[Prognostic importance of diagnosticated peripheral arterial disease through the ankle brachial index in spanish general population]. / Importancia pronóstica de la enfermedad arterial periférica diagnosticada mediante el índice tobillo-brazo en población general española.

OBJECTIVE: The objectives have been to determine the prognostic value of having a low ankle-brachial index (ABI) for different cardiovascular diseases and whether it improves the predictive capacity of the main cardiovascular risk scores proposed for Spain. DESIGN: Population-based cohort study LOCATION: A health area of the province of Badajoz (Spain) PARTICIPANTS: 2,833 subjects, representative of residents, between 25 and 79 years old, MEASUREMENTS: The ABI was measured at baseline and the first episode of ischemic heart disease or stroke, cardiovascular and total mortality, was recorded during 7 years of follow-up. The hazard ratio (HR) adjusted for cardiovascular risk factors and net reclassification index (NRI) by category, clinical and continuous for the risk functions REGICOR, FRESCO coronary heart disease, FRESCO cardiovascular disease and SCORE, were calculated. RESULTS: 2,665 subjects were analysed after excluding people with cardiovascular history and loss of follow-up. Low ABI was associated with adjusted HR (95% CI): 6.45 (3.00 - 13.86), 2.60 (1.15 - 5.91), 3.43 (1.39 - 8.44), 2.21 (1.27 - 3.86) for stroke, ischemic heart disease, cardiovascular mortality and total mortality respectively. The ABI improved the NRI (95% CI) in the intermediate risk category according to FRESCO cardiovascular equation by 24.1% (10.1 - 38.2). CONCLUSIONS: Low ABI is associated with a significant increase in the risk of stroke, ischemic heart disease, cardiovascular mortality and total mortality in our population. The inclusion of ABI improved the reclassification of people at intermediate risk, according to FRESCO cardiovascular, so its use in that risk category would be justified.

[Prognostic Value of Isolated High Serum Cystatin C Levels Without Glomerular Filtration Rate Reduction]. / Valor pronóstico de la elevación aislada de los niveles de cistatina C sin reducción del filtrado glomerular.

OBJECTIVES: Cystatin C is increasingly used as a marker of renal function as a complement to serum creatinine and glomerular filtration rate (GFR). We have assessed its efficacy as a predictor of mortality in a group of patients with increased cystatin C but GFR> 60mL/min. DESIGN AND METHODS: We included 608 patients, 65.9% male, 34.6% had diabetes mellitus. The mean age was 58.5±14.5 years and a mean GFR of 64.1±33.5mL/min. Patients were divided into 3 groups: CONTROL (normal cystatin C and GFR> 60mL/min, age 53.3±12.8years, GFR 96.6±22.4mL/min,n=193), INCREASED CYSTATIN (cystatin C>1.03mg/l and GFR>60mL/min, age 58.9±13,1years, GFR 72.2±10.4mL/min, n=40) and CKD (chronic kidney disease, increased cystatin C and GFR <60mL/min, age 61.4±14.8years, GFR 36.0±12.7mL/min, n=160). The relationship with overall mortality was analyzed using the Kaplan-Meier method. RESULTS: Mean cystatin C was 0.75±0.13 versus 1.79±0.54 in CKD group and 1.14±0.14mg/l, p <0.001). In CONTROL group survival was 93.9% at 5y, compared to 78.8% in the ERC group and 82.3% in the INCREASED CYSTATIN group (p <0.001) Five-year survival before renal replacement therapy was also different for the ERC group (73%, p <0.001 Log Rank) but not between the other two groups (CONTROL 99.0%, INCREASED CYSTATIN 94.3% p=0.08). CONCLUSIONS: Increased plasmatic levels of cystatin C in patients with GFR> 60mL/min was a predictor of increased mortality but not of progression to end-stage renal failure. These results confirm the interest of routinely measuring cystatin C.

Impact of Remote Monitoring on Standardized Outcomes in Nephrology-Peritoneal Dialysis.

Introduction: This study aimed to evaluate the association between the use of remote patient monitoring (RPM) in patients on automated peritoneal dialysis (APD) and the Standardized Outcomes in Nephrology in peritoneal dialysis (SONG-PD) clinical outcomes. Methods: A prospective and multicenter cohort study was conducted on patients with advanced chronic kidney disease on APD, recruited at 16 Spanish Hospitals, between June 1 and December 31, 2021. Patients were divided into 2 cohorts, namely patients on APD with RPM (APD-RPM) and patients on APD without RPM. The primary endpoints were the standardized outcomes of the SONG-PD clinical outcomes: PD-associated infection, cardiovascular disease (CVD), mortality rate, technique survival, and life participation (assessed as health-related quality of life [QoL]). Propensity score matching (PSM) was used to evaluate the association of RPM exposure with the clinical outcomes. Results: A total of 232 patients were included, 176 (75.9%) in the APD-RPM group and 56 (24.1%) in the APD-without-RPM group. The mean patient follow-up time was significantly longer in the APD-RPM group than in the APD-without-RPM group (10.4 ± 2.8 vs. 9.4 ± 3.1 months, respectively; P = 0.02). In the overall study sample, the APD-RPM group was associated with a lower mortality rate (hazard ratio [HR]: 0.08; 95% confidence interval [CI]: 0.01 to 0.69; P = 0.020) and greater technique survival rate (HR: 0.25; 95% CI: 0.11 to 0.59; P = 0.001). After PSM, APD-RPM continued to be associated with better technique survival (HR: 0.23; 95% CI: 0.06 to 0.83; P = 0.024). Conclusion: The use of RPM programs in patients on APD was associated with better survival of the technique and lower mortality rates. However, after PSM, only technique survival was significant.

Prognostic Significance of Amino Acid and Biogenic Amines Profiling in Chronic Kidney Disease.

There is a pressing need for more precise biomarkers of chronic kidney disease (CKD). Plasma samples from 820 subjects [231 with CKD, 325 with end-stage kidney disease (ESKD) and 264 controls] were analyzed by liquid chromatography with tandem mass spectrometry (LC-MS/MS) to determine a metabolic profile of 28 amino acids (AAs) and biogenic amines to test their value as markers of CKD risk and progression. The kynurenine/tryptophan ratio showed the strongest correlation with estimated glomerular filtration rate values (coefficient = -0.731, p < 0.0001). Models created with orthogonal partial least squares-discriminant analysis (OPLS-DA) containing the metabolic signature showed a high goodness of fit and predictability for controls/CKD (R2X:0.73:R2Y:0.92:Q2:0.92, p < 0.0001) and lower values for CKD/ESKD (R2X:0.56:R2Y:0.59:Q2:0.55, p < 0.0001). Based on generated VIP scores, the most relevant markers for segregating samples into control/CKD and CKD/ESKD groups were citrulline (1.63) and tryptophan (1.47), respectively. ROC analysis showed that the addition of the metabolic profile to a model including CKD classic risk factors improved the AUC from 86.7% (83.6-89.9) to 100% (100-100) for CKD risk (p < 0.0001) and from 63.0% (58.2-67.8) to 96.5% (95.3-97.8) for the risk of progression from CKD to ESKD (p < 0.0001). Plasma concentrations of AAs and related amines may be useful as diagnostic biomarkers of kidney disease, both for CKD risk and for progression of CKD patients to ESKD.

[Study of the effect of chronic kidney disease on the incidence of cardiovascular events in a native Spanish population]. / Efecto de la enfermedad renal crónica sobre la incidencia de episodios cardiovasculares en población española.

AIMS: To evaluate the relationship between chronic kidney disease and the patient's cardiovascular risk measured through the incidence of major adverse cardiovascular events in a sample of Spanish population. DESIGN AND METHODS: The sample consisted of 2,668 subjects. Mean age was 50.6±14.5 years and 54.6% were female. In all, 3.5% of subjects had a glomerular filtration rate (GFR) below 60ml/min and 4.3% a urinary albumin excretion (UAE) above 30mg/g. GFR was estimated from serum creatinine using the CKD-EPI equation. UAE was measured in first morning urine sample as mg/g of creatinine. We examined the multivariable association between the estimated GFR and the risks of cardiovascular events and death. The median follow-up was 81 (75-89) months. RESULTS: In CKD patients the hazard ratio (HR) was 1.36 (95% CI 0.97-1.91) (P=.079) for cardiovascular events and 1.62 (95% CI 0.53-4.91) (P=.396) for cardiovascular mortality. Increased UAE was also associated with higher cardiovascular risk (HR 2.38; 95% CI 1.51-3.74; P<.001) as well as increased cardiovascular mortality (HR 4.78; 95% CI 2.50-9.11; P<.001). For patients with UAE between 30 and 300mg/g HR for cardiovascular events was 2.09 (95% CI 1.34-3.50; P=.005) and 3.80 (95% CI 1.81-7.96; P<.001) for cardiovascular mortality. CONCLUSIONS: An independent association was found between reduced GFR and cardiovascular event incidence and mortality. Increased UAE showed a higher prognostic value than decreased GFR. Our findings highlight the clinical and public health importance of routinely measuring UAE.

A Custom Target Next-Generation Sequencing 70-Gene Panel and Replication Study to Identify Genetic Markers of Diabetic Kidney Disease.

Diabetic kidney disease (DKD) has been pointed out as a prominent cause of chronic and end-stage renal disease (ESRD). There is a genetic predisposition to DKD, although clinically relevant loci are yet to be identified. We utilized a custom target next-generation sequencing 70-gene panel to screen a discovery cohort of 150 controls, DKD and DKD-ESRD patients. Relevant SNPs for the susceptibility and clinical evolution of DKD were replicated in an independent validation cohort of 824 controls and patients. A network analysis aiming to assess the impact of variability along specific pathways was also conducted. Forty-eight SNPs displayed significantly different frequencies in the study groups. Of these, 28 with p-values lower than 0.01 were selected for replication. MYH9 rs710181 was inversely associated with the risk of DKD (OR = 0.52 (0.28-0.97), p = 0.033), whilst SOWAHB rs13140552 and CNDP1 rs4891564 were not carried by cases or controls, respectively (p = 0.044 and 0.023). In addition, the RGMA rs1969589 CC genotype was significantly correlated with lower albumin-to-creatinine ratios in the DKD patients (711.8 ± 113.0 vs. 1375.9 ± 474.1 mg/g for TC/TT; mean difference = 823.5 (84.46-1563.0); p = 0.030). No biological pathway stood out as more significantly affected by genetic variability. Our findings reveal new variants that could be useful as biomarkers of DKD onset and/or evolution.

Genetics Variants in the Epoxygenase Pathway of Arachidonic Metabolism Are Associated with Eicosanoids Levels and the Risk of Diabetic Nephropathy.

Genes in the epoxygenase pathway of arachidonic acid metabolism leading to vasoactive eicosanoids, mainly 20-hydroxyeicosatetraenoic (20-HETE) and epoxyeicosatrienoic (EETs) acids, have been related to glucose-induced renal damage in preclinical reports. We genotyped 1088 diabetic kidney disease (DKD) patients and controls for seven polymorphisms in five genes (CYP2C8, CYP2J2, CYP4F2, CYP4A11, and EPHX2) along this metabolic route and evaluated their effect on DKD risk, clinical outcomes, and the plasma/urine levels of eicosanoids measured by LC/MS/MS and immunoenzymatic assays. The CYP4F2 433M variant allele was associated with lower incidence of DKD (OR = 0.65 (0.48-0.90), p = 0.008), whilst the CYP2C8*3/*3 genotype was related to increased risk (OR = 3.21 (1.05-9.87), p = 0.036). Patients carrying the 433M allele also showed lower eGFR [median and interquartile range vs. wildtype carriers: 30.8 (19.8) and 33.0 (23.2) mL/min/1.73 m2, p = 0.037). Finally, the 433VM/MM variant genotypes were associated with lower urinary levels of 20-HETE compared with 433VV (3.14 (0.86) vs. 8.45 (3.69) ng/mg Creatinine, p = 0.024). Our results indicate that the CYP4F2 V433M polymorphism, by decreasing 20-HETE levels, may play an important role in DKD.

Plasma and urinary concentrations of arachidonic acid-derived eicosanoids are associated with diabetic kidney disease.

Preclinical studies indicate that arachidonic acid (AA)-derived eicosanoids contribute to hyperglycemia-induced kidney injury. We aimed to determine whether plasma and/or urinary levels of dihydroxyeicosatrienoic (DHETs) and 20-hydroxyeicosatetraenoic (20-HETE) acids are associated with diabetic kidney disease (DKD). A total of 334 subjects (132 DKD patients and 202 non-diabetic individuals) were studied. Plasma levels of 11,12-DHET, 14,15-DHET and 20-HETE were measured by LC/MS/MS. Urinary 20-HETE concentrations were determined by immunoenzymatic assay. Subjects with normoalbuminuria had larger 20-HETE-to-creatinine urinary ratios (20-HETE/Cr) than those with micro and macroalbuminuria (p=0.012). Likewise, participants with eGFR>60 ml/min/1.73 m2 had higher plasma levels of 14,15-DHET (p=0.039) and 20-HETE/Cr ratios (p=0.007). Concentrations of 14,15-DHET, 11,12-DHET and 20-HETE/Cr were significantly lower in DKD patients. Median values for non-diabetic vs. DKD were, respectively, 493 (351.0-691.5) vs. 358 (260.5-522) ng/L, p=3e-5; 262 (183.5-356.0) vs. 202 (141.5-278.0) ng/L, p=1e-4 and 5.26 (1.68-11.65) vs. 2.53 (1.01-6.28) ng/mgCr, p=0.010. In addition, 20-HETE/Cr ratios were higher in patients with non-proteinuric DKD than in those with typical DKD (p=0.020). When only individuals with impaired filtration were considered, 14,15-DHET and 11,12-DHET levels were still higher in non-diabetic subjects (p=0.002 and p=0.006, respectively). Our results indicate that AA-derived eicosanoids may play a relevant role in DKD.

Nighttime blood pressure fall in renal disease patients.

OBJECTIVE: There are controversial reports in the prevalence of abnormal nighttime blood pressure fall in renal patients. It has been evaluated nocturnal BP in renal patients using 24 h blood pressure monitoring (ABPM) in comparison with nontreated control subjects either normotensives or hypertensives. DESIGN AND METHODS: It has been reviewed 137 ABPM studies performed in renal patients (47.8 +/- 15.4 years, 76 men and 61 women). The control group includes 119 subjects without kidney disease, 65 were normotensives, and 49 were hypertensives, aged 46.8 +/- 12.1 years, 59 men and 60 women. The ambulatory BP was measured noninvasively for 24h by the SpaceLabs 90207 device programmed to measure BP every 15 min during daytime and every 20 min during nighttime. The definition of daytime and nighttime was made on the basis of wakefulness and sleep or bed rest periods, obtained from a diary kept by each subject. RESULTS: SBP, but not DBP, was higher (133.9/81.7) in renal disease patients when compared to nonrenal subjects (127.9/80.8, p < 0.01). When the control group was split into normotensive and hypertensive patients there were still significant differences, but hypertensives had higher BP than renal disease patients (139.0/89.7, p < 0.05). Nocturnal SBP fall in renal disease patients was reduced (5.8%, p < 0.001) and so was DBP fall (11.1%, p < 0.001) compared with the overall nonrenal patients sample (SBP 10.8; DBP 15.3%). The frequency of nondipper status in renal disease patients (39.6%) was higher than in control patients (18.4%, p < 0.001). Nontreated normotensive renal disease patients did not show any difference in either SBP or DBP nighttime fall with respect to control normotensives. Neither do nontreated hypertensive renal patients as compared with control hypertensives. There were not differences between proteinuric and nonproteinuric patients in nocturnal BP fall. The same result was obtained when hypertensive and normotensive nontreated renal patients were compared. The presence of renal failure did not induce a reduction of nocturnal BP fall. Most of treated renal patients were mainly receiving drug therapy during the morning and frequently this was the single daily dose. CONCLUSIONS: Altered diurnal rhythm should not be considered as a usual complication of renal disease. Inadequate antihypertensive pharmacotherapy could be related to the abnormalities of nighttime BP fall when it is detected.