Risk Analysis of Denosumab-Induced Hypocalcemia in Bone Metastasis Treatment: Renal Dysfunction Is Not a Risk Factor for Its Incidence in a Strict Denosumab Administration Management System with Calcium/Vitamin D Supplementation.

We have reported that a strict denosumab administration management system with oral calcium/vitamin D supplementation attenuates denosumab-induced hypocalcemia in 158 cancer patients with bone metastasis. In this report, 27.8% of the patients experienced hypocalcemia, including 0.6% with grade 2. So far, the risk factors for ≥grade 2 hypocalcemia incidence have been identified in denosumab-treated cancer patients, including patients without calcium/vitamin D supplementation. Therefore, the present study aimed to reveal the factors that affect all-grade hypocalcemia incidence with calcium/vitamin D supplementation and team medical care according to the management system. A receiver operating characteristic curve analysis suggested that the cutoff of baseline serum calcium level for all-grade hypocalcemia incidence was 9.3 mg/dL. Multivariate analysis revealed that age ≥65 years (odds ratio, 95% confidence interval: 2.57, 1.11-5.95, p = 0.03), grade 1 or higher serum alkaline phosphatase elevation (3.70, 1.71-8.00, p < 0.01), an adjusted serum calcium level of less than 9.3 mg/dL (3.21. 1.25-8.24, p = 0.02) at baseline, and co-administration of cytotoxic agents (2.33, 1.06-7.11, p = 0.03) are risk factors for the incidence of all-grade hypocalcemia. However, renal dysfunction, which has been suggested to be a risk factor in previous reports, was not a factor. In conclusion, we revealed the risk factors for all-grade hypocalcemia in calcium/vitamin D supplementation and awareness, as demonstrated by the management system. Moreover, renal dysfunction was not a risk factor in our strict denosumab administration management system. Our results support the value of early detection of hypocalcemia incidence to guide the selection of an appropriate management strategy.

Association between Longer Travel Distance for Transplant Care and Access to Kidney Transplantation and Graft Survival in the United States.

BACKGROUND: Transplant candidates may gain an advantage by traveling to receive care at a transplant center that may have more favorable characteristics than their local center. Factors associated with longer travel distance for transplant care and whether the excess travel distance (ETD) is associated with access to transplantation or with graft failure are unknown. METHODS: This study of adults in the United States wait-listed for kidney transplantation in 1995-2015 used ETD, defined as distance a patient traveled beyond the nearest transplant center for initial waiting list registration. We used linear regression to examine patient and center characteristics associated with ETD and Fine-Gray models to examine the association between ETD (modeled as a spline) and time to deceased or living donor transplantation or graft failure. RESULTS: Of 373,365 patients, 11% had an ETD≥50 miles. Traveling excess distance was more likely among patients who were of non-Black race or those whose nearest transplant center had lower annual living donor transplant volume. At an ETD of 50 miles, we observed a lower likelihood of deceased donor transplantation (subhazard ratio [SHR], 0.85; 95% confidence interval [95% CI], 0.84 to 0.87) but higher likelihood of living donor transplantation (SHR, 1.14; 95% CI, 1.12 to 1.16) compared with those who received care at their nearest center. ETD was weakly associated with higher risk of graft failure. CONCLUSIONS: Patients who travel excess distances for transplant care have better access to living donor but not deceased donor transplantation and slightly higher risk of graft failure. Traveling excess distances is not clearly associated with better outcomes, especially if living donors are unavailable.

One-stop assessment of renal function and renal artery in hypertensive patients with suspected renal dysfunction: non-enhanced MRI using spatial labeling with multiple inversion pulses.

OBJECTIVES: To assess whether spatial labeling with multiple inversion pulses (SLEEK) sequence can be employed as a one-stop assessment method for evaluating renal function and displaying renal artery in hypertensive patients with suspected renal dysfunction. METHODS: A total of 78 patients with suspected hypertensive renal damage were enrolled in this retrospective study. All patients underwent MRI examinations, and both SLEEK and DWI sequences were performed simultaneously. According to estimated glomerular filtration rate (eGFR), patients were divided into three groups (Group 1, eGFR> 90; Group 2, eGFR = 60-90; Group 3, eGFR< 60). Twenty-two of these patients also underwent CT angiography (CTA) examination. Comparison between CTA, DWI, and eGFR was performed to assess the value of SLEEK in evaluating renal function and displaying renal artery. RESULTS: The performance of SLEEK to display renal artery was highly consistent with the results of CTA (kappa = 0.713). The corticomedullary contrast ratio positively correlated with eGFR (p = 0.004, r = 0.322) and was significantly higher in SLEEK images than in DWI images in all three groups (p < 0.001). There was no significant difference in corticomedullary contrast ratio in SLEEK images between Group 1 and Group 2 (p = 0.285). However, the minimal renal cortical thickness, which significantly correlated with eGFR (p < 0.001, r = 0.866), was significantly different between Group 1 and Group 2 (p < 0.001). ROC analysis showed good diagnostic performance when differentiating patients with eGFR> 60 from those with eGFR< 60. CONCLUSIONS: The SLEEK sequence could evaluate simultaneously renal function through corticomedullary differentiation and renal arteries, enabling one-stop assessment in hypertensive patients with suspected renal dysfunction. KEY POINTS: • Spatial labeling with multiple inversion pulses (SLEEK) improves renal corticomedullary differentiation in hypertensive patients with renal dysfunction compared with DWI. • SLEEK clearly displays renal artery in hypertensive patients with renal dysfunction. • SLEEK could be utilized as a one-stop assessment method for evaluating renal function and renal artery in hypertensive patients.

Opportunities for Subspecialization in Nephrology.

The interface between nephrology and other fields of medicine continues to expand. With the advent of novel therapies in cancer, diagnostics and therapeutics in lithology, novel devices in cardiology, advances in women's health issues, novel diagnostics and therapies in glomerular diseases, and the national priority in home-based dialysis, several subspecialties in nephrology have emerged. This article will discuss the subspecialties of onconephrology, cardionephrology, obstetric nephrology, uronephrology, glomerular disease specialization, and home-based dialysis in nephrology. We discuss the current state of each subspecialty, recommended educational content, length of training, available training opportunities, and potential career pathways for each.

Cardiovascular disease risk assessment in patients with familial Mediterranean fever related renal amyloidosis.

Chronic inflammation and proteinuria is a risk factor for cardiovascular disease (CVD) in patients with chronic kidney diseases and rheumatologic disorders. Our aim was to investigate the CVD events (CVDEs) and survival between the patients with FMF-related AA amyloidosis and glomerulonephropathies (GN) to define possible predictors for CVDEs. A prospective follow-up study with FMF-amyloidosis and glomerulonephropathy (GN) was performed and patients were followed for CVDEs. Flow-mediated dilatation (FMD), FGF-23, serum lipid, hsCRP levels, BMI and HOMA were assessed. A Cox regression analysis was performed to evaluate the risk factors for CVDEs. There were 107 patients in the FMF-amyloidosis group and 126 patients with GN group. Forty-seven CVDEs were observed during the 4.2-years follow up; all 28 patients in the FMF-amyloidosis group and 14/19 patients with GN developed CVDEs before the age of 40 (p = 0.002). CVD mortality was 2.8 times higher (95% CI 1.02-7.76) in patients with FMF-amyloidosis. Across both groups, FMD and FGF23 (p < 0.001) levels were independently associated with the risk of CVDEs. Patients with FMF-amyloidosis are at increased risk of early CVDEs with premature mortality age. FGF 23, FMD and hsCRP can stratify the risk of early CVD in patients with FMF-related AA amyloidosis.

The effect of community hypertension management on blood pressure control and its determinants in southwest China.

BACKGROUND: Hypertension is a leading cause of cardiovascular disease (CVD). The purpose of this study was to examine the effectiveness of community healthcare in controlling blood pressure (BP) and mitigating related risk factors after 5 y of follow-up. METHODS: Hierarchical clustering sampling was employed to choose a representative sample of 10 rural and 10 urban community populations (N=4235). The 5y prospective cohort study was completed by the medical group in the community clinical centre. RESULTS: The study included 4235 patients, median age 69 y (range 61-76), with hypertension in 2009; 2533 (59.81%) were female. The rate of BP control increased from 28.33% in 2009 to 64.05% in 2014. The BP control rate was higher in patients with CVD and kidney disease and lower in those with obesity than in those without. Comparing 2009 and 2014 values, the intervention resulted in median systolic BP and diastolic BP reductions of 7.0 mmHg and 6.5 mmHg, respectively. Age, medication treatment, antihypertensive agents, BP at baseline and follow-up, complications of diabetes, CVD, obesity and kidney disease, the aspartate aminotransferase:aminotransferase ratio and smoking were identified as risk factors for BP control. CONCLUSIONS: Community management of hypertension by general practitioners achieved significant BP control over 5 y of intervention.

Incorporating patient-reported outcomes (PROs) into dialysis policy: Current initiatives, challenges, and opportunities.

Governments at national and state levels regulate dialysis care in the United States to ensure safe practices, and continually elevate the quality of care. An objective of these regulatory policies is the independent evaluation of dialysis unit outcomes by patients, caregivers, and the community to facilitate choices as well as to advance equal access to high quality dialysis care. These polices recognized decades ago that it was fundamental to include the patient perspective in the assessment and evaluation of dialysis care quality by requiring both individual and aggregate patient reported outcomes (PROs). Although there is support for integrating the patient perspective, concerns persist about the implementation of these polices including selection of PRO measures, administration timing and reach, as well as interpretation of results including benchmarking to permit comparisons across organizations. The experience from the early adoption of PROs into dialysis policies in conjunction with advances in electronic health records, personal data capture and monitoring, and analytics is poised to address these concerns. The dialysis community has the opportunity to lead the way in innovation related to PRO implementation not only in kidney disease care, but also for other healthcare conditions or contexts such as oncology, surgical, and acute care.

Assessment of renal fibrosis in a rat model of unilateral ureteral obstruction with diffusion kurtosis imaging: Comparison with α-SMA expression and 18F-FDG PET.

PURPOSE: To investigate the utility of diffusion kurtosis imaging (DKI) MRI for evaluation of renal fibrosis in rats with unilateral ureteral obstruction (UUO). METHODS: Twenty-five rats had UUO, and ten rats were subjected to sham operation as control. DKI was performed on a 3.0 T MRI scanner on days 1, 3, 5, and 7 after ligation. All rats then underwent 18F-FDG dynamic PET to evaluate unilateral renal function, followed by histological analysis to examine α-smooth muscle actin (α-SMA) expression. DKI metrics were assessed among the time points and between two sides, and compared with maximum standardized uptake value (SUVmax), serum levels of creatinine and urea, and fibrosis marker α-SMA. RESULTS: Mean kurtosis (MK) on day 7, axial kurtosis (Ka) on days 3 and 7, mean diffusivity (MD) on days 1, 3, 5, and 7, and fractional anisotropy (FA) on days 3, 5, and 7 of cortex and medulla between the UUO and contralateral sides were significantly different (all p < 0.05). Over the course of UUO progression, there were significant changes in Ka, MD and FA of medulla (all p < 0.05). FA of medulla was positively correlated with SUVmax (r = 0.641, p < 0.001), and MD of cortex was negatively correlated with urea (r = -0.534, p = 0.001). MD of cortex was negatively correlated with α-SMA on UUO sides (r = -0.710, p < 0.001). CONCLUSIONS: DKI shows the potential for noninvasive assessment of renal fibrosis and unilateral renal function induced by UUO.

Burden, access and disparities in kidney disease.

Kidney disease is a global public health problem, affecting over 750 million persons worldwide. The burden of kidney disease varies substantially across the world. In many settings, rates of kidney disease and the provision of its care are defined by socio-economic, cultural and political factors leading to significant disparities. World Kidney Day 2019 offers an opportunity to raise awareness of kidney disease and highlight disparities in its burden and current state of global capacity for prevention and management. Here we highlight the need for strengthening basic infrastructure for kidney care services for early detection and management of acute kidney injury and chronic kidney disease across all countries and advocate for more pragmatic approaches to providing renal replacement therapies. Achieving universal health coverage worldwide by 2030 is a World Health Organization Sustainable Development Goal. While universal health coverage may not include all elements of kidney care in all countries, understanding what is locally feasible and important with a focus on reducing the burden and consequences of kidney disease would be an important step towards achieving kidney health equity.

Cause of kidney disease and cardiovascular events in a national cohort of US patients with end-stage renal disease on dialysis: a retrospective analysis.

AIMS: End-stage renal disease (ESRD) is a strong cardiovascular risk factor. We aimed to determine the extent to which cause of kidney disease independently contributes to this risk. METHODS AND RESULTS: Using a national US ESRD registry, we selected patients with eight different causes of ESRD who initiated dialysis 1997-2014. We used proportional sub-distribution hazard models, with non-cardiovascular death or kidney transplantation as competing risks, to estimate hazard ratios (HRs) for a first composite cardiovascular event (myocardial infarction, ischaemic stroke, or cardiovascular or cerebrovascular death), by cause of ESRD. The population was restricted to those using Medicare insurance at Day 91 after dialysis initiation (when most patients become Medicare eligible). Outcomes were ascertained from Medicare claims or Death Notifications. Among the 658 168 patients identified, composite event rates ranged from 3.5/100 person-years in IgA nephropathy to 14.6/100 person-years in diabetic nephropathy (DN). After adjusting for demographics, socioeconomic factors, comorbidities, dialysis modality, and laboratory values, cardiovascular event HRs differed significantly by cause of ESRD. Comparing to IgA nephropathy, the adjusted HR was highest for DN [aHR = 2.97, 95% confidence interval (CI) 2.77-3.20], next highest for lupus nephritis (aHR = 1.86, 95% CI 1.71-2.03), and thereafter ranged from 1.29 (95% CI 1.19-1.39) in autosomal dominant polycystic kidney disease to 1.67 (95% CI 1.52-1.83) in membranous nephropathy. CONCLUSION: High cardiovascular event rates in dialysis patients vary considerably by cause of ESRD. Determining underlying reasons for these differences might provide new insights in to cardiovascular disease mechanisms as well as inform future drug development and clinical trial design.

Subjective Global Assessment-Dialysis Malnutrition Score and arteriovenous fistula outcome: A comparison with Charlson Comorbidity Index.

INTRODUCTION:: Malnutrition is a well-recognized risk factor for all-cause mortality in hemodialysis patients. However, its role for arteriovenous fistulas outcome has not been exhaustively investigated. Our aim was to point out the impact of Subjective Global Assessment-Dialysis Malnutrition Score as independent predictor of arteriovenous fistulas thrombosis (vascular access thrombosis) and/or significant stenosis (vascular access stenosis). In addition, we compared it with the widespread Charlson Comorbidity Index. METHODS:: We assessed 57 hemodialysis patients for a 2-year interval and evaluated the incidence of vascular access thrombosis and/or stenosis. Linear regression analysis was used to test the relation of variables with Subjective Global Assessment-Dialysis Malnutrition Score at baseline. Logistic and Cox regression analysis evaluated markers as predictors of both vascular access thrombosis and stenosis. Receiver operating characteristic curve analysis was used to compare area under the curve values of Subjective Global Assessment-Dialysis Malnutrition Score, Charlson Comorbidity Index, and modified Charlson Comorbidity Index. RESULTS:: Age and Charlson Comorbidity Index were positively related to Subjective Global Assessment-Dialysis Malnutrition Score: B = 0.06 (95% CI = 0.01; 0.11) and B = 0.31 (95% CI = 0.01; 0.63). Higher albumin and normalized protein catabolic rate levels had a protective role against vascular access failure: OR = 0.67 (95% CI = 0.56; 0.81) and OR = 0.46 (95% CI = 0.32; 0.67), respectively. Higher Subjective Global Assessment-Dialysis Malnutrition Score and Charlson Comorbidity Index values were significant risk factors: HR = 1.42 (95% CI = 1.04; 1.92) and HR = 1.48 (95% CI = 1.01; 2.17), respectively. Area under the curve of Subjective Global Assessment-Dialysis Malnutrition Score was significantly higher than those of both Charlson Comorbidity Index and modified Charlson Comorbidity Index: 0.70 (95% CI = 0.50; 0.88) versus 0.61 (95% CI = 0.41; 0.80) and 0.55 (95CI% = 0.41; 0.70). CONCLUSION:: Subjective Global Assessment-Dialysis Malnutrition Score, as well as Charlson Comorbidity Index, are useful tools to predict vascular access failure and should be carefully and periodically evaluated in order to check significant variations that may compromise vascular access survival.

Relationships of high cardiac output with ventricular morphology, myocardial energetics, and energy costs in hemodialysis patients with preserved ejection fraction.

Hemodialysis patients have conditions that increase cardiac output (CO), including arteriovenous fistula, fluid retention, vasodilator use, and anemia. We sought to determine the relationships between these factors and CO and to evaluate the effects of the high-output states on ventricular morphology, function, and myocardial energetics in hemodialysis patients, using noninvasive load-insensitive indices. Cardiovascular function was assessed in hemodialysis patients with high output [ejection fraction ≥ 50%, cardiac index (CI) > 3.5 L/min/m2, n = 30], those with normal output (CI < 3.0 L/min/m2, n = 161), and control subjects without hemodialysis (n = 155). As compared to control subjects and hemodialysis patients with normal CI, patients with elevated CI were anemic and displayed decreased systemic vascular resistance index (SVRI), excessive left ventricular (LV) contractility, larger LV volume, and tachycardia. Lower hemoglobin levels were correlated with decreased SVRI, excessive LV contractility, and higher heart rate, while estimated plasma volume and interdialytic weight gain were associated with larger LV volume, thus increasing CO. High output patients displayed markedly increased pressure-volume area (PVA) and PVA/stroke volume ratio, which were correlated directly with CO. The use of combination vasodilator therapy (angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker and calcium channel blocker) was not associated with high-output states. In conclusion, anemia and fluid retention are correlated with increased CO in hemodialysis patients. The high-output state is also associated with excessive myocardial work and energy cost.

Intravoxel incoherent motion MRI-derived parameters and T2* relaxation time for noninvasive assessment of renal fibrosis: An experimental study in a rabbit model of unilateral ureter obstruction.

PURPOSE: To evaluate the association of apparent diffusion coefficient (ADC), intravoxel incoherent motion (IVIM) MRI-derived parameters, and T2* relaxation time with histopathological changes observed during renal fibrogenesis in a rabbit model of unilateral ureter obstruction (UUO). METHODS: Twenty New Zealand White rabbits underwent baseline MRI followed by surgery (sham or UUO) and then follow-up MRI at postoperative day (POD) 0, 3, 7, and 14. Hematoxylin and eosin and Masson's trichrome staining was performed to evaluate cell density and area of fibrosis. Spearman rank correlation and Pearson correlation tests and one-way analysis of variance were used for statistical analyses. RESULTS: There was a continuous increase in the area of fibrosis and cell density: rho = 0.900 (95% confidence interval [CI] = 0.760, 0.960; p < 0.0001) and 0.904 (95% CI = 0.769, 0.962; p < 0.0001), respectively. There was a tendency for all MRI variables to decrease at POD 3 and partly recover at POD 7. ADC, D, f, and T2* relaxation time showed significant correlation with area of fibrosis and cell density (r = -0.5177 and -0.6962, -0.5395 and -0.7851, -0.7168 and -0.7902, and -0.6808 and -0.7212, respectively; p = 0.0052-0.0481) while D* did not (p = 0.1997 and 0.7853, respectively). CONCLUSIONS: ADC, IVIM MRI-derived parameters, and T2* relaxation time were significantly associated with the area of fibrosis and cell density during renal fibrogenesis in a rabbit model of UUO. After validation in future studies, MRI may have potential for noninvasive assessment modality of renal fibrosis.

Is laboratory screening prior to antiretroviral treatment useful in Johannesburg, South Africa? Baseline findings of a clinical trial.

BACKGROUND: Screening for renal, hepatic and haematological disorders complicates the initiation of current first-line antiretroviral therapy (ART). Each additional test done adds substantial costs, both through direct laboratory expenses, but also by increasing the burden on health workers and patients. Evaluating the prevalence of clinically relevant abnormalities in different population groups could guide decisions about what tests to recommend in national guidelines, or in local adaptations of these. METHODS: As part of enrolment procedures in a clinical trial, 771 HIV-positive adults, predominantly from inner-city primary health care clinics, underwent laboratory screening prior to ART. Participants had to be eligible for ART, based on the then CD4 eligibility threshold of 350 cells/µL, antiretroviral naïve and have no symptoms of peripheral neuropathy. RESULTS: Participants were mostly female (57%) and a mean 34 years old. Creatinine clearance rates were almost all above 50 mL/min (99%), although 5% had microalbuminuria. Hepatitis B antigenaemia was common (8% of participants), of whom 40% had a raised AST/ALT, though only 2 had transaminase levels above 200 IU/L. Only 2% of participants had severe anaemia (haemoglobin <8 g/dl) and 1% neutropaenia (neutrophils <0.75 × 10^9/L). Costs per case detected of hepatitis B infection was USD135, but more than USD800 for a raised creatinine. CONCLUSIONS: Hepatitis B continues to be a common co-infection in HIV-infected adults, and adds complexity to management of ART switches involving tenofovir. Routine renal and haematological screening prior to ART detected few abnormalities. The use of these screening tests should be assessed among patients with higher CD4 counts, who may even have fewer abnormalities. Formal evaluation of cost-effectiveness of laboratory screening prior to ART is warranted.

Impact of Renal Disease on Patients with Hepatitis C: A Retrospective Analysis of Disease Burden, Clinical Outcomes, and Health Care Utilization and Cost.

BACKGROUND/AIMS: Few studies explore the magnitude of the disease burden and health care utilization imposed by renal disease among patients with hepatitis C virus (HCV). We aimed to describe the characteristics, outcomes, and health care utilization and costs of patients with HCV with and without renal impairment. METHODS: This retrospective analysis used 2 administrative claims databases: the US commercially insured population in Truven Health MarketScan® data (aged 20-64 years), and the US Medicare fee-for-service population in the Medicare 20% sample (aged ≥65 years). Baseline characteristics and comorbid conditions were identified from claims during 2011; patients were followed for up to 1 year (beginning January 1, 2012) to identify health outcomes of interest and health care utilization and costs. RESULTS: In the MarketScan and Medicare databases, 35,965 and 10,608 patients with HCV were identified, 8.5 and 26.5% with evidence of renal disease (chronic kidney disease [CKD] or end-stage renal disease [ESRD]). Most comorbid conditions and unadjusted outcome rates increased across groups from patients with no evidence of renal disease to non-ESRD CKD to ESRD. Health care utilization followed a similar pattern, as did the costs. CONCLUSIONS: Our findings suggest that HCV patients with concurrent renal disease have significantly more comorbidity, a higher likelihood of negative health outcomes, and higher health care utilization and costs.

History of Erythropoiesis-Stimulating Agents, the Development of Biosimilars, and the Future of Anemia Treatment in Nephrology.

BACKGROUND: Exogenous replacement of erythropoietin (EPO) by recombinant human EPO has been considered a standard of care for the treatment of anemia in patients with chronic kidney disease for more than 20 years. Genetically engineered biologic proteins derived from human, animal, or microorganism sources are a major area of growth in modern medical care, accounting for one-third of new drug approvals in the past decade. Despite benefit to patients, the use of biologics comes at a significant cost, representing one of the fastest growing segments of strained healthcare budgets around the world. SUMMARY: Biosimilars, or biologic drugs that are designed to be highly similar to approved reference biologic drugs, have been available in Europe for more than 10 years with no unusual or unexpected effects compared to their reference biologics whose patents have expired. Given the success of the biosimilar approval pathway pioneered in Europe, it has served as a global reference for other regulatory authorities to establish and implement biosimilar licensure frameworks, including the United States (US), the largest pharmaceutical market in the world. Given 10 of the top 25 drugs sold in 2014 were biologics, and considering the rising costs of healthcare, biosimilars have the potential to become a significant part of the US market. Key Messages: For the nephrology community, the recent patent expiries for epoetin alfa (Epogen®, Amgen and Procrit®, Johnson & Johnson) have created the opportunity to develop biosimilar EPOs. And while no biosimilar in this therapeutic class is approved in the US, there are proposed biosimilars in development.