Drug-induced Thrombotic Microangiopathy with Concurrent Proteasome Inhibitor Use in the Treatment of Multiple Myeloma: A Case Series and Review of the Literature.

Thrombotic microangiopathy (TMA) is a life-threatening clinical syndrome characterized by hemolytic anemia, thrombocytopenia, and microvascular thrombosis, resulting in ischemia and organ damage. Multiple myeloma (MM) is a neoplasm arising from clonal plasma cells within the bone marrow. The treatment frequently includes multi-agent immunochemotherapy, often with the use of proteasome inhibitors (PIs) such as bortezomib, carfilzomib, or ixazomib. There are increasing reports of TMA in association with PI exposure. This review summarizes the epidemiology, pathogenesis, and diagnosis of PI-related drug-induced TMA. We will outline the definition and diagnosis of TMA and explore an important cause of hemolysis in patients with MM: drug-induced TMA after PI exposure, an increasingly recognized therapeutic complication. This will be emphasized through the description of 3 novel cases of TMA. These illustrative cases occurred after treatment with high-dose weekly carfilzomib, cyclophosphamide, and dexamethasone as part of the MCRN003/MYX1 phase II clinical trial (NCT02597062) in relapsed MM.

Insulin resistance is associated with Fibroblast Growth Factor-23 in stage 3-5 chronic kidney disease patients.

AIM: To determine the associations between insulin resistance, fibroblast growth factor 23 (FGF-23), and coronary artery calcification (CAC) in chronic kidney disease (CKD) patients. INTRODUCTION: FGF-23 is associated with atherosclerosis and cardiovascular disease, but its association with insulin resistance in CKD has not been explored. SUBJECTS: Cross sectional study of 72 stage 3-5 CKD patients receiving care in Ontario, Canada. MATERIALS AND METHODS: Insulin resistance was measured by the homeostasis model assessment of insulin resistance (HOMA-IR), FGF-23 was measured by carboxyl terminal enzyme linked immunoassay (ctFGF-23) and CAC was measured by multi-slice computed tomography. RESULTS: Median HOMA-IR was 2.19µU/ml (interquartile range 1.19 to 3.94). Patients with HOMA-IR>2.2 had greater ctFGF-23 (179.7 vs 109.6; P=0.03), and 40% higher log CAC scores (2.09±0.87 vs 1.58±1.26; P=0.049). Multivariable linear regression adjusted for 1,25 dihydroxyvitamin D, kidney function, and parathyroid hormone revealed insulin resistance was a risk factor for greater log ctFGF-23 levels (log HOMA IR ß=0.37; 95% confidence interval 0.14 to 0.59; P=0.002). CONCLUSIONS: Insulin resistant CKD patients demonstrated higher FGF-23 levels, and increased CAC, while PO4 levels remained normal, suggesting a potential link between insulin resistance and PO4 homeostasis in CKD.

Associations of epicardial fat with coronary calcification, insulin resistance, inflammation, and fibroblast growth factor-23 in stage 3-5 chronic kidney disease.

BACKGROUND: Epicardial fat, quantified in a single multi-slice computed tomography (MSCT) slice, is a reliable estimate of total epicardial fat volume (EFV). We sought to determine risk factors for EFV detected in a single-slice MSCT measurement (ssEFV) in pre-dialysis chronic kidney disease (CKD) patients. Our primary objective was to determine the association between ssEFV and coronary artery calcification (CAC). METHODS: 94 pre-dialysis stage 3-5 CKD patients underwent MSCT to measure ssEFV and CAC. ssEFV was quantified at the level of the left main coronary artery. Measures of inflammation, traditional and kidney-related cardiovascular disease risk factors were collected. RESULTS: Mean age: 63.7 ± 14 years, 56% male, 39% had diabetes, and mean eGFR: 25.1 ± 11.9 mL/min/1.73 m2. Mean ssEFV was 5.03 ± 2.4 cm3. By univariate analysis, body mass index (BMI) (r = 0.53; P = <0.0001), abdominal obesity (r = 0.51; P < 0.0001), high density lipoprotein (HDL) cholesterol (r = - 0.39; P = <0.0001), insulin resistance (log homeostasis model assessment of insulin resistance (log HOMA-IR)) (r = 0.38, P = 0.001), log interleukin-6 (IL-6) (r = 0.34; P = 0.001), and log urinary albumin to creatinine ratio (UACR) (r = 0.30, P = 0.004) demonstrated the strongest associations with ssEFV. Log coronary artery calcification (log CAC score) (r = 0.28, P = 0.006), and log fibroblast growth factor-23 (log FGF-23) (r = 0.23, P = 0.03) were also correlated with ssEFV. By linear regression, log CAC score (beta =0.40; 95% confidence interval (CI), 0.01-0.80; P = 0.045), increasing levels of IL-6 (beta = 0.99; 95% CI, 0.38 - 1.61; P = 0.002), abdominal obesity (beta = 1.86; 95% CI, 0.94 - 2.8; P < 0.0001), lower HDL cholesterol (beta = -2.30; 95% CI, - 3.68 to -0.83; P = 0.002) and albuminuria (log UACR, beta = 0.81; 95% CI, 0.2 to 1.4; P = 0.01) were risk factors for increased ssEFV. CONCLUSIONS: In stage 3-5 CKD, coronary calcification and IL-6 and were predictors of ssEFV. Further studies are needed to clarify the mechanism by which epicardial fat may contribute to the pathogenesis of coronary disease, particularly in the CKD population.

Body mass index, coronary artery calcification, and kidney function decline in stage 3 to 5 chronic kidney disease patients.

OBJECTIVE: To determine whether body mass index (BMI) and coronary artery calcification (CAC) are risk factors for kidney function decline in predialysis chronic kidney disease (CKD) patients. DESIGN: Prospective cohort study of 125 stage 3 to 5 predialysis CKD patients. SUBJECTS AND SETTING: CKD patients receiving care in Kingston, Ontario, Canada. METHODS: BMI, CAC, and kidney function were measured at baseline. CAC was measured by multislice computed tomography scan. Kidney function was determined by the 4-variable reexpressed Modification of Diet in Renal Disease Study equation. At study end, kidney function decline among patients was compared according to baseline BMI and CAC. MAIN OUTCOME: Kidney function decline was defined as a 1-year decline in estimated glomerular filtration rate (eGFR) of ≥ 5%. RESULTS: Individuals with a decline in eGFR of ≥ 5% at 1 year had higher baseline BMI (33.5 ± 8.3 vs. 28.4 ± 4.9 kg/m(2); P = .0001) and higher baseline median CAC scores (239 vs. 25 Agatston units; P = .01) compared with subjects without such a decline. BMI (r = 0.35; P < .0001) and logarithmically transformed CAC score (r = 0.22; P = .01) correlated with an eGFR decline of ≥ 5%. Both crude and adjusted logistic regression analyses showed escalating CAC (with CAC reported in quintiles and CAC score = 0 Agatston unit as the reference group) was associated with an increased risk of eGFR decline of ≥ 5%. CONCLUSIONS: CAC and BMI were associated with kidney function decline over 1 year. The risk of kidney function decline was greater in those with increasing burden of CAC, which remained robust in the adjusted analysis accounting for the risk factors for CKD progression. Larger studies will be required for independent validation of the associations of BMI, CAC, and kidney function decline, and to investigate whether obesity and CAC treatment strategies are efficacious in attenuating kidney function decline in predialysis CKD patients.

Is the calcium correct? Measuring serum calcium in dialysis patients.

Abnormalities in calcium concentration are frequent in patients receiving dialysis therapy. Most cases of both hypo- and hypercalcemia are mild and asymptomatic. There is concern, however, that, on the one hand, hypocalcemia can drive hyperparathyroidism and eventually lead to gland hypertrophy and autonomous function. Hypercalcemia, on the other hand, can be associated with increased extraosseous calcium and phosphate deposition leading to vascular calcification with an attendant mortality and morbidity. Calcium exists in three main forms in the blood: the physiologically active free or ionized fraction (terms often used interchangeably), a protein bound fraction, and a fraction complexed to other anions. Although the ionized calcium can readily be measured using ion-specific electrodes, it is the total calcium that is most commonly measured because of sample handling and cost concerns. As it is the free or ionized form that is biologically active (and therefore of most relevance), a number of adjustment formulae have been derived to "correct" the total calcium for changes in albumin, protein, and complexing ion concentrations. These formulae show good statistical correlation with measured ionized calcium in populations studied as a whole, but are generally poor predictors of true ionized hypo- or hypercalcemia in individual patients. International guideline committees in nephrology recommend frequent assessment of calcium levels in dialysis patients and recommend that these levels be kept within the normal reference range. These guidelines are less clear on which measurement of calcium should be used to guide clinical decision making. This review examines the merits of making any adjustment to the total calcium measurement, and suggests when it is appropriate to measure the ionized or free calcium.

Prevalence and associations of coronary artery calcification in patients with stages 3 to 5 CKD without cardiovascular disease.

BACKGROUND: Patients with chronic kidney disease (CKD) have a high prevalence of coronary artery calcification, suggesting that CKD itself is a risk factor for its occurrence. Existing studies are confounded by the inclusion of patients who may not have CKD by means of diagnostic criteria and by failing to account for existing cardiovascular disease. STUDY DESIGN: Cross-sectional study. PARTICIPANTS & SETTING: 119 patients with CKD stages 3 to 5 (excluding dialysis) without known cardiovascular disease receiving care at a single center in Kingston, Ontario, Canada. PREDICTORS: Glomerular filtration rate was estimated (eGFR) by using the 4-variable Modification of Diet in Renal Disease Study equation. Traditional and nontraditional coronary artery calcification risk factors were defined a priori. OUTCOMES: Coronary artery calcification was measured by means of multislice computed tomographic scan. RESULTS: Mean and median coronary artery calcification scores were 566.5 +/- 1,108 and 111 (interquartile range, 2 to 631.5), respectively. A total of 32.8% of patients showed little calcification (score, 0 to 10). Calcification correlated with age (r = 0.44; P < 0.001), body mass index (r = 0.28; P = 0.002), high-density lipoprotein cholesterol level (r = -0.23; P = 0.01), diabetes mellitus (r = 0.23; P = 0.01), and cardiovascular risk score (r = 0.35; P < 0.001). By means of multivariable linear regression controlling for eGFR and diabetes mellitus, age (beta = 0.05; 95% confidence interval, 0.03 to 0.06; P < 0.001), body mass index (beta = 0.04; 95% confidence interval, 0.02 to 0.07; P = 0.001), and serum calcium level (beta = 0.9; 95% confidence interval, 0.15 to 1.6; P = 0.02), were risk factors for coronary artery calcification. LIMITATIONS: Inadequate sample size and uncontrolled confounding are possible limitations, but are unlikely to have changed the main study findings. CONCLUSIONS: In this study, traditional cardiovascular disease risk factors and serum calcium level were associated with coronary artery calcification. No association was shown with eGFR. Studies exploring protective mechanisms against coronary artery calcification are needed.

Warfarin and aortic valve calcification in hemodialysis patients.

BACKGROUND: This retrospective cohort study was designed to determine the association between long-term exposure to warfarin and severity of aortic valve (AV) calcification in hemodialysis (HD) patients. METHODS: One hundred and eight HD patients underwent a study-specific echocardiogram. A grading scheme was used to classify AV calcification as none, mild, moderate and severe. Demographic, biochemical and medication data were abstracted by chart review. RESULTS: One hundred and eight subjects were enrolled. A minority had no calcification (n=17, 15.7%), the majority had mild calcification (n=62, 57.4%), and fewer had calcification rated as moderate (n=16, 14.8%) or severe (n=13, 12%). Dialysis vintage was associated with severity of AV calcification (p=0.04). The 18 subjects with long-term warfarin exposure (36.7 +/- 19.7 months) were more likely to have severe AV calcification (p=0.04). The odds ratio of falling into a higher category of AV calcification following 18 months of warfarin was 3.77 (95% confidence ratio, 0.97-14.70; p=0.055). There was an association between lifetime months of warfarin exposure and severity of AV calcification (p=0.004) that was independent of dialysis vintage, calcium and calcitriol intake. CONCLUSIONS: The data suggest that warfarin may be associated with severity of AV calcification in HD patients and support the need for prospective studies.

Are hemodialysis access flow measurements by ultrasound dilution the standard of care for access surveillance?

Maintenance of vascular access function is vital to the delivery of adequate hemodialysis therapy. Failure of function is associated with significant morbidity and cost. Thus, access surveillance programs are suggested. The most common cause for access dysfunction is stenosis formation within the graft fistula. This may lead to reduced blood flow. The measurement of access blood flow has thus been recommended as the preferred method for surveillance. This article reviews blood flow among other methods for the screening of access dysfunction, the techniques used to measure it, the predictability of access flow measurements in determining the presence of access stenosis and allowing successful; intervention and finally the cost-effectiveness of such surveillance. Review of available evidence would suggest that access flow measurements are the best tests currently available to screen for access dysfunction, and as preventative interventions, such as angioplasty and surgery, are successful, they should be regarded as the present standard of care. This would appear to be a cost-effective strategy. Furthermore, the method of choice for access flow measurement is by ultrasound dilution technology.