Association of ALOX12 gene polymorphism with all-cause and cardiovascular mortality in diabetic nephropathy.

PURPOSE: Cardiovascular (CV) events are the first cause of death in patients with chronic renal disease (CKD) and in patients with type 2 diabetes mellitus (DM2). The combination of CKD and DM2 elevates the risk of both cardiovascular disease (CVD) and death in this high-risk population. Besides traditional risk factors, such as dyslipidemia, smoking, obesity, and carotid atherosclerosis, novel factors are under investigation such as genetic polymorphisms. Lipoxygenases (LOXs) and their genes are of critical importance in oxidative stress, inflammation, and atherosclerosis. The aim of the study is to clarify a potential ALOX12 role in CVD presence and progress of diabetic patients in different stages of nephropathy. METHODS: We studied 145 patients with a documented history of DM2 for at least 10 years and diabetic nephropathy (DN), mean age 68 ± 9 years, body mass index 31 ± 5 kg/m2, and different stages of renal disease, depending on glomerular filtration rate. The sample population consisted of two groups: 108 DM2 patients with DN in all five stages of CKD and 37 DM2 patients as controls. Anthropometric and clinical characteristics, interview for history of previous CV event, and assessment of carotid intima-media thickness (cIMT) were recorded at baseline. All patients were genotyped for ALOX12 polymorphisms with focus on rs14309. Genotypes (AA, AG, and GG) were evaluated for any possible role in CVD, and grouping was performed on A genotype, which is the dominant model. All participants were followed over a period of 7 years, and the end points studied were all-cause mortality, CV mortality, and CV events. CV events were defined as myocardial infarction (MI), stroke, or peripheral artery disease. RESULTS: The GG genotype has been significantly associated with cIMT levels above 0.86 mm and with history of MI. Regarding the presence of an atherosclerotic plaque in either carotid artery, no significant association was found when the genotypes were assessed on their own. After grouping, though, GG genotype revealed a significant association between carotid plaque formation and atheromatosis. Kaplan-Meier analysis revealed that ALOX12 gene GG genotype predicted all-cause mortality, CV mortality, and CV events. Similarly, when AA and AG genotypes were grouped, Kaplan-Meier analysis showed that patients with GG genotype presented an even more significant higher all-cause mortality, CV mortality, and CV events compared with AA and AG genotypes combined. After adjustment for several traditional risk factors, multivariate Cox proportional hazard analysis showed that patients with the GG genotype had a significant higher risk of all-cause mortality, a threefold increase in CV mortality, and a twofold increased risk for CV events compared to patients with the AA or the AG genotype. CONCLUSION: ALOX12 rs14309 GG genotype expression was found to be significantly associated with MI, higher cIMT, increased CV events, CV, and overall mortality. This phenomenon could be partially explained by the increased platelet proaggregatory activity of AA products and the control they exert in thrombotic occurrence and plaque formation.

Diabetic patients on peritoneal dialysis.

During the past two decades, a number of studies have tried to evaluate the clinical status of dialyzed diabetic patients and the factors that may affect their outcomes. However, only a small number of diabetic patients on peritoneal dialysis (PD) have been followed for over 5 years, which is largely because of the presence of various comorbid conditions at the start of dialysis, the coexisting, far-advanced, target-organ damage that may gradually progress during the course of dialysis and limit the long-term survival on PD. On the contrary, among renal replacement therapies, survival of diabetic patients undergoing either PD or hemodialysis (HD) is probably similar, while diabetic patients on PD and HD have a lower actuarial survival than nondiabetic counterparts. This paper reviews our experience and the literature concerning the long-term outcome of diabetic patients on PD.

Peritoneal dialysis in patients with acute renal failure.

Of the two main renal replacement therapies, peritoneal dialysis (PD) was the modality first used for the treatment of patients with acute renal failure (ARF) because of its inherent advantages. Highly trained personnel, expensive and complex apparatus, and systemic anticoagulation were not needed, and so the procedure could be simply and quickly initiated. Further, because of the gradual removal of fluid and solutes, PD results in better hemodynamic stability. Manually or cycler-assisted ("automated") PD has been successfully used in many ARF patients, especially those at risk of bleeding or with hemodynamic instability, and in infants and children with ARF or circulatory failure. Recently, technological developments in hemodialysis techniques (bicarbonate dialysis, hemofiltration, hemodiafiltration) and the continuous renal replacement therapies (CRRTs), have limited the indications for PD in critically ill patients with ARF. In addition, better knowledge about the connection between early and adequate dialysis dose and improved outcomes has led to a tendency to increase the dialysis dose given to ARF patients, furthering the development of newer techniques. Although PD has been considered less effective than hemodialysis and CRRTs are in patients with severe acute illness (pulmonary edema, poisoning, extreme catabolysis) and ARF, PD remains an effective therapy that is easily and simply instituted, especially for infants and children with ARF, both within and outside of intensive care settings.

Effects of hemodialysis dose on anemia, hypertension, and nutrition.

There is good evidence that by improving dialysis adequacy, morbidity, and mortality of hemodialysis (HD) patients decrease. Dialysis adequacy has also been related to the better control of arterial blood pressure (BP), anemia and improvement of patients' nutritional status. This is a self-control study of 34 HD patients, (23 males, 11 females), aged 52.6 +/- 15.5 years, HD duration 55.9 +/- 61.2 months, referring to the effect of increasing delivered dialysis dose, over a two-year period, on their clinical and laboratory parameters. Delivered HD dose increased statistically significantly: Urea reduction ratio (URR) increased from 52 +/- 8 to 71 +/- 7% and Kt/V from 0.93 +/- 0.19 to 1.55 +/- 0.29 (p < 0.001). Hb increased statistically significantly from 10.4 +/- 1.7 to 11.0 +/- 1.3 g/dL (p < 0.05) while no difference has been noticed in weekly EPO dose. Both systolic and diastolic BP decreased statistically significantly (from 147 +/- 24 to 133 +/- 25mmHg and from 73 +/- 12 to 66 +/- 13 mmHg respectively, p = 0.001). Serum albumin increased from 4.3 +/- 0.4 to 4.6 +/- 0.3g/dL (p = 0.002) and nPCR from 0.93 +/- 0.16 to 1.20 +/- 0.17 (p < 0.001). We conclude that increasing dialysis dose results in both clinical and laboratory improvement regarding hypertension, nutritional status and control of HD patients' anemia.

Lipoprotein abnormalities in hemodialysis and continuous ambulatory peritoneal dialysis patients.

Lipid abnormalities are important variables in the development of vascular atherosclerotic lesions in ESRD patients while Lp(a) represents an independent risk factor. In order to evaluate lipid changes in HD and CAPD patients, serum cholesterol (TC), HDLc, LDLc, TG, apolipoproteins (AI,AII,B,E), Lp(a), and albumin levels were estimated in 109 ESRD dialyzed patients, 46 in HD and 63 in CAPD (mean duration 50 +/- 40 and 25 +/- 19 months, respectively), and 45 volunteers with high serum levels of C and TG, without renal insufficiency. Both HD and PD group revealed statistically significantly higher levels than controls for TC, TG, LDL-C, Apo-B,-E, while HDL-C levels were significantly lower. Except for the lower serum albumin levels in both dialyzed groups after six months lower ApoAI levels and higher ApoB levels were observed in HD and PD patients respectively. Lp(a) levels remained unchanged in HD group, while a statistically significant increase appeared in PD patients that was negative correlated with the decreased serum albumin levels. These results indicate that renal replacement modalities result in a different effect in lipoprotein metabolism that may play an important role in atherosclerotic vascular disease of dialyzed ESRD patients.

Is arterial hypertension an underlying factor in the increased serum Lp(a) levels in ESRD dialyzed patients?

Except for the disorders in lipoprotein metabolism several other factors have been involved in the development of atherosclerotic changes in ESRD patients, including arterial hypertension. Serum lipid profile (total cholesterol (TC), triglycerides (TG), apolipoproteins (AI,AII,B,E) and Lp(a)) was evaluated in 109 ESRD dialyzed patients, 46 in HD and 63 in CAPD and 45 hyperlipidemic patients without renal failure (HL-group). According to the presence of arterial hypertension the dialyzed patients were divided in two groups: group A of 42 hypertensive patients, (mean age 62.3 +/- 15.5 years), which were satisfactorily controlled with anti-hypertensive medication, and group B of 67 non-hypertensive patients, (mean age 66.6 +/- 11.9 years). Lp(a) levels were statistically significantly higher than HL group in both HD (p = 0.001) and PD (p < 0.05) patients. Besides, by dividing HD and PD group in hypertensive and non-hypertensive patients, Lp(a) levels were statistically significantly higher in hypertensive patients, while such a difference was not observed among non-renal failure patients. These results indicate that arterial hypertension may play an important role in Lp(a) serum titles, in ESRD patients undergoing either HD or PD.

The Clinical Impact of Increasing the Hemodialysis Dose.

Good evidence suggests that improvements in dialysis efficiency reduce morbidity and mortality of hemodialysis (HD) patients. Dialysis efficiency has also been related to better control of arterial blood pressure (BP), anemia, and serum phosphorus levels, and to improvement in patients' nutritional status. Over a 2-year period, the present self-controlled study of 34 HD patients (23 men, 11 women; age, 52.6 ± 14.5 years; HD duration, 55.9 ± 61.2 months) looked at the effect on clinical and laboratory parameters of increasing the delivered dialysis dose under a strict dry-weight policy. Dialysis dose was increased without increasing dialysis time and frequency. A statistically significant increase was seen in delivered HD dose: the urea reduction ratio (URR) increased to 60% ± 10% from 52% ± 8%, and then to 71% ± 7% (p < 0.001); Kt/Vurea increased to 1.22 ± 0.28 from 0.93 ± 0.19, and then to 1.55 ± 0.29 (p < 0.001). A statistically significant increase in hemoglobin concentration also occurred-to 10.8 ± 1.9 g/dL from 10.4 ± 1.7 g/dL, and then to 11.0 ± 1.3 g/dL (p < 0.05 as compared to baseline)-with no significant difference in weekly erythropoietin dose. Statistically significant decreases occurred in the systolic and diastolic blood pressures during the first year; they then remained unchanged. Systolic blood pressure decreased to 131 ± 23 mmHg from 147 ± 24 mmHg (p < 0.001); diastolic blood pressure decreased to 65 ± 11 mmHg from 73 ± 12 mmHg (p < 0.001). Serum albumin increased insignificantly to 4.4 ± 0.4 g/dL from 4.3 ± 0.4 g/dL, and then significantly to 4.6 ± 0.3 g/dL (p = 0.002 as compared to both previous values). Normalized protein catabolic rate increased significantly to 1.16 ± 0.15 g/kg/day from 0.93 ± 0.16 g/kg/ day (p < 0.001), and then to 1.20 ± 0.17 g/kg/day (p < 0.001 as compared to baseline). We conclude that the increases achieved in average Kt/Vurea per hemodialysis session by increasing dialyzer membrane area, and blood and dialysate flows, without increasing dialysis time above 4 hours, in patients hemodialyzed thrice weekly, coupled with strict dry-weight policy, resulted in improvements in hypertension, nutritional status, and anemia.

Arterial Hypertension Is Associated with Increased Serum Lipoprotein(a) Levels in End-Stage Renal Disease Patients.

In addition to disorders in lipoprotein metabolism, several other factors are involved in the development of atherosclerotic changes in end-stage renal disease (ESRD) patients. One of these is arterial hypertension. We evaluated serum lipids-total cholesterol (TC), triglycerides (TG), apolipoproteins (AI , A II , B, E), lipoprotein(a) [Lp(a)]-in 109 ESRD patients on dialysis [46 on hemodialysis (HD); 63 on continuous ambulatory peritoneal dialysis (CAPD)] and in 45 hyperlipidemic patients without renal failure (HL group). Dialysis patients were divided in two groups. Group A included 42 hypertensive patients (mean age: 62.3 ± 15.5 years) whose blood pressure (BP) was satisfactorily controlled with anti-hypertensive medications. Group B included 67 non hypertensive patients (mean age: 66.6 ± 11.9 years). Levels of Lp(a) were significantly higher in both the HD (p = 0.001) and the CAPD (p < 0.05) patients as compared with the HL group. When the HD and CAPD groups were divided into hypertensive and non hypertensive patients, Lp(a) levels were significantly higher in the hypertensive patients; this difference was not observed among non renal failure patients. These results indicate that arterial hypertension is associated with elevated Lp(a) serum levels in ESRD patients undergoing either HD or CAPD.

The Progression of Uremic Polyneuropathy in Patients on Hemodialysis and Hemofiltration: A Two-Year Study.

Uremic polyneuropathy is one of the major complications of long-term end-stage renal disease. In the present study, we performed an electrophysiologic evaluation in 17 patients having a mean age of 49 ± 11 years. The patients were divided into two groups according to dialysis method. Group A included 9 patients who were undergoing conventional hemodialysis (mean age, 44.2 ± 12.5 years; mean duration on dialysis, 21.7 ± 4.3 months); group B included 8 patients undergoing hemofiltration (mean age, 55.2 ± 5.2 years; mean duration on treatment, 27 ± 7.6 months). Measurements of the distal latency time of the sensory fibers (median, ulnar, and sural nerves), and measurements of the distal latency time and peripheral conduction velocity of the motor fibers (median and peroneal nerves) were performed. In addition, we recorded somatosensory evoked potentials after peripheral stimulation of the median and peroneal nerves. The electrophysiologic evaluations were repeated two times at intervals of 12 months. In group A, a statistically significant worsening of motor and sensory conductance in the upper and lower limbs was observed; in group B, a statistically significant improvement was found. These findings suggest that hemofiltration has a more beneficial effect on motor and sensory conductivity than does conventional hemodialysis.