Attilio Losito

Increased acid excretion in kidney stone formers with essential hypertension

BACKGROUND Although several studies have reported that kidney stone disease and hypertension are associated, the link between the two conditions has not been identified. This study investigated urinary excretion of different solutes, particularly citrate and acids, in kidney stone formers and examined their association with high blood pressure. METHODS The retrospective study included 234 consecutive subjects, aged 47.0 +/- 15.6, attending our metabolic clinic after episodes of kidney stones. Essential hypertension was present in 82 patients (35.0%). A difference in the urinary excretion of some of the investigated components was found between subjects with normal blood pressure and those with hypertension. RESULTS The results showed that hypertensive subjects were older and had a higher body mass index (BMI) and serum uric acid. They had a significantly lower urinary pH (5.6 +/- 0.4 versus 6.0 +/- 0.5) and citrate (2.55 +/- 1.36 versus 2.83 +/- 1.65 mmol/24 h), higher titratable acid (38.8 +/- 19.0 versus 26.8 +/- 15.0 mEq/24 h) and ammonium (41.6 +/- 17.6 versus 34.2 +/-12.4 mmol/24 h). Logistic regression analysis with the presence of hypertension as the dependent variable produced a model with the following predictors: age (P < 0.0001), BMI (P = 0.026), titratable acid (P = 0.025) and low urinary citrate level (P = 0.033). Urinary acid excretion increased with the stage of hypertension. No difference was found in the urinary excretion of other solutes. CONCLUSIONS These findings suggest that essential hypertension and acid excretion are linked in stone formers.

ACE gene polymorphism and survival in atherosclerotic renovascular disease

Renovascular disease (RVD) is an important cause of end-stage renal disease and is associated with a high mortality rate, mostly because of coexisting cardiovascular and cerebrovascular disease. The deletion (DD) polymorphism of the angiotensin-converting enzyme (ACE) gene has been described in association with severe vascular disease affecting major organs. To investigate whether DD genotype is a risk factor for mortality in RVD, we performed a follow-up study of 61 patients with this disease. Patients (age, 68.0 +/- 6.5 years) affected by atherosclerotic vascular disease were enrolled after angiographic demonstration of a renal artery stenosis. The average follow-up was 48.1 +/- 14.9 months. Genotype was insertion/deletion (I/D) in 30 patients, DD in 27 patients, and II in 4 patients. At enrollment, a complete assessment of heart, blood vessels, and renal function was performed. During the follow-up period, 13 patients died (9 DD, 4 ID) and 7 patients evolved into end-stage renal failure. The cumulative survival rate at 5 years was 45.4% +/- 13.4%. Factors associated with mortality were analyzed with Cox proportional hazard regression. The multivariate analysis showed that DD genotype, severe carotid disease, and smoking were independent predictors of mortality. The multivariate analysis of predictors of renal failure showed that the only significant association was found with baseline serum creatinine level of 265 micromol/L or greater. We conclude that the DD genotype of the ACE gene is a marker for mortality in RVD.

Angiotensin-converting enzyme gene I/D polymorphism and carotid artery disease in renovascular hypertension.

There is evidence linking the activation of the renin-angiotensin system (RAS) with target organ damage in renovascular hypertension (RVH). A genetic association of the DD genotype of the angiotensin-converting enzyme (ACE) gene with cardiovascular complications has been found in various clinical conditions. The aim of our study was to determine whether the insertion/deletion (I/D) polymorphism of the ACE gene is associated with the high prevalence of target organ damage reported in RVH. A total of 65 atherosclerotic patients (age 68.2 +/- 5.2 years) with RVH and 49 atherosclerotic patients (age 68.0 +/- 6.3 years) with essential hypertension (EH) were sequentially enrolled when attending the outpatient clinic for specialist assessment of their vascular disorder. Cardiac, renal, and vascular involvement were assessed in both groups and blood was taken for genetic analysis. Patients with RVH had a higher prevalence of left ventricular hypertrophy (LVH), carotid artery disease, and albuminuria than those with EH. In RVH, but not in EH, the DD genotype was significantly associated with severe arterial disease. In RVH, carotid disease (lumen narrowing >60%) was present in 62% of DD patients versus 25% of the other genotypes (OR = 4.90, 95% CI: 1.70-14.13). Such an association was also present in peripheral vascular disease: 72.4% in DD patients versus 41.6% in the other genotypes (OR = 3.67, 95% CI = 1.29-10.36). Logistic regression analysis showed that the DD genotype was the strongest predictor of risk of severe carotid disease. We conclude that, in atherosclerotic RVH, there is an association of the severity of vascular disease with the DD genotype of the ACE gene.

Reduced kidney function and outcome in acute ischaemic stroke: relationship to arterial hypertension and diabetes

BACKGROUND Stroke is a dangerous long-term complication of kidney failure, yet its occurrence early in disease is poorly characterized. Our aim was to investigate the association of reduced kidney function, hypertension and diabetes with acute ischaemic stroke and the outcome thereof. METHODS In this prospective cohort study, the association of reduced kidney function, hypertension and diabetes with stroke and 2-year all-cause mortality was investigated. Glomerular filtration rate (eGFR) was estimated by the simplified Modification of Diet in Renal Disease formula in 13 365 consecutive patients (671 with acute ischaemic stroke) admitted to our clinical facility over a 12-month period. RESULTS Ischaemic stroke, after adjustment for age and gender, was significantly associated with eGFR <60 mL/min/1.73m(2) [odds ratio (OR) 1.53, 95% confidence interval (CI) 1.30-1.81], hypertension (2.77, 95% CI 2.33-3.28) and diabetes (1.30, 95% CI 1.04-1.63). Multivariate analysis of interaction indicated the absence of an additive effect between eGFR, hypertension and diabetes, on the risk of stroke. Age and gender-adjusted survival analysis by Cox regression showed an association of mortality with reduced eGFR alone (HR = 4.29, 95% CI 1.02-19.60). CONCLUSIONS In patients acutely admitted to hospital, reduced kidney function, hypertension and diabetes are independently associated with ischaemic stroke, but do not exert a synergic effect. After hospital discharge, mortality is strongly associated with reduced eGFR but with neither hypertension nor diabetes.

Association of the –159C/T Polymorphism of the Endotoxin Receptor (CD14) with Carotid Artery Disease and Cardiovascular Mortality in Dialysis Patients

Background: Atherosclerosis is a major problem in end-stage renal disease (ESRD) patients treated by hemodialysis and the prevalence of carotid artery disease is much higher in this group than in the general population. Repeated exposure to cytokine-inducing material, derived from dialysate, may induce a chronic inflammatory state, that could contribute to the atherosclerotic process. Endotoxin is mainly cleared from plasma by the sCD14, the soluble form of the endotoxin receptor CD14. The levels of sCD14 are associated with a polymorphism, –159 C/T, of the CD14 gene. Methods and Results: We determined the genotype for the –159 C/T polymorphism in 158 haemodialysis patients and 168 healthy controls. In patients we investigated the association between the CD14 polymorphism and carotid artery disease. With a prospective follow-up study we assessed whether the CD14 polymorphism shows any relationship with cardiovascular mortality. The polymorphic frequency was comparable between patients and controls. In patients, we found a significant difference in the prevalence of carotid artery disease between groups divided by genotype: CC 87.0%, CT 71.7%, TT 48.9% (p = 0.0093). In dialysis patients with hypertension the CC polymorphism was associated with an increased cardiovascular mortality. Conclusions: These results demonstrate an association between the –159 C/T polymorphism of the CD14 gene and carotid artery disease in dialysis patients. We hypothesize that the low plasma clearance of endotoxin associated with the CC genotype facilitates the atherogenic action of endotoxin-derived cytokines in haemodialysis patients.

Thrombotic microangiopathic nephropathy, pulmonary hypertension and nephromegaly: case report of a patient treated with endothelin receptor antagonist.

The coexistence of thrombotic microangiopathic nephropathy and pulmonary hypertension has only been described in association with malignancy and its treatment. Here we describe a 14-year-old boy with no prior medical history who presented with hypertension, proteinuria and nephromegaly, and then developed progressive pulmonary hypertension. Renal histology showed lesions consistent with glomerulopathy due to thrombotic microangiopathy (TMA). Pulmonary hypertension was controlled by the use of an oral endothelin receptor antagonist (bosentan). Although renal function deteriorated at the onset of pulmonary hypertension, an improvement was observed after the bosentan treatment. Nephromegaly persisted, but current creatinine clearance values are within the normal range. While this case exemplifies how thrombotic microangiopathic nephropathy may be associated with pulmonary hypertension, a therapeutic role of endothelin antagonists is suggested, not only for pulmonary hypertension but also for microangiopathic nephropathy.

Postdialysis Hypertension: Associated Factors, Patient Profiles, and Cardiovascular Mortality

BACKGROUND AND OBJECTIVES A postdialytic increase in blood pressure (BP) is a recognized but often an overlooked complication. The epidemiology and predisposing factors are still not well defined. We studied a large sample of Italian dialysis patients to assess the prevalence of postdialysis hypertension (PDHYPER), defined as any increase of systolic BP (SBP) >10mm, Hg above the predialysis value, the associated factors and its role in cardiovascular (CV) mortality. PATIENTS AND METHODS In this observational study, we assessed dialysis associated changes in BP in 4,292 hemodialysis (HD) patients over 1 month (51,504 sessions). We compared the clinical characteristics of the patients with stable BP values during the HD session with those with PDHYPER. We also assessed the impact of PDHYPER on CV mortality. RESULTS A total of 994 (23.1%) patients had PDHYPER. Patients with PDHYPER were more likely to be hypertesive, older, have a shorter dialysis vintage, be male, have lower SBP, lower changes in weight during HD, and receive more antihypertensive medications. These predictive factors were shown to be associated with an interaction between weight loss and dialysis, suggesting a volume-related mechanism in its pathogenesis. PDHYPER was also associated with CV mortality. CONCLUSIONS In our study on a large Italian cohort of dialysis patients, the prevalence of PDHYPER was higher than what was previously reported and is a significant risk factor for CV mortality in dialysis patients. The pathogenesis is multifactorial but hypertensive state, antihypertensive medications, and extracellular volume expansion appear to play a major role.

Blood Pressure and Cardiovascular Mortality in Dialysis Patients With Left Ventricular Systolic Dysfunction

BACKGROUND In patients chronically treated with hemodialysis, the prevalence of heart failure is high with a consequently poor prognosis. The role played by blood pressure (BP) on cardiovascular (CV) mortality of these patients has not been clearly defined. METHODS In this follow-up study, we investigated the relationship of pre- and postdialysis measurements of BP with CV and all-cause mortality in a cohort of 557 dialysis patients with a left ventricular (LV) ejection fraction <50%. RESULTS During the follow-up (mean = 21.6 ± 8.8 months), 179 deaths were recorded. Ninety-eight patients died from CV causes. By the Cox multivariable analysis, we constructed a predictive model of CV mortality including age, duration on dialysis, diabetes, serum albumin, diffusive dialysis technique, predialysis mean arterial pressure (MAP) (hazard ratio (HR) = 0.978; 95% confidence interval (CI) = 0.956-0.999), and postdialysis MAP (HR = 1.035; 95% CI = 1.010-1.061). The relationship with mortality was inverse for predialysis MAP and direct for postdialysis MAP. In a subsequent analysis, we found that pre- and postdialysis systolic BP, but not diastolic BP, were predictive of CV mortality. Predialysis MAP was in a direct relationship with body mass index. Postdialysis MAP had an inverse relationship with weight loss during dialysis session. CONCLUSIONS CV mortality in dialysis patients with LV dysfunction is associated with both pre- and postdialysis BP interacting in a complex relationship. Nutritional state and fluid balance and removal are possible clues to this relationship.

Characteristics of the Relationship of Kidney Dysfunction with Cardiovascular Disease in High Risk Patients with Diabetes

We aimed at comparing the relationship of reduced estimated glomerular filtration rate (eGFR) with cardiovascular disease (CVD) and mortality between high risk patients with and without type 2 diabetes mellitus (T2DM). The cross-sectional study evaluated 16,298 participants (1,627 T2DM) acutely admitted to hospital. The longitudinal study comprised 7,508 patients (673 with diabetes and 6,835 without). eGFR was categorized into 6 stages from >90 to <15 mL/min/1.73 m2. Kidney dysfunction was defined by an eGFR < 60 mL/min/1.73 m2. Patients with T2D showed a higher prevalence of CVD (37.9% versus 23.6%; P < 0.001) and kidney dysfunction (25% versus 13.2%; P < 0.001) than in the general population. An association with CVD was found with eGFR stages from 30 to 90 mL/min/1.73 m2 in T2D and from <15 to 90 mL/min/1.73 m2 in general population, in whom the association of eGFR with coronary heart disease was in an inverse relationship (P < 0.01 for trend). Survival, in diabetes, was lower (P = 0.037) but not associated with kidney dysfunction. Conclusions. In a high risk population, patients admitted to hospital, the relationship of kidney function with CVD is different between T2D and the general population. Competing mortality and the presence of other major risk factors in diabetes may be responsible for this difference.