Hypertension in Kidney Transplant Recipients: Where Are We Today?

PURPOSE OF REVIEW: Cardiovascular disease is the leading cause of death and allograft loss among kidney transplant recipients, and hypertension is an independent risk factor for cardiovascular morbidity of this patient population. The etiology of hypertension is multifactorial, including pre-transplant volume overload, post-transplant recipient and donor-associated variables, and transplant-specific causes (immunosuppressive medications, allograft dysfunction and surgical complications such as transplant artery stenosis). RECENT FINDINGS: No randomized controlled trials have assessed the optimal blood pressure targets and explored the best antihypertensive regimen for kidney transplant recipients. According to the large observational studies, it is reasonable to achieve a blood pressure goal of equal to or less than 130/80 mmHg in the long-term follow-up for minimizing the cardiovascular morbidity. The selection of antihypertensive agents should be based on the patient's co-morbidities; however, the initial choice could be calcium channel blockers especially in the first few months of transplantation. In patients with cardiovascular indications of renin-angiotensin-aldosterone system inhibition, given the well-described benefits in diabetic and proteinuric patients, it is reasonable to consider the use of renin-angiotensin-aldosterone system inhibitors. There is a need for future prospective trials in the transplant population to define optimal blood pressure goals and therapies.

[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 Role of Hyponatremia in Heart Failure Patients Depending on Renal Disease: Clinical Evidence.

AIM: Hyponatremia is very often associated with renal disease in patients with heart failure (HF) and, when present, determines a poor outcome. We investigated the role of hyponatremia in HF patients in whom the presence or absence renal insufficiency was accurately predefined. METHODS: This was a cohort study based on the Spanish National Registry on Heart Failure (RICA), a multicenter, prospective registry that enrolls patients admitted for decompensated HF who were subsequently followed up for 1 year. We classified patients into 4 groups according to the presence or absence of renal disease defined by the hematocrit, urea, and gender formula (HUGE) and then according to the presence of hyponatremia (Na ≤135 mEq/L). RESULTS: A total of 3,478 patients were included. Hyponatremia was more prevalent in the group with renal disease (22.1%) than without (18.4%). During admission, both groups with hyponatremia had more complications than those with normal serum sodium. During the 1-year follow-up, patients with hyponatremia and renal disease had a significantly worse outcome (HF mortality and readmission), HR 1.87, 95% CI 1.54-2.29, p < 0.001, compared to those with hyponatremia without renal disease, HR 1.01, 95% CI 0.79-1.3, p = 0.94. CONCLUSIONS: Hyponatremia is more prevalent in patients with renal insufficiency, and outcome is poorest when both renal disease and hyponatremia coexist. Patients with hyponatremia without renal disease show no differences in outcome compared to those without hyponatremia.

Anemia as very late-onset cytomegalovirus disease after kidney transplantation.

Very late-onset cytomegalovirus (CMV) disease after solid organ transplantation is not associated with classic risk factors; therefore, it does not follow a pattern of predictable appearance. A high index of suspicion is necessary to make an accurate diagnosis. Anemia has multiple etiologies among kidney transplanted recipients, and CMV could be one of them. We report the case of a kidney recipient with anemia refractory to treatment which proved to be secondary to extremely late CMV digestive disease.

A comparison of cystatin C concentrations between patients with chronic interstitial nephritis and glomerular diseases.

AIMS: Cystatin C have shown to be a renal function parameter with higher sensitivity and specificity than serum creatinine. In tubular diseases, cystatin C degradation and an increase in its urinary elimination would be observed. We have tried to define if different kinds of kidney diseases may significantly affect the serum levels of cystatin C. DESIGN AND METHODS: Four hundred and four patients were studied: 249 men and 155 women, mean age was 64.3±10.1 years. Patients were classified into three groups: (1) Chronic interstitial nephropathy (CIN), (2) Glomerular nephropathy (GN), and (3) Non- CKD patients (control). GFR was estimated though the CKD-EPI equation and the Hoek formula. RESULTS: Median of serum creatinine levels was higher in CIN group than in GN and control groups. Median cystatin C levels were lower in control group compared with CIN and GN groups. No significant differences were found between CIN group and GN group. Nevertheless, the cystatin/creatinine rate was lower in the CIN group patients (0.94, 0.81-1.11) than in the GN group (1.02,I 0.85-1.25) as well as the control group (1.02, I 0.88-1.20). The cystatin C-estimated GFR/creatinine-estimated GFR rate was higher in the CIN group (1.18, 1.03-1.36) than in the GN patients (1.03, 0.88-1.21) and control ones (1.07, 0.88-1.20). CONCLUSIONS: Patients with CIN had lower serum levels of cystatin C defined as cystatin C/creatinine rate when they were compared with GN subject and control ones. In the same way, the index between cystatin C-estimated GFR and creatinine-estimated GFR was higher in CIN patients.

Serum uric acid levels and outcome during admission in acute ischaemic stroke, depending on renal function.

BACKGROUND: The relationship between serum uric acid (SUA) levels and stroke is controversial. The discrepancies in the results could be due to the uneven setting of comorbidity. It is known that hyperuricaemia increases in parallel with the decline in renal function; however, there are few studies that adjust for renal disease. AIM: To investigate the relationship between SUA levels in the acute phase of ischaemic stroke according to the presence or absence of chronic kidney disease and clinical outcomes during admission. METHODS: Retrospective cross-sectional analysis of patients recruited through a unicentric stroke registry. The sample was divided according to its quartiles of SUA. Renal disease was defined based on the haematocrit, urea and Gender (HUGE) formula. The outcome was determined by the National Institutes of Health Stroke Scale (NIHSS) score. Statistically robust methods were used with R (version 3.3.2). RESULTS: A total of 412 patients (53.8% male) were analysed. The NIHSS score decreased as the SUA levels increased (p < 0.0009). Robust linear regression analysis showed a significant association between quantitative SUA levels and NIHSS score (p < 0.0003), even when patients were categorized according to renal function (p < 0.05). In an adjusted multivariate model, SUA levels showed an independent protective effect on the severity of stroke (OR = 0.67, 95% CI 0.51-0.88, p = 0.004). CONCLUSIONS: Our results support the hypothesis that hyperuricaemia plays a protective role in the prognosis of stroke, independently from renal function, and that even in patients with chronic kidney disease, it remains as a protective agent.

[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.

Beta-Blockers and Hypertension: Some Questions and Answers.

INTRODUCTION: International guidelines have removed b-blockers from first-line treatment of hypertension, limiting their use to patients with compelling indications. The position of guidelines stems from the results of studies performed with the 1st and 2nd generation of b-blockers, which concluded that these drugs have lower cardiovascular protection, compared with other antihypertensive agents. AIM: The aim of our mini review is to answer to some questions about the effect of b-blockers on hypertension and cardiovascular protection and if these effects are different from those of other antihypertensive drugs, particularly in young and elderly patients. METHODS: We evaluated the relevant systematic reviews and meta-analyses, which reported the effectiveness of b-blockers on blood pressure and cardiovascular outcomes, compared with placebo/no treatment and with other antihypertensive agents. RESULTS: Beta-blockers, decreased high blood pressure with no significant difference from other common antihypertensive agents. Moreover b-blockers, compared with placebo, lowered the risk of major cardiovascular outcomes, while, compared with other drug classes, the reported results are very heterogeneous. Therefore it is difficult, globally, to find a difference between b-blockers and other drug classes. CONCLUSIONS: Rather than looking for differences in the cardiovascular protective effect between b-blockers and other antihypertensive agents, we have to consider the different pathophysiology of hypertension in young [sympathetic hyperactivity] and elderly patients [arterial stiffness, high aortic systolic pressure]. Considering these aspects, non-vasodilating b-blockers are preferred, as first-line, in young/middle aged hypertensive subjects, while vasodilating b-blockers, are most appropriate, in elderly patients, for the favourable hemodynamic profile.

Do Statins Counteract the Effect of Antidiabetic Drugs? Results of the SCEAD Study.

PURPOSE: Diabetes and dyslipidemia are leading causes of mortality and morbidity. According to international guidelines, statins are the cornerstone of treatment in patients with diabetes and/or dyslipidemia. However, statins and antidiabetic agents have opposite pharmacological effects, because statins, particularly atorvastatin and rosuvastatin, impair glucose homeostasis, increasing the risk of new-onset diabetes, whereas antidiabetic drugs improve glycemic homeostasis. The aim of this study was to investigate the effect of atorvastatin, rosuvastatin, and pitavastatin on glucose homeostasis in patients with type 2 diabetes mellitus (T2DM) and dyslipidemia during stable treatment with hypoglycemic drugs. MATERIALS AND METHODS: The study was conducted as a pilot, prospective, randomized, open label, parallel group with blinded-endpoints (PROBE) study. Of 180 recruited patients with T2DM and dyslipidemia, 131 were randomized to atorvastatin (n=44), rosuvastatin (n=45), and pitavastatin (n=42) and treated for 6 months. RESULTS: Fasting plasma glucose (FPG) marginally decreased in patients assigned to atorvastatin (-3.5 mg/dL, p=0.42) and rosuvastatin (-6.5 mg/dL, p=0.17), while it decreased much more in patients treated with pitavastatin (-19.0 mg/dL, p<0.001). Mean glycated hemoglobin A1c (HbA1c ) values remained unchanged during treatment with atorvastatin (-0.10%, p=0.53) and rosuvastatin (0.20%, p=0.40), but were significantly reduced with pitavastatin (-0.75%, p=0.01). Atorvastatin, rosuvastatin, and pitavastatin significantly lowered (p<0.001) plasma levels of total cholesterol, low-density lipoprotein-cholesterol, and triglycerides, while high-density lipoprotein-cholesterol (HDL-C) levels increased significantly (p=0.04) only in the pitavastatin group. CONCLUSION: The results of the present study suggest that pitavastatin affects FPG and HbA1c less than atorvastatin and rosuvastatin in patients with T2DM and concomitant dyslipidemia. Lipid-lowering efficacies were not significantly different among the three statins, with the exception of HDL-C, which increased significantly with pitavastatin. Although the pharmacological mechanism of pitavastatin on glucose homeostasis in patients with T2DM during stable antidiabetic therapy is not known, it can be assumed that pitavastatin has less drug interaction with hypoglycemic agents or that it increases plasma levels of adiponectin.

Autosomal dominant polycystic kidney disease in young adults.

Background: The clinical manifestations of autosomal dominant polycystic kidney disease (ADPKD) usually appear in adulthood, however pediatric series report a high morbidity. The objective of the study was to analyze the clinical characteristics of ADPKD in young adults. Methods: Family history, hypertension, albuminuria, estimated glomerular filtration rate (eGFR) and imaging tests were examined in 346 young adults (18-30 years old) out of 2521 patients in the Spanish ADPKD registry (REPQRAD). A literature review searched for reports on hypertension in series with more than 50 young (age <30 years) ADPKD patients. Results: The mean age of this young adult cohort was 25.24 (SD 3.72) years. The mean age at diagnosis of hypertension was 21.15 (SD 4.62) years, while in the overall REPQRAD population was aged 37.6 years. The prevalence of hypertension was 28.03% and increased with age (18-24 years, 16.8%; 25-30 years, 36.8%). Although prevalence was lower in women than in men, the age at onset of hypertension (21 years) was similar in both sexes. Mean eGFR was 108 (SD 21) mL/min/1.73 m2, 38.0% had liver cysts and 3.45% of those studied had intracranial aneurysms. In multivariate analyses, hematuria episodes and kidney length were independent predictors of hypertension (area under the curve 0.75). The prevalence of hypertension in 22 pediatric cohorts was 20%-40%, but no literature reports on hypertension in young ADPKD adults were found. Conclusions: Young adults present non-negligible ADPKD-related morbidity. This supports the need for a thorough assessment of young adults at risk of ADPKD that allows early diagnosis and treatment of hypertension.

The coexistence of diabetic retinopathy and diabetic nephropathy is associated with worse kidney outcomes.

Background: Up to 50-60% of patients with diabetes have non-diabetic kidney disease (NDKD) on kidney biopsy. Diabetic retinopathy (DR) is a microvascular complication of diabetes frequently associated with diabetic nephropathy (DN). The objective of the current study was to investigate the kidney outcomes and survival in patients with biopsy diagnoses of DN and NDKD according to the presence of DR. Methods: We conducted an observational, multicentre and retrospective study of the pathological findings of renal biopsies from 832 consecutive patients with diabetes from 2002 to 2014 from 18 nephrology departments. The association of DR with kidney replacement therapy (KRT) or survival was assessed by Kaplan-Meier and Cox regression analyses. Results: Of 832 patients with diabetes and renal biopsy, 768 had a retinal examination and 221/768 (22.6%) had DR. During a follow-up of 10 years, 288/760 (37.9%) patients with follow-up data needed KRT and 157/760 (20.7%) died. The incidence of KRT was higher among patients with DN (alone or with NDKD) and DR [103/175 (58.9%)] than among patients without DR [88/216 (40.7%), P < .0001]. The incidence of KRT was also higher among patients with only NDKD and DR than among those without DR [18/46 (39.1%) versus 79/331 (23.9%), P < .0001]. In multivariate analysis, DR or DN were independent risk factors for KRT {hazard ratio [HR] 2.48 [confidence interval (CI) 1.85-3.31], P < .001}. DN (with or without DR) was also identified as an independent risk factor for mortality [HR 1.81 (CI 1.26-2.62), P = .001]. Conclusions: DR is associated with a higher risk of progression to kidney failure in patients with histological DN and in patients with NDKD.

Estimated glomerular filtration rate from serum cystatin C: significant differences among several equations results.

OBJECTIVES: Several equations for the estimation of glomerular filtration rate (GFR) from serum cystatin C have been reported. We compared the results obtained using these equations to test the homogeneity of their results as well as their usefulness in clinical practice. DESIGN AND METHODS: Seven hundred and twenty-seven outpatients were studied. Of these, 439 were male and 288 were female, and their mean age was 60.8 ± 24.1 years. GFR was estimated from serum creatinine using the abbreviated Modification of Diet in Renal Disease (MDRD-4) equation. GFR was estimated from serum cystatin C levels using five different equations. RESULTS: The simplest (100/cystatin C) formula rendered the highest estimated GFR and the Hoek's equation rendered the lowest GFR, even significantly lower than the MDRD-4 equation (p < 0.001, Student's t-test). From the simplest formula to the Hoek equation the mean difference calculated was 25.1 ± 8.7 mL/min (p < 0.001, Student's t-test). No differences by gender were found among the results of different equations. All cystatin C-derived equations reduced the number of patients diagnosed of chronic renal failure when compared with MDRD-4 formula. No patient with normal renal function was shifted to the renal disease group. CONCLUSIONS: A higher value could be expected when GFR is estimated from cystatin C. Nevertheless, vast differences were found in the results when tested using several equations. Physicians should be aware of this problem to avoid a wrong clinical diagnosis of renal function.

Pitavastatin: Coronary Atherosclerotic Plaques Changes and Cardiovascular Prevention.

Stains remain the first therapeutic approach in patients with dyslipidemia to control plasma lipids levels and cardiovascular risk. Multiple clinical trials have demonstrated the benefits of statins in reducing major cardiovascular adverse events in primary and secondary prevention. Moreover, in patients with coronary artery disease, statins decrease coronary atherosclerotic plaque volume and composition, inducing atheroma stabilization. Pitavastatin, is a new-generation lipophilic statin, indicated for the treatment of dyslipidemia and prevention of cardiovascular diseases. The purpose of this review, the first at our knowledge on this topic, is to summarize and examine the current knowledge about the effectiveness of pitavastatin in patients with coronary artery disease. The available data suggest that pitavastatin significantly, lowers the rate of adverse cardiovascular events, in patients at a high risk of atherosclerotic disease, with stable angina pectoris or with acute coronary syndrome. Moreover intravascular ultrasound have shown that pitavastatin induces favorable changes in plaque morphology, increasing the fibrous cap thickness, and decreasing both plaque and lipid volume indexes. Globally the efficacy of pitavastatin is greater or similar to other statins.

Lipid profile of patients treated with evolocumab in Spanish hospital nephrology units (RETOSS NEFRO).

BACKGROUND AND OBJECTIVE: To describe the clinical characteristics, the reasons for initiating therapy and the effects of treatment in the initial phase of evolocumab availability in the Nephrology Units of Spain. MATERIAL AND METHODS: Retrospective, observational and multicentric study that included patients initiating treatment with evolocumab (from February 2016 to August 2018), in 15 Nephrology Units in Spain. The demographic and clinical characteristics of the patients, the lipid lowering treatment and the evolution of the lipid profiles between 24 weeks pre-initiation and 12±4 weeks post-initiation of evolocumab were reviewed. RESULTS: 60 patients were enrolled: 53.3% women; mean (SD) age, 56.9 (12.8) years, 45.0% with familial hypercholesterolemia (FH) (5.0% homozygous and 40.0% heterozygous) and 65.0% with atherosclerotic cardiovascular disease. The mean (SD) eGFR was 62.6 (30.0) ml/min/1.73m2 (51.7% of patients had eGFR <60ml/min/1.73m2 [CKD stage>2]), 50.0% had proteinuria (>300mg/g) and 10.0% had nephrotic syndrome. Other CV risk factors were hypertension (75.0%), diabetes (25.0%), and smoking (21.7%). A 40.0% of patients were statin intolerant. At evolocumab initiation, 41.7% of patients were on a high intensity statin, 18.3% on moderate intensity statin and 50.0% were receiving ezetimibe. Mean (SD) LDL-c at evolocumab initiation was 179.7 (62.9) mg/dL (53.4% of patients with LDL-c ≥160mg/dL and 29.3% ≥190mg/dL). After 12 weeks, evolocumab resulted in LDL-c reductions of 60.1%. At week 12, 90.0% of patients reached LDL-c levels <100mg/dL, 70.0% <70mg/dL, and 55.0% <55mg/dL, while mean eGFR levels and statin use remained stable. CONCLUSION: In Nephrology Units of Spain, evolocumab was predominantly prescribed in patients with FH, chronic renal disease (CRD>2) and secondary prevention, with LDL-c levels above those recommended by the guidelines. Evolocumab used in clinical practice significantly reduced the LDL-c levels in all patients included in the study.

Symmetrical Ambulatory Arterial Stiffness Index: relationship with serum cystatin C levels.

OBJECTIVE: Increased central arterial stiffening is the consequence of many disease states such as diabetes, atherosclerosis, and chronic renal disease. Symmetrical Ambulatory Arterial Stiffness Index (Sym-AASI) may provide a simple clinical approach to evaluate arterial stiffness. This study has tried to evaluate the relationship of Sym-AASI with cystatin C levels. DESIGN AND METHODS: The sample subjects were 53 males and 34 females (mean age = 59.3 ± 13.5 years). Kidney function was evaluated by measuring serum cystatin C and estimated glomerular filtration rate (eGFR). The ambulatory BP was measured noninvasively for 24 h. RESULTS: Patients in the highest quartile showed an older age (p < 0.001) and worse eGFR (p < 0.001). Pulse pressure (PP) increased as cystatin C was higher. Mean Sym-AASI showed an increase from the first to the last cystatin C quartile. Correlation test showed a significant relationship of Sym-AASI with age (r = 0.573), serum creatinine (r = 0.237), eGFR (-0.323), cystatin C (r = 0.427), systolic blood pressure (r = 0.525), and PP (r = 0.647). Multivariate regression analysis showed that age, cystatin C, nocturnal systolic blood pressure reduction, and nocturnal diastolic blood pressure fall were independently related to Sym-AASI. There was not any independent association between eGFR and Sym-AASI or between cystatin C and PP. CONCLUSIONS: Increased Sym-AASI seems to be independently associated with serum cystatin C levels. Sym-AASI seems to be better than PP to detect changes in the arterial wall. This could be a simple and easy method to evaluate arterial stiffness in hypertensive patients without needing more complex devices.

[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.

Genetic Variants in PGE2 Receptors Modulate the Risk of Nephrosclerosis and Clinical Outcomes in These Patients.

Prostaglandin E2 (PGE2) is a major actor mediating renal injury. We aimed to determine genetic variability in the genes coding for its receptors (PTGER1-4) and study associations with nephrosclerosis risk and clinical outcomes. We identified 96 tag-SNPs capturing global variability in PTGER1-4 and screened 1209 nephrosclerosis patients and controls. The effect of these variants was evaluated by multivariate regression analyses. Two PTGER3 SNPs, rs11209730 and rs10399704, remained significant in a backward elimination regression model with other non-genetic variables (OR = 1.45 (1.07-1.95), p = 0.016 and OR = 0.71 (0.51-0.99), p = 0.041, respectively). In the nephrosclerosis patients, a proximal region of PTGER3 was tagged as relevant for eGFR (p values for identified SNPs ranged from 0.0003 to 0.038). Two consecutive PTGER3 SNPs, rs2284362 and rs2284363, significantly decreased systolic (p = 0.005 and p = 0.0005), diastolic (p = 0.039 and p = 0.005), and pulse pressure values (p = 0.038 and 0.014). Patients were followed for a median of 47 months (7-54) to evaluate cardiovascular (CV) risk. Cox regression analysis showed that carriers of the PTGER1rs2241360 T variant had better CV event-free survival than wild-type individuals (p = 0.029). In addition, PTGER3rs7533733 GG carriers had lower event-free survival than AA/AG patients (p = 0.011). Our results indicate that genetic variability in PGE2 receptors, particularly EP3, may be clinically relevant for nephrosclerosis and its associated CV risk.

Systolic Blood Pressure and Outcomes in Stable Outpatients with Recent Symptomatic Artery Disease: A Population-Based Longitudinal Study.

OBJECTIVES: The most appropriate targets for systolic blood pressure (SBP) levels to reduce cardiovascular morbidity and mortality in patients with symptomatic artery disease remain controversial. We compared the rate of subsequent ischemic events or death according to mean SBP levels during follow-up. DESIGN: Prospective cohort study. FRENA is an ongoing registry of stable outpatients with symptomatic coronary (CAD), cerebrovascular (CVD) or peripheral artery disease (PAD). SETTING: 24 Spanish hospitals. PARTICIPANTS: 4789 stable outpatients with vascular disease. RESULTS: As of June 2017, 4789 patients had been enrolled in different Spanish centres. Of these, 1722 (36%) had CAD, 1383 (29%) CVD and 1684 (35%) PAD. Over a mean follow-up of 18 months, 136 patients suffered subsequent myocardial infarction, 125 had ischemic stroke, 74 underwent limb amputation, and 260 died. On multivariable analysis, CVD patients with mean SBP levels 130-140 mm Hg had a lower risk of mortality than those with levels <130 mm Hg (hazard ratio (HR): 0.39; 95% CI: 0.20-0.77), as did those with levels >140 mm Hg (HR: 0.46; 95% CI: 0.26-0.84). PAD patients with mean SBP levels >140 mm Hg had a lower risk for subsequent ischemic events (HR: 0.57; 95% CI: 0.39-0.83) and those with levels 130-140 mm Hg (HR: 0.47; 95% CI: 0.29-0.78) or >140 mm Hg (HR: 0.32; 95% CI: 0.21-0.50) had a lower risk of mortality. We found no differences in patients with CAD. CONCLUSIONS: In this real-world cohort of symptomatic arterial disease patients, most of whom are not eligible for clinical trials, the risk of subsequent events and death varies according to the levels of SBP and the location of previous events. Especially among patients with large artery atherosclerosis, PAD or CVD, SBP <130 mm Hg may result in increased mortality. Due to potential factors in this issue, Prospective, well designed studies are warranted to confirm these observational data.

Lipid profile of patients treated with evolocumab in Spanish hospital nephrology units (RETOSS NEFRO). / Perfil clínico de los pacientes tratados con evolocumab en unidades hospitalarias de nefrología en España (RETOSS-NEFRO).

BACKGROUND AND OBJECTIVE: To describe the clinical characteristics, the reasons for initiating therapy and the effects of treatment in the initial phase of evolocumab availability in the Nephrology Units of Spain. MATERIAL AND METHODS: Retrospective, observational and multicentric study that included patients initiating treatment with evolocumab (from February 2016 to August 2018), in 15 Nephrology Units in Spain. The demographic and clinical characteristics of the patients, the lipid lowering treatment and the evolution of the lipid profiles between 24 weeks pre-initiation and 12±4 weeks post-initiation of evolocumab were reviewed. RESULTS: Sixty patients were enrolled: 53.3% women; mean (SD) age, 56.9 (12.8) years, 45.0% with familial hypercholesterolemia (FH) (5.0% homozygous and 40.0% heterozygous) and 65.0% with atherosclerotic cardiovascular (CV) disease. The mean (SD) eGFR was 62.6 (30.0)ml/min/1.73m2 (51.7% of patients had eGFR<60ml/min/1.73m2 [CKD stage>2]), 50.0% had proteinuria (>300mg/g) and 10.0% had nephrotic syndrome. Other CV risk factors were hypertension (75.0%), diabetes (25.0%), and smoking (21.7%). A 40.0% of patients were statin intolerant. At evolocumab initiation, 41.7% of patients were on a high-intensity statin, 18.3% on moderate intensity statin and 50.0% were receiving ezetimibe. Mean (SD) LDL-c at evolocumab initiation was 179.7 (62.9)mg/dL (53.4% of patients with LDL-c≥160mg/dL and 29.3%≥190mg/dL). After 12 weeks, evolocumab resulted in LDL-c reductions of 60.1%. At week 12, 90.0% of patients reached LDL-c levels <100mg/dL, 70.0% <70mg/dL, and 55.0% <55mg/dL, while mean eGFR levels and statin use were remained stable. CONCLUSION: In Nephrology Units of Spain, evolocumab was predominantly prescribed in patients with FH, chronic renal disease (CRD>2) and secondary prevention, with LDL-c levels above those recommended by the guidelines. Evolocumab used in clinical practice significantly reduced the LDL-c levels in all patients included in the study.