Recurrent podocytopathy in a patient with systemic lupus erythematosus.

Podocytopathy in systemic lupus erythematosus is characterised by diffuse foot process effacement without significant peripheral capillary wall immune deposits as seen on electron microscopy. Lupus podocytopathy falls outside the scope of the current International Society of Nephrology and the Renal Pathology Society classification of lupus nephritis. We present a case of relapsing podocytopathy with nephrotic syndrome occurring simultaneously with two extra-renal and serological disease flares, which makes it likely that podocytopathy was related to systemic lupus erythematosus activity. This case adds to the growing body of evidence that lupus podocytopathy must be considered in the differential diagnosis of systemic lupus erythematosus patients presenting with nephrotic syndrome.

Insulin resistance and vascular dysfunction in chronic kidney disease: mechanisms and therapeutic interventions.

Insulin resistance (IR) is a novel cardiovascular risk factor that has been implicated in the pathogenesis of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Beyond its metabolic effects, insulin can potentially mediate the increased risk for CVD through its vasoactive properties. This review examines key clinical data and potential mechanisms linking IR and cardiovascular risk in CKD. While lifestyle interventions and pharmacotherapies with known insulin-sensitizing properties are promising therapeutic targets to reduce the CVD burden in this population, clinical trial data on the effect of insulin sensitization on vascular function in CKD are either lacking or conflicting and are limited by small sample size and short duration of intervention. Affirming the role of IR in lowering CVD risk in CKD will require prospective randomized controlled studies with sufficient sample size and hard clinical outcomes. Future research efforts should be directed at assessing the efficacy, safety and mechanisms by which novel insulin sensitizers such as bile acid sequestrant, selective and dual peroxisome proliferator-activated receptor modulators and modulators of gut microbiota and uraemic toxins alter vascular function in patients with CKD.

Insulin resistance and the metabolic syndrome are associated with arterial stiffness in patients with chronic kidney disease.

BACKGROUND: Insulin resistance (IR) and the metabolic syndrome (MetS) may contribute to cardiovascular risk in chronic kidney disease (CKD). We examine the association between IR and vascular function in CKD. Furthermore, we define the prevalence of MetS and examine the association between defining MetS and vascular function. METHODS: This cross-sectional study of 71 stage 3-4 CKD subjects assessed arterial stiffness (pulse wave velocity (PWV) and endothelial dysfunction (ED). IR was assessed using Homeostasis Model Assessment-IR (HOMA-IR). MetS was defined by the unified International Diabetes Federation and American Heart Association/National Heart Lung and Blood Institute criteria. RESULTS: CKD subjects with HOMA-IR score above the median had significantly higher body mass index and waist circumference. They also had higher PWV, higher triglycerides with lower high-density lipoprotein concentration (P < 0.05). Age, systolic blood pressure, and HOMA-IR were independently associated with PWV, even after exclusion of diabetic subjects (n = 16) (P ≤ 0.05). MetS was more prevalent in CKD (78.9%) than controls (2.5%). MetS in CKD was associated with increased PWV (MetS(+) geometric mean = 9.5 m/s, 95% confidence interval (95% CI) = 8.9-10.2 m/s; vs. MetS(-) 8.1 m/s, 95% CI = 7.1-9.3 m/s; P = 0.03) but not ED. In a multiple logistic regression analysis, PWV higher than the median was independently associated with dysglycemia. CONCLUSIONS: IR is independently associated with arterial stiffness, even in nondiabetic CKD. MetS is common and identified a subgroup of CKD patients with increased arterial stiffness, which is associated with dysglycemia.

Association of a change in immunosuppressive regimen with hemodynamic and inflammatory markers of cardiovascular disease after kidney transplantation.

BACKGROUND: Although rejection rates and short-term graft survival have significantly improved in kidney transplantation with the introduction of calcineurin inhibitor (CNI), cardiovascular disease (CVD) and metabolic complications are being increasingly recognized as important causes of morbidity and mortality. We hypothesize that non-CNI proliferation signal inhibitor (PSI)-based immunosuppressive regimen is associated with improved arterial stiffness after kidney transplantation compared with CNI-based immunosuppressive regimens. METHODS: This is a prospective, single-center study of renal transplant (RT) recipients comparing the metabolic, cardiovascular (pulse wave velocity and aortic augmentation index (AI) adjusted for heart rate (AI × 75)), inflammatory cytokines (interleukins (ILs) 6, 12, and 18) and graft-related outcomes at 3 and 15 months posttransplantation between RT recipients maintained on CNI- (CNI-CNI) or PSI-based (CNI-PSI) regimens including sirolimus and everolimus. RESULTS: Fifty and 17 RT recipients maintained on CNI-CNI and CNI-PSI, respectively, were included in this study. Median time to PSI conversion from CNI was 5 months. Compared with CNI-CNI recipients, CNI-PSI recipients had significantly lower fasting blood glucose in nondiabetics (coefficient = -16.2; 95% confidence interval (CI) = -14.4 to -18.0; P < 0.01), lower IL-18 levels (coefficient = -229.16; 95% CI = -343.94 to -114.38; P < 0.01), and lower AI × 75 (coefficient = -5.14; 95% CI = -9.99 to -0.28; P = 0.04) at 15 months posttransplant in the multivariable models. CONCLUSIONS: Our study suggests from the elimination of CNI for PSI may lower AIx75 and IL-18, both surrogate markers of CVD, but adequately powered, randomized, controlled studies are required to establish the causal relationship between immunosuppressive agents and CVD risk.

Compared with younger peritoneal dialysis patients, elderly patients have similar peritonitis-free survival and lower risk of technique failure, but higher risk of peritonitis-related mortality.

BACKGROUND: The number of elderly patients with end-stage kidney disease (ESKD) is increasing worldwide, but the proportion of elderly patients commencing peritoneal dialysis (PD) is falling. The reluctance of elderly ESKD patients to consider PD may be related to a perception that PD is associated with greater rates of complications. In the present study, we compared outcomes between younger and older PD patients. METHODS: Using Australia and New Zealand Dialysis Registry data, all adult ESKD patients commencing PD between 1991 and 2007 were categorized into under 50, 50 - 64.9, and 65 years of age or older groups. Time to first peritonitis, death-censored technique failure, and peritonitis-associated and all-cause mortality were evaluated by multivariate Cox proportional hazards model analysis. RESULTS: Of the 12 932 PD patients included in the study, 3370 (26%) were under 50 years of age, 4386 (34%) were 50 - 64.9 years of age, and 5176 (40%) were 65 years of age or older. Compared with younger patients (<50 years), elderly patients (≥ 65 years) had a similar peritonitis-free survival and a lower risk of death-censored technique failure [hazard ratio (HR): 0.85; 95% confidence interval (CI): 0.79 to 0.93], but they had higher peritonitis-related (HR: 2.31; 95% CI: 1.68 to 3.18) and all-cause mortality (HR: 2.90; 95% CI: 2.60 to 3.23). CONCLUSIONS: Not unexpectedly, elderly patients have higher peritonitis-related and all-cause mortality, which is likely a consequence of a greater prevalence of comorbid disease. However, compared with younger patients, elderly patients have superior technique survival and similar peritonitis-free survival, suggesting that PD is a viable renal replacement therapy in this group of patients.

Rosiglitazone does not improve vascular function in subjects with chronic kidney disease.

BACKGROUND: Thiazolidinediones such as rosiglitazone (RSG) are insulin-sensitizing agents, which may improve inflammation and vascular function, and thus potentially lower cardiovascular risk in patients with chronic kidney disease (CKD). However, there is growing concern about the adverse cardiovascular effects of RSG in diabetic patients without CKD, and the data in patients with CKD remain conflicting. This study examines the effect of RSG on vascular function in patients with CKD. METHODS: A randomized, double-blind placebo-controlled study comparing RSG 4 mg daily (n = 35) with placebo (n = 35) for 8 weeks was performed in CKD subjects. Primary outcome measures were flow-mediated dilatation (FMD), systemic arterial compliance (SAC) and augmentation index (AIx). Secondary outcomes included glyceryl trinitrate-mediated dilatation (GTN-MD), pulse-wave velocity (PWV), lipids, blood pressure, homoeostasis model assessment (HOMA), adiponectin, high-sensitivity C-reactive protein (hs-CRP) and high-sensitivity interleukin 6 (hs-IL-6) and in vivo marker of endothelial function [von Willebrand Factor (vWF)]. RESULTS: RSG lowered HOMA score [RSG geometric mean 1.7 (95% confidence interval 1.3-2.3); placebo 1.9 (1.4-2.5), P = 0.04], hs-CRP [RSG 1.2 (0.9-1.7) mg/L; placebo 1.6 (1.2-2.3), P = 0.04] and vWF [RSG mean 126.1 ± SD 45.7%; placebo 132.7 ± 41.7, P = 0.01] but not hs-IL-6. RSG did not significantly change arterial function (FMD, GTN-MD, SAC), arterial stiffness (AIx, PWV) or blood pressure. RSG increased triglyceride concentration [RSG 1.8 (1.3-1.9) mmol/L; placebo 1.5 (1.3-1.9), P = 0.01] without affecting other lipid and lipoprotein concentrations. CONCLUSION: Short-term RSG therapy reduced insulin resistance, in vivo markers of inflammation and abnormal endothelial function but had no effect on arterial function and stiffness in patients with CKD.

Plasma apolipoprotein C-III metabolism in patients with chronic kidney disease.

Moderate chronic kidney disease (CKD) (defined by an estimated glomerular filtration rate of 30-60 ml/min) is associated with mild hypertriglyceridemia related to delayed catabolism of triglyceride-rich lipoprotein particles. Altered apolipoprotein C-III (apoC-III) metabolism may contribute to dyslipidemia in CKD. To further characterize the dyslipidemia of CKD, we investigated the kinetics of plasma apoC-III in 7 nonobese, nondiabetic, non-nephrotic CKD subjects and 7 age- and sex-matched healthy controls, using deuterated leucine ([5, 5, 5, ²H3]leucine), gas chromatography-mass spectrometry, and multicompartmental modeling. Compared with controls, CKD subjects had higher concentrations of plasma and VLDL triglycerides and plasma and VLDL apoC-III (P < 0.05). The increased plasma apoC-III concentration was associated with a decreased apoC-III fractional catabolic rate (FCR) (1.21 ± 0.15 vs. 0.74 ± 0.12 pools/day, P = 0.03). There were no differences between apoC-III production rates of controls and those of CKD subjects. In CKD subjects, plasma apoC-III concentration was significantly and negatively correlated with apoC-III FCR (r = -0.749, P = 0.05) but not with apoC-III production rate. Plasma apoC-III concentration was positively correlated with plasma and VLDL triglycerides and VLDL apoB concentrations and negatively correlated with VLDL apoB FCR (P < 0.05 for all). ApoC-III FCR was negatively correlated with plasma and VLDL triglycerides and VLDL apoB concentration and positively correlated with VLDL apoB FCR (P < 0.05 for all). Altered plasma apoC-III metabolism is a feature of dyslipidemia in moderate CKD. Modification of apoC-III catabolism may be an important therapeutic target for reducing cardiovascular disease risk in moderate CKD.

Chronic kidney disease delays VLDL-apoB-100 particle catabolism: potential role of apolipoprotein C-III.

To determine the relative contribution of obesity and/or insulin resistance (IR) in the development of dyslipidemia in chronic kidney disease (CKD), we investigated the transport of apolipoprotein (apo) B-100 in nonobese, nondiabetic, nonnephrotic CKD subjects and healthy controls (HC). We determined total VLDL, VLDL(1), VLDL(2), intermediate density lipoprotein (IDL), and LDL-apoB-100 using intravenous D3-leucine, GC-MS, and multicompartmental modeling. Plasma apoC-III and apoB-48 were immunoassayed. In this case control study, we report higher plasma triglyceride, IDL-, VLDL-, VLDL(1)-, and VLDL(2)-apoB-100 concentrations in CKD compared with HC (P < 0.05). This was associated with decreased fractional catabolic rates [FCRs (pools/day)] [IDL:CKD 3.4 (1.6) vs. HC 5.0 (3.2), P < 0.0001; VLDL:CKD 4.8 (5.2) vs. HC 7.8 (4.8), P = 0.038; VLDL(1):CKD 10.1 (8.5) vs. HC 29.5 (45.1), P = 0.007; VLDL(2):CKD 5.4 (4.6) vs. HC 10.4 (3.4), P = 0.001] with no difference in production rates. Plasma apoC-III and apoB-48 were significantly higher in CKD (P < 0.001) and both correlated with impaired FCRs of VLDL, VLDL(1), and VLDL(2) apoB-100 (P < 0.05). In CKD, apoC-III concentration was the only independent predictor of clearance defects in VLDL and its subfractions. Moderate CKD in the absence of central adiposity and IR is associated with mild hypertriglyceridemia due to delayed catabolism of triglyceride rich lipoproteins, IDL, and VLDL, without changes in production rate. Altered apoC-III metabolism may contribute to dyslipidemia in CKD, and this requires further investigation.

Dyslipidaemia and cardiorenal disease: mechanisms, therapeutic opportunities and clinical trials.

Dyslipidaemia is an important risk factor for the development of chronic kidney disease (CKD) and cardiovascular disease (CVD). CKD generates an atherogenic lipid profile, characterised by high triglycerides, low high-density lipoprotein (HDL) cholesterol and accumulation of small dense low-density lipoprotein (LDL) particles, comparable to that in the metabolic syndrome. These changes are due specifically to the effects of CKD on key enzymes, transfer proteins and receptors involved in lipid metabolism. Dyslipidaemia is further compounded by dialysis, immunosuppressive drugs, and concomitant diseases such as diabetes mellitus. Post hoc analyses from large intervention trials suggest the benefit of statins in patients with early CKD, but prospective clinical trials in haemodialysis (HD) and renal transplant recipients have not conclusively shown improvements in hard cardiovascular end-points. The lack of efficacy of statins in late-stage CKD could be a consequence of other disease processes, such as calcific arteriopathy and insulin resistance, which are not modified by lipid-lowering agents. Despite uncertainty and pending the results of ongoing statin trials such as Study of Heart and Renal Protection (SHARP) and AURORA (A study to evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis: an Assessment of survival and cardiovascular events), major international guidelines continue to support statin therapy in CKD and renal transplant patients to reduce cardiovascular risk burden. Because of increased risk of toxicity, particularly myopathy, statins and other lipid-regulating agents should be used cautiously in CKD and renal transplant recipients.

Insulin resistance, dyslipidaemia, inflammation and endothelial function in nephrotic syndrome.

BACKGROUND: Nephrotic syndrome (NS) is associated with an increased risk of cardiovascular disease (CVD). We have shown previously that endothelial function, measured by post-ischaemic flow-mediated dilatation (FMD) of the brachial artery, is impaired in NS. In this study our aim was to assess the potential roles of insulin resistance, plasma non-esterified fatty acids (NEFAs) and inflammation in endothelial dysfunction in NS patients. METHODS: FMD was compared between NS patients (n=19) and controls (CS, n=19). Plasma glucose, insulin and NEFAs were measured. Insulin resistance was calculated using the Homeostasis Model Assessment (HOMA) score. C-reactive protein (CRP), interleukin-6 (IL-6), tumour necrosis factor alpha (TNFalpha) and fibrinogen were measured as markers of inflammation. RESULTS: FMD was significantly lower in the NS group (mean+/-standard error, NS 5.1+/-0.7%, CS 7.3+/-0.7%, P=0.02). Fasting insulin (NS 12.5+/-1.5 mU/l, CS 6.8+/-0.7 mU/l, P<0.01), fasting glucose (NS 5.3+/-0.2, CS 4.8+/-0.1, P=0.02) and the HOMA score (NS 3.0+/-0.4, CS 1.5+/-0.2, P=0.001) were significantly higher in NS. These differences persisted after adjusting for waist circumference. Of the inflammatory markers, only fibrinogen (P<0.01) and IL-6 (P=0.01) were significantly increased in NS. Despite significantly lower plasma NEFAs in NS, the NEFA:albumin ratio showed a non-significant trend to higher levels in NS (NS 10.7+/-0.1 micro mol/g, CS 8.7+/-0.1 micro mol/g, P=0.06). Within the NS group, multivariate backward regression analysis showed that NEFAs (P<0.01) and low-density lipoprotein (LDL) cholesterol (P=0.05) were significant negative independent predictors of FMD. CONCLUSION: Endothelial function in NS is inversely correlated with plasma concentrations of NEFAs and LDL cholesterol. Dyslipoproteinaemia and NEFAs probably contribute to the increased risk of CVD seen in NS. We also postulate that in NS, hypoalbuminaemia increases the delivery of NEFAs to endothelial cells thereby impairing the synthesis and release of nitric oxide.

Prevention of tunneled hemodialysis catheter-related infections using catheter-restricted filling with gentamicin and citrate: a randomized controlled study.

Tunneled catheters are widely used for the provision of hemodialysis. Long-term catheter survival is limited by tunneled catheter-related infections (CRI). This study assesses the efficacy of catheter-restricted filling with gentamicin and citrate in preventing CRI in hemodialysis patients. A double-blind randomized study was conducted to compare heparin (5000 U/ml) with gentamicin/citrate (40 mg/ml and 3.13% citrate; ratio 2:1) as catheter-lock solutions. A total of 112 tunneled catheters in 83 patients were enrolled at the time of catheter insertion for commencement or maintenance of hemodialysis. The primary end point was CRI. Catheter malfunction, defined as blood flow rate of <200 ml/min for three consecutive dialyses and/or the use of urokinase, was also assessed as a secondary end point. Infection rates per 100 catheter-days were 0.03 in the gentamicin group versus 0.42 in the heparin group (P = 0.003). Kaplan-Meier survival analyses showed mean infection-free catheter survival of 282 d (95% CI, 272 to 293 d) in the gentamicin group versus 181 d (95% CI, 124 to 237 d) in the heparin group (log rank, 9.58; P = 0.002). Cox regression analyses showed a relative risk for infection-free catheter survival of 0.10 (95% CI, 0.01 to 0.92) in the gentamicin group when adjusted for gender, race, diabetes mellitus, catheter malfunction, and hemoglobin (P = 0.042). The incidence of catheter malfunction was not significantly different between groups. Predialysis gentamicin levels were significantly higher in patients randomized to gentamicin (gentamicin/citrate: median 2.8 mg/L [range, 0.6 to 3.5 mg/L], n = 5; heparin: median <0.2 mg/L [range <0.2 to 0.2 mg/L], n = 5; P = 0.008). Tunneled hemodialysis catheter-restricted filling with gentamicin and citrate is a highly effective strategy for prevention of CRI. Although citrate as a catheter-lock solution provides adequate anticoagulation for the interdialytic period, gentamicin levels suggest significant risk for chronic aminoglycoside exposure and associated ototoxicity. Before this technique is adopted, these preliminary observations warrant replication in future studies that will examine the efficacy and safety of lower doses of gentamicin or alternative agents with a reduced potential for toxicity.

Statin therapy improves brachial artery endothelial function in nephrotic syndrome.

BACKGROUND: Patients with nephrotic syndrome have impaired endothelial function probably related to dyslipidemia. This study evaluated the effects of statin therapy on dyslipidemia and endothelial function in patients with nephrotic syndrome. METHODS: A sequential, open-label study of the effects of statins on endothelial dysfunction in 10 nephrotic patients treated with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II (Ang II) receptor antagonist. Endothelial function was assessed at baseline, after 12 weeks of treatment with statins, and after an 8-week washout. Brachial artery endothelial function was measured as post-ischemic flow-mediated dilation (FMD) using ultrasonography. Endothelium-independent, glyceryl trinitrate-mediated vasodilation (GTNMD) also was measured. RESULTS: Serum lipids were significantly lower following statin: total cholesterol mean 8.2 +/- 0.4 (standard error) mmol/L versus 5.2 +/- 0.3 mmol/L, triglycerides 2.6 +/- 0.4 mmol/L versus 1.6 +/- 0.2 mmol/L, non-HDL-cholesterol 6.7 +/- 0.4 mmol/L versus 3.7 +/- 0.2 mmol/L (all P < 0.001). There was a trend to an increase in serum albumin (31.0 +/- 1.3 g/L vs. 33.8 +/- 1.5 g/L; P = 0.078) and FMD improved significantly following treatment (3.7 +/- 1.1% vs. 7.0 +/- 0.8%, P < 0.01). After washout, FMD deteriorated significantly to 3.5 +/- 1.4% (P < 0.05) versus week 12 FMD. GTNMD was unchanged. In multivariate regression, reduction in non-high-density lipoprotein (HDL)-cholesterol (beta - 0.736, P = 0.027) and increase in serum albumin (beta 0.723, P = 0.028), but not the on-treatment level of non-HDL-cholesterol, were significant independent predictors of improvement in FMD after adjusting for change in resting brachial artery diameter. Changes in serum lipoprotein and albumin concentrations off treatment were not associated with deterioration in FMD. CONCLUSION: Statin therapy significantly improves dyslipidemia and brachial artery endothelial function in patients with nephrotic syndrome. Improvement in brachial artery endothelial function may be in part related to a non-lipid effect of statins. The findings also suggest a role for dyslipidemia in endothelial dysfunction and the risk for cardiovascular disease in nephrotic syndrome.