Compliance Index, a Marker of Peripheral Arterial Stiffness, may Predict Renal Function Decline in Patients with Chronic Kidney Disease.

BACKGROUND: Compliance index derived from digital volume pulse (CI-DVP), measuring the relationship between volume and pressure changes in fingertip, is a surrogate marker of peripheral arterial stiffness. This study investigated if CI-DVP can predict renal function deterioration, cardiovascular events and mortality in patients with chronic kidney disease (CKD). METHODS: In this prospective observational study, 149 CKD patients were included for final analysis. CI-DVP and brachial-ankle pulse wave velocity (baPWV) were measured, decline in renal function was assessed by the estimated glomerular filtration rate (eGFR) slope. Composite renal and cardiovascular outcomes were evaluated, including ≥50% eGFR decline, start of renal replacement therapy, and major adverse events. RESULTS: Patients in CKD stages 3b to 5 had higher baPWV and lower CI-DVP values than those in patients with CKD stages 1 to 3a. Stepwise multivariate linear regression analysis showed that lower CI-DVP (p =0.0001) and greater proteinuria (p =0.0023) were independent determinants of higher eGFR decline rate. Multivariate Cox regression analysis revealed that CI-DVP (HR 0.68, 95% CI 0.46-1.00), baseline eGFR (HR 0.96, 95% CI 0.94-0.98) and serum albumin (HR 0.17, 95% CI 0.07-0.42) were independent predictors for composite renal and cardiovascular outcomes. CONCLUSIONS: Compliance index, CI-DVP, was significantly associated with renal function decline in patients with CKD. A higher CI-DVP may have independent prognostic value in slower renal function decline and better composite renal and cardiovascular outcomes in CKD patients.

Signals mediating Klotho-induced neuroprotection in hippocampal neuronal cells.

The erythropoietin (Epo) receptor (EpoR) is expressed in the brain and was shown to have neuroprotective effects against brain damage in animal models. A recent study indicated that EpoR and its activity are the downstream effectors of Klotho for cytoprotection in the kidney. Thus, we propose that Klotho can stimulate the expression of EpoR in neuronal cells to enhance Epo-mediated protection. H19-7 hippocampal neuronal cells were treated with recombinant Klotho. In H19-7 cells, Klotho increased the expression of both the EpoR protein and mRNA. Klotho also enhanced the transcription activity of the EpoR promoter in H19-7 cells. Moreover, Klotho augmented the Epo-triggered phosphorylation of Jak2 and Stat5 and protected H19-7 cells from hydrogen peroxide cytotoxicity. The silencing of EpoR abolished the protective effect of Klotho against peroxide-induced cytotoxicity. Finally, the silencing of GATA1 diminished the Klotho-induced increase in EpoR protein and mRNA expression as well as its promoter activity. In conclusion, Klotho increased EpoR expression in neuronal cells through GATA1, thereby enabling EpoR to function as a cytoprotective protein against oxidative injury.

Rosiglitazone increases cerebral klotho expression to reverse baroreflex in type 1-like diabetic rats.

Reduced baroreflex sensitivity (BRS) is widely observed in diabetic human and animals. Rosiglitazone is one of the clinically used thiazolidinediones (TZD) known as PPAR γ agonist. Additionally, the klotho protein produced from choroid plexus in the central nervous system is regulated by PPAR γ . In an attempt to develop the new therapeutic strategy, we treated streptozotocin-induced diabetic rats (STZ) with rosiglitazone (STZ + TZD) orally at 10 mg/kg for 7 days. Also, STZ rats were subjected to intracerebroventricular (ICV) infusion of recombinant klotho at a dose of 3 µ g/2.5 µ L via syringe pump (8 µ g/hr) daily for 7 days. The BRS and heart rate variability were then estimated under challenge with a depressor dose of sodium nitroprusside (50 µ g/kg) or a pressor dose of phenylephrine (8 µ g/kg) through an intravenous injection. Lower expression of klotho in medulla oblongata of diabetic rats was identified. Cerebral infusion of recombinant klotho or oral administration of rosiglitazone reversed BRS in diabetic rats. In conclusion, recovery of the decreased klotho in brain induced by rosiglitazone may restore the impaired BRS in diabetic rats. Thus, rosiglitazone is useful to reverse the reduced BRS through increasing cerebral klotho in diabetic disorders.

Association of arterial stiffness indexes, determined from digital volume pulse measurement and cardiovascular risk factors in chronic kidney disease.

BACKGROUND: Progression of atherosclerosis with increased arterial stiffness is associated with increased cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). Compliance index (CI) derived from digital volume pulse (DVP), measuring the relationship between volume and pressure changes in fingertip, can evaluate the local arterial stiffness. The purpose of this study was to measure the stiffness of different arteries and determine the relationships of CI-DVP with clinical characteristics and renal function in CKD patients. METHODS: This cross-sectional pilot study included 186 CKD and 46 healthy subjects. Evaluation of different arterial stiffness was performed by DVP using dual-channel photoplethysmography and measured as CI (CI-DVP) and pulse wave velocity (PWV)-DVP. RESULTS: CKD patients had lower CI-DVP and higher PWV-DVP than that in the healthy group. There was a trend of stepwise decrease in CI-DVP and increase in PWV-DVP related to the advance of CKD from early to late stage. Decrease of CI-DVP was associated with the increase in number of cardiovascular risk factors. Multivariate linear regression analysis revealed that CI-DVP (B = 4.59, P < 0.01) was independently associated with estimated glomerular filtration rate (eGFR). Male gender, eGFR, and systolic blood pressure (BP) were independent determinants for CI-DVP (B = -0.25, P = 0.01; B = 0.007, P = 0.03; and B = -0.03, P < 0.0001; whole model R(2) = 0.28, P < 0.0001). CONCLUSIONS: Our data demonstrate a significant association between CI-DVP, a new surrogate marker of arterial stiffness different from PWV, and renal function and cardiovascular risk factors in CKD patients.

Decrease of Klotho in the kidney of streptozotocin-induced diabetic rats.

The klotho gene is expressed in a limited number of tissues, most notably in distal convoluted tubules in the kidney and choroid plexus in the brain. A previous study suggested that Klotho increases resistance to oxidative stress. However, changes of Klotho expression in high glucose-induced oxidative stress remain unclear. In the present study, we used streptozotocin-induced diabetic rats (STZ rats) to examine the effects of insulin, phloridzin or antioxidant, tiron on diabetic nephropathy. Both insulin and phloridzin reversed the lower Klotho expression levels in kidneys of STZ rats by the correction of hyperglycemia. Also, renal functions were improved by these treatments. In addition to the improvement of renal functions, the decrease of Klotho expression in kidney of STZ rats was also reversed by tiron without changing blood glucose levels. The reduction of oxidative stress induced by high glucose can be considered for this action of tiron. This view was further confirmed in vitro using high glucose-exposed Madin-Darby canine kidney (MDCK) epithelial cells. Thus, we suggest that decrease of oxidative stress is not only responsible for the improvement of renal function but also for the recovery of Klotho expression in kidney of STZ rats.

The antioxidative effect of bone morphogenetic protein-7 against high glucose-induced oxidative stress in mesangial cells.

Bone morphogenetic protein-7 (BMP-7) protects kidneys from diabetic nephropathy (DN), and high glucose (HG)-induced oxidative stress is involved in DN. We investigated the antioxidative ability of BMP-7 using HG-treated mesangial cells. We treated rat mesangial cells (RMCs) with recombinant human BMP-7 (rhBMP-7) and examined changes in reactive oxygen species (ROS) levels and intracellular signals in response to HG-induced oxidative stress. rhBMP-7 decreased the level of ROS in HG-treated RMCs. In contrast, lowering endogenous BMP-7 by siRNA or BMP receptor II (BMP-RII) by anti-BMP-RII antibodies increased the level of ROS in HG-treated RMCs. rhBMP-7 increased Smad-1,5,8 phosphorylation, decreased PKCzeta and c-Jun N-terminal kinase (JNK) phosphorylation, and decreased fibronectin and collagen IV synthesis in HG-treated RMCs. In conclusion, we found that BMP-7 could protect mesangial cells from HG-induced oxidative stress by activating BMP-RII. The antioxidative activity of BMP-7 was primarily due to inhibition of PKCzeta, JNK phosphorylation, and c-jun activation.

Arterial stiffness correlated with cardiac remodelling in patients with chronic kidney disease.

BACKGROUND: It is well known that both pressure and volume overloads contribute to left ventricular hypertrophy (LVH) and left ventricular dilatation in patients with chronic kidney disease (CKD). Few studies have evaluated the association between increased pulse wave velocity (PWV) and LVH in CKD patients not yet receiving dialysis. The purpose of this study was to assess the relationship between arterial stiffness and cardiac remodelling in patients with CKD, and to determine the independent factors associated with increased left ventricular mass index (LVMI) and left ventricular volume index (LVVI). METHODS: This cross-sectional study included 96 patients with CKD. Echocardiography and measurement of arterial stiffness by PWV were performed. Clinical and echocardiographic parameters were compared and analysed. RESULTS: Associated with the increase of PWV, there were significant trends for progressive increase in LVMI, LVH, LVVI, left ventricular dilatation and left atrium in CKD patients. Multivariate regression analysis revealed that decreased PWV, in addition to increased haemoglobin and the use of beta-blocker, was an independent determinant associated with decrease in LVMI and LVVI. CONCLUSION: Our study demonstrated the progressive structural remodelling of left ventricle and left atrium in CKD patients associated with increased severity of arterial stiffness. PWV was an important determinant of LVMI and LVVI in CKD patients.

Clinical characteristics and outcomes of new uremic patients with extreme azotemia in southern Taiwan.

Serum creatinine (SCr) had been considered to be an important predictor of mortality in end-stage renal disease (ESRD) patients at the start of renal replacement therapy (RRT). However, the data were limited about initially extreme azotemia (EA), exclusively defined as blood urea nitrogen (BUN) > or = 300 mg/dL, SCr > or = 30 mg/dL, or both. This retrospective study was conducted to clarify the characteristics and outcome in our EA patients. We had 1682 new ESRD patients from July 1988 to December 1996. With frequency match for age, gender, and starting RRT in the same period, 20 EA patients and 60 controls were included. Fifty percent of our EA patients had unknown etiology. The EA patients had significantly lower prevalence of underlying diabetic nephropathy, and comorbid hypertension. All the EA patients had late referral to nephrologists within 4 weeks before the initiation of RRT, and 90% of them had taken Chinese herbals. The EA group had significantly higher BUN, SCr, and iron storage as well as a higher prevalence of severe anemia, hyperkalemia, hypocalcemia, and acidemia. However, the similar prevalence of cardiomegaly and left ventricular hypertrophy as well as the similar early mortality rate and long-term survival were noted. Age over 40 years, comorbid diabetes mellitus, and hypoalbuminemia were independent predictors of poor survival. Our EA patients had different initial presentations from other uremic ones at the start of RRT. However, the short-term and long-term mortality rates were similar. The lower prevalence of underlying diabetic nephropathy and comorbid hypertension among the EA patients might contribute to their fair outcome.

Diffuse calcinosis and intradermal tophi in a uremic pateint: effect of low-calcium hemodialysis and mechanism of hypercalcemia.

Soft tissue calcification is a frequent complication in end-stage renal disease (ESRD) patients with a high serum calcium-phosphate product, but systemic involvement of both the visceral organs and skin is rarely seen. We report on a newly diagnosed ESRD patient with gouty nephropathy who had initial presentations of extensive intradermal tophi, diffuse calcinosis, and hypercalcemia. He received maintenance hemodialysis (HD) with low-calcium dialysate (1.25 mEq/l) for 11 months. Although the above complications diminished, serum calcium remained elevated. Thereafter, unexpected cervical lymphadenitis from a Mycobacterium tuberculosis (TB) infection with high extra-renal production of calcitriol was found. Serum calcium levels normalized only after anti-TB treatment for 2 months. We thought that this patient might have had occult TB infection before the start of HD, which resulted in calcitriol production and hypercalcemia. In addition, concomitant hyperphosphatemia in chronic renal failure contributed to severe diffuse calcinosis. After the initiation of HD therapy, both the elevated serum calcitriol levels and accelerated resolution and mobilization of diffuse calcinosis from low-calcium HD contributed to persistent hypercalcemia.