Luca De Nicola

Additive antiproteinuric effect of converting enzyme inhibitor and losartan in normotensive patients with IgA nephropathy

We tested the hypothesis that the combination of converting enzyme inhibitor (CEI) with losartan (LOS) produces a more profound antiproteinuric effect than either drug alone in normotensive patients with immunoglobulin A (IgA) nephropathy. Eight normotensive (mean blood pressure, 88.9 +/- 2.1 mm Hg) patients with biopsy-proven IgA nephropathy, nonnephrotic proteinuria (protein, 1 to 3 g/d), and normal or slightly reduced creatinine clearance (range, 69 to 119 mL/min) were studied. Clinical evaluations and laboratory tests were performed (1) before CEI treatment (basal) and after (2) CEI alone (CEI, 12 weeks); (3) the combination of CEI and LOS, the latter at a dosage of 50 mg/d (CEI + LOS, 4 weeks); (4) LOS alone (LOS; 50 mg/d; 12 weeks); (5) the combination of LOS and CEI (LOS + CEI, 4 weeks, at the same dosage as CEI + LOS); and (6) a doubled dose of either CEI alone or LOS alone for 4 weeks. CEI and LOS as monotherapy significantly reduced proteinuria by 38% and 30%, respectively. No further reduction of proteinuria was achieved by doubling the dose of CEI or LOS. Both combinations induced a more remarkable reduction of proteinuria (73%; P < 0.05 v other periods) than either drug administered alone. The antiproteinuric effect of CEI or LOS and the more remarkable effect achieved with both combinations was not dependent on the reduction of blood pressure and/or creatinine clearance. In conclusion, this study provides first-time evidence that the combination of CEI and LOS in normotensive patients with IgA nephropathy produces a more profound decrease in proteinuria than either drug. This additive antiproteinuric effect is not dependent on changes in systemic blood pressure and creatinine clearance. Nevertheless, a larger controlled study is required to confirm this novel observation.

Current indications for renal biopsy : A questionnaire-based survey

Indications for renal biopsy are still ill defined. We recently sent a detailed questionnaire to 360 nephrologists in different areas of the world with the aim of providing information on this critical issue by evaluating the replies. The questionnaire was organized in four sections that included questions on renal biopsy indications in patients with normal renal function, renal insufficiency, and a transplanted kidney. In addition, the questions included methods applied to each renal biopsy procedure and to specimen processing. We received 166 replies; North Europe (50 replies), South Europe (47 replies), North America (31 replies), Australia and New Zealand (24 replies), and other countries (14 replies). In patients with normal renal function, primary indications for renal biopsy were microhematuria associated with proteinuria, particularly greater than 1 g/d of protein. In chronic renal insufficiency, kidney dimension was the major parameter considered before renal biopsy, whereas the presence of diabetes or serological abnormalities was not considered critical. In the course of acute renal failure (ARF) of unknown origin, 20% of the respondents would perform renal biopsy in the early stages, 26% after 1 week of nonrecovery, and 40% after 4 weeks. In a transplanted kidney, the majority of nephrologists would perform a renal biopsy in the case of graft failure after surgery, ARF after initial good function, slow progressive deterioration of renal function, and onset of nephrotic proteinuria. The last section provided comprehensive information on the technical aspects of renal biopsy. This survey represents the first attempt to provide a reliable consensus that can be used in developing guidelines on the use of kidney biopsy.

Early Changes in Bioelectrical Estimates of Body Composition in Chronic Kidney Disease

The aim of this study was to detect the potential occurrence of early abnormalities of body composition in patients with chronic kidney disease (CKD) at first referral to an outpatient nephrology clinic. Eighty-four patients with CKD (49 men and 35 women) were compared with 604 healthy control subjects (298 men and 306 women). Anthropometry and bioelectrical impedance analysis (BIA) were performed in all participants, whereas renal function, laboratory tests for nutritional status, and nutrient intake were assessed in the CKD group only. Creatinine clearance was 27.8 +/- 13.8 and 27.4 +/- 13.0 ml/min per 1.73 m(2) in male and female patients with CKD, respectively. No patient showed peripheral edema; frank malnutrition, defined by presence of serum albumin <3.5 g/dl plus body mass index <20 kg/m(2); or protein intake <0.6 g/kg per d. At the BIA, patients with CKD showed lower resistance (R) and abnormal mean impedance vectors for the bivariate normal distribution of R/height and reactance/height. Phase angle also was reduced (-22%), especially in patients with diabetes. When BIA-derived data were considered, total body water was slightly higher (+4.3% in men; +3.5% in women) and body cell mass was lower (-6.7% in men; -7.7% in women) in patients with CKD. No difference in either BIA parameters or nutritional indexes was observed among various CKD stages. Despite the absence of overt malnutrition, patients with CKD exhibit altered BIA variables from the early phases of renal disease. These alterations are related to the renal dysfunction, are more marked in the presence of diabetes, and mainly indicate the presence of overhydration in the absence of edema. Therefore, BIA represents an attractive clinical tool to detect impairment of body composition from the early stages of CKD.

Detection and Awareness of Moderate to Advanced CKD by Primary Care Practitioners: A Cross-sectional Study From Italy

BACKGROUND Chronic kidney disease (CKD) is a strong independent predictor of cardiovascular disease. Although general practitioners (GPs) represent the first line for identification of these high-risk patients, their diagnostic approach to CKD is ill defined. STUDY DESIGN Cross-sectional evaluation of database of Italian GPs. SETTING & PARTICIPANTS Representative sample of adult Italian population regularly followed up by GPs in 2003. OUTCOMES Frequency of serum creatinine testing, prevalence of CKD (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m(2)), awareness of CKD assessed from use of diagnostic codes (Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]) for CKD, and referral to nephrologists. RESULTS Of 451,548 individuals in the entire practice population, only 77,630 (17.2%) underwent serum creatinine testing. Female sex (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.06 to 1.12), advanced age (OR, 2.70; 95% CI, 2.63 to 2.78), diabetes (OR, 1.31; 95% CI, 1.20 to 1.42), hypertension (OR, 1.10; 95% CI, 1.02 to 1.19), autoimmune diseases (OR, 1.42; 95% CI, 1.11 to 1.82), and recurrent urinary tract infections (OR, 1.63; 95% CI, 1.10 to 2.42) were all associated with serum creatinine testing. Conversely, use of either nonsteroidal anti-inflammatory drugs (OR, 1.03; 95% CI, 0.89 to 1.21) or aminoglycosides or contrast media (OR, 0.78; 95% CI, 0.54 to 1.14) was not associated with serum creatinine testing. In the subgroup with serum creatinine data, the age-adjusted prevalence of CKD was 9.33% (11.93% in women, 6.49% in men). However, in patients with eGFR less than 60 mL/min/1.73 m(2), serum creatinine values were apparently normal (<1.2 mg/dL in women, <1.4 mg/dL in men) in 54%, and GPs used ICD-9-CM codes for CKD in only 15.2%. Referral to nephrologists ranged from 4.9% for patients with eGFR of 59 to 30 mL/min/1.73 m(2) to 55.7% for those with eGFR less than 30 mL/min/1.73 m(2). LIMITATIONS The prevalence of decreased kidney function may be overestimated because of the more frequent serum creatinine testing in sicker individuals and lack of creatinine calibration. CONCLUSIONS In primary care, CKD stages 3 to 5 are frequent, but its awareness is scarce because of limited rates of serum creatinine testing and difficulty recognizing decreased eGFR in the absence of increased serum creatinine testing.

Antiproteinuric response to dual blockade of the renin-angiotensin system in primary glomerulonephritis: meta-analysis and metaregression.

BACKGROUND In patients with primary glomerulonephritis (GN), antiproteinuric response to angiotensin-converting enzyme (ACE) inhibitors plus angiotensin receptor blockers (ARBs) versus either monotherapy is undefined because of the small size of studies and high heterogeneity of response. STUDY DESIGN Meta-analysis/metaregression. SETTING & POPULATION Randomized clinical trials (RCTs). SELECTION CRITERIA FOR STUDIES RCTs published from January 1996 to April 2007. Studies were excluded if information about levels of proteinuria was not available, patients had kidney disease other than primary GN, or if they had end-stage renal disease. INTERVENTION ACE inhibitor plus ARB versus monotherapy with 1 of these drug classes. OUTCOMES Absolute changes in proteinuria (primary), blood pressure, serum potassium level, and glomerular filtration rate (GFR; secondary). RESULTS We found 13 RCTs including 425 patients with primary GN with proteinuria ranging from 0.8 to 7.9 g/d of protein and age from 25 to 60 years. Combination treatment decreased proteinuria by 0.60 g/d (95% confidence interval, 0.40 to 0.80) versus ACE-inhibitor monotherapy and 0.54 g/d (95% confidence interval, 0.30 to 0.78) versus ARB monotherapy. Baseline levels of proteinuria explained most between-study variability of the antiproteinuric response to combination therapy versus monotherapies. Systolic and diastolic blood pressure, GFR, age, and diagnosis of immunoglobulin A nephropathy did not modify antiproteinuric response. ACE-inhibitor plus ARB therapy did not change GFR, whereas it increased serum potassium levels (by 0.10 mEq/L versus ACE-inhibitor and 0.19 mEq/L versus ARB therapy) and decreased blood pressure. LIMITATIONS Only published data are included. CONCLUSIONS The antiproteinuric response to ACE-inhibitor plus ARB therapy versus either monotherapy is consistently greater and strictly related to baseline proteinuria, associated with only moderate increase in serum potassium levels, and not peculiar to immunoglobulin A nephropathy.

Sodium/Glucose Cotransporter 2 Inhibitors and Prevention of Diabetic Nephropathy: Targeting the Renal Tubule in Diabetes

Optimal prevention and treatment of chronic kidney disease in diabetes requires implementing therapies that specifically interfere with the pathogenesis of diabetic nephropathy. In this regard, significant attention has been given to alterations of the proximal tubule and resulting changes in glomerular filtration rate. At the onset of diabetes mellitus, hyperglycemia causes increases in proximal tubular reabsorption secondary to induction of tubular growth with associated increases in sodium/glucose cotransport. The increase in proximal reabsorption leads to a decrease in solute load to the macula densa, deactivation of the tubuloglomerular feedback, and increases in glomerular filtration rate. Because glomerular hyperfiltration currently is recognized as a risk factor for progression of kidney disease in diabetic patients, limiting proximal tubular reabsorption constitutes a potential target to reduce hyperfiltration. The recent introduction of sodium/glucose cotransporter 2 (SGLT2) inhibitors opens new therapeutic perspectives for this high-risk patient population. Experimental studies have shown that these new agents attenuate the progressive nature of diabetic nephropathy by blood glucose-dependent and -independent mechanisms. SGLT2 inhibition may prevent glomerular hyperfiltration independent of the effect of lowering blood glucose levels while limiting kidney growth, inflammation, and albuminuria through reductions in blood glucose levels. Clinical data for the potential role of the proximal tubule in the pathophysiology of diabetic nephropathy and the nephroprotective effects of SGLT2 inhibitors currently are limited compared to the more extensive experimental literature. We review the evidence supporting this working hypothesis by integrating the experimental findings with the available clinical data.

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.

Renal anaemia and EPO hyporesponsiveness associated with vitamin D deficiency: the potential role of inflammation

Resistance to erythropoiesis-stimulating agents (ESAs) has been observed in a considerable proportion of patients with chronic kidney disease (CKD) and it is reportedly associated with adverse outcomes, such as increased cardiovascular morbidity, faster progression to end-stage renal disease (ESRD) and all-cause mortality. The major causes of ESA resistance include chronic inflammation producing suppressive cytokines of early erythroid progenitor proliferation. In addition, pro-inflammatory cytokines stimulate hepcidin synthesis thus reducing iron availability for late erythropoiesis. Recent studies showing an association in deficiencies of the vitamin D axis with low haemoglobin (Hb) levels and ESA resistance suggest a new pathophysiological co-factor of renal anaemia. The administration of either native or active vitamin D has been associated with an improvement of anaemia and reduction in ESA requirements. Notably, these effects are not related to parathyroid hormone (PTH) values and seem to be independent on PTH suppression. Another possible explanation may be that calcitriol directly stimulates erythroid progenitors; however, this proliferative effect by extra-renal activation of 1α-hydroxylase enzyme is only a hypothesis. The majority of studies concerning vitamin D deficiency or supplementation, and degree of renal anaemia, point out the prevalent role of inflammation in the mechanism underlying these associations. Immune cells express the vitamin D receptor (VDR) which in turn is involved in the modulation of innate and adaptive immunity. VDR activation inhibits the expression of inflammatory cytokines in stromal and accessory cells and up-regulates the lymphocytic release of interleukin-10 (IL-10) exerting both anti-inflammatory activity and proliferative effects on erythroid progenitors. In CKD patients, vitamin D deficiency may stimulate immune cells within the bone marrow micro-environment to produce cytokines, inducing impaired erythropoiesis. Immune activation involves the reticuloendothelial system, increasing hepcidin synthesis and functional iron deficiency. Consequences of this inflammatory cascade are erythropoietin (EPO) resistance and anaemia. Given the key role of inflammation in the response to EPO, the therapeutic use of agents with anti-cytokines properties, such as vitamin D and paricalcitol, may provide benefit in the prevention/treatment of ESA hyporesponsiveness.

Early Impairment of Renal Hemodynamic Reserve in Patients With Asymptomatic Heart Failure Is Restored by Angiotensin II Antagonism

BACKGROUND The early/asymptomatic stages of heart failure (HF) are characterized by sodium retention secondary to derangement of sodium reabsorption at the proximal nephron level. Because this phenomenon is reversed by ACE inhibition, abnormalities of renal sodium handling may depend on intrarenal changes of angiotensin II (AII)/nitric oxide (NO) levels. Renal hemodynamic reserve (ie, the glomerular vasodilatory response to amino acid infusion) has been proposed as a reliable test to assess in vivo AII/NO balance. METHODS AND RESULTS In this study, the effects of 6 weeks of treatment with 5 mg/d of enalapril or with 50 mg/d of losartan on systemic hemodynamics and renal function were assessed, at baseline and after amino acid infusion (AA), in patients with mild HF (NYHA class I) and in healthy volunteers. Untreated HF patients showed a basal renal function comparable to that of healthy subjects. After AA, glomerular filtration rate and renal plasma flow significantly increased in healthy subjects (+29.0% and +30.4%, respectively), whereas no vasodilatory response was observed in HF. Although they did not affect basal renal hemodynamics, both enalapril and losartan restored a normal response to AA in HF patients. Blood pressure and heart rate were comparable in HF subjects and healthy subjects at baseline and were not modified by either treatment. Left ventricular ejection fraction was depressed in HF but did not change after either drug. Urinary excretions of cGMP and nitrate (indexes of NO activity in the kidney), comparable in healthy subjects and in HF patients, were unchanged by either enalapril or losartan and did not correlate with renal reserve. CONCLUSIONS (1) Renal functional reserve is absent in patients with early/asymptomatic HF and normal renal function and (2) both enalapril and losartan restore a normal vasodilatory response to AA in these patients without affecting basal systemic and renal hemodynamics. These data suggest a major role of AII in the development of early abnormalities in patients with HF.

Association of Body Mass Index with Clinical Outcomes in Non-Dialysis-Dependent Chronic Kidney Disease: A Systematic Review and Meta-Analysis

Background: Previous studies have not shown a consistent link between body mass index (BMI) and outcomes such as mortality and kidney disease progression in non-dialysis-dependent chronic kidney disease (CKD) patients. Therefore, we aimed to complete a systematic review and meta-analysis study on this subject. Methods: We searched MEDLINE, EMBASE, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Cochrane Central Register of Controlled Trials (CENTRAL), and screened 7,123 retrieved studies for inclusion. Two investigators independently selected the studies using predefined criteria and assessed each studys quality using the Newcastle-Ottawa quality assessment scale. We meta-analyzed the results based on the BMI classification system by the WHO. Results: We included 10 studies (with a total sample size of 484,906) in the systematic review and 4 studies in the meta-analyses. The study results were generally heterogeneous. However, following reanalysis of the largest reported study and our meta-analyses, we observed that in stage 3-5 CKD, being underweight was associated with a higher risk of death while being overweight or obese class I was associated with a lower risk of death; however, obesity classes II and III were not associated with risk of death. In addition, reanalysis of the largest available study showed that a higher BMI was associated with an incrementally higher risk of kidney disease progression; however, this association was attenuated in our pooled results. For earlier stages of CKD, we could not complete meta-analyses as the studies were sparse and had heterogeneous BMI classifications and/or referent BMI groups. Conclusion: Among the group of patients with stage 3-5 CKD, we found a differential association between obesity classes I-III and mortality compared to the general population, indicating an obesity paradox in the CKD population.