Journal of the American Society of Nephrology Chronic Kidney Disease

Abrogation of Protein Uptake through Megalin-Deficient Proximal Tubules Does Not Safeguard against Tubulointerstitial Injury

2007-05-25

Sustained proteinuria and tubulointerstitial damage have been closely linked with progressive renal failure. Upon excess protein endocytosis, tubular epithelial cells are thought to produce mediators that promote inflammation, tubular degeneration, and fibrosis. This concept was tested in a transgenic mouse model with megalin deficiency. Application of an anti–glomerular basement membrane serum to transgenic megalin-deficient mice [Cre(+)/GN] and megalin-positive littermates [Cre(–)/GN] produced the typical glomerulonephritis (GN) with heavy proteinuria in both groups. Tubulointerstitial damages correlated closely with glomerular damages in pooled Cre(+)/GN and Cre(–)/GN mice. Owing to a mosaic pattern of megalin expression in the mutant mice, Cre(+)/GN kidneys permitted side-by-side analysis of megalin-deficient and megalin-positive tubules in the same kidney. Protein endocytosis was found only in megalin-positive cells. TGF-ß, intercellular adhesion molecule, vascular cellular adhesion molecule, endothelin-1, and cell proliferation were high in megalin-positive cells, whereas apoptosis, heat-shock protein 25, and osteopontin were enhanced in megalin-deficient cells. No fibrotic changes were associated with either phenotype. Tubular degeneration with interstitial inflammation was found only in nephrons with extensive crescentic lesions at the glomerulotubular junction. In sum, enhanced protein endocytosis indeed led to an upregulation of profibrotic mediators in a megalin-dependent way; however, there was no evidence that endocytosis played a pathogenetic role in the development of the tubulointerstitial disease.

Estimated Glomerular Filtration Rate and Urinary Albumin Excretion Are Independently Associated with Greater Arterial Stiffness: The Hoorn Study

2007-05-25

Mild renal insufficiency is a risk factor for cardiovascular disease (CVD). Both a decline in GFR and (micro)albuminuria are associated with greater cardiovascular mortality. In ESRD, arterial stiffness, an important cause of CVD, is known to be greater, but few data exist in individuals with mild renal insufficiency or microalbuminuria. This study investigated the association of impaired renal function expressed as lower GFR or greater urinary albumin excretion with arterial stiffness. In a population-based study in 806 individuals (402 men), mean age 68 yr (range 50 to 87), peripheral arterial stiffness (by compliance and distensibility of the carotid, brachial, and femoral arteries and by the carotid elastic modulus [E_inc]) and central arterial stiffness (by total systemic arterial compliance, carotid-femoral transit time, and aortic augmentation index) were measured ultrasonically. GFR was estimated (eGFR) by the Modification of Diet in Renal Disease (MDRD) formula. Urinary albumin excretion was expressed as urinary albumin/creatinine ratio (UACR). eGFR was 60.6 ± 11.1 ml/min per 1.73 m². Median UACR was 0.57 mg/mmol (range 0.1 to 26.6). After adjustment for age, mean arterial pressure (MAP), gender, and glucose tolerance status (GTS), each 5-ml/min per 1.73 m² lower eGFR was associated with a lower distensibility coefficient of the carotid (regression coefficient ß –0.20 10^–3/kPa; 95% confidence interval [CI] –0.34 to –0.07 10^–3/kPa) and brachial artery (–0.15 10^–3/kPa; 95% CI –0.28 to –0.03 10^–3/kPa) and a greater carotid E_inc (0.02 kPa; 95% CI 0.0004 to 0.04 kPa). No statistically significant association was found of eGFR with other arterial stiffness indices. After adjustment for age, MAP, gender, and GTS, a greater UACR (per quartile) was associated with a greater E_inc (0.03 kPa; 95% CI 0.001 to 0.07 kPa) and a trend to a lower distensibility coefficient (–0.24 10^–3/kPa; 95% CI –0.49 to 0.02 10^–3/kPa) of the carotid artery. After adjustment for age, MAP, gender, and GTS, a greater UACR (per quartile) was in addition associated with a shorter carotid-femoral transit time (–1.67 ms; 95% CI –3.24 to –0.10 ms). These associations were not substantially changed by mutual adjustment for eGFR and UACR. In individuals with mild renal insufficiency, both a lower eGFR and a greater albumin excretion, even below levels that are considered to reflect microalbuminuria, are independently associated with greater arterial stiffness. Moreover, these associations were mutually independent. These findings may explain, in part, why eGFR and microalbuminuria are associated with greater risk for CVD and suggest that amelioration of arterial stiffness could be a target of intervention.

Myocardial Ultrasound Tissue Characterization in Patients with Chronic Renal Failure

2007-05-25

The objective of this study was to detect ultrastructural changes in myocardium related to collagen content by ultrasound tissue characterization in patients with chronic kidney disease (CKD) and in uncomplicated hypertensive control subjects. In 25 hemodialysis (HD) patients, in 25 patients with moderate to severe chronic renal failure (CRF), and in 10 patients with essential hypertension (EH) and normal renal function matched for age, BP, and left ventricular mass index, left ventricular anatomy and function were evaluated by conventional echocardiography, and integrated backscatter signal (IBS) was analyzed by acoustic densitometry. IBS mean reflectivity increased from 48% in patients with EH to 56% in patients with CRF to 62% in HD patients (ANOVA P < 0.01). IBS mean cyclic variation was progressively increased from 4.35 ± 1.2 dB in HD patients to 5.27 ± 0.90 in patients with CRF to 6.50 ± 1.6 dB in patients with EH (ANOVA P < 0.01). At multivariate analysis, IBS mean reflectivity was positively related to age and serum creatinine (ß 0.351, P = 0.036; and ß = 0.408, P = 0.016, respectively). IBS mean cyclic variation was inversely related to age and serum creatinine (ß = –0.274, P = 0.025; and ß = –0.262, P = 0.025, respectively) and positively related to left ventricular midwall fractional shortening and transmitral E/A ratio (ß = 0.269, P < 0.05; and ß = 0.314, P < 0.001, respectively). The data support the hypothesis that interstitial collagen deposition may appear early in the course of CKD and suggest that acoustic densitometry may represent a useful tool for the assessment of myocardial tissue changes in patients with CKD.

Progression Risk, Urinary Protein Excretion, and Treatment Effects of Angiotensin-Converting Enzyme Inhibitors in Nondiabetic Kidney Disease

2007-05-25

It is unclear whether patients with nondiabetic kidney disease benefit from angiotensin-converting enzyme inhibitor (ACEI) therapy when they are at low risk for disease progression or when they have low urinary protein excretion. With the use of a combined database from 11 randomized, clinical trials (n = 1860), a Cox proportional hazards model, based on known predictors of risk and the composite outcome kidney failure or creatinine doubling, was developed and used to stratify patients into equal-sized quartiles of risk. Outcome risk and treatment effect were examined across various risk strata. Use of this risk model for targeting ACEI therapy was also compared with a strategy based on urinary protein excretion alone. Control patients in the highest quartile of predicted risk had an annualized outcome rate of 28.7%, whereas control patients in the lowest quartile of predicted risk had an annualized outcome rate of 0.4%. Despite the extreme variation in risk, there was no variation in the degree of benefit of ACEI therapy (P = 0.93 for the treatment x risk interaction). Significant interaction was detected between baseline urine protein and ACEI therapy (P = 0.003). When patients were stratified according to their baseline urinary protein excretion, among the subgroup of patients with proteinuria ≥500 mg/d, significant treatment effect was seen across all patients with a measurable outcome risk, including those at relatively low risk (1.7% annualized risk for progression). However, there was no benefit of ACEI therapy among patients with proteinuria <500 mg/d, even among higher risk patients (control outcome rate 19.7%). Patients with nondiabetic kidney disease vary considerably in their risk for disease progression, but the treatment effect of ACEI does not vary across risk strata. Patients with proteinuria <500 mg/d do not seem to benefit, even when at relatively high risk for progression.

Carotid Intima Media Thickness Predicts Cardiovascular Diseases in Chinese Predialysis Patients with Chronic Kidney Disease

2007-05-25

Patients with chronic kidney disease (CKD) have a high risk for cardiovascular disease. Ultrasound measurements of the intima media thickness (IMT) in the carotid arteries is a strong predictor for cardiovascular events in the general population and dialysis patients. However, it is unclear whether carotid IMT is useful for the prediction of cardiovascular events in predialysis patients with CKD. The prediction power of carotid ultrasonography for cardiovascular event, rate of renal function decline, and all-cause mortality was tested in a cohort of 203 Chinese patients with stages 3 to 4 CKD. The average IMT was 0.808 ± 0.196 mm; 121 (59.6%) patients had atherosclerotic plaques visualized. IMT correlated with patient age (r = 0.373, P < 0.001), serum LDL level (r = 0.164, P = 0.021), Charlson’s comorbidity score (r = 0.260, P < 0.001), and serum C-reactive protein (r = 0.279, P < 0.001). Carotid IMT was significantly higher in patients with diabetes than in those without diabetes (0.930 ± 0.254 versus 0.794 ± 0.184; P = 0.002). At 48 mo, the cardiovascular event-free survival was 94.4, 89.8, 77.7, and 65.9% for IMT quartiles I, II, III, and IV, respectively (log rank test, P = 0.006). By multivariate analysis with the Cox proportional hazard model, each higher quartile of IMT conferred 41.6% (95% confidence interval 6.4 to 88.4%; P = 0.017) excess hazard for developing cardiovascular event. The actuarial survival at 48 mo was 96.3, 98.0, 95.7, and 85.7% for IMT quartiles I, II, III and IV, respectively (log rank test, P = 0.127), and the difference was not statistically significant after Cox proportional hazard model to adjust for confounders. Carotid IMT did not correlate with the rate of renal function decline in these patients. Carotid IMT is a strong predictor of cardiovascular disease in Chinese predialysis patients and may be usefully applied for risk stratification in this group of patients.