Faculty Bibliography

BACKGROUND: Dialysis adequacy is currently judged by measures of urea clearance. However, urea is relatively non-toxic and has properties distinct from large classes of other retained solutes. In particular, intracellularly sequestered solutes are likely to behave differently than urea. METHODS: We studied an example of this class, the aliphatic amine monomethylamine (MMA), in stable haemodialysis outpatients (n = 10) using an HPLC-based assay. RESULTS: Mean MMA levels pre-dialysis in end-stage renal disease subjects were 76 +/- 15 microg/L compared to 32 +/- 4 microg/L in normal subjects (n = 10) (P < 0.001). Mean urea reduction was 62% while the reduction ratio for MMA was 43% (P < 0.01). MMA levels rebounded in the 1 hour post-dialytic period to 85% of baseline, whereas urea levels rebounded only to 47% of baseline. MMA had a much larger calculated volume of distribution compared to urea, consistent with intracellular sequestration. Measures of intra-red blood cell (RBC) MMA concentrations confirmed greater levels in RBCs than in plasma with a ratio of 4.9:1. Because of the intracellular sequestration of MMA, we calculated its clearance using that amount removed from whole blood. Clearances for urea averaged 222 +/- 41 ml/min and for MMA 121 +/- 14 ml/min, while plasma clearance for creatinine was 162 +/- 20 ml/min (P < 0.01, for all differences). Using in vitro dialysis, in the absence of RBCs, solute clearance rates were similar: 333 +/- 6, 313 +/- 8 and 326 +/- 4 ml/min for urea, creatinine and MMA, respectively. These findings suggest that the lower MMA clearance relative to creatinine in vivo is a result of MMA movement into RBCs within the dialyser blood path diminishing its removal by dialysis. CONCLUSION: In conclusion, we find that, in conventional haemodialysis, MMA is not cleared as efficiently as urea or creatinine and raise the possibility that RBCs may limit its dialysis not merely by failing to discharge it, but by further sequestering it as blood passes through the dialyser

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

BACKGROUND: Olfactory function is impaired in patients with end-stage renal disease (ESRD) and may contribute to uremic anorexia. Only limited correlations of olfactory function and nutritional status were reported. This study examines the relationship of impaired olfactory function to malnutrition and levels of the retained uremic solutes monomethylamine, ethylamine, indoxyl sulfate, and P-cresol sulfate. STUDY DESIGN: Cross-sectional observational study. SETTING & PARTICIPANTS: 31 stable maintenance hemodialysis patients from an urban outpatient dialysis unit and 18 people with normal renal function participated. PREDICTOR: Nutritional status assigned by using Subjective Global Assessment (SGA) score; SGA score of 7 indicates normal nutritional status; SGA score of 5 to 6, mild malnutrition; and SGA score of 3 to 4, moderate malnutrition. OUTCOMES & MEASUREMENTS: The primary outcome is olfactory function, assessed using the University of Pennsylvania Smell Identification Test. Levels of retained uremic solutes were measured from a predialysis serum sample. Demographic data and laboratory values for nutritional status, adequacy of dialysis, and inflammation were collected. RESULTS: Mean smell scores were 34.9 +/- 1.4 for controls, 33.5 +/- 3.3 for patients with SGA score of 7, 28.3 +/- 5.8 for patients with SGA score of 5 to 6, and 27.9 +/- 4.4 for patients with SGA score of 3 to 4 (P < 0.001 comparing healthy patients with all patients with ESRD). There was no difference in mean smell scores for healthy controls and patients with SGA score of 7. However, patients with lower smell scores had significantly lower SGA scores (P = 0.02) and higher C-reactive protein levels (P = 0.02). Neither smell score nor nutritional status was associated with levels of retained uremic solutes. LIMITATIONS: Small sample size, only cross-sectional associations can be described. CONCLUSIONS: Our results suggest an association between poor nutritional status and impaired olfactory function in patients with ESRD. Additional research is needed to discover the uremic toxins mediating these processes

Albuminuria associated with sclerosis of the glomerulus leads to a progressive decline in renal function affecting millions of people. Here we report that activation of the Notch pathway, which is critical in glomerular patterning, contributes to the development of glomerular disease. Expression of the intracellular domain of Notch1 (ICN1) was increased in glomerular epithelial cells in diabetic nephropathy and in focal segmental glomerulosclerosis. Conditional re-expression of ICN1 in vivo exclusively in podocytes caused proteinuria and glomerulosclerosis. In vitro and in vivo studies showed that ICN1 induced apoptosis of podocytes through the activation of p53. Genetic deletion of a Notch transcriptional partner (Rbpj) specifically in podocytes or pharmacological inhibition of the Notch pathway (with a gamma-secretase inhibitor) protected rats with proteinuric kidney diseases. Collectively, our observations suggest that Notch activation in mature podocytes is a new mechanism in the pathogenesis of glomerular disease and thus could represent a new therapeutic target