective cohort study of 5092 patients with CKD receiving multidisciplinary care between 2003 and 2015. Incidence of ESRD, ACS, and death during follow-up were determined. Variability in first-year eGFR and longitudinal change scales were based on all first-year measurements, including coefficient of variation of eGFR (EGFR-CV), percent change (eGFR-PC), absolute difference (eGFR-AD), slope (eGFR-slope), and area under the curve (eGFR-AUC).
There were 786 incident ESRD events, 292 ACS events, and 410 deaths during follow-up. In multiple Cox regression, the fully adjusted hazard ratio (HR) of progression to ESRD was 1.03 (95% confidence interval [CI], 1.02-1.04) for each unit change in eGFR-CV, 1.04 (95% CI, 1.03-1.04) for eGFR-PC, 1.16 (95% CI, 1.14-1.18) for eGFR-AD, 1.16 (95% CI, 1.14-1.17) for eGFR-slope, and 1.04 (95%CI, 1.03-1.04) for eGFR-AUC.
The adjusted HRs for incident ESRD comparing the extreme with the reference quartiles were 2.67 (95% CI, 2.11-3.38) for eGFR-CV, 8.34 (95% CI, 6.33-10.98) for eGFR-PC, 19.08 (95% CI, 11.89-30.62) for eGFR-AD, 13.08 (95% CI, 8.32-20.55) for eGFR-slope, and 6.35 (95% CI, 4.96-8.13) for eGFR-AUC.
In the 2 ´ 2 risk matrices, the risk of all outcomes was highest in patients with the highest quartile of eGFR-CV and concomitantly with the most severely declining quartiles of any other longitudinal eGFR change scale.
In conclusion, the researchers said, “The dynamics of eGFR changes, both overall variability and longitudinal changes, over the first year following pre-ESRD program enrollment are crucial prognostic factors for the risk of progression to ESRD, ACS, and death among patients with CKD. A risk matrix combining the first-year eGFR variability and longitudinal change scales following pre-ESRD enrollment is a novel approach for risk characterization in CKD care. Randomized trials in CKD may be required to ascertain comparable baseline eGFR dynamics.”
Sodium Bicarbonate and Kidney Function: The BASE Pilot Trial
Journal of the American Society of Nephrology. 2020;31(10:161-174
Kidney function in patients with chronic kidney disease may be preserved with treatment with oral sodium bicarbonate (NaHCO3); the benefit may be present even in patients with normal serum bicarbonate level. In part because the optimal dose for testing is unknown, there have not been adequately powered trials to test this hypothesis.
Kalani L. Raphael, MD, MS, and colleagues conducted a multicenter pilot trial designed to assess the safety, tolerability, adherence, and pharmacodynamics of two doses of NaHCO3 over 28 weeks in adults with estimated glomerular filtration rate 20 to 44 or 45 to 40 mL/min/1.73 m2 with urinary albumin-to-creatinine ratio (ACR) ≥50 mg/g and serum bicarbonate 20 to 28 meq/L.
A total of 194 patients from 10 clinical sites were randomly assigned to receive higher dose (HD-NaHCO3; 0.8 meq/kg of lean body weight per day; n=90) or lower dose (LD-NaHCO3; 0.5 meq/kg of lean body weight per day; n=52) NaHCO3 or matching placebo (n=52). Dose was adjusted based on side effects. The primary outcome of interest was the prescribed dose at 28 weeks; an acceptable dose was identified as acceptable for a full-scale trial if ≥67% of participants were on full dose and ≥80% were on ≥25% of the per-protocol dose.
At baseline, mean eGFR was 36 mL/min/1.73 m2, serum bicarbonate was 24 meq/L, and median ACR was 191 mg/g. Both doses of NaHCO3 were well tolerated; there were no significant changes in blood pressure, weight, or serum potassium level. Both groups had similar proportions of adverse events and hospitalizations. At week 28, 87% of participants in the HD-NaHCO3 group, 96% in the LD-NaHCO3 group, and 87% in the placebo group were on full dose; in addition, 91% in the HD-NaHCO3 group, 98% in the LD-NaHCO3 group and 92% in the placebo group were on ≥25% of the per-protocol dose.
At week 28, compared with the LD-NaHCO3 group, mean urinary ammonium excretion was 25% lower and serum bicarbonate concentration was 1.3 meq/L higher in the HD-NaHCO3 group. However, mean ACR increased by 12% in the LD-NaHCO3 group and 30% in the HD-NaHCO3 group.
In conclusion, the researchers said, “Both NaHCO3 doses were well tolerated over 28 weeks with no significant difference in adverse events or hospitalization, compared with placebo. The higher dose lowered urinary ammonium excretion and increased serum bicarbonate more than the lower dose but was associated with a greater increase in ACR. The higher 0.8 meq/kg of body weight per day dose of NaHCO3 may be a reasonable choice for future trials.”
Slowing CKD Progression in Patients with HCV Infection
Kidney International. doi.org/10.1016/j.knit.2019.04.030
Hepatitis C virus infection (HCV) is a common comorbidity of chronic kidney disease (CVD) and may lead to accelerated CKD progression. Rates of sustained viral remission have been seen with direct-acting antiviral (DAA) therapies against HCV; however, the effect on kidney function is unknown. Meghan E. Sise, MD, and colleagues conducted a retrospective, observational cohort study to compare the slopes of estimated glomerular filtration rate (eGFR) decline in the 3 years prior to DAA therapy with the slope after the therapy. Pre- and post-treatment albuminuria values were also compared.
HCV-infected patients receiving DAA therapies from 2013 to 2017 were eligible for the study. A total of 1178 patients were included. Mean age was 56 years, 64% were male, 71% were white, 21% were diabetic, and 42% had cirrhosis.
Among patients with eGFR <60 mL/min/1.73 m2, the annual decline in eGFR in the 3-year prior treatment period was –5.98 mL/min per year (95% confidence interval [CI], –7.30 to –4.67) and improved to –1.32 mL/min per year (95% CI, –4.50 to 1.88) following DAA therapy. Among patients with eGFR >60 mL/min per year, the annual decline in eGFR in the pre-treatment period was –1.43 mL/min per year (95% CI, –1.78 to –1.08); following treatment with DAA therapies, the annual decline was –2.32 mL/min per year (95% CI, –3.36 to –1.03).
There was significant improvement in albuminuria in patients without diabetes. Predictors of improvement in eGFR were having CKD at baseline and being nondiabetic. Events of acute kidney injury (AKI) were rare and unrelated to antiviral therapy in 76% of the 29 patients who developed AKI.
“DAA therapy for HCV infection may slow CKD progression,” the researchers said.
HYPERKALEMIA
Economic Impact of Management of Patients with CKD and Hyperkalemia
The International Journal of Clinical Practice. doi.org/10.1111/ijcp.13475
Hyperkalemia, defined as potassium level ≥5.0 mEq/L, is associated with poor clinical outcomes in patients with chronic kidney disease (CKD). Michele Provenzano, MD, and colleagues conducted a study to compare management costs of patients with CKD with normokalemia versus those with persistent hyperkalemia treated in renal clinics in Italy.
The researchers developed a Markov model over life-time horizon. An observational multicenter database was used to derive time to end-stage renal disease (ESRD) and time to death among 1665 patients with non-dialysis CKD stage 1 to 5 receiving nephrology care in Italy. Follow-up was 15 years.
In addition to delayed onset of ESRD by 2.29 years and increased survival by 1.79 years, management of patients with normokalemia versus persistent hyperkalemia was associated with a cost-savings of €16,059. Total survival and dialysis-free survival in patients with normokalemia decreased incrementally from early to advanced disease. The cost-savings associated with normokalemia increased at more advanced CKD; however, cost-savings were seen at early stages (€3388.97 at stages 1-3a). The cost-savings associated with normokalemia were confirmed across all parameter variations.
The researchers said, “This model is the first to simulate the impact of hyperkalemia in non-dialysis CKD patients on economic and clinical outcomes using real-world data from nephrology clinics. In these patients, persistent hyperkalemia results into higher lifetime costs, besides poorer clinical outcomes, that are evident since the early stages of CKD. Maintaining normokalemia should therefore be of main concern in CKD treatment planning to improve long-term economic and clinical outcomes.”
Review of Trials and Guidelines in the Treatment of Hyperkalemia
Nephrology Dialysis Transplantation. 2019;34(Supplement 3):iii51-iii61
Stefano Bianchi, MD, and Giuseppe Regolisti, MD, recently conducted a review of pivotal clinical trials, meta-analyses, and current guidelines in the treatment of hyperkalemia. Hyperkalemia, an electrolyte disturbance in patients with advanced chronic kidney disease (CKD), is associated with an increased risk of fatal arrhythmias and has a significant impact on patients’ prognosis and quality of life. In patients with heart failure and diabetes mellitus, treatment commonly includes renin-angiotensin-aldosterone system (RAAS) inhibitors. RAAS inhibitors are cardio-nephro-protective drugs; however, treatment with RAAS inhibitors per se increases serum potassium values.
The onset or recurrence of hyperkalemia is frequently associated with not starting, titrating down, or withdrawing RAAS inhibitor therapy and may be an indication to initiate renal replacement therapy in patients with end-stage renal disease.
Treatments that include restriction of dietary potassium, the use of sodium bicarbonate or diuretics, withdrawal or down-titration of RAAS inhibitors, or the administration of old potassium binders have limited efficacy and are poorly tolerated.
“The development of new potassium binders may change the treatment landscape. This review summarizes the current evidence on the treatment of chronic hyperkalemia in cardio-renal patients,” the researchers said.
LUPUS NEPHRITIS
Biopsy-based Management May Reduce Lupus Nephritis Flare Rate
Kidney International. doi.org/10.1016/j.kint.2019.07.018
Currently, there is no consensus on the optimal duration of maintenance immunosuppression therapy for patients with lupus nephritis who have achieved clinical remission. In addition, according to Ana Malvar, MD, and colleagues, “Clinical and histologic remission are often discordant.”
Dr. Malvar et al. recently conducted a prospective cohort study to test the hypothesis that continuing therapy for patients with persistent histologic activity on kidney biopsies done during maintenance and discontinuing therapy only for patients without histologic activity would minimize subsequent lupus nephritis flares.
The study included a cohort of 75 patients with proliferative lupus nephritis who were managed using kidney biopsies performed during maintenance therapy. Eligible patients had been on immunosuppression therapy for a minimum of 42 months, had responded, and maintained clinical response for a minimum of 12 months prior to a repeat of the kidney biopsy. If the biopsy showed an activity index of zero, maintenance was withdrawn. If the biopsy showed an activity index of one or more, maintenance was continued.
Seven patients experienced a lupus nephritis flare during the average 50 months from the third biopsy and the final clinic visit, for a flare rate of 1.5 per year (significantly less than reported flare rates).
Baseline clinical parameters (serum creatinine, proteinuria) and serologic parameters (complement C3, C4, and anti-dsDNA) were not predictors of activity index of zero in the third biopsy or who would experience a lupus nephritis flare. Four patients developed de novo chronic kidney disease; no patient developed end-stage renal disease. There were no serious biopsy-related adverse events.
In conclusion, the researchers said, “Thus, at an experienced center, biopsy-informed management of maintenance immunosuppression is safe and may improve the lupus nephritis flare rate compared to conventional clinical management.”
TRANSPLANTATION
Long-term Outcomes of Acute Rejection
Journal of the American Society of Nephrology. 2019;30(9):1697-1707
Amid declining rates of acute rejection, the 1-year graft survival rate among patients with acute rejection is high, prompting a re-examination of acute rejection as an outcome of transplantation in trials and in clinical practice. However, there are few data available on the possible direct or indirect effects of acute rejection on longer-term outcomes for recipients of kidney transplantation.
Philip A. Clayton, MD, and colleagues conducted an analysis of data from the Australia and New Zealand Dialysis and Transplant Registry to examine the long-term effect of acute rejection on transplant outcomes. The analysis included data on 13,614 recipients of a primary kidney-only transplant between 1997 and 2017, with a minimum of 6 months of graft function. Cox models adjusted for baseline donor, recipient, and transplant characteristics were used to determine associations between acute rejection within 6-months post-transplant and subsequent cause-specific graft loss and death.
Acute rejection occurred in 21.4% of the recipients (n=2906); there were associations between acute rejection and graft loss attributed to chronic allograft nephropathy (hazard ratio [HR], 1.39; 95% confidence interval [CI], 1.23-1.56) and recurrent acute rejection beyond month 6 (HR, 1.85; 95% CI, 1.39-2.46). There was also an association between early acute rejection and death with a functioning graft (HR, 1.22; 95% CI, 1.08-1.36) and with death due to cardiovascular disease (HR, 1.30; 95% CI, 1.11-1.53) and with cancer (HR, 1.35; 95% CI, 1.12-1.64). Results were similar in sensitivity analyses restricted to subgroups with either biopsy-proven, antibody-mediated, or vascular rejection, or stratified by treatment response.
In conclusion, the researchers said, “Acute rejection is associated with increased risks of longer-term graft failure and death, particularly death from cardiovascular disease and cancer. The results suggest acute rejection remains an important short-term outcome to monitor in kidney transplantation and clinical trials.”
Early Steroid Withdrawal and Acceptable Outcomes
In recipients of kidney transplantation, there is an association between early steroid withdrawal and acceptable outcomes. However, transplant recipients with delayed graft function may have a suboptimal allograft milieu, potentially altering the risk/benefit equation for early steroid withdrawal.
Sunjae Bae and colleagues conducted an analysis of data from the Scientific Registry of Transplant Recipients of 110,019 adult deceased-donor kidney transplant recipients between 2005 and 2015. The analysis was designed to examine the association of delayed graft function with the use of early steroid withdrawal compared with continued steroid maintenance across kidney transplant centers. Using multivariable logistic and Cox regression with delayed graft function-early steroid withdrawal interaction terms, the researchers also sought to quantify the association between early steroid withdrawal and acute rejection, graft failure, and mortality.
Overall, 29.2% of the kidney transplant recipients underwent early steroid withdrawal. The odds of early steroid withdrawal were lower among recipients with delayed graft function. There was variation across the 261 kidney transplant centers in the strength of that association, with center-specific adjusted odds ratio of <0.5 at 31 centers and >1.0 at 22 centers. There were associations between early steroid withdrawal and benefits and harms among recipients with immediate graft function, but only with harms among recipients with delayed graft function.
Among recipients with immediate graft function, early steroid withdrawal was associated with increased acute rejection, and slightly increased graft failure, but decreased mortality. Among recipients with delayed graft function, there were associations between early steroid withdrawal and a similar increase in rejection, a more pronounced increased in graft failure, and no improvement in mortality. The interaction between delayed graft function and early steroid withdrawal was statistically significant for graft failure (P=.04) and mortality (P=.003), but not for rejection (P=.6).
In conclusion, the researchers said, “Kidney transplant centers in the United States use early steroid withdrawal inconsistently in recipients with delayed graft function. Our findings suggest early steroid withdrawal may lead to worse kidney transplant outcomes in recipients with delayed graft function.”
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