ACUTE KIDNEY INJURY
Use of Renin-Angiotensin System Blocker and Recurrent AKI
Clinical Journal of the American Society of Nephrology. 2020;15(1):26-34
The treatment of choice for management of patients who survived hospitalized acute kidney injury (AKI) is unclear; the use of renin-angiotensin system blockers in that patient population may increase the risk of recurrent AKI. Chi-yuan Hsu, MD, MS, and colleagues conducted a cohort study to examine outcomes in patients who experienced AKI and survived a hospitalization between January 1, 2006, and December 31, 2103.
The cohort included 10,242 members of an integrated healthcare delivery system in Northern California. Eligible patients did not have prior heart failure or use of angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) up to 5 years prior to the index hospitalization. Outpatient health plan pharmacy databases were used to identify new receipt and time-updated exposure of ACE-Is/ARBs.
The primary outcome of interest was a subsequent episode of hospitalized AKI after discharge from an initial index hospitalization complicated by AKI. Acute changes in serum creatinine concentrations were used to define recurrent AKI. Marginal structural models adjusted for baseline and potential time-dependent confounders.
Of the 10,242 patients, 47% had a documented estimated glomerular filtration rate <60 mL/min/1.73 m2 or documented proteinuria prior to hospitalization. During a median 3 years of follow-up (interquartile range, 1-5 years), 18% of patients (n=1853) initiated use of ACE-Is/ARBs and 21% (n=2124) experienced recurrent AKI. The crude rate of recurrent AKI was 6.1 per 100 person-years off ACE-Is/ARBs and 5.7 per 100 person-years on ACE-Is/ARBs.
Following adjustment for baseline and potential time-dependent confounders, marginal structural causal inference models found no association between exposure to ACE-Is/ARBs use and higher incidence of recurrent AKI (adjusted odds ratio, 0.71; 95% confidence interval, 0.45-1.12).
In conclusion, the researchers said, “In this study of AKI survivors without heart failure, new use of ACE-Is/ARB therapy was not independently associated with risk of recurrent hospitalized AKI.”
Changes in Proximal Tubular Secretion in Patients with ADPKD
Clinical Journal of the American Society of Nephrology. 2020;15(1):80-88
In patients with autosomal dominant polycystic kidney disease (ADPKD), glomerular filtration rate (GFR) commonly remains normal despite significant nephron loss; proximal tubular secretory clearance may be reduced in that patient population prior to detectable changes in GFR.
Researchers, led by Ke Wang, MD, used targeted mass spectrometry to quantify secretory solutes from blood and urine samples from 31 patients with ADPKD and preserved GFR (mean estimated GFR [eGFR], 111 mL/min/1.73 m2) and 25 healthy controls as well as from 95 patients with ADPKD and reduced GFR (mean eGFR, 53 mL/min/1.73 m2) and 92 individuals with non-ADPKD chronic kidney disease (CKD). Among 112 patients with ADPKD, associations between solute fractional excretion and height-adjusted total kidney volume were determined using linear regression.
Following adjustment for demographics, clinical characteristics, and measures of kidney function, the fractional excretions of three secretory solutes were lower in patients with ADPKD and preserved GFR compared with healthy individuals: cinnamoylglycine excretion, 52% lower (95% confidence interval [CI], 24%-70%); tiglylglycine excretion, 53% lower (95% CI, 23%-71%); and xanthosine excretion, 91% lower (95% CI, 83%-95%).
Patients with ADPKD and reduced GFR also demonstrated 37% lower dimethyluric acid excretion (95% CI, 21%-50%), 58% lower hippurate excretion (95% CI, 48%-66%), 48% lower isovalerylglycine excretion (95% CI, 37%-56%) and 31% lower pyridoxic acid excretion (95% CI, 16%-42%) compared with patients with non-ADPKD CKD and comparable GFR.
There were no associations between solute fractional excretions and differences in kidney volume in patients with ADPKD.
“Patients with APDKD and preserved and reduced GFR demonstrate lower tubular secretory solute excretion compared with healthy controls and patients with non-ADPKD CKD,” the researchers said. “Our results suggest that tubular secretion is impaired in ADPKD independent of GFR.”
CHRONIC KIDNEY DISEASE
FGF23 and Fractional Excretion of Sodium
Nephrology Dialysis Transplantation. 2019;34(12):2015-2057
Results of recent studies suggest that the phosphaturic hormone fibroblast growth factor 23 (FGF23) is involved in regulation of renal sodium excretion and blood pressure. There are data demonstrating direct effects via regulation of the sodium-chloride symporter in the distal tubule, and indirect effects through interactions with the renin-angiotensin-aldosterone system. However, according to Hong Xu, MD, and colleagues, there are few clinical data regarding the association between FGF23 and renal sodium regulation. The researchers conducted a cross-sectional study to examine the associations of FGF23 and renal sodium handling and blood pressure in patients with non-dialysis dependent chronic kidney disease (CKD).
The study included 180 patients with stages one to five CKD who underwent renal biopsy. Baseline measurements included plasma intact FGF23, 24-hour urinary sodium excretion, fractional excretion of sodium (FENa), and blood pressure. Multivariate regression analysis was used to examine the association between FGF23 and renal sodium handling.
Median age of the cohort was 52.8 years, 60.6% were men, and median estimated glomerular filtration rate (eGFR) was 50.6 mL/min/1.73 m2. In univariate analysis, there was a positive association between FENa (Spearman’s rho=0.47; P<.001) and systolic blood pressure (rho=0.17; P<.05). There was no association with plasma sodium, 24-hour urinary sodium excretion, or mean arterial blood pressure.
Following adjustment for potential confounders, the association between FGF23 and FENa remained significant. The association was stronger among the 107 individuals with eGFR <60 mL/min/1.73 m2 and in the 73 individuals on any diuretics. There was no change in the relationships following adjustment for measured GFR.
In conclusion, the researchers said, “FGF23 is independently associated with increased FENa in non-dialysis CKD patients. These data do not support the notion that FGF23 causes clinically significant sodium retention. Further studies are warranted to explore the mechanism underlying this association.”
Racial and Ethnic Differences in Dialysis Discontinuation Rates
Journal of the American Society of Nephrology. 2020;31(1):149-160
Previous studies have shown that racial and ethnic minorities on dialysis survive longer than whites, and are less likely to discontinue dialysis therapy. Abdulkareem Agunbiade, MD, and colleagues conducted a retrospective cohort study to determine whether racial and ethnic differences in dialysis discontinuation reflect better health among those patient populations. The cohort included patients on maintenance dialysis in the US Renal Data System following hospitalization for stroke (n=60,734), lung cancer (n=4100), dementia (n=40,084), or failure to thrive (n=42,950) between 2003 and 2014.
The researchers assessed the frequency of dialysis discontinuation and used simulations to estimate survival in minorities relative to whites if minorities had the same pattern of dialysis discontinuation as whites.
In each hospital cohort, the frequency of dialysis discontinuation was substantially lower in blacks, Hispanics, and Asians than in whites. Blacks, Hispanics, and Asians also had lower observed risks for mortality. In simulation models that assigned discontinuation patterns similar to those found among whites to racial and ethnic groups, the differences in survival were attenuated and hazard ratios approached 1.0. American Indians and Alaska Natives had survival and dialysis discontinuation frequencies similar to those of whites.
In conclusion, the researchers said, “Racial and ethnic differences in dialysis discontinuation were present among patients hospitalized with similar health events. Among these patients, survival differences between racial and ethnic minorities and whites were largely attributable to differences in the frequency of discontinuation of dialysis.”
Hyperkalemia and Risk of RAAS Inhibitor Treatment Cessation
Nephrology Dialysis Transplantation. doi.org/10.1093/ndt/gfz263
There are few data available regarding the rates of hyperkalemia in users of renin angiotensin aldosterone system (RAAS) inhibitors and factors associated with treatment interruptions and cessation.
Researchers, led by James B. Wetmore, MD, MS, identified RAAS inhibitor users in the linked UK Clinical Practice Research Datalink-Hospital Episodes Statistics data set, from 2009 to 2015. Treatment interruptions were defined as no active prescription followed by reappearance. Interruptions and cessations were examined. Hyperkalemia was defined as serum potassium >5.5 mmol/L.
Time-varying Cox regression models were used to calculate rates of hyperkalemia and the factors associated with interruptions and cessations; hyperkalemia was included as a time-dependent variable.
The data set revealed 434,027 users of RAAS inhibitors. Among those, the rate of hyperkalemia was 1.30 (95% confidence interval [CI], 1.28-1.32) per 100 patient-years. A total of 73.7% of patients experienced periods of off treatment. Of those, 57.6% experienced interruption, 7.5% experienced cessation, and 8.6% experienced both interruption and cessation. Approximately one-third of patients experienced interruption or cessation within 1 year of initiation of RAAS inhibitor treatment.
The hazard ratios for patients with severe hyperkalemia were 1.10 (95% CI, 1.05-1.16) for treatment interruptions and 3.37 (95% CI, 3.25-3.50) for treatment cessation. In comparison with individuals with no chronic kidney disease (CKD), the risks of interruption for stages 4 and 5 were 1.20 (95% CI, 1.16-1.25) and 1.57 (95% CI, 1.44-1.72), respectively. The risks of cessation were 2.20 (95% CI, 2.07-2.33) and 2.87 (95% CI, 2.56-3.22), respectively.
For patients with heart failure and diabetes, the risks of interruption increased: 1.04 (95% CI, 1.02-1.05) and 1.13 (95% CI, 1.12-1.14), respectively. However, the risk of cessation decreased in patients with heart failure and diabetes: 0.85 (95% CI, 0.82-0.87) and 0.92 (95% CI, (0.90-0.94), respectively.
The researchers said, “Risk of RAAS inhibitor interruption and cessation increased as CKD stage progressed. Efforts targeting reasons for interruptions and, especially, cessations, such as hyperkalemia prevention, could decrease off-treatment periods for patients who would otherwise benefit, such as those with CKD, heart failure, or diabetes.”
Potentially Nephrotoxic Medication Prescriptions to Children with CKD
Clinical Journal of the American Society of Nephrology. 2020;15(1):61-68
Management of pediatric chronic kidney disease (CKD) focuses on limiting kidney injury, including avoidance of nephrotoxic medications. There are few data available on nephrotoxic medication prescription practices for children with CKD. Claire E. Lefebvre, MD, and colleagues conducted a retrospective, matched population-based cohort study to examine the prevalence and rates of primary care prescriptions for potentially nephrotoxic medications in children with CKD versus without CKD.
The cohort included patients <18 years of age registered at a general practice that participated in the UK Clinical Practice Research Datalink (CPRD) from 1997 to 2017. Children with an incident diagnosis of CKD were matched 1:4 to patients without CKD on CKD diagnosis date, sex, age, CPRD practice, and number of general practitioner visits in the year prior to cohort entry.
The researchers calculated the prevalence and rate of prescriptions for potentially nephrotoxic medications during the follow-up period in patients with versus without CKD. Primary analyses included aminoglycosides, antivirals, nonsteroidal anti-inflammatory drugs, salicylates, proton pump inhibitors, and immunomodulators. In secondary analyses, the researchers used an expanded definition of nephrotoxicity that included, among others, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Multivariable binomial regression models were used to calculate adjusted prescription rates.
From a total of 1,535,816 eligible individuals, the final study cohort included 1018 patients with incident CKD and 4072 non-CKD matches. Mean age was 9.8 years, 52% were male, and median follow-up time was 3.3 years. During follow-up, 26% of patients with CKD and 15% of those without CKD were prescribed one or more potentially nephrotoxic medications. The overall rate of nephrotoxic medication prescriptions in patients with CKD was 71 prescriptions per 100 person-years versus eight prescriptions per 100 person-years in those without CKD (adjusted rate ratio, 4.1; 95% confidence interval, 2.7-6.1).
“Potentially nephrotoxic medications are prescribed at high rates to children with CKD,” the researchers said.