Geeta Gyamlani

Assessment of 24,25(OH)2D levels does not support FGF23-mediated catabolism of vitamin D metabolites

Progressive elevations of fibroblastic growth factor 23 [FGF23] in chronic kidney disease may reduce serum 25-hydroxyvitamin D [25(OH)] and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels, via stimulation of 24-hydroxylase (Cyp24A1) mediated catabolism of these vitamin D metabolites. To test this possibility, we measured serum concentrations of 24,25-dihydroxyvitamin D [24,25(OH)2D], a product of Cyp24A1 hydroxylation of 25(OH)D, in the Col4α3 knockout mouse, a model of Alport syndrome-derived chronic kidney disease, and in patients with chronic kidney disease of variable severity. There was an inverse correlation between serum FGF23 and both 25(OH)D and 1,25(OH)2D in the mouse model but no significant relationship was observed in the cross-sectional patient cohort. The FGF23-dependent increase in Cyp24a1 mRNA expression in the mouse kidneys was consistent with the possibility that FGF23 induces vitamin D catabolism. There was, however, a reduction in serum 24,25(OH)2D levels, rather than the expected elevation, in both the mice and patients with chronic kidney disease. Low 25(OH)D and elevated FGF23 and parathyroid hormone levels were correlated with the reduced serum 24,25(OH)2D concentrations of these patients. Thus, we failed to find support for FGF23-mediated catabolism of vitamin D metabolites in chronic kidney disease assessed by 24,25(OH)2D levels.

Activation of FGF-23 Mediated Vitamin D Degradative Pathways by Cholecalciferol

CONTEXT The optimal circulating concentration of 25(OH) vitamin D is controversial. OBJECTIVE The aim was to investigate if FGF-23 and 24,25(OH)2D can guide cholecalciferol replacement. DESIGN Oral cholecalciferol (10,000 IU weekly) administered to subjects with 25(OH)D levels < 20 ηg/mL and eGFR > 60 mL/min/1.73 m(2) (n = 25), chronic kidney disease (CKD) (n = 27), or end stage renal disease (ESRD) (n = 14). SETTING The study was conducted at the Veterans Affairs clinics. MAIN OUTCOME MEASURE Serum FGF-23, PTH, 25(OH)D, 1,25(OH)2D, 24,25(OH)2D, calcium, and phosphorous concentrations, and urinary excretion of calcium and phosphorus at baseline and after 8 weeks of treatment. RESULTS Cholecalciferol treatment increased concentrations of serum 25(OH)D by (19.3 ± 8 ηg/mL, P = .001; 12.2 ± 9 ηg/mL, P = .0001) and 24,25(OH)2D (1.14 ± 0.89 ηg/mL, P = .0024; 1.0 ± 0.72 ηg/mL P = .0002), and reduced serum PTH (-11 ± 21 pg/mL, P = .0292; -42 ± 68 pg/mL, P = .0494) in normal and CKD subjects, respectively. Cholecalciferol increased serum FGF-23 levels only in normal subjects (44 ± 57 ηg/mL, P = .01). Increments in serum 25(OH)D positively correlated with serum FGF-23 and 24,25(OH)2D and negatively correlated with PTH. In ESRD, cholecalciferol administration increased 25(OH)D by (16.6 ± 6.6 ηg/mL P ≤ .05) without changing 24,25(OH)2D, FGF-23 or PTH levels. CONCLUSION Modest elevations of serum 25(OH)D levels after cholecalciferol treatment are sufficient to induce compensatory degradative pathways in patients with sufficient renal reserves, suggesting that optimal circulating 25(OH)D levels are approximately 20 ηg/mL. In addition, catabolism of 25(OH)D may also contribute to the low circulating vitamin D levels in CKD, since elevations of FGF-23 in CKD are associated with increased 24,25(OH)2D after cholecalciferol administration.

Depression, Screening and Quality of Life in Chronic Kidney Disease

Introduction:To determine the prevalence of positive screens for depression and to assess quality of life (QoL) and usefulness of the brief and easily administered Patient Health Questionnaire-2 (PHQ-2) for depression screening in the chronic kidney disease (CKD) population; and to explore the relationship between depressive symptoms and markers of inflammation. Methods:Seventy-one adult patients with estimated glomerular filtration rate <60 mL/min/1.73 m2 or proteinuria, but not on dialysis, were enrolled. QoL was assessed using the Short Form-36. The Center for Epidemiological Studies Depression Scale (CES-D) and PHQ-2 were used to screen for depression. Serum ferritin, albumin, C-reactive protein and hematocrit were also measured as markers of inflammation. Results:The PHQ-2 and CES-D were significantly correlated (P < 0.05). Positive scores on the CES-D or PHQ-2 had significantly lower Short Form-36 scores. Mean hemoglobin values were significantly lower in patients who screened positive for depression either by CES-D (12.2 ± 1.7 versus 13.2 ± 1.7, P < 0.05) or by PHQ-2 (12 ± 1.6 versus 13.4 ± 1.6, P < 0.01). Neither PHQ-2 nor CES-D correlated with other markers of inflammation in this sample. Conclusion:Both the CES-D and the PHQ-2 can identify patients with CKD who need further evaluation for depression. The PHQ-2 seems to be a useful screen for depression and impaired QoL in a renal clinic setting. Patients with CKD and lower hemoglobin may be at greater risk for depression than those with normal values.

Early Mortality Associated with Inpatient versus Outpatient Hemodialysis Initiation in a Large Cohort of US Veterans with Incident End-Stage Renal Disease

Background: Mortality in the immediate post-hemodialysis transition period is extremely high. Many end-stage renal disease (ESRD) patients in the US start dialysis in an inpatient setting, but the characteristics of patients starting dialysis as inpatients, and the association of inpatient hemodialysis transition with mortality remain unclear. Methods: We examined 48,261 US veterans who transitioned to hemodialysis between October 2007 and September 2011. Associations of inpatient hemodialysis starting with all-cause mortality were examined in Cox proportional hazard models, with adjustments for demographics, comorbidities, vascular access type, pre-dialysis nephrology care and medication use, and last pre-ESRD estimated glomerular filtration rate and hemoglobin. Results: A total of 22,338 (46.3%) patients received the first hemodialysis treatment in an inpatient setting. Inpatient hemodialysis transition was associated with older age, presence of a tunneled catheter, higher comorbidity burden, and lack of pre-dialysis nephrology care. A total of 8,674 patients died (mortality rate 405/1,000 patient-years, 95% CI 397-413) during the first 6 months after transition to hemodialysis. The starting of inpatient vs. outpatient hemodialysis was associated with significantly higher crude all-cause mortality, but this association was attenuated after multivariable adjustments. Conclusions: Transition to hemodialysis in an inpatient setting is more common in older and sicker individuals, and in patients without pre-dialysis nephrology care and those who used a catheter for vascular access. Future studies are needed to determine if a higher proportion of patients could start hemodialysis treatment in outpatient clinics, through interventions targeting modifiable risk factors such as timely vascular access placement or earlier nephrology referrals.

Kidney disease in pregnancy: (Women's Health Series).

Abstract Kidney disease and pregnancy may exist in two general settings: acute kidney injury that develops during pregnancy, and chronic kidney disease that predates conception. In the first trimester of pregnancy, acute kidney injury is most often the result of hyperemesis gravidarum, ectopic pregnancy, or miscarriage. In the second and third trimesters, the common causes of acute kidney injury are severe preeclampsia, hemolysis-elevated liver enzymes–low platelets syndrome, acute fatty liver of pregnancy, and thrombotic microangiopathies, which may pose diagnostic challenges to the clinician. Cortical necrosis and obstructive uropathy are other conditions that may lead to acute kidney injury in these trimesters. Early recognition of these disorders is essential to timely treatment that can improve both maternal and fetal outcomes. In women with preexisting kidney disease, pregnancy-related outcomes depend upon the degree of renal impairment, the amount of proteinuria, and the severity of hypertension. Neonatal and maternal outcomes in pregnancies among renal transplant patients are generally good if the mother has normal baseline allograft function. Common renally active drugs and immunosuppressant medications must be prescribed, with special considerations in pregnant patients.

Association of serum albumin level and venous thromboembolic events in a large cohort of patients with nephrotic syndrome

Background. Prior small studies have suggested an association between low serum albumin and increased risk of venous thromboembolic (VTE) events in patients with nephrotic syndrome (NS). Methods. From a nationally representative prospective cohort of over 3 million US veterans with baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2, we identified 7037 patients with NS based on ICD-9 codes. Association between serum albumin and risk of incident VTE was assessed using Cox regression analysis with adjustments for age, gender, race, comorbidities, eGFR, body mass index and anticoagulant treatment. Results. Mean age was 57 ± 11 years, patients were 96% male, 32% African-American and 60% diabetic. There were a total of 158 VTE events over a median follow-up of 8.1 years; 16 events [absolute event rate (AER) 4.1%, event rate 8.5/1000 patient-years (PY)] in patients with albumin <2.5 g/dL, 18 events (AER 3.4%, event rate 5.7/1000 patient-years) in patients with albumin 2.5–2.99 g/dL, 89 events (AER 2.5%, event rate 3.4/1000 patient-years) in patients with albumin 3–3.99 g/dL and 35 events (AER 1.4%, event rate 1.9/1000 patient-years) in patients with albumin ≥4 g/dL. Compared with patients with albumin ≥4 g/dL, those with albumin levels of 3–3.99 g/dL [adjusted hazard ratio (HR): 1.51, 95% confidence interval (CI): 1.01–2.26], 2.5–2.99 g/dL (HR: 2.24, 95% CI: 1.24–4.05) and <2.5 g/dL (HR: 2.79, 95% CI: 1.45–5.37) experienced a linearly higher risk of VTE events. Conclusions. Lower serum albumin is a strong independent predictor for VTE events in NS. The risk increases proportionately with declining albumin levels. Clinical trials are needed to determine benefit of prophylactic anticoagulation in NS patients with moderately lower serum albumin levels.

Effect of Age on the Association of Vascular Access Type with Mortality in a Cohort of Incident End-Stage Renal Disease Patients

Background/Aims: All hemodialysis (HD) patients are generally recommended to create a fistula first; but to create a mature arteriovenous fistula (AVF) can be challenging in elderly individuals. It is unclear if elderly incident HD patients derive a survival benefit from an AVF over an arteriovenous graft (AVG) or a tunneled central venous catheter (TDC). Methods: We examined the association of vascular access type (AVF, AVG, and TDC with and without a maturing AVF/AVG at dialysis transition) at HD initiation with all-cause, cardiovascular (CV), and infection-related mortality in 46,786 US veterans using Cox models with adjustment for confounders. Effect modification by age was examined by examining associations in pre-specified age subgroups (<60, 60-<70, 70-<80, and ≥80 years old), and by including interaction terms. Results: Patients numbering 8,940 (19%) started HD with an AVF, 1,090 (3%) with an AVG, 8,262 (18%) with a TDC and a maturing AVF/AVG and 28,494 (61%) with a TDC without a maturing AVF/AVG. A total of 13,303 all-cause, 4,392 CV, and 1,058 infection-related deaths were observed in the first year after HD transition. Compared to patients with AVF, those with AVG and TDC with and without maturing AVF/AVG had incrementally higher overall risk of all-cause mortality and CV mortality. Only TDC use was associated with higher infection-associated mortality. These associations were not modified by age. Conclusion: Although most of our patients consisted of male veterans and the results may not be generalized to the general population, the use of TDCs is associated with poor outcomes even in the most elderly incident HD patients.

Primary Aldosteronism: Diagnosis and Management ☆

ABSTRACT Primary aldosteronism (PA) is an important and commonly unrecognized cause of secondary hypertension. Idiopathic hyperaldosteronism and aldosterone‐producing adenomas account for more than 95% of PA and are characterized, respectively, by bilateral or unilateral involvement of the adrenal glands. When there is suspicion for the presence of PA, a plasma aldosterone to renin ratio should be obtained initially. Localization to determine adrenal gland involvement is done by imaging, with computerized tomography or magnetic resonance imaging. After imaging, adrenal vein sampling is done to establish treatment options. Patients with unilateral disease, who are good surgical candidates, are most appropriately managed with adrenalectomy. A biochemical cure is almost certain following adrenalectomy; however, only 30‐50% of patients would show adequate blood pressure improvement. Patients with bilateral adrenal disease and those believed not to be surgical candidates are managed with mineralocorticoid antagonists.

Successful use of rituximab in fibrillary glomerulopathy

Abstract Fibrillary glomerulopathy (FG) can occur either alone or co-existing with other proteinuric glomerular disorders. FG has been associated with poor renal outcomes leading to End Stage Renal Disease (ESRD). Since FG is a relatively rare disorder, limited information is available concerning treatment protocols. We present two patients with FG who were treated with rituximab after they had already progressed to stage 3 chronic kidney disease (CKD) with worsening proteinuria. Rituximab therapy resulted in long-term stabilization of renal function.

Changes in biochemical and vascular parameters with lanthanum carbonate, calcium acetate and dietary phosphorus restriction in patients with CKD: a randomized controlled trial

Introduction Abnormal phosphorus homeostasis develops early in chronic kidney disease (CKD). It is unclear if its correction results in improved clinical outcomes in non–dialysis dependent CKD. Methods We conducted a randomized controlled, parallel design clinical trial in 120 patients with estimated glomerular filtration rate 15 to 59 ml/min per 1.73 m2 and abnormal phosphorus homeostasis (serum phosphorus >4.6 mg/dl, parathyroid hormone [PTH] >70 pg/ml or tubular reabsorption of phosphorus [TRP] <80%). Patients were randomized to open-label lanthanum carbonate versus calcium acetate versus dietary intervention over 1 year. The co-primary outcomes were month 12 (vs. baseline) biochemical (serum phosphorus, TRP, PTH, calcium, bone-specific alkaline phosphatase [bALP], and fibroblast growth factor 23 [FGF23]) and vascular parameters (coronary artery calcium score, pulse wave velocity, and endothelial dysfunction) in all patients. Secondary outcomes were between-treatment differences in change for each parameter between month 12 and baseline. All analyses were intention to treat. Results Baseline characteristics were similar in the 3 groups. A total of 107 patients (89%) completed 12 months of follow-up. Differences were not significant at month 12 (vs. baseline) for any of the outcomes except bALP (median [25th, 75th] percentile at month 12 versus baseline: 13.8 [10.6, 17.6] vs. 15.8 [12.1, 21.1], P < .001) and FGF23 (132 [99, 216] vs. 133 [86, 189], P = .002). Changes for all outcomes were similar in the 3 arms except for PTH, which was suppressed more effectively by calcium acetate (P < .001). Conclusion A 1-year intervention to limit phosphorus absorption using dietary restriction or 2 different phosphorus binders resulted in decreased bALP suggesting improved bone turnover, but no other significant changes in biochemical or vascular parameters in patients with CKD stage 3/4. (ClinicalTrials.gov: NCT01357317)