CHRONIC KIDNEY DISEASE
Benefits of Phosphorus Binder Use among Non-Dialysis CKD Patients
American Journal of Nephrology. 2017;45(5);431-441.
It is unknown whether the benefits of phosphorus binders extend to patients with chronic kidney disease (CKD) but without end-stage renal disease. In a retrospective cohort study conducted by Simran Bhandari, MD, and colleagues, the researchers sought to evaluate phosphorus binder use and compare risk of mortality between patients prescribed and not prescribed binders in a large diverse non-dialysis dependent CKD population.
Among 10,165 study patients, 27% (n=2733) received phosphorus binders. Using a traditional multivariable model, compared with the group not receiving phosphorus binders, the hazard ratio [HR} for mortality among the binder group was 0.86 (95% confidence interval [CI], 0.79-0.94. Results from an inverse probability of treatment-weighted model, the HR in the binder group was 0.86 (95% CI, 0.80-0.93). When patients who were prescribed binders >180 days following the index date, there was no difference in mortality between the binder group and the non-binder group.
The researchers said, “Our findings from a real-world clinical environment revealed that 27% of hyperphosphatemic non-dialysis CKD patients were prescribed binders. They also had a lower risk of mortality compared to those not prescribed phosphorus binders. However, the lower mortality risk was not observed when we accounted for immortal time bias. Whether phosphorus binder use in CKD improves survival remains to be determined.”
Phase 2a Trial of Vadadustat for Anemia Secondary to CKD
American Journal of Nephrology. 2017;45(5):380-388.
There are limited therapeutic options for the treatment of anemia secondary to chronic kidney disease (CKD). Edouard Martin, MD, and colleagues reported results of a phase 2a, multicenter, randomized, double-blind, placebo-controlled, dose-ranging trial of vadadustat (AKB-6548), an oral hypoxia-inducible factor prolyl-hydroxylase domain (HIF-PHD) inhibitor. The trial (NCT01381094) is being conducted to assess the use of vadadustat in patients with anemia secondary to CKD stage 3 or 4.
Patients were evenly randomized to five groups based on dose: 240, 370, 500, or 630 mg of oral vadadustat once daily, or placebo. All participants received 50 mg of supplemental oral iron once daily. The primary end point was the mean absolute change in hemoglobin from baseline to the end of treatment.
The study randomized 93 subjects. Compared with placebo, there was a significant increase in hemoglobin with vadadustat after 6 weeks in a dose-dependent manner (analysis of variance; P<.001). Vadadustat increased the total iron-binding capacity and decreased concentrations of ferritin and hepcidin. Safety was similar between the groups treated with vadadustat and the group treated with placebo.
In conclusion, the researchers said, “Vadadustat increased hemoglobin levels and improved biomarkers of iron mobilization and utilization in patients with anemia secondary to stage 3 or 4 CKD. Global multicenter, randomized phase 3 trials are ongoing in non-dialysis dependent and dialysis-dependent patients.”
Serum Uric Acid and Total Bilirubin Associated with Renal Dysfunction
International Urology and Nephrology. doi: 10.1007.s11255-017-1633-8
In a study conducted in a remote village in Japan designed to determine whether serum uric acid and total bilirubin produce an additive interactive for the risk of renal dysfunction, Ryuichi Kawamoto, MD, PhD, and colleagues examined the relationship between serum uric acid and total bilirubin and renal function by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease Study Group equation.
Results of stepwise multiple regression analysis using eGFR as an objective variable showed significant and independent associations between serum uric acid, age, drinking status, and the presence of antihypertensive medication and eGFR; there was no association between total bilirubin and eGFR. The group in the highest tertile of serum uric acid, total bilirubin was significantly and independently associated with eGFR; however, in the group with the lowest to middle tertile of serum acid, there was no association between total bilirubin and eGFR.
The interaction between serum uric acid and total bilirubin, as well as age, drinking status, presence of antihypertensive medication, serum uric acid, and total bilirubin, was a significant and independent determinant for eGFR.
“Our data demonstrated that low total bilirubin could be important as a potential risk factor for renal dysfunction in those with high serum uric acid,” the researchers said.
Febuxostat Improves Endothelial Dysfunction in Dialysis Patients
American Journal of Nephrology. 2017;45(5):452-459
In patients with end-stage renal disease, endothelial dysfunction is a major risk factor for cardiovascular disease. Previous studies have shown a positive effect of febuxostat in improving endothelial dysfunction; however, there are few data on the effect of febuxostat in patients on maintenance hemodialysis.
Febuxostat is a novel xanthine oxidase inhibitor. Mona Alshahawey and colleagues recently conducted a prospective, placebo-controlled, block-randomized, double-blinded study to assess the effect of oral febuxostat on endothelial dysfunction in patients on hemodialysis. Fifty-seven patients were randomized to receive either 40 mg of febuxostat three times a week or placebo. At baseline and at the end of the 2-month study, serum asymmetric dimethylarginine, serum uric acid, and serum high sensitivity C-reactive protein were measured. At baseline and again at the end of the study, serum alanine aminotransferase, serum aspartate aminotransferase, and the occurrence of pancytopenia were tested as safety parameters.
In the febuxostat group, there was a significant decrease in serum uric acid (from 7.5 to 5.1 mg/dL); there was no significant change in the placebo group. The febuxostat group also had significant decreases in serum asymmetric dimethylarginine level (1.027 to 0.944 µmol/L) and serum high sensitivity C-reactive protein level (12.5 to 12.2 mg/L). There were no differences in the prespecified safety markers between the two groups.
The researchers said, “Febuxostat appears to improve hyperuricemia and endothelial dysfunction and ameliorate inflammation in hemodialysis patients with no safety concerns.”
Factors Associated with Progression of CKD in Elderly Patients
International Urology and Nephrology. 2017;49(6):1033-1040
There has been a steady rise in the prevalence of chronic kidney disease (CKD) in the elderly population. Pradeep Arora, MD, and colleagues recently conducted an observational study designed to examine the rate of CKD in the elderly and the factors associated with disease progression to help identify patients with CKD likely to progress to end-stage renal disease.
The study included 4562 patients >65 years of age who had two outpatient estimated glomerular filtration rates (eGFRs) of <60 mL/min/1.73 m2 a minimum of 90 days apart with no intervening eGFR >60 mL/min/1.73 m2 at Veterans Administration healthcare facilities. Exclusion criteria included eGFR <15 mL/min/1.73 m2. The annual rate of eGFR decline was examined and classified as <1 mL/min/1.73 m2, 1 to 4 mL/min/1.73 m2, and >4 mL/min/1.73 m2.
Mean age of participants was 77.2 years, 24.3% had diabetes, and 4.3% had proteinuria. Multivariable mixed model analyses found an association between a significantly increased rate of progression of CKD and increasing age, body mass index, and the presence of cardiovascular disease, diabetes mellitus, and proteinuria. There was an inverse association of serum albumin and hemoglobin with progression of CKD.
“CKD progresses at a slower rate in the elderly population. We have identified risk factors associated with an increased risk of progression of CKD in the elderly. This may help to improve health care planning and resource utilization,” the researchers said.
Management of Thiazide-Associated Hyponatremia Is Often Poor
American Journal of Nephology. 20176;45(5):420-430
Use of thiazide diuretics may result in hyponatremia, a potentially life-threatening adverse side effect. Volker Burst, MD, and colleagues recently conducted a sub-analysis of the Hyponatremia Registry database that focused on current management practices of hyponatremia related to thiazide use and compared differences between thiazide-associated hyponatremia and syndrome of inappropriate antidiuretic hormone secretion.
The researchers analyzed data on 477 patients from 225 sites in the United States and Europe. All patients were receiving a thiazide diuretic. Of the 477 patients, 118 met criteria for true thiazide-induced hyponatremia.
In only 57% of diagnoses of thiazide-associated hyponatremia was the diuretic withdrawn; in those patients, the median rate of sodium change was significantly higher than in those who continued treatment with thiazide. The most frequently employed therapies were isotonic saline (29.6%), fluid restriction (19.9%), a combination of those two (8.2%), and hypertonic saline (5.2%). The greatest change in sodium was achieved with hypertonic saline, followed by a combination of fluid restriction and normal saline and normal saline alone. Fluid restriction was markedly less effective.
In conclusion, the researchers said, “Despite its high incidence and potential risks, the management of thiazide-associated hyponatremia is often poor. Immediate withdrawal of the thiazide is crucial for treatment success. Hypertonic saline is most effective in correcting hyponatremia but associated with a high rate of overly rapid correction. We could not establish a diagnostic laboratory-based test to differentiate thiazide-induced hyponatremia from a syndrome of inappropriate antidiuretic hormone secretion.”
Circulating HLA/DSAs Associated with Premature and Accelerated Allograft Fibrosis
Kidney International. http://dx.doi.org/10.1016/j.Kint.2017.03.033
One of the challenges for improving long-term transplantation outcomes is addressing the causes of kidney allograft-accelerated aging. Clément Gosset, MD, and colleagues recently conducted a study to investigate the role of circulating donor-specific anti-HLA antibodies (HLA-DSAs) in the development and progression of kidney allograft fibrosis with inclusion of traditional risk factors for allograft fibrosis.
The prospective study enrolled 1539 consecutive recipients of kidney transplant at two centers. The researchers examined interstitial fibrosis and tubular atrophy (IF/TA) in biopsies performed at one year post-transplantation. The HLA-DSAs and all traditional indicators of IF/TA were recorded at the time of transplantation and again within the first year following transplantation, identifying 498 patients with severe IF/TA.
Following inclusion of 37 determinants, there was a significant association between severe IF/TA and HLA-DSAs (adjusted odds ratio, 1.53; 95% confidence interval, 1.16-2.01). The primary contributor was HLA-DSAs (11% of cases), followed by T-cell mediated rejection (9% of cases), calcineurin-inhibitor toxicity (8% of cases), acute tubular necrosis (6% of cases), pyelonephritis (5% of cases), and BK virus-associated nephropathy (4% of cases).
Compared with 344 patients with severe IF/TA without HLA-DSAs, 144 patients with HLA-DSA–associated severe IF/TA showed significantly increased microvascular inflammation, transplant glomerulopathy, C4d deposition in capillaries, and decreased allograft survival. Compared with 1161 patients without HLA-DSAs in the one-year post-transplantation biopsies, 378 patients with post-transplant HLA-DSAs exhibited significantly accelerated progression of IF/TA.
“Circulating HLA-DSAs are major determinants of premature and accelerated allograft fibrosis acting independently of traditional risk factors and antibody-mediated rejection,” the researchers said.
Significant Cause of Allograft Failure
Kidney International. http://dx.doi.org/10.1016/j.kint.2017.03.015
Patients who experience recurrent glomerulonephritis following kidney transplantation are at risk for negative graft outcomes. Penelope J. Allen, MD, and colleagues recently conducted a study utilizing 30-year data from the Australia and New Zealand Dialysis and Transplant Registry. Using Cox proportional hazard and competing risk modeling, the researchers determined the incidence, risk factors, and outcomes of recurrent glomerulonephritis in recipients of kidney transplants.
The study followed 6597 transplant recipients with biopsy-proven glomerulonephritis for a total of 51,871 person-years (mean, 7.7 years). The four most common types of glomerulonephritis were: (1) IgA nephropathy, n=2501); (2) focal segmental glomerulosclerosis (n=1403); (3) membranous (n=376); and (4) membranoproliferative (n=357). Among those patients, recurrence was reported in 479 of 4637 patients; of those, 212 experienced allograft failure due to the recurrence. There was an association between older age at time of transplantation and lower risk of recurrence (adjusted hazard ratio [per year increase], 0.96 (95% confidence interval, 0.95-0.97).
For patients with recurrent membranoproliferative glomerulonephritis, the 5-year graft survival was 30%; for those with focal segmental glomerulosclerosis, IgA, and membranous nephropathy, 5-year graft survival was 57% to 59%. Among recipients with recurrent disease, the risk of losing their allograft was twice that of those without recurrent disease (adjusted hazard ratio, 2.04).
In conclusion, the researchers said, “Recurrent glomerulonephritis remains a significant cause of graft loss in transplant recipients.”