Silvio Borrelli

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.

Burden of Resistant Hypertension in Hypertensive Patients with Non-Dialysis Chronic Kidney Disease

Background/Aims: In chronic kidney disease (CKD), no data on resistant hypertension (RH) are so far available despite the high prevalence of uncontrolled hypertension. We evaluated frequency, correlates and prognosis of RH in 300 consecutive incident hypertensive CKD patients in an academic renal clinic. Methods: RH was defined as office blood pressure (BP) ≧130/80 mm Hg despite ≧3 drugs at full dose including a diuretic, or as BP at goal with ≧4 full-dose drugs. Patients were evaluated at referral and after 6 months of nephrology management; thereafter, they were included in a renal survival analysis lasting 37.6 months. Results: On referral, glomerular filtration rate was 41.3 ± 16.6 ml/min/1.73 m2 and BP 148 ± 23/81 ± 12 mm Hg. After 6 months, BP decreased by 8 ± 23/3 ± 12 mm Hg. From referral to month 6, RH detection increased from 26 to 38% due to the significant increment in full-dose antihypertensive medications (from 2.0, IQR 1.0–3.0 to 2.5, IQR 2.0–3.0). Diabetes and proteinuria predicted the incidence of RH at month 6. Presence of RH at month 6 was associated with greater risk of renal death (HR, 1.85, 95% CI, 1.13–3.03), independent of main clinical features and degree of BP control. Conclusion: In CKD, RH is prevalent and associated with decreased renal survival, independent of BP levels.

Associations of Left Ventricular Hypertrophy and Geometry with Adverse Outcomes in Patients with CKD and Hypertension

BACKGROUND AND OBJECTIVES Left ventricular hypertrophy (LVH) and abnormal left ventricular (LV) geometry predict adverse outcomes in the general and hypertensive populations, but findings in CKD are still inconclusive. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We enrolled 445 patients with hypertension and CKD stages 2-5 in two academic nephrology clinics in 1999-2003 who underwent both echocardiography and ambulatory BP monitoring. LVH (LV mass >100 g/m(2) [women] and >131 g/m(2) [men]) and relative wall thickness (RWT) were used to define LV geometry: no LVH and RWT≤0.45 (normal), no LVH and RWT>0.45 (remodeling), LVH and RWT≤0.45 (eccentric), and LVH and RWT>0.45 (concentric). We evaluated the prognostic role of LVH and LV geometry on cardiovascular (CV; composite of fatal and nonfatal events) and renal outcomes (composite of ESRD and all-cause death). RESULTS Age was 64.1±13.8 years old; 19% had diabetes, and 22% had CV disease. eGFR was 39.9±20.2 ml/min per 1.73 m(2). LVH was detected in 249 patients (56.0%); of these, 125 had concentric LVH, and 124 had eccentric pattern, whereas 71 patients had concentric remodeling. Age, women, anemia, and nocturnal hypertension were independently associated with both concentric and eccentric LVH, whereas diabetes and history of CV disease associated with eccentric LVH only, and CKD stages 4 and 5 associated with concentric LVH only. During follow-up (median, 5.9 years; range, 0.04-15.3), 188 renal deaths (112 ESRD) and 103 CV events (61 fatal) occurred. Using multivariable Cox analysis, concentric and eccentric LVH was associated with higher risk of CV outcomes (hazard ratio [HR], 2.59; 95% confidence interval [95% CI], 1.39 to 4.84 and HR, 2.79; 95% CI, 1.47 to 5.26, respectively). Similarly, greater risk of renal end point was detected in concentric (HR, 2.33; 95% CI, 1.44 to 3.80) and eccentric (HR, 2.30; 95% CI, 1.42 to 3.74) LVH. Sensitivity analysis using LVH and RWT separately showed that LVH but not RWT was associated with higher cardiorenal risk. CONCLUSIONS In patients with CKD, LVH is a strong predictor of the risk of poor CV and renal outcomes independent from LV geometry.

Hypertension and Prehypertension and Prediction of Development of Decreased Estimated GFR in the General Population: A Meta-analysis of Cohort Studies.

BACKGROUND Whether blood pressure (BP) plays an independent predictive role in the onset of decreased glomerular filtration rate (GFR) remains ill-defined because existing meta-analyses have incorporated data from studies that included individuals with low GFRs at baseline. This question is critical to optimize chronic kidney disease prevention in the general population. STUDY DESIGN Systematic review and meta-analysis of longitudinal cohort studies. SETTING & POPULATION Adults from general population. SELECTION CRITERIA FOR STUDIES We identified in PubMed, EMBASE, and the Cochrane Library database all cohort studies evaluating the role of BP in the incidence of decreased estimated GFR (eGFR; defined as eGFR<60 mL/min/1.73 m2) in individuals without decreased kidney function at baseline. PREDICTORS Hypertension (BP>140/90 mmHg), prehypertension (systolic BP of 120-139 and/or diastolic BP of 80-89 mmHg), and BP as a continuous variable. OUTCOMES Risk for decreased eGFR reported as relative risk (RR) and 95% CI. Heterogeneity (I2) was also evaluated. RESULTS Data from 16 cohorts (315,321 participants) were analyzed. All studies had a Newcastle-Ottawa score in the range of 6 to 8, denoting high quality. During a mean follow-up of 6.5 years, decreased eGFR occurred in 6.6% of participants. The presence of prehypertension and hypertension increased renal risk (RRs of 1.19 [95% CI, 1.07-1.33; I2=23.8%] and 1.76 [95% CI, 1.58-1.97; I2=37.7%], respectively). Similarly, we found that every 10-mm Hg increase in systolic and diastolic BPs associated with higher risk for decreased eGFR (RRs of 1.08 [95% CI, 1.04-1.11; I2=60.0%] and 1.12 [95% CI, 1.04-1.20; I2=51.4%], respectively). Metaregression analysis showed greater risk with older age (P=0.03), whereas other covariates were not significant. LIMITATIONS No individual patient-level data. CONCLUSIONS Prehypertension and hypertension, as BP levels, are independent predictors of decreased GFR in the general population, with the effect being more pronounced in the elderly. These findings are important for improving risk stratification in the general population.

Independent Role of Underlying Kidney Disease on Renal Prognosis of Patients with Chronic Kidney Disease under Nephrology Care

Primary kidney disease is suggested to affect renal prognosis of CKD patients; however, whether nephrology care modifies this association is unknown. We studied patients with CKD stage I-IV treated in a renal clinic and with established diagnosis of CKD cause to evaluate whether the risk of renal event (composite of end-stage renal disease and eGFR decline ≥40%) linked to the specific diagnosis is modified by the achievement or maintenance in the first year of nephrology care of therapeutic goals for hypertension (BP ≤130/80 mmHg in patients with proteinuria ≥150 mg/24h and/or diabetes and ≤140/90 in those with proteinuria <150 mg/24h and without diabetes) anemia (hemoglobin, Hb ≥11 g/dL), and proteinuria (≤0.5 g/24h). Survival analysis started after first year of nephrology care. We studied 729 patients (age 64±15 y; males 59.1%; diabetes 34.7%; cardiovascular disease (CVD) 44.9%; hypertensive nephropathy, HTN 53.8%; glomerulonephritis, GN 17.3%; diabetic nephropathy, DN 15.9%; tubule-interstitial nephropathy, TIN 9.5%; polycystic kidney disease, PKD 3.6%). During first year of Nephrology care, therapy was overall intensified in most patients and prevalence of main therapeutic goals generally improved. During subsequent follow up (median 3.3 years, IQR 1.9-5.1), 163 renal events occurred. Cox analysis disclosed a higher risk for PKD (Hazard Ratio 5.46, 95% Confidence Intervals 2.28–10.6) and DN (1.28,2.99–3.05), versus HTN (reference), independently of age, gender, CVD, BMI, eGFR or CKD stage, use of RAS inhibitors and achievement or maintenance in the first year of nephrology care of each of the three main therapeutic goals. No interaction was found on the risk of CKD progression between diagnostic categories and month-12 eGFR (P=0.737), as with control of BP (P=0.374), Hb (P=0.248) or proteinuria (P=0.590). Therefore, in CKD patients under nephrology care, diagnosis of kidney disease should be considered in conjunction with the main risk factors to refine renal risk stratification.

Plasma p-Cresol Lowering Effect of Sevelamer in Peritoneal Dialysis Patients: Evidence from a Cross-Sectional Observational Study

p-Cresol is a by-product of the metabolism of aromatic aminoacid operated by resident intestinal bacteria. In patients with chronic kidney disease, the accumulation of p-cresol and of its metabolite p-cresyl-sulphate causes endothelial dysfunction and ultimately increases the cardiovascular risk of these patients. Therapeutic strategies to reduce plasma p-cresol levels are highly demanded but not available yet. Because it has been reported that the phosphate binder sevelamer sequesters p-cresol in vitro we hypothesized that it could do so also in peritoneal dialysis patients. To explore this hypothesis we measured total cresol plasma concentrations in 57 patients with end-stage renal disease on peritoneal dialysis, 29 receiving sevelamer for the treatment of hyperphosphatemia and 28 patients not assuming this drug. Among the patients not assuming sevelamer, 16 were treated with lanthanum whereas the remaining 12 received no drug because they were not hyperphosphatemic. Patients receiving sevelamer had plasma p-cresol and serum high sensitivity C-reactive protein concentrations significantly lower than those receiving lanthanum or no drug. Conversely, no difference was observed among the different groups either in residual glomerular filtration rate, total weekly dialysis dose, total clearance, urine volume, protein catabolic rate, serum albumin or serum phosphate levels. Multiple linear regression analysis showed that none of these variables predicted plasma p-cresol concentrations that, instead, negatively correlated with the use of sevelamer. These results suggest that sevelamer could be an effective strategy to lower p-cresol circulating levels in peritoneal dialysis patients in which it could also favorably affect cardiovascular risk because of its anti-inflammatory effect.

Resistant Hypertension in Nondialysis Chronic Kidney Disease

Resistant hypertension (RH) is defined as blood pressure (BP) that remains above the target of less than 140/90 mmHg in the general population and 130/80 mmHg in people with diabetes mellitus or chronic kidney disease (CKD) in spite of the use of at least three full-dose antihypertensive drugs including a diuretic or as BP that reaches the target by means of four or more drugs. In CKD, RH is a common condition due to a combination of factors including sodium retention, increased activity of the renin-angiotensin system, and enhanced activity of the sympathetic nervous system. Before defining the hypertensive patient as resistant it is mandatory to exclude the so-called “pseudoresistance.” This condition, which refers to the apparent failure to reach BP target in spite of an appropriate antihypertensive treatment, is mainly caused by white coat hypertension that is prevalent (30%) in CKD patients. Recently we have demonstrated that “true” RH represents an independent risk factor for renal and cardiovascular outcomes in CKD patients.

Effects of age on hypertensive status in patients with chronic kidney disease.

Objective To evaluate effect of age on hypertensive status in chronic kidney disease (CKD). Methods We studied 459 prevalent CKD patients (stages 2–5, no dialysis), grouped by age (< 55, 55–64, 65–74, ≥ 75 years), undergoing clinical blood pressure (CBP) and ambulatory blood pressure (ABP) measurement. Results Prevalence of diabetes, left ventricular hypertrophy and previous cardiovascular disease progressively increased with aging; glomerular filtration rate (GFR) and hemoglobin decreased. Achievement of CBP target decreased from 16% in patients < 55 years to 6% in those ≥ 75 years (P = 0.023). ABP 24-h systolic rose while diastolic decreased, with a consequent pulse pressure increase from 45 ± 8 to 65 ± 14 mmHg (P < 0.0001). Age, proteinuria, diabetes, cardiovascular disease and anemia but not GFR predicted higher 24-h pulse pressure. CBP overestimated systolic/diastolic daytime ABP by 14 ± 18/7 ± 11 mmHg on average, a greater difference in older than younger groups (P < 0.005). Conversely, CBP night-time ABP difference did not vary among groups (24 ± 20/16 ± 11 mmHg). These age-dependent differences determined a rising prevalence of white-coat hypertension (from 19 to 40%, P = 0.001) and night/day ratio of at least 0.9 (from 43 to 66%, P = 0.0004). Age, diabetes, left ventricular hypertrophy and anemia but not GFR predicted nondipping status. Among the oldest patients, 13% had diastolic CBP below 70 mmHg, with 48% below the corresponding values of daytime (< 69 mmHg) or night-time ABP (< 60 mmHg). Conclusion In CKD, prevalence of white-coat hypertension, nondipping status and potentially dangerous low diastolic ABP increases with aging. This suggests wider use of ABP monitoring in older patients and need for trials addressing identification of an age-specific blood pressure target.

Controversial issues in CKD clinical practice: position statement of the CKD-treatment working group of the Italian Society of Nephrology

This position paper of the study group “Conservative treatment of Chronic Kidney Disease—CKD” of the Italian Society of Nephrology addresses major practical, unresolved, issues related to the conservative treatment of chronic renal disease. Specifically, controversial topics from everyday clinical nephrology practice which cannot find a clear, definitive answer in the current literature or in nephrology guidelines are discussed. The paper reports the point of view of the study group. Concise and practical advice is given on several common issues: renal biopsy in diabetes; dual blockade of the renin–angiotensin–aldosterone system (RAAS); management of iron deficiency; low protein diet; dietary salt intake; bicarbonate supplementation; treatment of obesity; the choice of conservative therapy vs. dialysis. For each topic synthetic statements, guideline-style, are reported.

Intradialytic Changes of Plasma Amino Acid Levels: Effect of Hemodiafiltration with Endogenous Reinfusion versus Acetate-Free Biofiltration

During hemodialysis, amino acids (AA) are lost in the ultrafiltrate with consequent modification of their plasma profile. The aim of this cross-sectional study was to evaluate intradialytic changes of plasma AA levels during a single session of hemodiafiltration with endogenous reinfusion (HFR) versus acetate-free biofiltration (AFB). 48 patients chronically treated with HFR or AFB were matched 1:1 for age, gender, Kt/V and diabetes. Blood samples were collected at the beginning and the end of dialysis. Baseline plasma levels (µmol/l) of total AA (3,176 ± 722), essential AA (889 ± 221), and branched chain AA (459 ± 140) levels in HFR were similar to those in AFB (3,399 ± 621, 938 ± 277, and 463 ± 71, respectively). Plasma intradialytic AA levels did not change in HFR, while in AFB there was a reduction by about 25%. In conclusion, as compared with AFB, HFR has a sparing effect on AA loss due to the lack of adsorption by cartridge and to their complete reinfusion in blood.