Faculty Bibliography

BACKGROUND: Vitamin D has key roles in regulating systems that could be important in the pathobiological state of proteinuria. Because of this, it could be helpful in treating patients with proteinuric renal diseases. The objective is to determine the effect of oral paricalcitol on protein excretion in patients with proteinuric chronic kidney disease. STUDY DESIGN: Double-blind randomized study. SETTING & PARTICIPANTS: 61 patients with estimated glomerular filtration rate of 15 to 90 mL/min/1.73 m(2) and protein excretion greater than 400 mg/24 h. INTERVENTION: Randomization to 6 months of treatment with paricalcitol, 1 mug/d, or placebo. OUTCOMES & MEASUREMENTS: The predefined primary end point was to compare change in mean spot urinary protein-creatinine ratio between the baseline measurement and the last study evaluation (6 months in study completers) between the 2 groups. Every 4 weeks, there was measurement of serum intact parathyroid hormone, serum calcium, serum phosphorus, serum creatinine, and urine spot protein and creatinine. RESULTS: At baseline, mean urinary protein-creatinine ratios were 2.6 and 2.8 g/g in the placebo and paricalcitol groups, respectively. At final evaluation, mean ratios were 2.7 and 2.3, respectively. Changes in protein excretion from baseline to last evaluation were +2.9% for controls and -17.6% for the paricalcitol group (P = 0.04). A 10% decrease in proteinuria occurred in controls (7 of 27; 25.9%) and the paricalcitol group (16 of 28; 57.1%; P = 0.03). LIMITATIONS: The relatively small sample size limits the extent to which results should be generalized. CONCLUSIONS: Paricalcitol resulted in a significant reduction in protein excretion in patients with proteinuric renal disease.

The mechanisms regulating key fate decisions such as self-renewal and differentiation in hematopoietic stem and progenitor cells (HSPC) remain poorly understood. We report here a screening strategy developed to assess modulators of human hematopoiesis using a lentiviral short hairpin RNA (shRNA) library transduced into cord blood-derived stem/progenitor cells. To screen for modifiers of self-renewal/differentiation, we used the limited persistence of HSPCs under ex vivo culture conditions as a baseline for functional selection of shRNAs conferring enhanced maintenance or expansion of the stem/progenitor potential. This approach enables complex, pooled screens in large numbers of cells. Functional selection identified novel specific gene targets (exostoses 1) or shRNA constructs capable of altering human hematopoietic progenitor differentiation or stem cell expansion, respectively, thereby demonstrating the potential of this forward screening approach in primary human stem cell populations.