Dipping Status, Ambulatory Blood Pressure Control, Cardiovascular Disease, and Kidney Disease Progression: A Multicenter Cohort Study of CKD.

RATIONALE & OBJECTIVE: Ambulatory blood pressure (BP) monitoring allows concurrent evaluation of BP control and nocturnal BP dipping status, both related to adverse outcomes. However, few studies have assessed the prognostic role of combining information on dipping status and achieved ambulatory BP in patients with chronic kidney disease (CKD). STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 906 patients with hypertension and CKD attending 1 of 3 Italian nephrology clinics. EXPOSURE: Four groups were defined by simultaneously classifying systolic ambulatory BP levels as being at goal (daytime SBP <135 and nighttime SBP <120 mm Hg) or above goal, and the presence or absence of nocturnal dipping (nighttime to daytime SBP ratio of <0.9 versus ≥0.9). OUTCOME: The composite of time to initiation of maintenance dialysis or estimated glomerular filtration rate (eGFR) decline ≥50%, and the composite of fatal and nonfatal cardiovascular events. ANALYTICAL APPROACH: Multivariable Cox proportional hazards models were used to estimate risks of kidney disease progression and cardiovascular disease in the 4 exposure groups where nocturnal dipping with systolic ambulatory BP at goal was the reference group. RESULTS: The mean patient age was 63.8 years, 61% were male, and 26.4% had diabetes; eGFR was 41.1 ± 20.8 mL/min/1.73 m2. The dipping prevalence in each of the 4 groups was as follows: nocturnal dipping with ambulatory BP at goal, 18.6%; no nocturnal dipping with ambulatory BP at goal, 20.5%; nocturnal dipping with ambulatory BP above goal, 11.8%; and no nocturnal dipping with ambulatory BP above goal, 49.1%. Among patients with ambulatory BP above goal, the risk of cardiovascular events was greater in the absence (HR, 2.79 [95% CI, 1.64-4.75]) and presence (HR, 2.05 [95% CI, 1.10-3.84]) of nocturnal dipping. The same held true for risk of kidney disease progression (HRs of 2.40 [95% CI, 1.58-3.65] and 2.11 [95% CI, 1.28-3.48] in the absence and presence of nocturnal dipping, respectively). Patients at the ambulatory BP goal but who did not experience nocturnal dipping had an increased risk of the cardiovascular end point (HR, 2.06 [95% CI, 1.15-3.68]) and the kidney disease progression outcome (HR, 1.82 [95% CI, 1.17-2.82]). LIMITATIONS: Lack of a diverse cohort (all those enrolled were White). Residual uncontrolled confounding. CONCLUSIONS: Systolic ambulatory BP above goal or the absence of nocturnal dipping, regardless of ambulatory BP, is associated with higher risks of cardiovascular disease and kidney disease progression among patients with CKD. PLAIN-LANGUAGE SUMMARY: Among patients with chronic kidney disease (CKD), ambulatory blood pressure (BP) monitoring improves the identification of individuals at high risk of clinical disease outcomes. Those with uncontrolled ambulatory BP are known to have a higher risk of developing cardiovascular disease and kidney disease progression, particularly when their ambulatory BP does not decline by at least 10% at night. Whether this is also true for patients with presence of optimal ambulatory BP levels but a BP pattern of no nighttime decline is largely unknown. We measured ambulatory BP in 900 Italian patients with CKD and followed them for several years. We found that, independent of ambulatory BP level, the absence of nighttime reductions in BP was associated with worsening of CKD and more frequent cardiovascular events. The absence of nighttime declines in BP is an independent risk factor for adverse events among patients with CKD. Future studies are needed to examine whether treating the absence of nighttime declines in BP improves clinical outcomes.

Risk of end-stage kidney disease in kidney transplant recipients versus patients with native chronic kidney disease: multicentre unmatched and propensity-score matched analyses.

BACKGROUND: In kidney transplant recipients (KTR), the end-stage kidney disease (ESKD) risk dependent on the risk factors acting in native chronic kidney disease (CKD) remains undefined. METHODS: We compared risk and determinants of ESKD between 757 adult KTR and 1940 patients with native CKD before and after propensity-score (PS) analysis matched for unmodifiable risk factors [(age, sex, diabetes, cardiovascular disease and estimated glomerular filtration rate (eGFR)]. RESULTS: In unmatched cohorts, eGFR was lower in CKD versus KTR (45.9 ± 11.3 versus 59.2 ± 13.4 mL/min/1.73 m2, P < 0.001). During a median follow-up of 5.4 years, the unadjusted cumulative incidence of ESKD was consistently lower in unmatched KTR versus CKD. Conversely, in PS-matched analysis, the risk of ESKD in KTR was 78% lower versus CKD at 1 year of follow-up while progressively increased over time resulting similar to that of native CKD patients after 5 years and 2.3-fold higher than that observed in CKD at 10 years. R2 analysis in unmatched patients showed that the proportion of the outcome variance explained by traditional ESKD determinants was smaller in KTR versus native CKD (31% versus 70%). After PS matching, the risk of ESKD [hazard ratio (HR), 95% confidence interval (95% CI)] was significantly associated with systolic blood pressure (1.02, 1.01-1.02), phosphorus (1.31, 1.05-1.64), 24-h proteinuria (1.11, 1.05-1.17) and haemoglobin (0.85, 0.78-0.93) irrespective of KTR status. Similar data were obtained after matching also for modifiable risk factors. CONCLUSIONS: In KTR, when compared with matched native CKD patients, the risk of ESKD is lower in the first 5 years and higher later on. Traditional determinants of ESKD account for one-third of the variability of time-to-graft failure.

Caring for Patients With Advanced Chronic Kidney Disease: Dietary Options and Conservative Care Instead of Maintenance Dialysis.

An expert advisory board discussed the prevention and treatment of chronic kidney disease (CKD), with a focus on dietary options. This is timely, given the uptake of value based models for kidney care in the United States. Timing of dialysis start is influenced by patients' clinical status and complex patient-clinician interactions. Patients value personal freedom and quality of life and may want to delay dialysis, whilst physicians are sometimes more concerned with clinical outcomes. Kidney-preserving therapy can prolong the dialysis-free period and preserve residual kidney function, thus patients are asked to adjust their lifestyle and diet, to follow a low- or very low-protein diet, with or without ketoacid analogues. Multi-modal approaches include pharmacotherapies, management of symptoms, and a gradual, individualized dialysis transition. Patient empowerment is vital, including CKD education and involvement in decision making. These ideas may help patients, their families, and clinical teams to improve the management of CKD.

Sex difference in ambulatory blood pressure control associates with risk of ESKD and death in CKD patients receiving stable nephrology care.

BACKGROUND: It is unknown whether faster progression of chronic kidney disease (CKD) in men than in women relates to differences in ambulatory blood pressure (ABP) levels. METHODS: We prospectively evaluated 906 hypertensive CKD patients (553 men) regularly followed in renal clinics to compare men versus women in terms of ABP control [daytime <135/85 and nighttime blood pressure (BP) <120/70 mmHg] and risk of all-cause mortality and end-stage kidney disease (ESKD). RESULTS: Age, estimated glomerular filtration rate and use of renin-angiotensin system inhibitors were similar in men and women, while proteinuria was lower in women [0.30 g/24 h interquartile range (IQR) 0.10-1.00 versus 0.42 g/24 h, IQR 0.10-1.28, P = 0.025]. No sex-difference was detected in office BP levels; conversely, daytime and nighttime BP were higher in men (134 ± 17/78 ± 11 and 127 ± 19/70 ± 11 mmHg) than in women (131 ± 16/75 ± 11, P = 0.005/P < 0.001 and 123 ± 20/67 ± 12, P = 0.006/P < 0.001), with ABP goal achieved more frequently in women (39.1% versus 25.1%, P < 0.001). During a median follow-up of 10.7 years, 275 patients reached ESKD (60.7% men) and 245 died (62.4% men). Risks of ESKD and mortality (hazard ratio and 95% confidence interval), adjusted for demographic and clinical variables, were higher in men (1.34, 1.02-1.76 and 1.36, 1.02-1.83, respectively). Adjustment for office BP at goal did not modify this association. In contrast, adjustment for ABP at goal attenuated the increased risk in men for ESKD (1.29, 0.98-1.70) and death (1.31, 0.98-1.77). In the fully adjusted model, ABP at goal was associated with reduced risk of ESKD (0.49, 0.34-0.70) and death (0.59, 0.43-0.80). No interaction between sex and ABP at goal on the risk of ESKD and death was found, suggesting that ABP-driven risks are consistent in males and females. CONCLUSIONS: Our study highlights that higher ABP significantly contributes to higher risks of ESKD and mortality in men.

Sex Differences in the Progression of CKD Among Older Patients: Pooled Analysis of 4 Cohort Studies.

RATIONALE & OBJECTIVE: Data for the association of sex with chronic kidney disease (CKD) progression are conflicting, a relationship this study sought to examine. STUDY DESIGN: Pooled analysis of 4 Italian observational cohort studies. SETTING & PARTICIPANTS: 1,311 older men and 1,024 older women with estimated glomerular filtration rate (eGFR)<45mL/min/1.73m2 followed up in renal clinics. PREDICTOR: Sex. OUTCOMES: End-stage kidney disease (ESKD), defined as maintenance dialysis or kidney transplantation, as the primary outcome; all-cause mortality and eGFR decline as secondary outcomes. ANALYTICAL APPROACH: Cox proportional hazard analysis to estimate the relative risk for ESKD and mortality and linear mixed models to estimate the rate of eGFR decline. RESULTS: Age, systolic blood pressure, and use of renin-angiotensin system inhibitors were similar in men and women. Baseline eGFRs were 27.6±10.2 in men and 26.0±10.6mL/min/1.73m2 in women (P<0.001), while median proteinuria was lower in women (protein excretion, 0.45 [IQR, 0.14-1.10] g/d) compared with men (0.69 [IQR 0.19-1.60] g/d; P<0.001). During a median follow-up of 4.2 years, 757 developed ESKD (59.4% men) and 471 died (58.4% men). The adjusted risks for ESKD and mortality were higher in men (HRs of 1.50 [95% CI, 1.28-1.77] and 1.30 [95% CI, 1.06-1.60], respectively). This finding was consistent across CKD stages. We observed a significant interaction between sex and proteinuria, with the risk for ESKD in men being significantly greater than for women at a level of proteinuria of ∼0.5g/d or greater. The slope of decline in eGFR was steeper in men (-2.09; 95% CI, -2.21 to-1.97mL/min/1.73m2 per year) than in women (-1.79; 95% CI, -1.92 to-1.66mL/min/1.73m2 per year; P<0.001). Although sex differences in eGFR decline were not different across CKD stages (P=0.3), the difference in slopes between men and women was progressively larger with proteinuria >0.5g/d (P = 0.04). LIMITATIONS: Residual confounding; only whites were included. CONCLUSIONS: Excess renal risk in men may, at least in part, be related to higher levels of proteinuria in men compared with women.

Reclassification of chronic kidney disease patients for end-stage renal disease risk by proteinuria indexed to estimated glomerular filtration rate: multicentre prospective study in nephrology clinics.

BACKGROUND: In non-dialysis chronic kidney disease (CKD), absolute proteinuria (Uprot) depends on the extent of kidney damage and residual glomerular filtration rate (GFR). We therefore evaluated, as compared with Uprot, the strength of association of proteinuria indexed to estimated GFR (eGFR) with end-stage renal disease (ESRD) risk. METHODS: In a multi-cohort prospective study in 3957 CKD patients of Stages G3-G5 referred to nephrology clinics, we tested two multivariable Cox models for ESRD risk, with either Uprot (g/24 h) or filtration-adjusted proteinuria (F-Uprot) calculated as Uprot/eGFR ×100. RESULTS: Mean ± SD age was 67 ± 14 years, males 60%, diabetics 29%, cardiovascular disease (CVD) 34%, eGFR 32 ± 13 mL/min/1.73 m2, median (interquartile range) Uprot 0.41 (0.12-1.29) g/24 h and F-Uprot 1.41 (0.36-4.93) g/24 h per 100 mL/min/1.73 m2 eGFR. Over a median follow-up of 44 months, 862 patients reached ESRD. At competing risk analysis, ESRD risk progressively increased when F-Uprot was 1.0-4.9 and ≥5.0 versus <1.0 g/24 h per 100 mL/min/1.73 m2 eGFR in Stages G3a-G4 (P < 0.001) and Stage G5 (P = 0.002). Multivariable Cox analysis showed that Uprot predicts ESRD in Stages G3a-G4 while in G5 the effect was not significant; conversely, F-Uprot significantly predicted ESRD at all stages. The F-Uprot model allowed a significantly better prediction versus the Uprot model according to Akaike information criterion. Net reclassification improvement was 12.2% (95% confidence interval 4.2-21.1), with higher reclassification in elderly, diabetes and CVD, as well as in diabetic nephropathy and glomerulonephritis, and in CKD Stages G4 and G5. CONCLUSIONS: In patients referred to nephrology clinics, F-Uprot predicts ESRD at all stages of overt CKD and improves, as compared with Uprot, reclassification of patients for renal risk, especially in more advanced and complicated disease.

Cardiorenal prognosis by residual proteinuria level in diabetic chronic kidney disease: pooled analysis of four cohort studies.

Background: No study has assessed whether the prognosis of coexisting diabetes mellitus and chronic kidney disease (DM-CKD) is dictated by DM per se or by the extent of proteinuria. Methods: In this pooled analysis of four prospective studies in CKD patients treated with drugs inhibiting the renin-angiotensin system, we compared the risk of all-cause mortality, fatal and non-fatal cardiovascular (CV) events and end-stage renal disease (ESRD) between patients with (n = 693) and without diabetes (n = 1481) stratified by proteinuria level (<0.15, 0.15-0.49, 0.5-1 and >1 g/day). Results: The group with DM-CKD was older (69 ± 11 versus 65 ± 15 years), had a higher body mass index (29.6 ± 5.4 versus 27.5 ± 4.8 kg/m2) and systolic blood pressure (143 ± 19 versus 136 ± 18 mmHg), prevalent CV disease (48% versus 29%) and lower estimated glomerular filtration rate (34.5 ± 17.9 versus 36.6 ± 19.0 mL/min/1.73 m2). During 4.07 years of follow-up, there were 466 patients with ESRD, 334 deaths and 401 CV events occurred. In the subgroup with urine protein <0.15 g/day (N = 662), the risks of ESRD, CV events and mortality were similar in diabetic and non-diabetic patients. Conversely, in DM-CKD patients, the mortality risk was higher in proteinuric patients {hazard ratio 1.92 [95% confidence interval (CI) 1.25-2.95); 1.99 (1.26-3.15) and 1.98 (1.28-3.06) for proteinuria 0.15-0.49, 0.5-1 and >1 g/day, respectively}, whereas in non-diabetics the mortality risk increased only for proteinuria 0.5-1 g/day [HR 1.60 (95% CI 1.07-2.40)] and >1 g/day [HR 1.69 (95% CI1.20-2.55)]. In both groups, CV risk had a trend similar to that of mortality. ESRD risk increased progressively across strata >0.5 g/day independent of diabetic status. Conclusions: We provide evidence that patients with non-proteinuric DM-CKD are not exposed to higher cardiorenal risk. In contrast, in the presence of moderate proteinuria and diabetes per se is associated with a higher risk of mortality and CV events, whereas the entity of abnormal proteinuria modulates ESRD risk independent of diabetes.

Mediterranean diet as the diet of choice for patients with chronic kidney disease.

Traditional dietary management of chronic kidney disease (CKD) focuses on the quantity within the diet of energy and protein, and the restriction of single micronutrients, with little mention of dietary quality. Dietary patterns that are more plant-based, lower in meat (including processed meat), sodium and refined sugar, and have a higher content of grains and fibres are now included in multiple clinical guidelines for chronic disease prevention. The Mediterranean diet (MD) has been associated with reduced cardiovascular disease incidence in both observational and interventional studies. A wealth of evidence links MD with other beneficial effects on chronic diseases such as diabetes, obesity or cognitive health. This review examines each constituent of the classical MD and evaluates their suitability for the management of patients with CKD. We also evaluate the potential hyperkalaemia risk of increasing fruit and vegetable intake. Overall, a decrease in net endogenous acid production and increase in fibre may lead to a better control of metabolic acidosis. This, together with other putative favourable effects of MD on endothelial function, inflammation, lipid profile and blood pressure, provide mechanistic pathways to explain the observed reduced renal function decline and improved survival in CKD patients adhering to an MD.

Safety and effectiveness of low-protein diet supplemented with ketoacids in diabetic patients with chronic kidney disease.

BACKGROUND: The impact of the low-protein diet on nutrition in CKD diabetics is uncertain. METHODS: The metabolic and nutritional effects of a low-protein (0.5-0.6 g/kg/d), normal-high energy (30-35 kcal/kg/d) diet supplemented with ketoacids (LPD-KA) were prospectively evaluated in CKD patients with (DM) and without (non-DM) diabetes mellitus. RESULTS: 197 patients on CKD stages 3-5 were enrolled. DM (n = 81) and non-DM (n = 116) were comparable for gender (Male 58 vs 55%), age (66 ± 9 vs 63 ± 18 years), renal function (eGFR 23 ± 13 vs 24 ± 13 mL/min). After 6-month, serum urea (DM: 131 ± 58 to 105 ± 49 mg/dl, p < 0.05; non-DM: 115 ± 52 to 88 ± 36, p < 0.05) and phosphate (DM: 4.5 ± 1.3 to 4.1 ± 1.2 mg/dl, p = 0.06; non-DM: 4.3 ± 1.0 to 3.7 ± 0.8, p < 0.05) declined. Fasting glucose decreased in DM (126 ± 52 to 103 ± 29 mg/dl, p < 0.05) without insulin dose increase. These effects were preserved after 3-year. Serum albumin did not change after 6 months (DM: 3.7 ± 0.6 to 3.8 ± 0.4 mg/dl; non-DM: 4.0 ± 0.6 to 4.0 ± 0.4) and in the long-term. Body weight (BW) declined after the diet start (DM: 68.9 ± 14.3 to 65.1 ± 12.1 kg, p < 0.05; non-DM: 66.6 ± 15.1 to 64.1 ± 15.1, p < 0.05) and was stable at 6 months and 3 years. Muscle strength at baseline was reduced in all patients and remained stable during the diet period. Changes of nutritional markers during the study were similar among groups and diabetes was not associated to any nutritional change at the multivariate analysis. As attain wasting, lower BMI (< 23 kg/m2) and albumin (< 3.8 g/dl) levels were present in 1/3 patients at start and along 3 years, cholesterol never dropped below the lower threshold (< 100 mg/dl) and poorer FM (< 10%) was less than 10% during the study in both groups. CONCLUSIONS: In diabetic CKD patients a low-protein diet supplemented with ketoacids improves uremia and diabetes, causes sudden decline of body weight which remains stable over time and has not a negative effect on wasting and muscle mass and fitness. In diabetic CKD patients the LPD-KA is safe and the nutritional impact is the same as in non-diabetics CKD.