Cataldo Abaterusso

Serum Uric Acid Levels and Incident Chronic Kidney Disease in Patients With Type 2 Diabetes and Preserved Kidney Function

OBJECTIVE Recent studies have suggested an association between hyperuricemia and adverse renal outcomes in nondiabetic populations. Data on the relationship between hyperuricemia and the risk of incident chronic kidney disease (CKD) in type 2 diabetic patients with normal or near-normal kidney function are lacking. We determined whether baseline serum uric acid levels predict the subsequent development of CKD in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS We followed 1,449 type 2 diabetic patients with normal kidney function and without overt proteinuria for 5 years for the occurrence of incident CKD (defined as overt proteinuria or estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2). RESULTS During a 5-year follow-up period, 194 (13.4%) patients developed incident CKD. The cumulative incidence of CKD was significantly greater in patients with hyperuricemia than in those without hyperuricemia (29.5 vs. 11.4%, P < 0.001). In univariate logistic regression analysis, the presence of hyperuricemia roughly doubled the risk of developing CKD (odds ratio [OR] 2.55 [95% CI 1.71–3.85], P < 0.001). After adjusting for age, sex, BMI, smoking status, diabetes duration, systolic blood pressure, antihypertensive treatment, insulin therapy, HbA1c, eGFR, and albuminuria, hyperuricemia was associated with an increased risk of incident CKD (adjusted OR 2.10 [1.16–3.76], P < 0.01). In continuous analyses, a 1-SD increment in the serum uric acid level was significantly associated with a 21% increased risk of CKD. CONCLUSIONS In type 2 diabetic individuals with preserved kidney function, hyperuricemia seems to be an independent risk factor for the development of incident CKD.

Prognosis of CKD Patients Receiving Outpatient Nephrology Care in Italy

BACKGROUND AND OBJECTIVES Prognosis in nondialysis chronic kidney disease (CKD) patients under regular nephrology care is rarely investigated. Design, setting, participants, & measurements We prospectively followed from 2003 to death or June 2010 a cohort of 1248 patients with CKD stages 3 to 5 and previous nephrology care ≥1 year in 25 Italian outpatient nephrology clinics. Cumulative incidence of ESRD or death before ESRD were estimated using the competing-risk approach. RESULTS Estimated rates (per 100 patient-years) of ESRD and death 8.3 (95% confidence interval [CI], 7.4 to 9.2) and 5.9 (95% CI 5.2 to 6.6), respectively. Risk of ESRD and death increased progressively from stages 3 to 5. ESRD was more frequent than death in stage 4 and 5 CKD, whereas the opposite was true in stage 3 CKD. Younger age, lower body mass index, proteinuria, and high phosphate predicted ESRD, whereas older age, diabetes, previous cardiovascular disease, ESRD, proteinuria, high uric acid, and anemia predicted death (P < 0.05 for all). Among modifiable risk factors, proteinuria accounted for the greatest contribution to the model fit for either outcome. CONCLUSIONS In patients receiving continuity of care in Italian nephrology clinics, ESRD was a more frequent outcome than death in stage 4 and 5 CKD, but the opposite was true in stage 3. Outcomes were predicted by modifiable risk factors specific to CKD. Proteinuria used in conjunction with estimated GFR refined risk stratification. These findings provide information, specific to CKD patients under regular outpatient nephrology care, for risk stratification that complement recent observations in the general population.

Prevalence of CKD in Northeastern Italy: Results of the INCIPE Study and Comparison with NHANES

BACKGROUND AND OBJECTIVES Sufficiently powered studies to investigate the CKD prevalence are few and do not cover southern Europe. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS For the INCIPE study, 6200 Caucasian patients ≥40 years old were randomly selected in northeastern Italy in 2006. Laboratory determinations were centralized. The albumin to creatinine ratio in urine and estimated GFR from calibrated creatinine (SCr) were determined. A comparison with 2001 through 2006 NHANES surveys was performed. RESULTS Prevalence of CKD was 13.2% in northeastern (NE) Italy (age and gender standardized to the U.S. 2007 Caucasian population). Prevalence of CKD in U.S. Caucasians is higher (20.3%), the major difference being in CKD 3. Risk factors for CKD are more prevalent in the United States than in Italy. With use of CKD 3a and 3b stages, CKD prevalence decreased in NE Italy (8.5%) and in the United States (12.8%). CONCLUSIONS The prevalence of CKD is high in NE Italy, but lower than that in the United States. A large part of the difference in CKD prevalence in NE Italy versus that in the United States is due to the different prevalence of CKD 3. The higher prevalence of a number of renal risk factors in persons from the United States explains in part the different dimensions of the CKD problem in the two populations.

Treating Elderly People with Diabetes and Stages 3 and 4 Chronic Kidney Disease

Dedicated European and US clinical guidelines for type 2 diabetes in the elderly have been released, but they do not specifically address the issue of advanced chronic kidney disease (CKD) in older patients with diabetes. General clinical guidelines have been published on the treatment of patients with diabetic nephropathy (DN), but these address the issue of how to prevent progression and treat advanced DN without distinguishing between different age groups. Elderly patients with diabetes and stages 3 to 4 CKD have particular needs that differ from those of younger patients with the same conditions. This is mainly due to their frailty and shorter life expectancy. Differently tailored therapeutic strategies are needed, which may have less stringent targets; and the use of common drugs should be critically evaluated. The management agenda (metabolic control, low-protein diet, controlling BP, preventing progression of advanced DN, preventing cardiovascular outcomes) for these patients is discussed in light of the limits and perspectives of current guidelines. Intensive, simultaneous management of all items on the agenda may not be feasible for a proportion of older patients, and clinicians may have to give priority to reducing some risk factors rather than others, choosing between different therapies.

The role of glycosaminoglycans and sulodexide in the treatment of diabetic nephropathy

Diabetic nephropathy occurs in 20–40% of diabetic patients, making it one of the most important causes of end-stage renal disease (ESRD). It has a large impact in terms of associated morbidity and mortality for the individual patient and in terms of costs for healthcare. Several studies have demonstrated that micro- and macroalbuminuria predict cardiovascular morbidity and mortality in patients with diabetes mellitus.Current nephroprotective therapies for diabetic nephropathy include the pursuit of normoglycemia and normotension, and a consensus is emerging that there is a necessity to also achieve as low a level of albuminuria as possible. However, the search for innovative and ancillary approaches to the prevention and treatment of this diabetic complication is warranted since strict metabolic control can be difficult, and sometimes dangerous, to achieve and even diabetic patients responding to ACE inhibitors (ACEIs) or angiotensin II receptor antagonists (angiotensin receptor blockers; ARBs) and metabolic control show progressive renal damage and eventually ESRD. A number of drugs are currently being investigated; glycosaminoglycans are particularly interesting since, in theory, they target the generalized endothelial dysfunction and metabolic defect in matrix and basement membrane synthesis which, according to the Steno hypothesis, are responsible for diabetic nephropathy and macroangiopathy.Treatment with glycosaminoglycans, and with sulodexide in particular, significantly improves albuminuria in type 1 and type 2 diabetic patients with micro- or macroalbuminuria. The albuminuria-lowering effect of sulodexide enhances the effect of ACEI/ARB therapy. Most studies have shown that the effect of sulodexide on albuminuria is sustained, strongly suggesting that favorable chemical and anatomic remodeling is induced by exogenous glycosaminoglycans in renal tisues, as observed in the experimental model.

Regulation of heparanase by albumin and advanced glycation end products in proximal tubular cells.

Diabetic nephropathy is one of the main causes of end-stage renal disease, in which the development of tubular damage depends on factors such as high glucose levels, albuminuria and advanced glycation end-product. In this study, we analyzed the involvement of heparanase, a heparan sulfate glycosidase, in the homeostasis of proximal tubular epithelial cells in the diabetic milieu. In vitro studies were performed on a wild-type and stably heparanase-silenced adult tubular line (HK2) and HEK293. Gene and protein expression analyses were performed in the presence and absence of diabetic mediators. Albumin and advanced glycation end-product, but not high glucose levels, increased heparanase expression in adult tubular cells via the AKT/PI3K signaling pathway. This over-expression of heparanase is then responsible for heparan sulfate reduction via its endoglycosidase activity and its capacity to regulate the heparan sulfate-proteoglycans core protein. In fact, heparanase regulates the gene expression of syndecan-1, the most abundant heparan sulfate-proteoglycans in tubular cells. We showed that heparanase is a target gene of the diabetic nephropathy mediators albumin and advanced glycation end-product, so it may be relevant to the progression of diabetic nephropathy. It could take part in several processes, e.g. extracellular-matrix remodeling and cell-cell crosstalk, via its heparan sulfate endoglycosidase activity and capacity to regulate the expression of the heparan sulfate-proteoglycan syndecan-1.

Early Creatinine Shifts Predict Contrast-induced Nephropathy and Persistent Renal Damage after Angiography

PURPOSE The purpose of this study was to evaluate incidence and predictors of contrast-induced nephropathy after coronary angiography and interventions, and to assess renal function at 30 days. The prognostic value of any early shift of serum creatinine compared with baseline was investigated; such measurement, being a delta, is largely independent of creatinine variations. METHODS There were 216 patients at risk for contrast-induced nephropathy prospectively evaluated at baseline and at 12, 24, and 48 hours after exposure to contrast media, and 190 (88%) evaluated 1 month after discharge. RESULTS Contrast-induced nephropathy occurred in 39 patients (18%), and 30-day renal damage was detected in 15 (7%). Contrast media/kg volume predicted contrast-induced nephropathy (P=.002), and percentage change of creatinine 12 hours from baseline was significantly higher in patients with nephropathy (P <.001). At multivariate analysis, percentage change of creatinine 12 hour-basal was the best predictor of nephropathy (P <.001). A 5% increase of its value yielded 75% sensitivity and 72% specificity (area under the curve 0.80; odds ratio 7.37; 95% confidence interval, 3.34-16.23) for early contrast-induced nephropathy detection. Furthermore, it strongly correlated with the development of renal impairment at 30 days (P=.002; sensitivity 87%, specificity 70%; area under the curve 0.85; odds ratio 13.29; 95% confidence interval, 2.91-60.64). CONCLUSION Minimal elevations of serum creatinine at 12 hours are highly predictive of contrast-induced nephropathy and 30-day renal damage after exposure to contrast media.

Metabolic Syndrome, Cardiovascular Disease, and Risk for Chronic Kidney Disease in an Italian Cohort: Analysis of the INCIPE Study

BACKGROUND Metabolic syndrome is a frequent condition that has been linked to cardiovascular disease (CVD) and mortality. Metabolic syndrome has been extensively shown to increase the risk of chronic nephropathies in Americans and Asians, but not in European populations. Renal disease increases the risk of CVD and mortality. However, the chronic nephropathy-CVD liaison has not been analyzed in the framework of the possible role of metabolic syndrome in both. METHODS We analyzed data from 3,757 subjects participating in the INCIPE survey (Initiative on Nephropathy, of relevance to public health, which is Chronic, possibly in its Initial stages, and carries a Potential risk of major clinical End-points), a cross-sectional study enrolling subjects from the general population in the Veneto region in Italy, and calculated the odds ratio (OR) and 95% confidence interval (CI) of the association between metabolic syndrome, and/or chronic kidney disease (CKD) and albuminuria, and/or previous CVD after adjustment for confounding factors. RESULTS Metabolic syndrome is associated with CKD (OR 2.17; P<0.001) and albuminuria (OR 2.28; P<0.001) and CVD (OR 1.58; P=0.002). There is a direct correlation between number of metabolic syndrome traits and nephropathy and CVD. CVD and nephropathies are associated even after adjustment for metabolic syndrome (OR 2.30; P<0.001). CONCLUSIONS In a homogeneous Caucasian European population, metabolic syndrome is associated with CKD and albuminuria, and CVD. Although metabolic syndrome is a risk factor for both CVD and nephropathy, it does not entirely explain the dangerous CVD-nephropathy liaison.

Anaemia in diabetic renal failure: is there a role for early erythropoietin treatment in preventing cardiovascular mortality?

The mortality rate in diabetics with chronic kidney disease (CKD) is seven times higher than end‐stage renal disease mainly because of cardiac causes. Anaemia may have a relevant role in the pathogenesis of cardiovascular (CV) disease in CKD. Anaemia occurs at an earlier stage of CKD in diabetic individuals than in those with other causes of CKD. Observational findings support the unfavourable influence of anaemia on mortality in CKD patients, and the combination of anaemia and CKD in diabetics identifies a group with a particularly high mortality risk. While the effect of erythropoietin on these patients’ quality of life is known, its impact on mortality and CV risk is uncertain. The recent Anaemia Correction in Diabetes (ACORD) trial in diabetic CKD patients, which targeted haemoglobin levels of 13–15 mg/dl, disclosed no statistically significant favourable or adverse effects on mortality or morbidity over the 2‐year follow‐up, while other studies endeavouring to nearly normalize haemoglobin have reportedly proved risky. Even if anaemia is causally involved, the pathogenesis of CV disease in diabetics with CKD is so complex that addressing just one factor (anaemia) may not suffice to prevent CV risk, and normalizing haemoglobin levels may even be harmful.

High chronic nephropathy detection yield in CKD subjects identified by the combination of albuminuria and estimated GFR

BACKGROUND AND OBJECTIVES Epidemiological studies have shown that the burden of chronic kidney disease (CKD) is huge. CKD is a non-specific diagnosis, however, and it is hard to say which renal disorders comprise the body of CKD diagnosed on the strength of the combination of albuminuria and estimated glomerular filtration rate (eGFR) in epidemiological studies, or just how efficient such studies are in detecting chronic nephropathies. METHODS The INCIPE study identified 524 CKD cases (using the K/DOQI definition based on albuminuria and eGFR) in a random sample of 4000 Italians >40 years old, 262 of whom were randomly chosen to be investigated in order to confirm their CKD and complete a diagnostic workup. We a priori defined diagnostic algorithms for 14 renal conditions based on personal family history, medical records, urine tests, kidney ultrasound with colour-Doppler and other tests. RESULTS Among the subjects whose CKD was confirmed, a diagnosis of chronic nephropathy was reached in 68% of cases recognized as having either a specific (38%) or an undetermined (30%) kidney disease. Almost 50% of subjects with a specific chronic nephropathy had a diabetic or vascular renal disease. Abnormalities consistent with a chronic nephropathy were found in 50, 68, 70 and 100% of subjects with CKD Stages 1, 2, 3 and 4, respectively. Lone low eGFR and lone microalbuminuria were observed in 20 and 12%, respectively. CONCLUSION In Caucasians >40 years old with a confirmed CKD condition, (i) an impressive 68% of subjects have an underlying chronic nephropathy, so eGFR and albuminuria are very efficient in detecting renal diseases; (ii) in 32%, the only disclosed renal abnormalities were a glomerular filtration rate <60 mL/min/1.73 m(2) or microalbuminuria; follow-up studies are needed to clarify whether these abnormalities do really identify a chronic nephropathy or just a cardiovascular risk condition.