Efficacy and Safety of Daprodustat for Treatment of Anemia of Chronic Kidney Disease in Incident Dialysis Patients: A Randomized Clinical Trial.

Importance: Daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated as an oral alternative to conventional erythropoiesis-stimulating agent (ESA) therapy. Few studies of anemia treatment in an incident dialysis (ID) population have been reported. Objective: To evaluate the efficacy and safety of daprodustat vs darbepoetin alfa in treating anemia of chronic kidney disease in ID patients. Design, Setting, and Participants: This prospective, randomized, open-label clinical trial was conducted from May 11, 2017, through September 24, 2020, in 90 centers across 14 countries. Patients with advanced CKD were eligible if they planned to start dialysis within 6 weeks from screening or had started and received hemodialysis (HD) or peritoneal dialysis (PD) within 90 days before randomization, had a screening hemoglobin (Hb) concentration of 8.0 to 10.5 g/dL (to convert to grams per liter, multiply by 10) and a randomization Hb of 8.0 to 11.0 g/dL, were ESA-naive or had received limited ESA treatment, and were iron-replete. Interventions: Randomized 1:1 to daprodustat or darbepoetin alfa. Main Outcomes and Measures: The primary analysis in the intent-to-treat population evaluated the mean change in Hb concentration from baseline to evaluation period (weeks 28-52) to assess noninferiority of daprodustat vs darbepoetin alfa (noninferiority margin, -0.75 g/dL). The mean monthly intravenous (IV) iron dose from baseline to week 52 was the principal secondary end point. Rates of treatment-emergent and serious adverse events (AEs) were also compared between treatment groups to assess safety and tolerability. Results: A total of 312 patients (median [IQR] age, 55 [45-65] years; 194 [62%] male) were randomized to either daprodustat (157 patients; median [IQR] age, 52.0 [45-63] years; 96 [61%] male) or darbepoetin alfa (155 patients; median [IQR] age, 56.0 [45-67] years; 98 [63%] male); 306 patients (98%) completed the trial. The mean (SD) Hb concentration during the evaluation period was 10.5 (1.0) g/dL for the daprodustat and 10.6 (0.9) g/dL for the darbepoetin alfa group, with an adjusted mean treatment difference of -0.10 g/dL (95% CI, -0.34 to 0.14 g/dL), indicating noninferiority. There was a reduction in mean monthly IV iron use from baseline to week 52 in both treatment groups; however, daprodustat was not superior compared with darbepoetin alfa in reducing monthly IV iron use (adjusted mean treatment difference, 19.4 mg [95% CI, -11.0 to 49.9 mg]). Adverse event rates were 76% for daprodustat vs 72% for darbepoetin alfa. Conclusions and Relevance: This randomized clinical trial found that daprodustat was noninferior to darbepoetin alfa in treating anemia of CKD and may represent a potential oral alternative to a conventional ESA in the ID population. Trial Registration: ClinicalTrials.gov Identifier: NCT03029208.

Advance care planning among African American patients on haemodialysis and their end-of-life care preferences.

BACKGROUND: African Americans in the general population have been shown to be less likely than White ethnic groups to participate in advance care planning; however, advance care planning in the population receiving dialysis has not been well explored. OBJECTIVE: We examined the prevalence of African American patients receiving haemodialysis' advance care planning discussions, and whether advance care planning impacts end-of-life care preferences. DESIGN: In-person interviewer-administered surveys of African American patients receiving in-centre haemodialysis. SETTING/PARTICIPANTS: About 101 participants at three large dialysis organisation units in Chicago. OUTCOMES: Self-reported advance care planning and preferences for life-extending treatments at end-of-life. RESULTS: Most patients (69%) report no advance care planning discussions with their healthcare providers. Nearly all patients (92%) without prior advance care planning reported their healthcare providers approached them about advance care planning. While the majority of patients indicated preference for aggressive life-extending care, prior conversations about end-of-life care wishes either with family members or a healthcare provider significantly decreased patients' likelihood of choosing aggressive life-extending care across three scenarios (all p < 0.05). Significantly more patients reported that common end-of-life scenarios related to increased dependence/disability were "not worth living through" compared with those associated with increased burden on family, decreased cognitive function, and severe pain/discomfort. CONCLUSION: African Americans with end-stage renal disease need more frequent, culturally-sensitive advance care planning discussions. Despite a preference for aggressive life-sustaining treatments, individuals with prior advance care planning discussions were significantly less likely to support aggressive end-of-life care. End-of-life care discussions that focus on the impact of life-extending care on patients' independence could be more concordant with the values and priorities of the African American patients.

A Clinical Prediction Score to Guide Referral of Elderly Dialysis Patients for Kidney Transplant Evaluation.

INTRODUCTION: Dialysis patients aged ≥70 years derive improved life expectancy through kidney transplantation compared to their waitlisted counterparts, but guidelines are not clear about how to identify appropriate transplantation candidates. We developed a clinical prediction score to identify elderly dialysis patients with expected 5-year survival appropriate for kidney transplantation (>5 years). METHODS: Incident dialysis patients in 2006-2009 aged ≥70 were identified from the United States Renal Data System database and divided into derivation and validation cohorts. Using the derivation cohort, candidate variables with a significant crude association with 5-year all-cause mortality were included in a multivariable logistic regression model to generate a scoring system. The scoring system was tested in the validation cohort and a cohort of elderly transplant recipients. RESULTS: Characteristics most predictive of 5-year mortality included age >80, body mass index (BMI) <18, the presence of congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), immobility, and being institutionalized. Factors associated with increased 5-year survival were non-white race, a primary cause of end stage renal disease (ESRD) other than diabetes, employment within 6 months of dialysis initiation, and dialysis start via arteriovenous fistula (AVF). 5-year mortality was 47% for the lowest risk score group (3.6% of the validation cohort) and >90% for the highest risk cohort (42% of the validation cohort). CONCLUSION: This clinical prediction score could be useful for physicians to identify potentially suitable candidates for kidney transplantation.

Medullary Microvascular Thrombosis and Injury in Sickle Hemoglobin C Disease.

Sickle cell nephropathy is a common complication in patients with sickle cell hemoglobinopathies. In these disorders, polymerization of mutated hemoglobin S results in deformation of red blood cells, which can cause endothelial cell injury in the kidney that may lead to thrombus formation when severe or manifest by multilayering of the basement membranes (glomerular and/or peritubular capillaries) in milder forms of injury. As the injury progresses, the subsequent ischemia, tubular dysfunction, and glomerular scarring can result in CKD or ESRD. Sickle cell nephropathy can occur in patients with homozygous hemoglobin SS or heterozygous hemoglobin S (hemoglobin SC, hemoglobin S/ß(0)-thalassemia, and hemoglobin S/ß(+)-thalassemia). Clinical manifestations resulting from hemoglobin S polymerization are often milder in patients with heterozygous hemoglobin S. These patients may not present with clinically apparent acute sickle cell crises, but these milder forms can provide a unique view of the kidney injury in sickle cell disease. Here, we report a patient with hemoglobin SC disease who showed peritubular capillary and vasa recta thrombi and capillary basement membrane alterations primarily involving the renal medulla. This patient highlights the vascular occlusion and endothelial cell injury in the medulla that contribute to sickle cell nephropathy.

The prevalence of vascular calcification in patients with end-stage renal disease on hemodialysis: a cross-sectional observational study.

BACKGROUND: This multicenter international cross-sectional observational study characterized vascular and valvular calcification burden and correlations with pulse pressure, diabetes, hypertension, and cardiovascular diseases in prevalent hemodialysis patients. METHODS: We enrolled 275 consecutive adults with end-stage renal disease on maintenance hemodialysis for ⩾3 months. Coprimary endpoints were prevalences of: (1) echocardiographic calcification in mitral valve, aortic valve or mitral annulus; (2) aortoiliac tree vascular calcifications by plain lateral lumbar X-ray. Correlations among calcification sites and with demographics and comorbidities were determined. Pulse pressures were determined. RESULTS: Subjects' mean ± standard deviation (SD) age was 56 ± 15.9 years; mean (SD) dialysis duration was 4.5 ± 4.3 years. Overall, 100% of echocardiographically imaged patients (n = 243) had calcification in aortic valve, mitral valve, or mitral annulus; 77.8% of X-rayed patients (n = 248) had abdominal aortic calcification. Radiographic abdominal aortic calcification score correlated significantly with calcification of aortic valve (p < 0.0001) and mitral annulus (p = 0.0001) but not mitral valve. Aortic valve, mitral valve, and mitral annulus calcification correlated significantly among themselves (p < 0.0001). Moderate/severe aortic valve calcification was significantly more prevalent in patients aged ⩾65 years than <65 years, men than women, and Whites than African Americans. Pulse pressure correlated significantly with vascular calcification score (p = 0.0049) but not with valvular calcification at any site. CONCLUSIONS: Vascular and valvular calcification are highly prevalent in the hemodialysis population. Peripheral vascular calcification correlates significantly with elevated pulse pressure and can be assessed easily using lateral lumbar X-ray. Further studies investigating the interaction between pulse pressure and development or progression of vascular calcification are of interest.

Patient and provider determinants of nephrology referral in older adults with severe chronic kidney disease: a survey of provider decision making.

BACKGROUND: Although chronic kidney disease (CKD) disproportionately affects older adults, they are less likely to be referred to a nephrologist. Factors that influence the referral decisions of primary care providers (PCPs) specifically for older CKD patients have been incompletely described. Patient factors such as dementia, functional disability, and co-morbidity may complicate the decision to refer an older adult. This study evaluated the role of patient and PCP factors in the referral decisions for older adults with stage 4 CKD. METHODS: We administered a two-part survey to study the decisions of practicing PCPs. First, using a blocked factorial design, vignettes systematically varied 6 patient characteristics: age, race, gender, co-morbidity, functional status, and cognitive status. CKD severity, patient preferences, and degree of anemia were held constant. Second, covariates from a standard questionnaire included PCP estimates of life expectancy, demographics, reaction to clinical uncertainty, and risk aversion. The main outcome was the decision to refer to the nephrologist. Random effects logistic regression models tested independent associations of predictor variables with the referral decision. RESULTS: More than half (62.5%) of all PCP decisions (n = 680) were to refer to a nephrologist. Vignette-based factors that independently decreased referral included older patient age (OR = 0.27; 95% CI, 0.15 to 0.48) and having moderate dementia (OR = 0.14; 95%CI, 0.07 to 0.25). There were no associations between co-morbidity or impaired functional activity with the referral decision. Survey-based PCP factors that significantly increased the referral likelihood include female gender (OR = 7.75; 95%CI, 2.07 to 28.93), non-white race (OR = 30.29; 95%CI, 1.30 to 703.73), those who expect nephrologists to discuss goals of care (OR = 53.13; 95%CI, 2.42 to 1168.00), those with higher levels of anxiety about uncertainty (OR = 1.28; 95%CI, 1.04 to 1.57), and those with greater risk aversion (OR = 3.39; 95%CI, 1.02 to 11.24). CONCLUSIONS: In this decision making study using hypothetical clinical vignettes, we found that the PCP decision to refer older patients with severe CKD to a nephrologist reflects a complex interplay between patient and provider factors. Age, dementia, and several provider characteristics weighed more heavily than co-morbidity and functional status in PCP referral decisions. These results suggest that practice guidelines should develop a more nuanced approach to the referral of older adults with CKD.

Acute hepatitis B infection in a long-term hemodialysis patient despite persistent natural immunity.

Hepatitis B infections are a distinct clinical problem in hemodialysis patients. Naturally acquired antibodies from a prior hepatitis B virus infection generally are considered to be immunoprotective for subsequent infections. We describe a new-onset hepatitis B virus infection in a hemodialysis patient despite persistent protective levels of naturally acquired antibodies to hepatitis B surface antigen. This case emphasizes that the immune response to hepatitis B virus is complex and still poorly understood. Current recommended screening guidelines may be incomplete in addressing acute hepatitis B virus infections in hemodialysis patients. Aggressive vaccination strategies should be considered to maintain immunity in patients at high risk of seroconversion. Stricter surveillance and use of modern virus detection assays may be required to detect subtle infections and minimize the risk of transmission of hepatitis B virus in hemodialysis units.

Older adults and chronic kidney disease decision making by primary care physicians: a scholarly review and research agenda.

BACKGROUND: Chronic kidney disease (CKD) is a growing public health concern that overwhelmingly affects older adults. National guidelines have called for earlier referral of CKD patients, but it is unclear how these should apply to older adults. OBJECTIVE: This scholarly review aims to explore the current literature about upstream referral decisions for CKD within the context of decisions about initiation of dialysis and general referral decisions. The authors propose a model for understanding the referral process and discuss future directions for research to guide decision making for older patients with CKD. RESULTS: While age has been shown to be influential in decisions to refer patients for dialysis and other medical therapies, the role of other patient factors such as competing medical co-morbidities, functional loss, or cognitive impairment in the decision making of physicians has been less well elucidated, particularly for CKD. CONCLUSIONS: More information is needed on the decision-making behavior of physicians for upstream referral decisions like those being advocated for CKD. Exploring the role of geriatric factors like cognitive and functional status may help facilitate more appropriate use of resources and improve patient outcomes.

Long-term outcomes of cinacalcet and paricalcitol titration protocol for treatment of secondary hyperparathyroidism.

Long-term outcomes of combined cinacalcet and paricalcitol therapy for secondary hyperparathyroidism (SHPT) in patients failing traditional therapies with phosphate binders and active vitamin D compound analogs are not well described. We implemented a titration protocol for cinacalcet and paricalcitol and assessed its long-term effects on bone metabolism and disease in hemodialysis (HD) patients. Thirty-five patients were started on 30 mg of cinacalcet daily. After 12 months, median cinacalcet dose was 60 mg. There was a 33% increase in number of patients receiving paricalcitol. Average corrected serum calcium (Ca) decreased from 9.5 to 8.8 mg/dl (p = 0.003, 95% CI 0.34-1.04); phosphorus (P) from 6.2 to 5.5 mg/dl (p = 0.047, 95% CI 0.01-1.34); Ca x P product from 58 to 48 (p = 0.001, 95% CI 4.2-15.7); and intact PTH (iPTH) from 426 +/- 274 to 300 +/- 228 pg/ml (p = 0.03, 95% CI 19.3-401.7). Number of patients achieving three or more K/DOQI criteria increased by 29% (p = 0.009).

African American ESRD patients have a high pre-dialysis prevalence of kidney stones compared to NHANES III.

If nephrolithiasis (NL) promotes progression to end stage renal disease (ESRD), requiring renal replacement therapy, one might expect a higher prevalence of pre-ESRD stones among ESRD versus non-ESRD subjects. We compared the prevalence of pre-ESRD stones in an African-American (AA) hemodialysis (HD) population to the estimated stone prevalence in a nationally representative cohort of AA persons as obtained by the Third National Health and Nutrition Survey (NHANES III). Face-to-face questionnaires were administered to a sample of 300 AA HD patients undergoing dialysis therapy at the University of Chicago to determine pre-ESRD NL prevalence. All data on pre-ESRD stone prevalence was confirmed by documented medical history, radiology and laboratory findings, where available. Prevalence of pre-ESRD NL in AA HD patients was 8.3% versus 2.8% in the age, race and sex adjusted NHANES III population (P < 0.001). After adjustment for age and sex, it was estimated that the prevalence of pre-ESRD kidney stones among AA HD patients is significantly higher than the prevalence of kidney stones found in the general AA population.

Cinacalcet-induced hungry bone syndrome.

Cinacalcet is a type II calcimimetic approved for treatment of secondary hyperparathyroidism in patients with end-stage renal disease. It is generally well tolerated with the most common side effects being nausea and vomiting. Symptomatic hypocalcemia is rare, and persistent hypocalcemia has not been reported to date. We present a case of a 66-year-old woman on chronic outpatient hemodialysis who was initiated on cinacalcet when her intact parathyroid hormone was 1091 pg/mL (normal 15-75 pg/dL). Two weeks later she developed diffuse muscle twitching. The patient required a 72-hour hospitalization and treatment with a continuous intravenous calcium infusion for symptomatic hypocalcemia. The intact parathyroid hormone level at this time was 176 pg/mL. This case is the first report of cinacalcet-induced prolonged and symptomatic hypocalcemia, closely resembling the hungry bone syndrome described in some patients with secondary hyperparathyroidism following surgical parathyroidectomy.

Evidence against a contribution of conventional urine risk factors to de novo ESRD renal stones.

BACKGROUND: The authors measured urine and blood stone risk factors in African-American (AA) haemodialysis (HD) patients with new onset of stones during dialysis. METHODS: Patients with nephrolithiasis (NL) newly manifested during dialysis were matched by age, sex and urine output and dialysis duration to AA HD patients without history or symptoms of stones. Two 24 h urine and serum samples were collected and analysed for conventional stone risk factors. RESULTS: Three percent of the patients formed new stones while on HD; none had formed stones prior to end-stage renal disease. Newly onset NL patients had higher urine citrate and lower serum potassium levels than HD patients without stones. CONCLUSION: Usual stone risk factors did not correlate with new stones during dialysis.