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.

Proteomic research on new urinary biomarkers of renal disease in canine leishmaniosis: Survival and monitoring response to treatment.

The objective of our study was to search for survival biomarkers (SB) and treatment response monitoring biomarkers (TRMB) in the urinary proteome of dogs with renal disease secondary to canine leishmaniosis (CanL), using UHPLC-MS/MS. The proteomic data are available via ProteomeXchange with identifier PXD042578. Initially, a group of 12 dogs was evaluated and divided into survivors (SG; n = 6) and nonsurvivors (NSG; n = 6). A total of 972 proteins were obtained from the evaluated samples. Then, bioinformatic analysis reduced them to 6 proteins like potential SB increased in the NSG, specifically, Haemoglobin subunit Alpha 1, Complement Factor I, Complement C5, Fibrinogen beta chain (fragment), Peptidase S1 domain-containing protein, and Fibrinogen gamma chain. Afterwards, SG was used to search for TRMB, studying their urine at 0, 30, and 90 days, and 9 proteins that decreased after treatment were obtained: Apolipoprotein E, Cathepsin B, Cystatin B, Cystatin-C-like, Lysozyme, Monocyte differentiation CD14, Pancreatitis-associated precursor protein, Profilin, and Protein FAM3C. Finally, enrichment analysis provided information about the biological mechanisms in which these proteins are involved. In conclusion, this study provides 15 new candidate urinary biomarkers and an improved understanding of the pathogenesis of kidney disease in CanL.

Influence of variability in the cyclooxygenase pathway on cardiovascular outcomes of nephrosclerosis patients.

Nephrosclerosis patients are at an exceptionally high cardiovascular (CV) risk. We aimed to determine whether genetic variability represented by 38 tag-SNPs in genes of the cyclooxygenase pathway (PTGS1, PTGS2, PTGES, PTGES2 and PTGES3) leading to prostaglandin E2 (PGE2) synthesis, modified CV traits and events in 493 nephrosclerosis patients. Additionally, we genotyped 716 controls to identify nephrosclerosis risk associations. The addition of three variants, namely PTGS2 rs4648268, PTGES3 rs2958155 and PTGES3 rs11300958, to a predictive model for CV events containing classic risk factors in nephrosclerosis patients, significantly enhanced its statistical power (AUC value increased from 78.6 to 87.4%, p = 0.0003). Such increase remained significant after correcting for multiple testing. In addition, two tag-SNPs (rs11790782 and rs2241270) in PTGES were linked to higher systolic and diastolic pressure [carriers vs. non-carriers = 5.23 (1.87-9.93), p = 0.03 and 5.9 (1.87-9.93), p = 0.004]. PTGS1(COX1) rs10306194 was associated with higher common carotid intima media thickness (ccIMT) progression [OR 1.90 (1.07-3.36), p = 0.029], presence of carotid plaque [OR 1.79 (1.06-3.01), p = 0.026] and atherosclerosis severity (p = 0.041). These associations, however, did not survive Bonferroni correction of the data. Our findings highlight the importance of the route leading to PGE2 synthesis in the CV risk experienced by nephrosclerosis patients and add to the growing body of evidence pointing out the PGE2 synthesis/activity axis as a promising therapeutic target in this field.

Polymorphisms in glucose homeostasis genes are associated with cardiovascular and renal parameters in patients with diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) has become the major cause of end-stage kidney disease and is associated to an extremely high cardiovascular (CV) risk. METHODS: We screened 318 DN patients for 23 SNPs in four glucose transporters (SLC2A1, SLC2A2, SLC5A1 and SLC5A2) and in KCNJ11 and ABCC8, which participate in insulin secretion. Regression models were utilised to identify associations with renal parameters, atherosclerosis measurements and CV events. In addition, 506 individuals with normal renal function were also genotyped as a control group. RESULTS: In the patient's cohort, common carotid intima media thickness values were higher in carriers of ABCC8 rs3758953 and rs2188966 vs. non-carriers [0.78(0.25) vs. 0.72(0.22) mm, p < 0.05 and 0.79(0.26) vs. 0.72(0.22) mm, p < 0.05], respectively. Furthermore, ABCC8 rs1799859 was linked to presence of plaque in these patients [1.89(1.03-3.46), p < 0.05]. Two variants, SLC2A2 rs8192675 and SLC5A2 rs9924771, were associated with better [OR = 0.49 (0.30-0.81), p < 0.01] and worse [OR = 1.92 (1.15-3.21), p < 0.05] CV event-free survival, respectively. With regard to renal variables, rs841848 and rs710218 in SLC2A1, as well as rs3813008 in SLC5A2, significantly altered estimated glomerular filtration rate values [carriers vs. non-carriers: 30.41(22.57) vs. 28.25(20.10), p < 0.05; 28.95(21.11) vs. 29.52(21.66), p < 0.05 and 32.03(18.06) vs. 28.14(23.06) ml/min/1.73 m2, p < 0.05]. In addition, ABCC8 rs3758947 was associated with higher albumin-to-creatinine ratios [193.5(1139.91) vs. 160(652.90) mg/g, p < 0.05]. The epistasis analysis of SNP-pairs interactions showed that ABCC8 rs3758947 interacted with several SNPs in SLC2A2 to significantly affect CV events (p < 0.01). No SNPs were associated with DN risk. CONCLUSIONS: Polymorphisms in genes determining glucose homeostasis may play a relevant role in renal parameters and CV-related outcomes of DN patients.

Urinary proteome of dogs with renal disease secondary to leishmaniosis.

Canine leishmaniosis is frequently associated with the development of renal disease. Its pathogenesis is complex and not fully understood. For this reason, this study aimed to describe the urinary proteome, and identify possible new biomarkers in dogs with kidney disease secondary to leishmaniosis. Urine samples were collected from 20 dogs, 5 from healthy dogs, and 15 from stages Leishvet III and IV. Urine samples were analyzed by UHPLC-MS/MS. The data are available via ProteomeXchange with identifier PXD029165. A total of 951 proteins were obtained. After bioinformatic analysis, 93 urinary proteins were altered in the study group. Enrichment analysis performed on these proteins showed an overrepresentation of the complement activation pathway, among others. Finally, 12 discriminant variables were found in dogs with renal disease secondary to leishmaniosis, highlighting C4a anaphylatoxin, apolipoprotein A-I, haptoglobin, leucine-rich alpha-2-glycoprotein 1, and beta-2-microglobulin. This study is the first to describe the urinary proteomics of dogs with renal disease caused by leishmaniosis, and it provides new possible biomarkers for the diagnosis and monitoring of this disease.

Tag-SNPs in Phospholipase-Related Genes Modify the Susceptibility to Nephrosclerosis and its Associated Cardiovascular Risk.

Nephrosclerosis patients have a high cardiovascular (CV) risk that is very often of more concern than the renal disease itself. We aimed to determine whether variants in phospholipase-related genes, associated with atherosclerosis and CV outcomes in the general population, could constitute biomarkers of nephrosclerosis and/or its associated CV risk. We screened 1,209 nephrosclerosis patients and controls for 86 tag-SNPs that were identified in the SCARB1, PLA2G4A, and PLA2G7 gene loci. Regression models were utilized to evaluate their effect on several clinical parameters. Most notably, rs10846744 and rs838880 in SCARB1 showed significant odds ratios (OR) of 0.66 (0.51-0.87), p = 0.003 and 1.48 (1.11-1.96), p = 0.007 for nephrosclerosis risk. PLA2G4A and PLA2G7 harboured several SNPs associated with atherosclerosis measurements in the patients, namely common carotid intima media thickness (ccIMT), presence of plaques, number of plaques detected and 2-years ccIMT progression (significant p-values ranging from 0.0004 to 0.047). Eight SNPs in PLA2G4A were independent risk factors for CV events in nephrosclerosis patients. Their addition to a ROC model containing classic risk factors significantly improved its predictive power from AUC = 69.1% (61.4-76.9) to AUC = 79.1% (73.1-85.1%), p = 0.047. Finally, PLA2G4A rs932476AA and rs6683619AA genotypes were associated with lower CV event-free survival after controlling for confounding variables [49.59 (47.97-51.21) vs. 51.81 (49.93-51.78) months, p = 0.041 and 46.46 (41.00-51.92) vs. 51.17 (50.25-52.08) months, p = 0.022, respectively]. Variability in phospholipase-related genes play a relevant role in nephrosclerosis and associated atherosclerosis measurements and CV events.

Body Fat Distribution, Adipocytokines Levels and Variability in Associated Genes and Kidney Transplant Outcomes.

Introduction: Body fat distribution is known to contribute to a variety of pathologies. Research Questions: We aimed to assess whether this distribution is associated with clinical outcomes in renal transplant recipients (RTR) and to examine its relationship with leptin and adiponectin gene variants and plasma concentrations. Design: Bioelectrical impedance analyses were performed in 236 RTR. Leptin/adiponectin levels were measured by immunoassay and relevant polymorphisms in the leptin receptor (LEPR) and adiponectin (ADIPOQ) genes were identified. Associations were assessed by logistic regression modeling. Results: The waist-to-height ratio (WHr) displayed a significant association with delayed graft function, acute rejection and post-transplant diabetes mellitus, with OR values of 2.04 (1.02-4.08) p = 0.045; 3.08 (1.22-7.79) p = 0.017 and 2.79 (1.16-6.74) p = 0.022, respectively. Waist circumference was linked to delayed graft function [OR = 1.03 (1.01-1.05), p = 0.025] and AR [OR = 1.041 (1.01-1.07), p = 0.009]. Leptin levels were significantly higher in patients who experienced rejection [19.91 ± 23.72 versus 11.22 ± 16.42 ng/ml; OR = 1.021 (1.01-1.04), p = 0.017]. The ADIPOQ rs1501299TT genotype showed a significant association with higher WHr (0.63 ± 0.11 vs 0.59 ± 0.87 for GG/GT genotypes; p = 0.015) and WC values (102.3 ± 14.12 vs 96.38 ± 14.65 for GG/GT genotypes; p = 0.021). Conclusion: WC, and especially WHr, are associated with adverse outcomes in renal transplantation and are affected by variability in the ADIPOQ gene.

Antiretroviral Treatment and Antihypertensive Therapy.

The presence of hypertension among the population with human immunodeficiency virus (HIV) has become a new threat to the health and well-being of people living with this disease, in particular, among those who received antiretroviral therapy. The estimated prevalence of high blood pressure in HIV-infected patients is significantly higher than the rate observed in HIV-uninfected subjects. The approach to the HIV-positive patient requires the assessment of individual cardiovascular risk and its consideration when designing the individualized target. On the other hand, the numerous pharmacological interactions of antiretroviral (ARV) drugs are essential elements to take into account. Serum levels of any kind of antihypertensive drugs may be influenced by the coadministration of protease inhibitors, non-nucleoside reverse transcriptase inhibitor, or other antiretroviral. Similarly, plasma concentrations of antiretroviral drugs can be increased by the concomitant use of calcium channel blockers or diuretics. In this regard, the treatment of high blood pressure in HIV patients should be preferentially based on ACE inhibitors or thiazide/thiazide-like diuretics or their combination.

Alfa-1-microglobulina: valor pronóstico en la enfermedad renal crónica / Alpha-1-microglobulin: Prognostic value in chronic kidney disease

Objetivos: La alfa-1-microglobulina (α1M) es una proteína tubular usada para detectar lesiones agudas del túbulo proximal. Se ha evaluado el uso de α1M como marcador de progresión de la enfermedad renal crónica (ERC) y de supervivencia vital.Diseño y métodosSe seleccionaron 163 pacientes (90 hombres), con una edad media de 61,6±16,4 años. La excreción de α1M en orina se analizó por nefelometría. Los pacientes se dividieron en 2 grupos según la excreción de α1M (valor de corte: 32,85mg/24h).ResultadosLa supervivencia libre de ERC terminal fue del 94,2% a los 5 años en pacientes con α1M baja. Para pacientes con una excreción más elevada la supervivencia fue del 72,7% (p=0,011). La supervivencia fue del 94,4% en pacientes con α1M baja; para los pacientes con una excreción elevada de α1M, la supervivencia fue del 54,2% (p=0,001). La regresión de Cox mostró una asociación independiente de la α1M con la progresión de la ERC.ConclusionesLa excreción urinaria de α1M se asoció con una progresión más rápida de la ERC y una mayor mortalidad. Serán precisos estudios más amplios para confirmar la relación causal entre α1M y mortalidad general. (AU)

Objectives: α1-microglobulin (α1M) is a tubular protein used for detecting acute lesions of proximal tubules. This study evaluated the use of urine α1M excretion as a marker of chronic kidney disease (CKD) progression and life survival.Design and methodsIn all 163 patients were recruited (90 men), mean age 61.6±16.4 years. Urinary α1M was evaluated using an immunonephelometric assay. Patients were divided into 2 groups according to urinary α1M excretion (cut-off value: 32.85mg/24h).ResultsEnd stage renal disease-free survival was 94.2% at 5 years for patients with lower α1M. For patients in the highest percentile, renal function survival was 72.7% (P=.011). Life survival was 94.4% for patients with α1M in the lower percentiles. For patients in the upper percentile, live survival was 54.2% (P=.001). The Cox regression analysis showed an independent association of CKD progression with high α1M excretion (P=.043).Conclusionsα1M urinary excretion was associated with faster CKD progression and higher mortality. Further studies are needed to determine whether the association between α1M urinary excretion and excess mortality risk represents a causal link. (AU)

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.

Validation of the QMon-20 oscillometric blood pressure monitor for professional office use in the general population according to the ANSI/ESH/ISO 81060-2:2018 protocol.

OBJECTIVE: we assessed the accuracy of the QMon-20 oscillometric upper-arm cuff device professional for office blood pressure (BP) in general population according to the Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Universal Standard (ISO 81060-2:2018). METHODS: Subjects were recruited according to AAMI/ESH/ISO Universal Standard in general population using the same arm sequential BP measurement method. Two cuffs of the test device were used for arm circumference 22-31 (medium) and 32-42 cm (large). RESULTS: One-hundred and fourteen subjects were recruited and 106 were analyzed. For validation criterion 1, the mean ± SD of the differences between the test device and reference BP readings was 0.8 ± 5.4/-0.5 ± 4.2 mmHg (systolic/diastolic). For criterion 2, the SD of the mean BP differences between the test device and reference BP per subject was 4.34/3.48 mmHg (systolic/diastolic). CONCLUSION: The QMon-20 oscillometric device for office BPs measurement fulfilled all the requirements of the AAMI/ESH/ISO Universal Standard (ISO 81060-2:2018) in general population and can be recommended for clinical use.

Cardiovascular risk assessment after one-year acute ischemic stroke based on uric acid levels and renal dysfunction. A clinical study.

BACKGROUND: The role of serum uric acid (SUA) after stroke is controversial and can be influenced by renal disease. AIM: to analyse the role of SUA in the acute phase of stroke based on the presence/absence of kidney disease and cardiovascular outcome. METHODS: Retrospective cohort of a stroke registry followed-up for one year. The sample was divided according to the presence of renal disease defined by haematocrit, urea and gender (HUGE) formula, along with a SUA cut-off point obtained by receiver operating characteristic curves based on SUA levels and on the primary end-point occurrence. RESULTS: 500 patients (268, 53.6% males) were analysed. Renal disease was present in 14.8% patients. The SUA cut-off for patients with renal disease was 404.46 µmol/L and 344.98 µmol/L for the remainder. Patients with higher SUA levels had decreased neurological disabilities (p = 0.04) and higher comorbidity (p = 0.00). Over a period of 42.3 (19) weeks, a primary end-point occurred in 17.4% patients. In the adjusted Cox model, SUA was associated with the primary end-point (HR 1.45, 95%CI 1.17-1.81, p = 0.01). Separated by the presence/absence of renal disease, SUA levels were associated with the primary endpoint for patients with renal disease (HR 1.29, 95%CI 1.06-1.58, p = 0.01) and for all other patients (HR 1.42, 95%CI 1.2-1.7, p = 0.00). CONCLUSIONS: We observed a relationship between SUA levels and a negative cardiovascular outcome after ischaemic stroke both in patients with and without renal disease, with the worst outcomes occurring in patients with renal insufficiency.

Alpha-1-microglobulin: Prognostic value in chronic kidney disease. / Alfa-1-microglobulina: valor pronóstico en la enfermedad renal crónica.

OBJECTIVES: α1-microglobulin (α1M) is a tubular protein used for detecting acute lesions of proximal tubules. This study evaluated the use of urine α1M excretion as a marker of chronic kidney disease (CKD) progression and life survival. DESIGN AND METHODS: In all 163 patients were recruited (90 men), mean age 61.6±16.4 years. Urinary α1M was evaluated using an immunonephelometric assay. Patients were divided into 2 groups according to urinary α1M excretion (cut-off value: 32.85mg/24h). RESULTS: End stage renal disease-free survival was 94.2% at 5 years for patients with lower α1M. For patients in the highest percentile, renal function survival was 72.7% (P=.011). Life survival was 94.4% for patients with α1M in the lower percentiles. For patients in the upper percentile, live survival was 54.2% (P=.001). The Cox regression analysis showed an independent association of CKD progression with high α1M excretion (P=.043). CONCLUSIONS: α1M urinary excretion was associated with faster CKD progression and higher mortality. Further studies are needed to determine whether the association between α1M urinary excretion and excess mortality risk represents a causal link.

Sacubitril-Valsartan Improves Anemia of Cardiorenal Syndrome (CRS).

BACKGROUND AND AIMS: Anemia is a common complication of heart failure and Chronic Kidney Disease (CKD). Sacubitril-valsartan is a novel therapy for the treatment of chronic Heart Failure with a reduced Ejection Fraction (HFrEF). We have evaluated the short-term effects of sacubitril- valsartan on the anemia of CRS. METHODS: The study group comprised 39 patients with HFrEF, who were followed-up for three months. The study is a retrospective analysis of clinical data. Data of 3 months' and baseline visits were recorded including plasmatic creatinine, glomerular filtration rate, cystatin C, kaliemia, haemoglobin, pro-BNP, and albuminuria. RESULTS: In all, 34 patients ended the follow-up. Mean sacubitril-valsartan dosage at baseline was 101 ± 62 mg/day and 126 ± 59 mg/day at end. Mean hemoglobin increased from 12.2 ± 1.1 g/dl at baseline to 12.9 ± 1.0 g/dl (p = 0.001,). Prevalence of anemia was 64.7% (95%CI, 47.9-78.5%) at baseline and 38.4 (95%CI, 23.9-55.0%) after the follow-up (p = 0.016). Serum cystatin C levels decreased from 2.71 ± 1.0 to 2.48 ± 1.0 mg/l (p = 0.028). Serum K levels remained unchanged (baseline 4.94 ± 0.60, three months visit 4.94 ± 0.61 mmol/l, p = 0.998). CONCLUSION: Sacubitril-valsartan improves anemia in CRS patients. An improvement in serum cystatin levels was observed. Few untoward effects were detected. These findings should be confirmed in wider clinical trials.

Polymorphisms in vasoactive eicosanoid genes of kidney donors affect biopsy scores and clinical outcomes in renal transplantation.

Cytochrome P450 (CYP) enzymes metabolize arachidonic acid to vasoactive eicosanoids such as epoxyeicosatrienoic acids (EETs) and 20-Hydroxyeicosatetraenoic acid (20-HETE), whilst soluble epoxide hydrolase, encoded by the EPHX2 gene, is in charge of EETs degradation. We aimed to analyze the influence of common, functional polymorphisms in four genes of the donor on the renal biopsy scores independently assigned by pathologists. Additionally, we examined whether this score or the presence of these SNPs were independent risk factors of clinical outcomes in the first year after grafting. A cohort of 119 recipients and their corresponding 85 deceased donors were included in the study. Donors were genotyped for the CYP4F2 V433M, CYP2C8*3, CYP2J2*7, EPHX2 3'UTR A>G, EPHX2 K55R and EPHX2 R287Q polymorphisms. The association of the donors' SNPs with the biopsy scores and clinical outcomes was retrospectively evaluated by multivariate regression analysis. The CYP2C8*3 polymorphism in the donor was significantly associated with higher scores assigned to pretransplant biopsies [OR = 3.35 (1.03-10.93), p = 0.045]. In turn, higher scores were related to an increased risk of acute rejection [OR = 5.28 (1.32-21.13), p = 0.019] and worse glomerular filtration rate (eGFR) (45.68±16.05 vs. 53.04±16.93 ml/min in patients whose grafts had lower scores, p = 0.010) one year after transplant. Patients whose donors carried the CYP4F2 433M variant showed lower eGFR values (48.96±16.89 vs. 55.94±18.62 ml/min in non-carriers, p = 0.038) and higher risk of acute rejection [OR = 6.18 (1.03-37.21), p = 0.047]. The CYP2J2*7 SNP in the donor was associated with elevated risk of delayed graft function [OR = 25.68 (1.52-43.53), p = 0.025]. Our results taken together suggest that donor genetic variability may be used as a predictor of tissue damage in the graft as well as to predict clinical outcomes and graft function in the recipient.

Dihydropyridine calcium channel blockers and renal disease.

Although blood pressure control is considered the main mechanism for preventing the progression of chronic kidney disease (CKD), angiotensin-converting enzyme inhibitors and angiotensin receptors blockers have an additional organ-protective role. The effects of calcium channel blockers (CCBs) in renal disease are not so clearly defined. CCBs have pleiotropic effects that might contribute to protection of the kidney, such as attenuating the mesangial entrapment of macromolecules, countervailing the mitogenic effect of platelet-derived growth factors and platelet-activating factors and suppressing mesangial cell proliferation. Some evidence has accumulated in recent years demonstrating that the new dihydropyridinic CCBs (such as lercanidipine or efonidipine) may affect both postglomerular and preglomerular vessels, resulting in a decreased filtration fraction and nephroprotective effect. Increasing clinical and experimental evidence supports this view and the use of CCBs in CKD hypertensive patients.

Lercanidipine in the Management of Hypertension: An Update.

Calcium channel blockers (CCBs), particularly dihydropyridine-CCBs, (DHP-CCBs), have an established role in antihypertensive therapy, either as monotherapy or in combination with other antihypertensive drugs. Two hundred and fifty-one papers published in PubMed in English between January 1, 1990, and October 31, 2016, were identified using the keyword "lercanidipine." Lercanidipine is a lipophilic third-generation DHP-CCB, characterized by high vascular selectivity and persistence in the smooth muscle cell membranes. Lercanidipine is devoid of sympathetic activation, and unlike the first and second generation of DHP-CCBs, it dilates both the afferent and the efferent glomerular arteries, while preserving the intraglomerular pressure. In addition, lercanidipine prevents renal damage induced by angiotensin II and demonstrates anti-inflammatory, antioxidant, and anti-atherogenic properties through an increasing bioavailability of endothelial nitric oxide. It is associated with a regression of microvascular structural modifications in hypertensive patients. The efficacy of lercanidipine has been demonstrated in patients with different degrees of hypertension, in the young and elderly and in patients with isolated systolic hypertension. In patients with diabetes and renal impairment, lercanidipine displays a renal protection with a significant decrease of microalbuminuria and improvement of creatinine clearance. Lercanidipine is well tolerated and is associated with a very low rate of adverse events, particularly ankle edema, compared with amlodipine and nifedipine. In conclusion, lercanidipine produces a sustained blood pressure-lowering activity with a high rate of responder/normalized patients, associated with a favorable tolerability profile.

Hypertension in the elderly.

Data collected over a 30-year period have demonstrated the increasing prevalence of hypertension with age. Aging is an inevitable part of life and brings along two inconvenient events: physiologic decline and disease state. High blood pressure (HBP) is an important risk factor for cardiovascular morbidity and mortality, particularly in the elderly. It is a significant and often asymptomatic chronic disease, which requires optimal control and persistent adherence to prescribed medication to reduce the risks of cardiovascular, cerebrovascular and renal disease. Hypertension in the elderly patients represents a management dilemma to geriatric and cardiovascular specialists and other practitioners. Furthermore, with the wide adoption of multiple drug strategies targeting subgroups of hypertensive patients with specific risk conditions to lower blood pressure (BP), difficult questions arise about how aggressive treatment of elderly patients should be. The purpose of the following chapter article is to review the pathophysiology of aging as well as the epidemiology and the clinical assessment of high blood pressure (HBP) in older people.