Kidney volume associations with subclinical renal and cardiovascular disease: the Diabetes Heart Study.

BACKGROUND: The prognostic significance of total kidney volume (TKV) in subjects with type 2 diabetes mellitus (T2DM) is unknown. METHODS: One hundred and seventy unrelated Caucasians with T2DM underwent multidetector-row computed tomography of the neck, chest, and abdomen to measure calcified plaque in the coronary artery (CorCP), carotid artery (CarCP), and infrarenal aorta (AorCP). Spearman's rank correlation coefficients were used to assess associations between TKV and subclinical renal and cardiovascular disease. Partial correlation coefficients were computed to adjust for the potential confounding effects of age, sex, body mass index, glomerular filtration rate (GFR), diabetes duration, and hemoglobin A(1c). Values are expressed as mean +/- SD (median in parentheses). RESULTS: The study group (51% female) had a mean age of 62.9 +/- 8.5 (62.3) years, a T2DM duration of 11.5 +/- 6.8 (10.0) years, a urinary albumin:creatinine ratio of 109.9 +/- 396 (17.6) mg/g, a GFR of 63.8 +/- 12.8 (63.2) ml/min, a TKV of 272.4 +/- 69.7 (261.9) cm(3), CorCP 2,170 +/- 3,394 (653), CarCP 374 +/- 673 (104), AorCP 14,569 +/- 17,480 (8,370), and a carotid artery intima-media thickness of 0.70 +/- 0.14 (0.68) mm. Adjusting for age, sex, body mass index, diabetes duration, GFR, and hemoglobin A(1c), the TKV was significantly associated with AorCP (r = 0.20, p = 0.016), but not with CorCP, CarCP, or carotid artery intima-media thickness (all p >or= 0.25). No significant associations were detected between TKV and blood pressure or albuminuria. CONCLUSIONS: In Caucasians with T2DM, TKV and calcified atherosclerotic plaque in the infrarenal abdominal aorta are positively associated. Common mechanisms linking renal matrix deposition with aortic atherosclerosis may underlie this association and require further study.

Efficacy and safety of low-dose heparin in hemodialysis.

INTRODUCTION: The dose of unfractionated heparin (UFH) administered during hemodialysis (HD) varies widely. This prospective study evaluated the safety and efficacy of UFH dose de-escalation. METHODS: Sixty-six prevalent patients on HD receiving UFH per standard-dose protocol (load dose [LD] 50-75 units/kg, maintenance dose [MD] 500-1000 units/hour) had heparin prescription converted to low-dose protocol (start LD 15 units/kg and MD 500 units/hour; dose adjusted in small increments based on assessments of extracorporeal blood circuit). Coagulation parameters, dialysis adequacy, dialyzer clotting, anemia management, and dialyzer reuse rates were compared based on the heparin protocol. FINDINGS: Mean(SD) UFH dose per HD session, before and after protocol conversion, was 6178(2644) and 2913(1116) units, respectively (P < 0.0001). This corresponded to LD 52.1(16.6) units/kg and MD 615(207) units/hour with standard-dose protocol, and LD 18.3(6.5) units/kg and MD 505(27) units/hour with low-dose protocol (P < 0.0001). Mid and postdialysis aPTT was 55.3(31.2) and 35.1(7.8) seconds before, and 37.3(12.9) and 31.5(5.3) seconds after conversion (P = 0.007 and 0.003, respectively); no significant changes in D-dimer levels occurred. Low-dose UFH was associated with a small increase in URR and spKt/V (73.0 and 1.54) compared with dialysis clearance on standard-dose UFH (71.2 and 1.48, respectively, P = 0.02). Weekly dose of ESA decreased by 2388 units postconversion (P = 0.03), while hemoglobin levels and the weekly dose of intravenous iron did not change (P = 0.16 and 0.78). A small rise in the rate of moderate dialyzer clotting at the end of HD was noted with low-dose UFH (5.7% vs. 7.5%, P = 0.002); the rate of severe dialyzer clotting events did not change (P = 0.91). No change in the dialyzer reuse rate was noted (18.5 vs. 17.0 treatments, P = 0.26). DISCUSSION: Low-dose heparinization did not compromise dialysis adequacy and permitted ESA dose reduction. Our findings suggest that in prevalent patients on HD, UFH dose of 15-20 units/kg loading and 500 units/hour maintenance was medically safe and effective.

Gene-gene and gene-environment interactions in HIV-associated nephropathy: A focus on the MYH9 nephropathy susceptibility gene.

HIV-associated nephropathy (HIVAN) is a leading cause of ESRD in African Americans. The HIV-1 virus infects podocytes, cells integral to formation of the glomerular filtration barrier, often leading to focal segmental glomerulosclerosis. HIVAN is typically a complication of late-stage HIV infection, associated with low CD4 cell counts and elevated serum HIV RNA levels. Highly active antiretroviral therapy is partially protective and has altered the natural history of HIV-associated kidney disease. Nonetheless, HIVAN remains an important public health concern among HIV-infected African Americans. Although polymorphisms in the MYH9 gene on chromosome 22 are strongly associated with HIVAN, as well as with idiopathic focal segmental glomerulosclerosis and global glomerulosclerosis (historically labeled "hypertensive nephrosclerosis"), the majority of HIV-infected patients who are genetically at risk from MYH9 do not appear to develop severe kidney disease. Therefore, we postulate that additional environmental exposures and/or inherited factors are necessary to initiate human HIVAN. Gene-environment interactions have also been proposed as necessary for the initiation of HIVAN in murine models. It is important that these novel risk factors be identified because prevention of environmental exposures and targeting of additional gene products may reduce the risk for HIVAN, even among those harboring 2 risk alleles in MYH9.

Cardiovascular disease in chronic kidney disease.

The presence of kidney disease, manifested by low glomerular filtration rates (GFR) and/or large amounts of protein in the urine, is independently associated with increased rates of cardiovascular disease (CVD). The severity of kidney disease is associated with graded increases in risk for CVD and death. Chronic kidney disease (CKD) should be recognized and treatment initiated early to maximize the chances for slowing nephropathy progression and reducing proteinuria. We recommend screening for CKD in all patients with CVD, including computing an estimated GFR and evaluating for proteinuria using a spot urine albumin:creatinine ratio. Aggressive management of traditional cardiovascular risk factors should be employed in this high-risk population, specifically rigorous hypertension control (including the use of angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blocking agents (ARB)), management of hyperglycemia, hyperlipidemia and smoking cessation. Further studies are needed to identify the unique renal failure-related (non-traditional) risk factors that contribute to accelerated atherosclerosis in this population and performance of randomized trials to assess the effects of cardiovascular interventions in individuals with CKD.

Complement mediates nephrin redistribution and actin dissociation in experimental membranous nephropathy.

BACKGROUND: The onset of proteinuria in passive Heymann nephritis, (PHN), a rat model of human membranous nephropathy (MN), is complement-dependent and is associated with altered podocyte slit diaphragm integrity and dissociation of nephrin from the actin cytoskeleton. These studies examined if complement is responsible for these podocyte changes. METHODS: PHN was induced with sheep anti-Fx1A. Controls were injected with normal sheep globulin. A third group was injected with anti-Fx1A and depleted of complement with cobra venom factor. Four days later, proteinuria was measured, slit diaphragm integrity was examined by electron microscopy, nephrin distribution was studied by immunofluorescence, and the glomerular content of nephrin and its association with actin were assessed by sequential extraction of isolated glomeruli and Western blotting. RESULTS: Four days after immunization, seven out of eight PHN rats were proteinuric, whereas none of the complement depleted group had proteinuria despite similar levels of antibody deposition. Complement depletion preserved slit diaphragm morphology. Immunofluorescence microscopy with an antibody to the extracellular domain of nephrin showed a normal staining pattern in the rats depleted of complement and a shift to a more dispersed and clustered pattern in the PHN group. Western blot analysis of the glomerular extracts showed a significant reduction in the total amount of nephrin and in the fraction of actin-associated nephrin in the PHN group, whereas the amounts in the complement-depleted rats were similar to normal controls. CONCLUSION: The onset of proteinuria in the PHN model of MN is coincident with complement-dependent alterations in the association of nephrin with the actin cytoskeleton and loss of podocyte slit diaphragm integrity.