April 2019 Abstract Roundup

CHRONIC KIDNEY DISEASE

Possible Beneficial Effect of Statin Therapy on Iron Metabolism in Patients with CKD

Renal Failure. doi:10.1080/0886022X.2018.1535983

Anna Masajtis-Zagajewska, MD, PhD, and colleagues conducted a double blind, randomized crossover study designed to examine the effect of 6-month administration of atorvastatin on hepcidin and hemojuvelin levels, inflammatory parameters, and iron metabolism in patients with chronic kidney disease (CKD) stages 3 and 4. The study cohort included 36 statin- and erythropoiesis-stimulating agent-naïve patients with low density lipoprotein cholesterol ≥100 mg/dL; study participants received atorvastatin or placebo for two 6-month periods.

In the course of the statin therapy, hepcidin decreased from 102 to 63 pg/mL (P>.001), but remained unchanged after placebo administration. There was no change in hemojuvelin after either part of the study. Following statin therapy, both interleukin-6 (IL-6) and high sensitivity C-reactive protein (hsCRP) decreased (from 8.7 to 8.1 pg/mL and from 4.7 to 4.0 mg/L, P=.4, respectively); there was no change in IL-6 or hsCRP after placebo administration.

There was a slight but significant increase in blood hemoglobin after 6 months of statin therapy; blood hemoglobin was unchanged after placebo administration. There was significant increase in total Iron binding capacity and unsaturated iron binding capacity after 6-month statin therapy, as well as a tendency for an increase in serum iron. There was no difference in change in estimated glomerular filtration rate between the two study periods.

The researchers said, “Statin may have a small but potentially beneficial effect on serum hepcidin, which may lead to improvement of anemia control in CKD patients.”

Efficacy of Bariatric Surgery Patients with CKD Varies with Stage

Obesity Surgery. doi:10.1007/s11695-019-03703-z

Obesity is a known risk factor for chronic kidney disease and a relative contraindication for kidney transplantation; bariatric surgery is an option to address this issue. Boris Hansel, MD, and colleagues, hypothesized that there is an association between severe CKD and loss of efficacy of bariatric surgery, offering possible justification for recommendation of bariatric surgery at an earlier stage of CKD.

The researchers conducted a retrospective study of 101 patients to compare differences in weight loss at 6 and 12 months. Patients were stratified according to estimated glomerular filtration rate (eGFR): <30 including patients on dialysis; 30 to 59, 60 to 90, and ≤90 mL/min/1.73 m2. Multivariate analyses were adjusted for sex, age, body mass index, surgical procedure, and diabetes. The researchers utilized a second method to confirm their hypothesis comparing weight loss in patients with stage 4 or 5 CKD, defined as eGFR <30 mL/min/1.73 m2 (n=17), and matched controls with eGFR ≥90 mL/min/1.73 m2.

In the first comparison, there was a positive association between eGFR and weight loss in the multivariate analysis. However, following exclusion of the subgroup of patients with eGFR <30 mL/min/1.73 m2, the difference between the groups was no longer significant.

The percent of total weight loss was significantly lower in patients with servere CKD compared with controls (–15% vs –23% at 6 months; P<.01; –17% vs –27% at 12 months; P<.01). At 1 year, the percent of weight loss reached 47% in patients with stage 4 to 5 CKD and 68% in control subjects (P<.01). In the group with advanced CKD, surgery was a success (weight loss >50% of excess weight) in 38%, compared with 88% of controls (P<.01).

In conclusion, the authors said, “The efficacy of bariatric surgery was reduced in patients with advanced CKD. These results suggest early bariatric surgery in patients with  early-to-moderate CKD.”

DIALYSIS

Early Withdrawal and Non-Withdrawal Death Following Initiation of Hemodialysis

Hemodialysis International. doi:org/10.1111/hdi.12723

Researchers conducted a retrospective cohort analysis designed to examine whether and how factors associated with elective hemodialysis withdrawal differ from those associated with non-withdrawal death soon after initiation of maintenance hemodialysis. James B. Wetmore, MD, MS, and colleagues utilized data from the United States Renal Data System from 2011 to 2014 to randomly categorize patients 2:1 into training (n=80,284) and validation (n=40,142) samples. A prediction model for three outcome categories (withdrawal, non-withdrawal death, survival at 6 months) as a function of demographic, comorbidity, and functional status was created using multinomial logistic regression.

Mean age of the training sample was 71.7 years, 44.9% were female, 72.9% were white, and 22.8% were black. At 6 months, 19.1% had died: 2022 (2.6%) withdrew and 13,223 (16.5%) died of a cause not related to non-withdrawal; 13.7% of all deaths were withdrawals. Baseline characteristics and event rates were similar among those in the validation sample.

The model was adequately calibrated and could discriminate moderately well between withdrawal and survival (area under the ROC curve [AUC]: 0.77) and between non-withdrawal death and survival (AUC: 0.73). However, discrimination between withdrawal and non-withdrawal death was relatively low (AUC: 0.62). There were associations between older age and white, compared with non-white, race and greater odds of death; those associations were stronger for withdrawal than for non-withdrawal death.

The researchers said, “Advanced age and white, as opposed to black, race were most strongly associated with early elective hemodialysis withdrawal compared with non-withdrawal death. However, it is difficult to differentiate between patients who will experience early withdrawal versus non-withdrawal death, as many factors are similarly associated with both outcomes.”

END-STAGE RENAL DISEASE

Incidence and Prevalence of ESRD Projected to 2030

Journal of the American Society of Nephrology. 2019;30(1):127-135

Projections of the incidence and prevalence of end-stage renal disease (ESRD) can inform long-range planning for resources needed to manage the ESRD population. Keith P. McCullough, MS, and colleagues utilized population rates of obesity, hypertension, diabetes, age, and race in simulation models to develop projections used in an open compartmental simulation model to estimate the incidence and prevalence of ESRD in the United States through 2030; the model used wide-ranging projections of population obesity and ESRD death rates. Data form the Centers for Disease Control and Prevention’s National Health and Nutrition Examination Survey and the US Census were used to determine population trends in age, race, hypertension, and diabetes.

In recent years, the increase in incidence rates of ESRD within age and race groups has leveled off and/or declined. However, the current model indicates that population changes in age and race distribution, prevalence of obesity and diabetes, and ESRD survival will result in an 11% to 18% increase in the crude incidence rate from 2015 to 2030. During the same time period, the trend in incidence rate coupled with reductions in ESRD mortality will result in an increase in the number of patients with ESRD by 29% to 68%, to between 971,000 and 1,259,000 patients in 2030.

“The burden of ESRD will increase in the United States population through 2030 due to demographic, clinical, and lifestyle shifts in the population and improvements in renal replacement therapy. Planning for ESRD resource allocation should allow for substantial continued growth in the population of patients with ESRD. Future interventions should be directed to preventing the progression of CKD to kidney failure,” the researchers said.

FABRY DISEASE

Prevalence of Fabry Disease in Transplant Recipients

Nephron. doi.org/10.1159/000496620

Fabry disease, an X-linked lysosomal storage disorder, results from a lack of alpha-galactosidase A (AGALA) activity in lysosomes. Serkan Feyyaz Yalın, MD, and colleagues conducted a multicenter study designed to evaluate the prevalence of Fabry disease in renal transplant recipients in Turkey. Dialysis patients were used as a control group. The researchers measured AGALA activity in all male patients. Mutation analysis was conducted in male patients with decreased AGALA activity and in female patients as the initial diagnostic assay.

A total of 5657 patients were screened; 17 mutations were identified. There was no significant difference seen between the groups regarding the prevalence of patients with mutation. Fabry disease was found even in patients with presumed primary kidney diseases. Seventy-one relatives were analyzed and mutation was detected in 43. The screening also detected a patient with a new, unknown mutation (p.Cys223) in the GLA gene.

“These are important implications of the screening. First, detection of the undiagnosed patients leads to starting appropriate therapies for these patients. Second, the transmission of the disease to future generations may be prevented by prenatal screening after appropriate genetic counseling. In conclusion, we suggest screening of kidney transplant candidates for Fabry disease, regardless of etiologies of chronic kidney disease,” the researchers said.

IGA NEPHROPATHY

Reduction in Proteinuria as a Surrogate End Point in IgA Nephropathy Trials

Clinical Journal of the American Society of Nephrology. doi.org/10.2215/CJN.0860

There are no approved therapies for the treatment of IgA nephropathy (IgAN), an important cause of end-stage renal disease (ESRD). Aliza Thompson, MD, MS, and colleagues recently conducted a Kidney Health Initiative designed to identify surrogate end points that could serve as reliable predictors of the effect of treatments on long-term kidney outcomes in IgAN and ultimately be used as a basis for approval.

Proteinuria was identified as the most widely recognized and well-studied risk factor for progression to ESRD in patients with IgAN. Epidemiologic data show a strong and consistent relationship between the level and duration of proteinuria and loss of kidney function.

In trial-level analyses of data from 13 controlled trials, there was also an association between treatment effects of percent reduction of proteinuria and treatment effects on a composite of time to doubling  of serum creatinine, ESRD, or death.

The researchers said, “We conclude that data support the use of proteinuria reduction as a reasonably likely surrogate end point for a treatment’s effect on progression to ES[R]D in IgAN. In the United States, reasonable likely surrogate end points can be used as a basis for accelerated approval of therapies intended to treat serious or life-threatening conditions, such as IgAN. The clinical benefit of products approved under this program would need to be verified in a postmarketing confirmatory trial.”

TRANSPLANTATION

Changes in Cognitive Function among Frail Transplant Recipients

Journal of the American Society of Nephrology. doi.org/10.1681/ASN.2018070726

Post-transplant restoration of kidney function generally improves cognitive function; however, there are few data on whether frail recipients, who are more susceptible to surgical stressors, achieve improvements in cognitive function following kidney transplantation or whether they experience a subsequent decline in cognitive function as they age with a functioning graft.

Nadia M. Chu, PhD, MPH, and colleagues recently conducted a two-center cohort study designed to examine pretransplant frailty (Fried physical frailty phenotype) and cognitive function (measured by the Modified Mini-Mental State Examination) in adult kidney transplant recipients. The researchers measured cognitive function up to 4 years post-transplant and characterized cognitive trajectories by pretransplant frailty using an adjusted mixed effects model with a random slope (time) and intercept (person).

A total of 665 transplant recipients were followed for a median of 1.5 years. Mean age was 52.0 years and 15.0% were frail. Following adjustment, pretransplant cognitive scores were significantly lower among the frail patients than among the nonfrail patients (89.0 vs 90.8 points).

At 3 months post-transplant, there was improvement in cognitive function for both frail (slope=0.22 points/week) and nonfrail (slope=0.14 points/week) patients. In nonfrail recipients, the improvements plateaued between 1 and 4 years post-transplant (slope=0.005 points/week); however, among frail recipients, cognitive function declined during that time period (slope=–0.04 points/week). Cognitive scores for frail recipients were 5.8 points lower than for nonfrail recipients at 4 years post-transplant.

“On average, both frail and nonfrail recipients experience short-term cognitive improvement post-transplant. However, frailty is associated with medium-term cognitive decline post-transplant. Interventions to prevent cognitive decline among frail recipients should be identified,” the researchers concluded.

Fructose and Metabolic Endotoxemia in Transplant Recipients

Transplantation. 2019;103(1):191-201

According to Winnie Chan, PhD, and colleagues, “The concepts that obesity is merely a consequence of overeating and that metabolic health then reflects obesity may be insufficient and potentially flawed.” There is increased attention being paid to the role of fructose intake and metabolic endotoxemia; however, there are few data in kidney transplantation recipients. The researchers conducted a cross-sectional observational study to examine the risk factors for metabolic syndrome, its components, and other associated markers in a population of kidney transplant recipients.

The study enrolled 128 kidney transplant recipients who were ≥1 year post-transplant; clinical, biochemical, anthropometric, and questionnaire assessments were completed.  Obesity (defined as body mass index ≥30 kg/m2) was found in 36.7% of the cohort and metabolic syndrome in 50%.

There were independent associations between increased intake of fructose and metabolic syndrome and between increased endotoxin level and metabolic syndrome (P<.01 and P=.02, respectively). Increased intake of fructose was associated with the central obesity (P=.01) and with hyperglycemia (P<.001) criteria of metabolic syndrome. Higher endotoxin level was associated with hypertriglyceridemia (P=.003) and low concentration of high-density lipoprotein cholesterol (P=.002) criteria.

There was no independent association between saturated fat or total caloric intake and obesity and metabolic syndrome; nor was there an independent association between obesity or central obesity with the dyslipidemia and hyperglycemia criteria of metabolic syndrome.

In conclusion, the researchers said, “Dietary modification through decreasing fructose intake and addressing systemic endotoxemia are plausible targets for improving the metabolic health of kidney transplant recipients.”