Faculty Bibliography

Background: Vitamin D deficiency, defined as a serum 25-hydroxyvitamin D [25(OH)D] concentration <20 ng/mL, is correlated with a more atherogenic lipid profile. However, oral vitamin D supplementation does not lower LDL-cholesterol concentrations or raise HDL-cholesterol concentrations. This uncoupling between association and causation may result from a failure of oral vitamin D to mimic the effect of dermally synthesized vitamin D in response to ultraviolet type B (UVB) light.Objective: We tested the hypothesis that, in vitamin D-deficient adults, the replenishment of vitamin D with UVB exposure would lower LDL-cholesterol concentrations compared with the effect of oral vitamin D₃ supplementation.Design: We performed a randomized clinical trial in vitamin D-deficient adults and compared vitamin D replenishment between subjects who received oral vitamin D₃ (n = 60) and those who received narrow-band UVB exposure (n = 58) ≤6 mo.Results: There was no difference in the change from baseline LDL-cholesterol concentrations between oral vitamin D₃ and UVB groups (difference in median of oral vitamin D₃ minus that of UVB: 1.5 mg/dL; 95% CI: -5.0, 7.0 mg/dL). There were also no differences within groups or between groups for changes in total or HDL cholesterol or triglycerides. Transcriptional profiling of skin and blood, however, revealed significant upregulation of immune pathway signaling with oral vitamin D₃ but significant downregulation with UVB.Conclusions: Correcting vitamin D deficiency with either oral vitamin D₃ or UVB does not improve the lipid profile. Beyond cholesterol, these 2 modalities of raising 25(OH)D have disparate effects on gene transcription. This trial was registered at clinicaltrials.gov as NCT01688102.

OBJECTIVE: Total renal volume and changes in kidney volume are markers of disease progression in autosomal-dominant polycystic kidney disease (ADPKD) but are not used in clinical practice in part because of the complexity of manual measurements. This study aims to assess the intra- and interobserver reproducibility of a semiautomated renal volumetric algorithm using fluid-sensitive MRI pulse sequences. SUBJECTS AND METHODS: Renal volumes of 17 patients with ADPKD were segmented from high-resolution coronal HASTE and true fast imaging with steady-state precession (FISP) MR acquisitions. Measurements performed independently by four readers were repeated, typically after 7 days. Intraobserver agreement indexes were calculated for total kidney volume for each patient. Interobserver agreement indexes were obtained for the six paired combinations of readers as well as for two readers after rigorous formalized training. Pearson and concordance correlation coefficients, coefficients of variation (CVs), and 95% limits of agreement were determined. RESULTS: The HASTE and true FISP sequences performed similarly with a median intraobserver agreement of greater than 98.1% and a CV of less than 2.4% across all readers. The median interobserver agreement was greater than 95.2% and the CV was less than 7.1%, across all reader pairs. Reader training further lowered interobserver CV. The mean total kidney volume was 1420 mL (range, 331-3782 mL) for HASTE imaging and 1445 mL (range, 301-3714 mL) for true FISP imaging, with mean image processing times per patient of 43 and 28 minutes, respectively. CONCLUSION: This semiautomated MR volumetric algorithm provided excellent intraobserver and very good interobserver reproducibility using fluid-sensitive pulse sequences that emphasize cyst conspicuity.

AbstractBackground and Objective.Ovarian cancer is usually diagnosed at an advanced stage, with most patients undergoing surgery followed by platinum- and taxane-based chemotherapy. After initial clinical remission, the majority recur, leading to additional treatments, including not only platinums and taxanes but also pegylated liposomal doxorubicin (PLD), gemcitabine, topotecan, and, more recently, bevacizumab, which may extend survival times. PLD, in particular, has been extensively studied by our group, with encouraging therapeutic results. We, however, observed instances of chronic kidney disease (CKD) developing among patients who received long-term treatment for recurrent ovarian cancer. To document the frequency and contributing factors to the emergence of CKD, we initiated a retrospective review at two institutions.Patients and Methods.Fifty-six consecutive patients with recurrent ovarian cancer receiving treatment at New York University Cancer Institute were reviewed for the presence of renal disease in 1997-2010. At Shaare Zedek Medical Center, 73 consecutive patients with ovarian cancer were reviewed in 2002-2010. Patients were diagnosed with CKD if they had an estimated GFR <60 mL/minute per 1.73 m(2) for >3 months and were staged according to the National Kidney Foundation guidelines.Results.Thirteen patients (23%) developed stage >/=3 CKD. Three patients had renal biopsies performed that showed thrombotic microangiopathy.Conclusions.CKD is emerging as a potential long-term consequence of current chemotherapy for recurrent ovarian cancer.

Chronic kidney disease (CKD) accelerates cardiovascular disease. The mechanisms that explain this independent, excess risk associated with CKD have not been fully elucidated. OBJECTIVES: We propose that impaired regression of atherosclerosis in renal disease represents a novel risk factor for the heightened morbidity and mortality and resistance to treatment observed in patients with CKD. METHODS AND RESULTS: Using a transplant model to study atherosclerosis regression, we transplanted atheromatous aortic segments generated in Apolipoprotein E knock-out (ApoE(-/-)) mice, into either control or moderately uremic, normolipidemic, wild-type mice. In non-uremic mice, lesions regressed 55%, whereas lesions in uremic mice increased in size by 17% (p<0.01 for control vs. uremic). The lesions in uremic mice were also characterized by a greater presence of macrophages (36,300 microm(2) vs. 12,600 microm(2), p<0.01). This finding was despite upregulation of chemokine receptor 7 (CCR7), normally a migration factor, in uremic lesion macrophages. Gene expression analysis of lesion macrophages showed relative down-regulation of serum response factor (SRF) target genes in the uremic group, consistent with impaired CCR7 signaling. CONCLUSION: Moderate kidney disease inhibits regression of atherosclerosis in a mouse transplant model. This inhibition may be a result of impaired CCR7 signaling

BACKGROUND AND OBJECTIVES: Autosomal dominant polycystic kidney disease (ADPKD) leads to kidney failure in half of those affected. Increased levels of adenosine 3;:5;-cyclic monophosphate (cAMP) play a critical role in disease progression in animal models. Water loading, by suppressing arginine vasopressin (AVP)-stimulated cAMP production, is a proposed therapy for ADPKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The effects of acute and sustained water loading on levels of urine osmolality (Uosm) and cAMP in 13 subjects with ADPKD and 10 healthy controls were studied. Uosm and cAMP concentrations were measured before and after water loading. RESULTS: Urine [cAMP] indexed to Uosm significantly decreased with acute water loading in both groups (58% in controls and 35% in ADPKD). Chronic water loading resulted in a nonsignificant 13% decrease in 24-hour urine cAMP excretion in ADPKD participants, despite an increase in 24-hour urine volume by 64% to 3.14 +/- 0.32 L and decrease in mean Uosm by 46%, to below that of plasma (270 +/- 21 mOsm/L). CONCLUSIONS: Increased water intake of 3 L per day decreased Uosm in most ADPKD subjects. While urine [cAMP] accurately reflects changes in Uosm during acute water loading in ADPKD subjects, chronic water loading did not lower 24-hour urine cAMP excretion, although subjects with higher baseline [cAMP] (>2 nmol/mg Cr) responded best. Decreases in urine [cAMP] and osmolality are consistent with decreased AVP activity. These results support the need for a larger study to evaluate the effect of chronic water loading on ADPKD progression

Cardiovascular disease continues to be the foremost cause of morbidity and mortality in dialysis patients. Compared with the general population, dialysis patients suffer from an accelerated disease course that is, at least in part, resistant to conventional therapy. While there are a myriad of potential explanations for this resistance, derangements in lipid metabolism probably play an important role. Here, we discuss the significance of altered lipid metabolism in uremia, such as oxidative lipoprotein modification and the pathophysiology of adipose tissue; limitations of conventional approaches to dyslipidemia such as statin therapy and traditional lipid profiles; and areas of investigation with potential for new therapy, such as reverse cholesterol transport

Kidney disease is an important complication of HIV, particularly in minority populations. We describe the burden of chronic kidney disease among 1239 adults followed at an urban AIDS center, with an estimated prevalence of 15.5% (n = 192). Independent predictors of kidney disease included older age, black race, hepatitis C virus exposure, and lower CD4 cell count. These data suggest that chronic kidney disease remains a common complication of HIV infection in the era of antiretroviral therapy