Cystatin C improves the diagnosis and stratification of chronic kidney disease, and the estimation of glomerular filtration rate in diabetes.

AIMS: Estimation of glomerular filtration rate (GFR) is recommended to diagnose and stratify chronic kidney disease (CKD). Can cystatin-C (cysC) assay improve the results in diabetic patients? METHODS: In 124 diabetic patients with a wide range of GFR, as determined by 51Cr-EDTA clearance (i-GFR), we estimated 'e-GFR' by: the recommended Cockcroft-Gault (CG) formula and Modification of Diet in Renal Disease (MDRD) study equation; the new Mayo Clinic quadratic (MCQ) equation; the recently proposed composite estimation including both serum creatinine and cysC; and a simplified approach dividing the MDRD by cysC if less than 1.10mg/L. RESULTS: The highest diagnostic accuracy (receiver operating characteristic [ROC] curves) and the highest proportions of well-stratified patients were obtained by cysC and the MDRD which, however, underestimated i-GFR for patients without CKD (-17%, P<0.001). The CG overestimated GFR in KDOQI stages 1 and 2, ignored stage 5 and was the least accurate. The MCQ equation overrepresented stage 2, overestimating GFR at this stage (+23%, P<0.005). The composite estimation (54.7+/-27.0mL per minute 1.73m(2)) correlated best with i-GFR (56.1+/-35.3; r=0.90, P<0.001), and did not significantly differ from it across the entire population and within each Kidney Disease Outcome Quality Initiative (KDOQI) stage but was also biased (Bland-Altman procedure). Simply dividing the MDRD by cysC ifless than1.10mg/L produced a comparable performance and eliminated the bias. CONCLUSION: The recommended creatinine-based estimations of GFR need to be improved. CysC assay helps in the diagnosis and stratification of CKD and leads to better estimates of GFR in diabetic patients without any substantial increase in complexity.

A simplified Cockcroft-Gault formula to improve the prediction of the glomerular filtration rate in diabetic patients.

AIM: The National Kidney Foundation recommends stratification of renal failure into moderate (Glomerular Filtration Rate: GFR = 30-60 mL/min/1.73 m2), severe (15-30) or terminal (<15) using the Cockcroft-Gault (CG) or the Modification of Diet in Renal Disease (MDRD) equations. We studied the biases in these methods in an attempt to improve the standard CG (MCG) and devise a strategy for stratification. METHODS: GFR was measured by 51Cr-EDTA clearance in 200 diabetic patients: 100 (Group 1: study of concordance) before 2003 and 100 thereafter (Group 2: validation of MCG). The CG was modified by replacing body weight by its mean value: 76. RESULTS: In group 1, the recommended equations only correctly stratified 50 patients. The CG, not the MDRD, underestimated GFR if BMI was normal, and overestimated it in obese patients. In group 2, the MCG was well correlated with GFR and not biased by weight. Over the whole population, the MCG and MDRD were more accurate for the diagnosis of moderate and severe renal failure. The MDRD showed the lowest differences with GFR, except if GFR > 60, where the MCG performed better. All formulae overestimated low GFR, the MDRD also underestimated high GFR. The best stratification (147/200) was obtained using the MCG if creatininemia < 120 micromol/l and the MDRD if creatininemia > or =120 micromol/l. CONCLUSION: The CG is biased by weight, the MCG corrects this. The more accurate MDRD cannot be used in all patients as it underestimates high GFR. The best stratification was obtained using the MCG at low and the MDRD at high creatininemia.

[Ac-SDKP, a marker of the angiotensin-converting enzyme activity?]. / L'Ac-SDKP: une clé pour comprendre certains effets des inhibiteurs de l'enzyme de conversion?

The tetra-peptide Acetyl-Ser-Asp-Lys-Pro (Ac-SDKP) generated by the cleavage of thymosine beta4 inhibits the proliferation of hematopoietic stem cells and the proliferation and secretion of fibroblasts in the myocardium and the glomeruli. The clinical administration of Ac-SDKP has been proposed and partially investigated. The peptide could protect hematopoietic stem cells during anti-neoplastic treatments leaving cancerous cells unprotected. As it opposes the effects of TGFbeta it could prevent fibrosis after myocardial infarcts and glomeruli fibrosis during the natural course of diabetic nephropathy. However, until now the expected benefits of such a treatment are based on an indirect consideration. Indeed, the degradation of Ac-SDKP is due to the action of the angiotensin-converting enzyme. Interestingly, the blocking of this enzyme both improves the above-mentioned fibrosis and increases the plasma levels of Ac-SDKP. Should the therapeutic effects prove solid, and therapeutic levels be established assaying Ac-SDKP could be an interesting marker of therapeutic efficiency.

[Primary hyperaldosteronism]. / Dépistage biologique de l'hyperaldostéronisme primaire. Revue de la littérature.

Diagnosing primary aldosteronism, a hypertensive endocrine disease, is difficult because of an ill-defined frequency, various clinical forms and multiple diagnostic criteria. Current recommendations rest upon aldosterone and renin or renin activity determinations, the main point being to investigate aldosterone secretion with regards to of its main stimulus, renin. Proponents of the renin assay argue that it is easy and reliable. Proponents of the renin activity assay favour this method because of multiple epidemiological studies. Whatever the method used, each laboratory has to establish its critical thresholds in relation to the kits used. Extensive comparative studies would be useful to appreciate their relative benefits.

Estimation of glomerular filtration rate in diabetic subjects: Cockcroft formula or modification of Diet in Renal Disease study equation?

OBJECTIVE: The Cockcroft-Gault formula is recommended for the evaluation of renal function in diabetic patients. The more recent Modification of Diet in Renal Disease (MDRD) study equation seems more accurate, but it has not been validated in diabetic patients. This study compares the two methods. RESEARCH DESIGN AND METHODS: In 160 diabetic patients, we compared the Cockcroft-Gault formula and MDRD equation estimations to glomerular filtration rates (GFRs) measured by an isotopic method ((51)Cr-EDTA) by correlation studies and a Bland-Altman procedure. Their accuracy for the diagnosis of moderately (GFR <60 ml . min(-1) . 1.73 m(-2)) or severely (GFR <30 ml . min(-1) . 1.73 m(-2)) impaired renal function were compared with receiver operating characteristic (ROC) curves. RESULTS: Both the Cockcroft-Gault formula (r = 0.74; P < 0.0001) and MDRD equation (r = 0.81; P < 0.0001) were well correlated with isotopic GFR. The Bland-Altman procedure revealed a bias for the MDRD equation, which was not the case for the Cockcroft-Gault formula. Analysis of ROC curves showed that the MDRD equation had a better maximal accuracy for the diagnosis of moderate (areas under the curve [AUCs] 0.868 for the Cockcroft-Gault formula and 0.927 for the MDRD equation; P = 0.012) and severe renal failure (AUC 0.883 for the Cockcroft-Gault formula and 0.962 for the MDRD equation; P = 0.0001). In the 87 patients with renal insufficiency, the MDRD equation estimation was better correlated with isotopic GFR (Cockcroft-Gault formula r = 0.57; the MDRD equation r = 0.78; P < 0.01), and it was not biased as evaluated by the Bland-Altman procedure. CONCLUSIONS: Although both equations have imperfections, the MDRD equation is more accurate for the diagnosis and stratification of renal failure in diabetic patients.

Skin autofluorescence is associated with past glycaemic control and complications in type 1 diabetes mellitus.

As skin autofluorescence (AF) can assess subcutaneous accumulation of fluorescent advanced glycation end-products (AGEs), this study aimed to investigate whether it was linked to glycaemic control and complications in patients with type 1 diabetes mellitus (T1DM). Using the AGE Reader™, AF was measured in T1DM patients referred to Haut-Levêque Hospital (Bordeaux, France); data on their HbA1c levels measured every 6months as far back as the last 5years were also collected. The association of AF with the patients' past glucose control, based on their latest HbA1c values, and the means of the last five and 10 HbA1c values, and with diabetic complications was also examined by linear regression analysis. The sample included 300 patients: 58% were male; the mean age was 49 (SD 17) years and the mean diabetes duration was 21 (SD 13) years. The median skin AF measurement was 2.0 [25th-75th percentiles: 1.7-2.4] arbitrary units (AU), and this was associated with age (ß=0.15 per 10years, P<0.001) and diabetes duration (ß=0.17 per 10years, P<0.001). After adjusting for age and estimated glomerular filtration rate (eGFR), the skin AF measurement was also related to the means of the last five and 10 HbA1c values (ß=0.10 per 1% of HbA1c, P=0.005, and ß=0.13 per 1% of HbA1c, P=0.001, respectively). In addition, the skin AF was associated with retinopathy (P<0.001), albuminuria (P<0.001) and decreased eGFR (P<0.001). In conclusion, the skin AF is related to the long-term glucose control and diabetic complications.

Non-invasive and quantitative assessment of sudomotor function for peripheral diabetic neuropathy evaluation.

AIMS: Perturbation of pain sensation is considered one of the major initiating risk factors for diabetic foot ulcer. Sweat dysfunction leading to abnormal skin conditions, including dryness and fissures, can increase foot ulcer risk. The aim of this study was to evaluate Sudoscan™, a new, quick, non-invasive and quantitative method of measuring sudomotor dysfunction as a co-indicator of the severity of diabetic polyneuropathy (DPN). METHODS: A total of 142 diabetic patients (age 62±18 years, diabetes duration 13±14 years, HbA(1c) 8.9±2.5%) were measured for vibration perception threshold (VPT), using a biothesiometer, and for sudomotor dysfunction, using electrochemical sweat conductance (ESC) based on the electrochemical reaction between sweat chloride and electrodes in contact with the hands and feet. Retinopathy status was also assessed, as well as reproducibility between two ESC measurements and the effect of glycaemia levels. RESULTS: ESC measurements in the feet of patients showed a descending trend from 66±17 µS to 43±39 µS, corresponding to an ascending trend in VPT threshold from <15 V to >25 V (P=0.001). Correlation between VPT and ESC was -0.45 (P<0.0001). Foot ESC was lower in patients with fissures, while VPT was comparable. Both VPT and foot ESC correlated with retinopathy status. Bland-Altman plots indicated good reproducibility between two measurements, and between low and high glycaemia levels. CONCLUSION: Sudoscan™ is a reproducible technique with results that are not influenced by blood glucose levels. Sweating status may be a quantitative indicator of the severity of polyneuropathy that may be useful for the early prevention of foot skin lesions.

Metabolic syndrome and cognitive decline in French elders: the Three-City Study.

OBJECTIVE: To examine associations between metabolic syndrome (MetS) and its individual components with risk of cognitive decline on specific cognitive functions. METHODS: Participants were 4,323 women and 2,764 men aged 65 and over enrolled in the longitudinal Three-City Study. Cognitive decline, defined as being in the worst quintile of the distribution of the difference between baseline score and either 2- or 4-year follow-up, was assessed by the Mini-Mental State Examination (MMSE, global cognitive function), the Isaacs Set Test (IST, verbal fluency), and the Benton Visual Retention Test (BVRT, visual working memory). MetS was defined by National Cholesterol Education Program-Adult Treatment Panel III criteria (at least 3 of 5 cardio-metabolic abnormalities: hypertension, high waist circumference, hypertriglyceridemia, low high-density lipoprotein [HDL] cholesterol, hyperglycemia). Proportional hazards models were adjusted for age, gender, educational level, center, baseline cognitive score, APOE4 genotype, and other potential confounders. RESULTS: MetS at baseline was associated with an increased risk of cognitive decline on MMSE (hazard ratio [HR] = 1.22 [1.08-1.37]; p = 0.001) and BVRT (HR = 1.13 [1.01-1.26]; p = 0.03) but not on IST (HR = 1.11 [0.95-1.29]; p = 0.18). Among MetS components, hypertriglyceridemia and low HDL cholesterol were significantly associated with higher decline on MMSE; diabetes, but not elevated fasting glycemia, was significantly associated with higher decline on BVRT and IST. CONCLUSIONS: MetS as a whole and several of its components had a negative impact on global cognitive decline and specific cognitive functions in older persons.

Estimation of renal function in patients with diabetes.

Diabetes is the leading cause of chronic kidney disease (CKD), which makes estimation of renal function crucial. Serum creatinine is not an ideal marker of glomerular filtration rate (GFR), which also depends on digestive absorption, and the production of creatinine in muscle and its tubular secretion. Formulas have been devised to estimate GFR from serum creatinine but, given the wide range of GFR, proteinuria, body mass index and specific influence of glycaemia on GFR, the uncertainty of these estimations is a particular concern for patients with diabetes. The most popular recommended formulas are the simple Cockcroft-Gault equation, which is inaccurate and biased, as it calculates clearance of creatinine in proportion to body weight, and the MDRD equation, which is more accurate, but systematically underestimates normal and high GFR, being established by a statistical analysis of results from renal-insufficient patients. This underestimation explains why the MDRD equation is repeatedly found to give a poor estimation of GFR in patients with recently diagnosed diabetes and is a poor tool for reflecting GFR decline when started from normal, as well as the source of unexpected results when applied to epidemiological studies with a 60mL/min/1.73m(2) threshold as the definition of CKD. The more recent creatinine-based formula, the Mayo Clinic Quadratic (MCQ) equation, and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) improve such underestimation, as both were derived from populations that included subjects with normal renal function. Determination of cystatin C is also promising, but needs standardisation.

Dietary patterns and risk of dementia: the Three-City cohort study.

BACKGROUND: Dietary fatty acids and antioxidants may contribute to decrease dementia risk, but epidemiologic data remain controversial. The aim of our study was to analyze the relationship between dietary patterns and risk of dementia or Alzheimer disease (AD), adjusting for sociodemographic and vascular risk factors, and taking into account the ApoE genotype. METHODS: A total of 8,085 nondemented participants aged 65 and over were included in the Three-City cohort study in Bordeaux, Dijon, and Montpellier (France) in 1999-2000 and had at least one re-examination over 4 years (rate of follow-up 89.1%). An independent committee of neurologists validated 281 incident cases of dementia (including 183 AD). RESULTS: Daily consumption of fruits and vegetables was associated with a decreased risk of all cause dementia (hazard ratio [HR] 0.72, 95% CI 0.53 to 0.97) in fully adjusted models. Weekly consumption of fish was associated with a reduced risk of AD (HR 0.65, 95% CI 0.43 to 0.994) and all cause dementia but only among ApoE epsilon 4 noncarriers (HR 0.60, 95% CI 0.40 to 0.90). Regular use of omega-3 rich oils was associated with a decreased risk of borderline significance for all cause dementia (HR 0.46, 95% CI 0.19 to 1.11). Regular consumption of omega-6 rich oils not compensated by consumption of omega-3 rich oils or fish was associated with an increased risk of dementia (HR 2.12, 95% CI 1.30 to 3.46) among ApoE epsilon 4 noncarriers. CONCLUSION: Frequent consumption of fruits and vegetables, fish, and omega-3 rich oils may decrease the risk of dementia and Alzheimer disease, especially among ApoE epsilon 4 noncarriers.

Bone loss in diabetic patients with chronic kidney disease.

OBJECTIVE: We investigated whether loss of bone is detectable during follow-up of diabetic patients with chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS: In 40 initially non-dialysed diabetic patients with CKD (isotopic glomerular filtration rate < 60 ml/min/1.73 m(2) or albumin excretion rate > 30 mg/24 h), body composition (DEXA scan) and glomerular filtration rate (GFR determined from (51)Cr-EDTA clearance) were measured at a 2-year interval, and compared by paired t-tests. RESULTS: The 40 patients, mainly with Type 2 diabetes (n = 28), were men (n = 28), aged 65 +/- 11 years, with diabetes duration 18 +/- 11 years. GFR was initially 38.0 (range 8-89) ml/min/1.73 m(2). CKD progressed during follow-up: eight started haemodialysis and GFR declined in the 32 others (P < 0.05 vs. initial). T-scores for total body (initial -0.61 +/- 1.11, final -1.11 +/- 1.40; P < 0.001) and femoral neck (initial -1.88 +/- 0.15, final -2.07 +/- 0.15; P < 0.05) declined. Ten patients were osteopaenic at baseline (no osteoporosis), whereas most were osteopaenic (n = 21, P < 0.05) and five were osteoporotic at final assessment. The 16 patients who became osteopaenic or osteoporotic during follow-up did not differ from the others for the type of diabetes, age, GFR, albumin excretion rate, HbA(1c), GFR reduction and the requirement for dialysis during follow-up. They were all men (P < 0.01 by chi-squared test), with reduced initial total body T-score (-1.20 +/- 0.82, others -0.32 +/- 1.13; P < 0.05) and a lower body mass index (24.6 +/- 4.3; others 27.7 +/- 4.3; P < 0.05). CONCLUSION: Bone loss, especially in the femoral neck, is progressive in diabetic patients with CKD.

Body composition in diabetic subjects with chronic kidney disease: interest of bio-impedance analysis, and anthropometry.

BACKGROUND/AIMS: Lean body mass (LBM) is reduced in uremia, but this has not been reported in diabetic nephropathy. SUBJECTS AND METHODS: We compared predicted % LBM to DEXA measurements in 10 non-diabetic uremic, 10 non-uremic diabetic and 10 uremic diabetic subjects matched for age, gender and BMI. We also measured % LBM by anthropometry, bio-impedance analysis (BIA) and compared them with DEXA in 49 diabetic subjects with a wide range of renal failure. The results were compared and a Bland & Altman procedure was performed. Associations between glomerular filtration rate (GFR) and % LBM were tested. RESULTS: In matched groups, predicted % LBM values were overestimated in non-diabetic uremic subjects, and underestimated in non-uremic diabetic subjects. In uremic diabetic subjects, the error was intermediary. As compared to DEXA (% LBM: 69.0 +/- 7.1%), measurement of % LBM by anthropometry (71.4 +/- 8.0%, p < 0.05) and BIA (67.2 +/- 7.6%, p < 0.05) were biased in the 49 diabetic subjects. The mean of anthropometric and BIA (Ant+BIA) were similar to DEXA results (69.3 +/- 6.8%, p = 0.64), with best correlation coefficients and Bland & Altman plots. GFR was correlated to % LBM assessed by DEXA, BIA and Ant+BIA. CONCLUSION: In diabetic subjects with chronic kidney disease, LBM should be measured, rather than predicted. A good evaluation is possible, even without DEXA.