CKD-MBD biomarkers and CKD progression: an analysis by the joint model.

BACKGROUND: Biomarkers of chronic kidney disease-mineral and bone disorder (CKD-MBD) have been implicated in CKD progression in follow-up studies focusing on single measurements of individual biomarkers made at baseline only. The simultaneous relationship between the time trend of these biomarkers over the course of CKD and renal outcomes has never been tested. METHODS: We applied the joint model (JM) to investigate the longitudinal relationship between repeated measurements of CKD-MBD biomarkers and a combined renal endpoint (estimated glomerular filtration rate reduction >30%, dialysis or transplantation) in 729 stage 2-5 CKD patients over a 36-month follow-up. RESULTS: In the survival submodel of the JM, the longitudinal series of parathyroid hormone (PTH) values was directly and independently related to the risk of renal events [hazard ratio (HR) (1 ln increase in parathyroid hormone (PTH) 2.0 (range 1.5-2.8), P < .001)] and this was also true for repeated measurements of serum phosphate [HR (1 mg/dl) 1.3924 (range 1.1459-1.6918), P = .001], serum calcium [HR (1 mg/dl) 0.7487 (range 0.5843-0.9593), P = .022], baseline fibroblast growth factor 23 [HR (1 pg/ml) 1.001 (range 1.00-1.002), P = .045] and 1,25-dihydroxyvitamin D [HR (1 pg/ml) 0.9796 (range 0.9652-0.9942), P = .006]. CONCLUSION: Repeated measurements of serum PTH, calcium and phosphate as well as baseline FGF23 and 1,25-dihydroxyvitamin D are independently related with the progression to kidney failure in a cohort of stage 2-5 CKD patients. This longitudinal study generates the hypothesis that interventions at multiple levels on MBD biomarkers can mitigate renal function loss in this population.

Distance from the outbreak of infection, ozone pollution and public health consequences of SARS-CoV-2 epidemic: the HOPE method.

BACKGROUND: Italy was the second country in the world, after China, to be hit by SARS-CoV-2 pandemic. Italy's experience teaches that steps to limit people's movement by imposing 'red zones' need to be put in place early by carefully identifying the cities to be included within these areas of quarantine. The assessment of the relationship between the distance from an established outbreak of SARS-CoV-2 infection with transmission-linked cases and mortality observed in other sites could provide useful information to identify the optimal radius of red zones. METHODS: We investigated the relationship between SARS-CoV-2 cases and the distance of each Italian province from the first outbreak of SARS-CoV-2 epidemic in Italy (the city of Lodi placed in the Lombardia region). In 38 provinces of Lombardia and neighboring regions, we performed a breakpoint analysis to identify the radius of the red zone around Lodi minimizing epidemic spread and mortality in neighboring cities. RESULTS: In all Italian provinces, a non-linear relationship was found between SARS-CoV-2 cases and distance from Lodi. In an analysis including the provinces of Lombardia and neighboring regions, SARS-CoV-2 cases and mortality increased when the distance from Lodi reduced below 92 and 140 km, respectively, and such relationships were amplified by ozone (O3) pollution. CONCLUSIONS: The breakpoint analysis identifies the radius around the outbreak of Lodi minimizing the public health consequences of SARS-CoV-2 in neighboring cities. Such an approach can be useful to identify the red zones in future epidemics due to highly infective pathogens similar to SARS-CoV-2.

Different rates of progression and mortality in patients with chronic kidney disease at outpatient nephrology clinics across Europe.

The incidence of renal replacement therapy varies across countries. However, little is known about the epidemiology of chronic kidney disease (CKD) outcomes. Here we describe progression and mortality risk of patients with CKD but not on renal replacement therapy at outpatient nephrology clinics across Europe using individual data from nine CKD cohorts participating in the European CKD Burden Consortium. A joint model assessed the mean change in estimated glomerular filtration rate (eGFR) and mortality risk simultaneously, thereby accounting for mortality risk when estimating eGFR decline and vice versa, while also correcting for the measurement error in eGFR. Results were adjusted for important risk factors (baseline eGFR, age, sex, albuminuria, primary renal disease, diabetes, hypertension, obesity and smoking) in 27,771 patients from five countries. The adjusted mean annual eGFR decline varied from 0.77 (95% confidence interval 0.45, 1.08) ml/min/1.73m2 in the Belgium cohort to 2.43 (2.11, 2.75) ml/min/1.73m2 in the Spanish cohort. As compared to the Italian PIRP cohort, the adjusted mortality hazard ratio varied from 0.22 (0.11, 0.43) in the London LACKABO cohort to 1.30 (1.13, 1.49) in the English CRISIS cohort. These results suggest that the eGFR decline showed minor variation but mortality showed the most variation. Thus, different health care organization systems are potentially associated with differences in outcome of patients with CKD within Europe. These results can be used by policy makers to plan resources on a regional, national and European level.

Neuropeptide Y and chronic kidney disease progression: a cohort study.

Background: Neuropeptide Y (NPY) is a sympathetic neurotransmitter that has been implicated in various disorders including obesity, gastrointestinal and cardiovascular diseases. Methods: We investigated the relationship between circulating NPY and the progression of the glomerular filtration rate (GFR) and proteinuria and the risk for a combined renal endpoint (>30% GFR loss, dialysis/transplantation) in two European chronic kidney disease (CKD) cohorts including follow-up of 753 and 576 patients for 36 and 57 months, respectively. Results: Average plasma NPY was 104 ± 32 pmol/L in the first CKD cohort and 119 ± 41 pmol/L in the second one. In separate analyses of the two cohorts, NPY associated with the progression of the estimated GFR (eGFR) and proteinuria over time in both unadjusted and adjusted {eGFR: -3.60 mL/min/1.73 m2 [95% confidence interval (CI): -4.46 to - 2.74] P < 0.001 and -0.83 mL/min/1.73 m2 (-1.41 to - 0.25, P = 0.005); proteinuria: 0.18 g/24 h (0.11-0.25) P < 0.001 and 0.07 g/24 h (0.005-0.14) P = 0.033} analyses by the mixed linear model. Accordingly, in a combined analysis of the two cohorts accounting for the competitive risk of death (Fine and Gray model), NPY predicted (P = 0.005) the renal endpoint [sub-distribution hazard ratio (SHR): 1.09; 95% CI: 1.03-1.16; P = 0.005] and the SHR in the first cohort (1.14, 95% CI: 1.04-1.25) did not differ (P = 0.25) from that in the second cohort (1.06, 95% CI: 0.98-1.15). Conclusions: NPY associates with proteinuria and faster CKD progression as well as with a higher risk of kidney failure. These findings suggest that the sympathetic system and/or properties intrinsic to the NPY molecule may play a role in CKD progression.

Competitive interaction between fibroblast growth factor 23 and asymmetric dimethylarginine in patients with CKD.

Both fibroblast growth factor 23 (FGF-23) and asymmetric dimethylarginine (ADMA) are associated with progression of CKD. We tested the hypothesis that ADMA and FGF23 are interactive factors for CKD progression in a cohort of 758 patients with CKD in Southern Europe (mean eGFR±SD, 36±13 ml/min per 1.73 m(2)) and in a central European cohort of 173 patients with CKD (MMKD study, mean eGFR, 64±39 ml/min per 1.73 m(2)). In the first cohort, 214 patients had renal events (decrease in eGFR of >30%, dialysis, or kidney transplantation) during a 3-year follow-up. Both intact FGF-23 and ADMA predicted the incidence rate of renal events in unadjusted and adjusted analyses (P<0.001). There was a strong competitive interaction between FGF-23 and ADMA in the risk of renal events (P<0.01 in adjusted analyses); the risk associated with raised ADMA levels was highest in patients with low FGF-23 levels. These results were confirmed in the MMKD cohort, in which FGF-23 level was again an effect modifier of the relationship between plasma ADMA level and renal events (doubling of baseline serum creatinine, dialysis, or kidney transplantation) in the adjusted analyses (P<0.01). Furthermore, in the MMKD cohort there was a parallel, independent competitive interaction between symmetric dimethylarginine level and c-terminal FGF-23 level for the risk for renal events (P=0.001). These findings indicate that the association of ADMA level with the risk of CKD progression is modified by FGF-23 level and provide further evidence that dysregulation of the nitric oxide system is involved in CKD progression.

High estimated pulmonary artery systolic pressure predicts adverse cardiovascular outcomes in stage 2-4 chronic kidney disease.

High estimated pulmonary artery systolic pressure (ePASP) is an established risk factor for mortality and cardiovascular (CV) events in the general population. High ePASP predicts mortality in dialysis patients but such a relationship has not been tested in patients with early CKD. Here we estimated the prevalence and the risk factors of high ePASP in 468 patients with CKD stage 2-4 and determined its prognostic power for a combined end point including cardiovascular death, acute heart failure, coronary artery disease, and cerebrovascular and peripheral artery events. High ePASP (35 mm Hg and above) was present in 108 CKD patients. In a multivariate logistic regression model adjusted for age, diabetes, hemoglobin, left atrial volume (LAV/BSA), left ventricular mass (LVM/BSA), and history of CV disease, age (OR, 1.06; 95% CI, 12 1.04-1.09) and LAV/BSA (OR, 1.05; 95% CI, 1.03-1.07) were the sole significant independent predictors of high ePASP. Elevated ePASP predicted a significantly high risk for the combined cardiovascular end point both in unadjusted analyses (HR, 2.70; 95% CI, 1.68-4.32) and in analyses adjusting for age, eGFR, hemoglobin, LAV/BSA, LVM/BSA, and the presence of diabetes and CV disease (HR, 1.75; 95% CI, 1.05-2.91). High ePASP is relatively common in patients with stage 2-4 CKD and predicts adverse CV outcomes independent of established classical and CKD-specific risk factors. Whether high ePASP is a modifiable risk factor in patients with CKD remains to be determined in randomized clinical trials.

A genetic marker of uric acid level, carotid atherosclerosis, and arterial stiffness: a family-based study.

BACKGROUND: Hyperuricemia associates with atherosclerosis complications, but it is uncertain whether this relationship is causal in nature. The urate transporter GLUT9 (encoded by the SLC2A9 gene) is a major genetic determinant of serum uric acid level in humans. Because polymorphisms are distributed randomly at mating (Mendelian randomization), studies based on GLUT9 polymorphisms may provide unconfounded assessment of the nature of the link between uric acid and atherosclerosis. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: Family-based study including 449 individuals in 107 families in a genetically homogeneous population in Southern Italy. FACTOR: Serum uric acid level, rs734553 allele, and age. OUTCOME: Ultrasound biomarkers of atherosclerosis (intima-media thickness [IMT] and internal diameter) and pulse wave velocity (PWV). RESULTS: Serum uric acid level was dose-dependently associated with the T allele of rs734553, a polymorphism in SLC2A9 (P=8×10(-6)). Serum uric acid level was a strong modifier of the relationship between age and IMT in fully adjusted analyses (ß=0.33; P=0.01), whereas no such relationship was found for internal diameter (ß=-0.15; P=0.3) or PWV (ß=0.10; P=0.6). The T allele coherently associated with carotid IMT, internal diameter, and PWV and emerged as an even stronger modifier of the age-IMT and age-internal diameter relationships in both crude and fully adjusted (ß=0.40 [P<0.001] and ß=0.48 [P=0.003], respectively) analyses. LIMITATIONS: This is a hypothesis-generating study. CONCLUSIONS: Results in this family-based study implicate uric acid as an important modifier of the age-dependent risk for atherosclerosis. Trials testing uric acid-lowering interventions are needed to prove this hypothesis.

Neuropeptide Y gene polymorphisms and chronic kidney disease progression.

BACKGROUND: Neuropeptide Y (NPY) is a neurotransmitter expressed in both the central and peripheral nervous systems, which is involved in regulating a multitude of physiological processes ranging from arterial pressure, energy balance, the immune response and inflammation and renal electrolyte transport. In a cohort of chronic kidney disease (CKD) patients, we recently showed that high plasma NPY levels predict renal disease progression independently of hypertension and other risk factors but the causal nature of this association remains unproven. METHODS: In the same cohort of the previous study, we tested the relationship of NPY gene variability, as assessed by five single nucleotide polymorphisms (SNPs) that explained the whole gene variability, with the incidence rate of a predefined combined renal endpoint (dialysis/transplantation/estimated glomerular filtration rate reduction >30%) over a median follow up of 36 months (inter-quartile range 35-37 months) in 735 ethnically homogeneous patients with stage 2-5 CKD. RESULTS: Two variants [rs16131 (recessive model for the T risk allele: TT, n  = 563; CT + CC, n  = 172) and rs16140 (dominant model for the G risk allele: GG + CG, n  = 413; CC, n  = 322)] were coherently associated with the incidence rate of renal events [hazard ratio (HR) ranging from 1.39 to 1.57, P  ≤ 0.015] and this was also true when the two SNPs were jointly introduced into the same Cox model ( P  ≤ 0.043). The analysis of the biological interaction showed a significant synergism between the NPY rs16131 and rs16140 variants. Indeed, patients harboring NPY rs16131 TT and NPY rs16140 GG + CG risk genotypes had a much higher HR of renal events [HR: 1.80, 95% confidence interval (CI):1.16-2.79, P  = 0.009] than that expected in the absence of biological interaction under both the additive and multiplicative models and the attributable proportion due to interaction (AP) was 25% and 38% on crude and adjusted analyses, respectively. CONCLUSION: This study, based on the Mendelian randomization approach and using NPY gene variants as instrumental variables to test the link between NPY and CKD progression, is in line with findings indicating that high plasma NPY levels predict an increased risk for renal events and lend support to the hypothesis that NPY is causally involved in renal disease progression.

ROC curve analysis: a useful statistic multi-tool in the research of nephrology.

In the past decade, scientific research in the area of Nephrology has focused on evaluating the clinical utility and performance of various biomarkers for diagnosis, risk stratification and prognosis. Before implementing a biomarker in everyday clinical practice for screening a specific disease context, specific statistic measures are necessary to evaluate the diagnostic accuracy and performance of this biomarker. Receiver Operating Characteristic (ROC) Curve analysis is an important statistical method used to estimate the discriminatory performance of a novel diagnostic test, identify the optimal cut-off value for a test that maximizes sensitivity and specificity, and evaluate the predictive value of a certain biomarker or risk, prediction score. Herein, through practical examples, we aim to present a simple methodological approach to explain in detail the principles and applications of ROC curve analysis in the field of nephrology pertaining diagnosis and prognosis.

Long-term visit-to-visit office blood pressure variability increases the risk of adverse cardiovascular outcomes in patients with chronic kidney disease.

Long-term visit-to-visit blood pressure (BP) variability predicts a high risk for cardiovascular events in patients with essential hypertension. Whether long-term visit-to-visit BP variability holds the same predictive power in predialysis patients with chronic kidney disease (CKD) is unknown. Here we tested the relationship between long-term visit-to-visit office BP variability and a composite end point (death and incident cardiovascular events) in a cohort of 1618 patients with stage 2-5 CKD. Visit-to-visit systolic BP variability was significantly and independently related to baseline office, maximal, and average systolic BPs, age, glucose, estimated glomerular filtration rate, and albumin, and to the number of visits during the follow-up. Both the standard deviation of systolic BP (hazard ratio: 1.11, 95% confidence interval: 1.01-1.20) and the coefficient of variation of systolic BP (hazard ratio: 1.15, 95% confidence interval: 1.02-1.29) were significant predictors of the combined end point independent of peak and average systolic BP, cardiovascular comorbidities, Framingham risk factors, and CKD-related risk factors. Antihypertensive treatment (ß-blockers and sympatholytic drugs) significantly abrogated the excess risk associated with high systolic BP variability. Thus, large visit-to-visit systolic BP variability in patients with CKD predicts a higher risk of death and nonfatal cardiovascular events independent of underlying BP levels.

Venous bicarbonate and CKD progression: a longitudinal analysis by the group-based trajectory model.

Background: Metabolic acidosis accelerates chronic kidney disease (CKD) progression towards kidney failure in animal models. Clinical trials testing the effect of bicarbonate on kidney outcomes are underpowered and/or of suboptimal quality. On the other hand, observational studies testing the same hypothesis are generally based on bicarbonate measured at a single time point. Methods: We studied the longitudinal relationship between repeated venous bicarbonate levels and a predefined composite renal outcome (a ≥30% estimated glomerular filtration rate reduction, dialysis or transplantation) by using group-based trajectory model (GBTM) analysis. The GBTM analysis was used to classify patients based on individual bicarbonate levels over time. The relationship between trajectory groups and renal outcomes was investigated using crude and adjusted Cox regression models. A total of 528 patients with stage 2-5 CKD were included in the analysis. Results: The GBTM analysis identified four distinct trajectories of bicarbonate levels: low, moderate, moderate-high and high. During the follow-up period, 126 patients experienced the combined renal endpoint. The hazard rate of renal events decreased dose-dependently from the lowest to the highest bicarbonate trajectory. After adjusting for potential confounders, there was a 63% risk reduction for the composite renal endpoint for patients in the high trajectory category compared with those in the low trajectory category. Conclusion: The study found that higher bicarbonate trajectories were associated with a lower risk of adverse renal outcomes in CKD patients. These results suggest that strategies to maintain higher bicarbonate levels may benefit patients with CKD. However, further high-quality randomised trials are needed to confirm these findings and recommend bicarbonate supplementation as a strategy to delay CKD progression.

Are there sex differences in cardiovascular outcomes in non-dialysis CKD patients?

Background: Sex differences for cardiovascular (CV) risk and outcomes in chronic kidney disease (CKD) patients not on dialysis have been scarcely or never investigated. We therefore studied this important aspect in a cohort of CKD stage 2-5 in the south of Italy. Methods: We tested the relationship between sex and fatal and non-fatal major CV events in a cohort of 759 stage 2-5 CKD patients followed up for a median time of 36 months. Results: Out of 759 patients, 455 were males (60%) and the remaining 304 patients were females (40%). During the follow-up, 42 patients died, and 118 had fatal and non-fatal CV events. On univariate Cox regression analyses, the male sex failed to be associated with all-cause mortality but was strongly related to the incidence rate of fatal and non-fatal major CV events [hazard ratio (HR) 1.75, 95% confidence interval (CI) 1.18-2.60, P = .006]. Data adjustment for a series of major potential confounders did not materially affect the strength of this relationship (HR 1.78, 95% CI 1.03-3.09). Further analysis testing the effect of age on major CV outcomes by sex showed an effect modification by this risk factor on the same outcome (P = .037) because the HR of male versus female CV events increased progressively with aging. Conclusion: Male patients in stage G2-5 CKD had a higher risk for CV events compared with female patients. Age was shown to be a risk modifier for the association between sex and CV events and this risk increased linearly across a wide age spectrum in CKD patients.

The fat-mass and obesity-associated gene (FTO) predicts mortality in chronic kidney disease of various severity.

BACKGROUND: Polymorphisms in the FTO (fat-mass and obesity-associated) gene have been associated with the body mass index, cancer, type 2 diabetes and hypertension. METHODS: We investigated the relationship between 17 tag single-nucleotide polymorphisms (SNPs) and all-cause mortality in three cohorts of dialysis patients (CREED-1, North Apulian and CREED-2 cohorts; n = 783) and in one cohort of stage 2-5 CKD patients (n = 757). RESULTS: We first explored the association between the 17 tag SNPs and all-cause mortality in the CREED-1 cohort and found that patients with the A allele of the FTO rs708259 polymorphism had an elevated risk of mortality (hazard ratio, HR: 1.52, 95% confidence interval (CI) 1.11-2.08; P = 0.008). Similarly, the A allele was associated with an increased risk of death also in the other two dialysis cohorts (North Apulian cohort, risk: +23%; CREED-2 cohort, risk: +21%). The elevated risk portended by this allele was even higher in the stage 2-5 CKD cohort (+97%). However, the risk of mortality associated with the A allele in the three confirmatory cohorts failed to achieve formal statistical significance. In a meta-analysis including the four cohorts (n = 1540; total deaths, n = 381), individuals with the A allele had a 42% excess risk of death (HR: 1.42, 95% CI 1.14-1.76, P = 0.002). CONCLUSION: The A allele of the FTO rs708259 polymorphism is an independent predictor of all-cause mortality in patients with CKD of various severity. These data support our hypothesis that the FTO gene may be a relevant genetic risk factor for mortality in this population.

ACE inhibition is renoprotective among obese patients with proteinuria.

Obesity may increase the risk for progression of CKD, but the effect of established renoprotective treatments in overweight and obese patients with CKD is unknown. In this post hoc analysis of the Ramipril Efficacy In Nephropathy (REIN) trial, we evaluated whether being overweight or obese influences the incidence rate of renal events and affects the response to ramipril. Of the 337 trial participants with known body mass index (BMI), 105 (31.1%) were overweight and 49 (14.5%) were obese. Among placebo-treated patients, the incidence rate of ESRD was substantially higher in obese patients than overweight patients (24 versus 11 events/100 person-years) or than those with normal BMI (10 events/100 person-years); we observed a similar pattern for the combined endpoint of ESRD or doubling of serum creatinine. Ramipril reduced the rate of renal events in all BMI strata, but the effect was higher among the obese (incidence rate reduction of 86% for ESRD and 79% for the combined endpoint) than the overweight (incidence rate reduction of 45 and 48%, respectively) or those with normal BMI (incidence rate reduction of 42 and 45%, respectively). We confirmed this interaction between BMI and the efficacy of ramipril in analyses that adjusted for potential confounders, and we observed a similar effect modification for 24-hour protein excretion. In summary, obesity predicts a higher incidence of renal events, but treatment with ramipril can essentially abolish this risk excess. Furthermore, the reduction in risk conferred by ramipril is larger among obese than nonobese patients.

Phosphate may promote CKD progression and attenuate renoprotective effect of ACE inhibition.

Phosphate may promote the onset and progression of chronic nephropathies. Here we evaluated the relationships between baseline serum phosphate levels, disease progression, and response to ACE inhibition in 331 patients with proteinuric nephropathies in the prospective Ramipril Efficacy In Nephropathy (REIN) trial. Independent of treatment, patients with phosphate levels in the highest two quartiles progressed significantly faster either to ESRD or to a composite endpoint of doubling of serum creatinine or ESRD compared with patients with phosphate levels below the median (P < 0.001). Results were similar when we analyzed phosphate as a continuous variable (P ≤ 0.004). The renoprotective effect of ramipril decreased as serum phosphate increased (P ≤ 0.008 for interaction); this modification of the treatment effect by phosphate persisted despite adjusting for potential confounders such as GFR and urinary protein. In summary, these data suggest that phosphate is an independent risk factor for progression of renal disease among patients with proteinuric CKD, and high levels of phosphate may even attenuate the renoprotective effect of ACE inhibitors. Future trials should test whether reducing serum phosphate improves renal outcomes and optimizes the renoprotective effect of ACE inhibition.

Fundamentals and Applications of the Receiver Operating Characteristic Curve Analysis in the Research of Endothelial Dysfunction in Chronic Kidney Disease.

Endothelial dysfunction (ED) starts early in chronic kidney disease (CKD) and is the hallmark of atherosclerosis in these patients. During recent years, numerous markers have emerged, aiming to predict the onset of ED in CKD patients. Therefore, there is a need to evaluate and assess the discriminatory ability (or diagnostic accuracy) of such a marker (i.e., the ability to correctly classify individuals as having a given disease or not) and identify the optimal cut-off value. A receiver operating characteristic (ROC) curve analysis has been used in the majority of the research papers evaluating the predictive ability of a marker of ED. It is a graphical plot combining pairs of sensitivity (true positive rate) on the y axis and the complement of specificity (1-specificity, false positive rate) in the x axis, corresponding to several of the cut-off values covering the complete range of possible values that this test/marker might take. Herein, using a series of practical examples derived from clinical studies on ED in the special population of CKD, we address the principles, fundamentals, advantages and limitations regarding the interpretation of the ROC analysis.

Methods to Analyze Time-to-Event Data: The Cox Regression Analysis.

The Cox model is a regression technique for performing survival analyses in epidemiological and clinical research. This model estimates the hazard ratio (HR) of a given endpoint associated with a specific risk factor, which can be either a continuous variable like age and C-reactive protein level or a categorical variable like gender and diabetes mellitus. When the risk factor is a continuous variable, the Cox model provides the HR of the study endpoint associated with a predefined unit of increase in the independent variable (e.g., for every 1-year increase in age, 2 mg/L increase in C-reactive protein). A fundamental assumption underlying the application of the Cox model is proportional hazards; in other words, the effects of different variables on survival are constant over time and additive over a particular scale. The Cox regression model, when applied to etiological studies, also allows an adjustment for potential confounders; in an exposure-outcome pathway, a confounder is a variable which is associated with the exposure, is not an effect of the exposure, does not lie in the causal pathway between the exposure and the outcome, and represents a risk factor for the outcome.

Methods to Analyse Time-to-Event Data: The Kaplan-Meier Survival Curve.

Studies performed in the field of oxidative medicine and cellular longevity frequently focus on the association between biomarkers of cellular and molecular mechanisms of oxidative stress as well as of aging, immune function, and vascular biology with specific time to event data, such as mortality and organ failure. Indeed, time-to-event analysis is one of the most important methodologies used in clinical and epidemiological research to address etiological and prognostic hypotheses. Survival data require adequate methods of analyses. Among these, the Kaplan-Meier analysis is the most used one in both observational and interventional studies. In this paper, we describe the mathematical background of this technique and the concept of censoring (right censoring, interval censoring, and left censoring) and report some examples demonstrating how to construct a Kaplan-Meier survival curve and how to apply this method to provide an answer to specific research questions.

Epidemiology of hyperkalemia in CKD patients under nephrological care: a longitudinal study.

Hyperkalemia is a potential life-threatening condition among chronic kidney disease (CKD) patients. Available estimates of the burden of this alteration in CKD are mainly derived from large administrative databases. Since K measurements in patients in these databases are often dictated by clinical reasons, longitudinal studies including pre-planned measurements of potassium independently of clinical complication/symptoms may produce more reliable estimates of the frequency and the risk factors underlying hyperkalemia in CKD patients. We estimated the prevalence and the incidence of hyperkalemia in a longitudinal study in 752 stages 2-5 CKD patients lasting 3 years and including up to seven pre-planned assessment of key biochemical measurements including K. At baseline, 203 out of 752 patients (27%) had serum K > 5.0 mM/L and 33% had acidosis (HCO3 ≤ 22 mmol/L). Among those without hyperkalemia at baseline (n = 549), 284 patients developed this alteration across the 3-year follow-up. The point prevalence of hyperkalemia rose from 27% (baseline) to 30% (last visit) (P = 0.001). In a multivariate model, hyperkalemia at baseline [odds ratio (OR):7.29, 95% CI 5.65-9.41, P < 0.001], venous bicarbonate levels [OR (1 mmol/l): 0.92, 0.89-0.96, P < 0.001], eGFR [OR (1 ml/min/1.73m2): 0.98, 0.97-0.99, P < 0.001], use of ACE inhibitors (OR: 1.68, 1.28-2.19, P < 0.001) and angiotensin II antagonists (OR: 1.30, 1.01-1.68, P = 0.045) were related to hyperkalemia over time. Of note, venous bicarbonate levels emerged as an independent risk factor of hyperkalemia over time also in a separate analysis of patients with and without hyperkalemia at baseline. In a cohort of CKD patients including pre-planned measurements of K, 27% of patients had hyperkalemia. Metabolic acidosis and the use of drugs interfering with renin-angiotensin system were the strongest modifiable risk factors for this potentially life-threatening alteration in CKD in longitudinal analyses in the whole study cohort and in patients developing de novo hyperkalemia over time.

Circulating soluble receptor of advanced glycation end product inversely correlates with atherosclerosis in patients with chronic kidney disease.

The soluble receptor of advanced glycation end product (sRAGE) prevents vascular damage in experimental animal models, and observational studies in the general population support the hypothesis that sRAGE may exert a protective role on the vasculature. To test this in patients with chronic kidney disease, we determined the relationship between plasma sRAGE and carotid atherosclerosis in 142 patients with an average estimated glomerular filtration rate (eGFR) of 32 ml/min per 1.73 m(2) and 49 healthy control individuals matched for age and gender. Plasma sRAGE was significantly higher in patients with chronic kidney disease than in the control cohort. In an aggregate analysis of the patients and controls, there was a significant inverse relationship between eGFR and sRAGE, with a breakpoint in the regression line at 64 ml/min per 1.73 m(2). Significant inverse relationships were found for sRAGE to intima-media thickness and plaque number in the patients with chronic kidney disease, but no such associations were found in the controls. On covariance analysis, the slopes of intima-media thickness and plaque number to sRAGE were significantly steeper in patients with chronic kidney disease than in the controls. Furthermore, a significant interaction was found between sRAGE and smoking for predicting atherosclerotic plaques in patients with chronic kidney disease. The pathophysiological significance of this correlation will have to await more mechanistic studies.