A Genetic Biomarker of Oxidative Stress, the Paraoxonase-1 Q192R Gene Variant, Associates with Cardiomyopathy in CKD: A Longitudinal Study.

Background. Oxidative stress is a hallmark of CKD and this alteration is strongly implicated in LV hypertrophy and in LV dysfunction. Methods and Patients. We resorted to the strongest genetic biomarker of paraoxonase-1 (PON1) activity, the Q192R variant in the PON1 gene, to unbiasedly assess (Mendelian randomization) the cross-sectional and longitudinal association of this gene-variant with LV mass and function in 206 CKD patients with a 3-year follow-up. Results. The R allele of Q192R polymorphism associated with oxidative stress as assessed by plasma 8-isoPGF2α (P = 0.03) and was dose-dependently related in a direct fashion to LVMI (QQ: 131.4 ± 42.6 g/m(2); RQ: 147.7 ± 51.1 g/m(2); RR: 167.3 ± 41.9 g/m(2); P = 0.001) and in an inverse fashion to systolic function (LV Ejection Fraction) (QQ: 79 ± 12%; RQ: 69 ± 9%; RR: 65 ± 10% P = 0.002). On longitudinal observation, this gene variant associated with the evolution of the same echocardiographic indicators [LVMI: 13.40 g/m(2) per risk allele, P = 0.005; LVEF: -2.96% per risk allele, P = 0.001]. Multivariate analyses did not modify these associations. Conclusion. In CKD patients, the R allele of the Q192R variant in the PON1 gene is dose-dependently related to the severity of LVH and LV dysfunction and associates with the longitudinal evolution of these cardiac alterations. These results are compatible with the hypothesis that oxidative stress is implicated in cardiomyopathy in CKD patients.

Differences in cardiac structure assessed by echocardiography between renal transplant recipients and chronic kidney disease patients.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in predialysis chronic kidney disease (CKD) and dialysis patients as well as in renal transplant recipients (RTRs). Left ventricular hypertrophy (LVH) starts early during the course of CKD and is a strong predictor of CVD in this population. Regression of LVH after a successful renal transplantation remains a debatable issue among investigators, whereas there is little data comparing echocardiographic measurements between patients with predialysis CKD and RTRs. AIM: The aim of this study was to compare echocardiographic measurements of LV structure and function between predialysis CKD patients and RTRs of similar renal function level. PATIENTS AND METHODS: We conducted a case control study with individual (1:2) matching from the Renal Transplant and the predialysis CKD Outpatient Clinic. For each of the 36 RTRs, two matched for gender, age and estimated glomerular filtration rate (eGFR) predialysis CKD outpatients (72 patients) were included. All patients underwent transthoracic echocardiography and LV mass, LV mass index [LVM and LVMI = LVM/BSA g/m(2)] and indices of systolic function were measured. In a subgroup of 12 RTRs we retrospectively assessed and compared the LVMI measurements at three different time points, during predialysis, dialysis and post transplant period. RESULTS: The prevalence of LVH was 33% in RTRs and 52% in CKD patients (ns). RTRs had significantly lower LVM and LVMI levels compared with predialysis CKD patients (P = .006 and P = .008) while the other echocardiographic indices did not differ. In the subgroup of 12 RTRs, post-transplant LVMI levels (105 ± 25 g/m(2)) were significantly lower in comparison with predialysis (147 ± 57 g/m(2)) and dialysis LVMI levels (169 ± 72 g/m(2)) (P = .01, P = .01, respectively). CONCLUSION: RTRs had significantly lower LVMI compared with predialysis CKD patients of similar age, renal function, hemoglobin and blood pressure level.

Assessment of nonimmunologic factors in kidney transplant recipients according to Kidney Disease Improving Global Outcomes.

INTRODUCTION: Cardiovascular disease is the primary cause of death among kidney transplant recipients (KTRs), whereas chronic allograft nephropathy (CAN) is the main reason leading to end-stage chronic kidney disease. The etiologies of both entities include immunologic and nonimmunologic factors. The management of modifiable nonimmunologic parameters has recently been identified by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines. The aim of our study was to assess the implementation of these guidelines in the outpatient kidney transplantation clinic of our hospital. PATIENT AND METHODS: We retrospectively monitored the records of 48 transplanted KTRs including 32 males of overall mean age 45.1 ± 10.7 years regarding control of anemia, dyslipidemia, mineral bone disorder (MBD), and blood pressure (BP) levels. Data were recorded every 6 months for 2 years, starting 1 year after renal transplantation. RESULTS: The estimated glomerular filtration rate of patients at baseline was 60.3 ± 18.8 mL/min/1.73 m(2) with no significant change during 2 years of follow-up. The control of anemia was satisfactory in 42 patients (88%) with hemoglobin values ≥ 11 g/dL during the follow-up. Regarding dyslipidemia management, the aggregate of patients showed fasting triglycerides ≤500 mg/dL in all measurements. The percentage of KTRs with LDL ≤100 mg/dL tended to improve from baseline versus the end of the study period (20.8% vs 41.7%). Serum calcium was satisfactorily controlled in 77% of patients, serum phosphorus in all patients, whereas parathyroid hormone (PTH) was abnormal in 60% of KTRs with chronic kidney disease stages 3-5. Finally, the BP goal of <130/80 mm Hg was achieved in approximately half of the patients. CONCLUSION: Control of nonimmunologic factors was satisfactory in terms of renal anemia and MBD, whereas dyslipidemia and BP levels were inadequately controlled. There is a clear need for better integration into clinical practice of KDIGO guidelines with regard to modifiable nonimmunologic factors.

Evolution of Fabry disease in male patients: the Greek experience.

Fabry disease is a progressive metabolic disorder with a clinical course characterized by different phases and a variety of disease manifestations. The first symptoms generally appear in childhood or early adolescence and are followed by late life-threatening complications involving vascular, renal, cardiac, and cerebral systems. We report the clinical and biochemical characteristics of 16 male patients from 10 unrelated families who represent almost the entire cohort of known Fabry patients in Greece. Despite the presence of early symptoms in almost every patient (mean age at onset of symptoms 15.6 years), the diagnosis was delayed for a mean of about 18 years (mean age of diagnosis 36 years). Patients are currently monitored and the majority (15 out 16 patients) treated with Enzyme Replacement Therapy.

Effect of the hemodialysis session on bcl-2 expression in peripheral blood mononuclear cells in vivo.

bcl-2 is a proto-oncogene with a regulatory role in many conditions due to its marked inhibitory action on apoptosis. Reports regarding the effect of hemodialysis (HD) on apoptosis of mononuclear cells and in association with bcl-2 expression in particular, are controversial. The aim of the present study was to examine in vivo the influence of an HD session on bcl-2 expression of lymphocytes and monocytes. We measured quantitative bcl-2 expression with flow cytometry, in terms of antibodies bound per cell, in blood samples taken from 44 HD patients before and after an HD session. 27 patients (group I) were dialyzed with synthetic-type membranes and 17 (group II) with cellulose-type membranes. bcl-2 expression increased statistically significantly in lymphocytes (1,616 +/- 718 to 1,894 +/- 715 molecules/cell, p < 0.01) at the end of HD. Monocyte expression of bcl-2 was lower than in lymphocytes and almost did not change after the HD session (654 +/- 446 to 698 +/- 375 molecules/cell, p = NS). Comparison between the two groups did not reveal a significant difference in either the baseline bcl-2 expression or in the value of the increase after HD. We conclude that HD seems to decrease lymphocyte apoptosis independent of the biocompatibility of the dialyzer membrane.

Life-threatening hemorrhage from abdominal aorta following a percutaneous renal biopsy.

We report on a case of life-threatening abdominal aorta hemorrhage following percutaneous renal biopsy. A 42-year-old woman with chronic kidney disease stage 2 and microscopic hematuria underwent a percutaneous renal biopsy to evaluate renal insufficiency. One hour following the biopsy procedure, she complained of an abdominal pain and developed signs ofoligemic shock. In despite of 4 blood units transfusion, the patient continued to be in shock. She was transmitted urgently to the operating room without any other examinations (such as abdominal computer tomography) and underwent an emergency laparotomy. A transverse tear in the abdominal aorta was identified as the bleeding site, and after occlusion, the hemorrhage was stopped. The patient gradually recovered and she was discharged in good clinical condition after a few days.

Effectiveness of aluminum hydroxide timing administration in relation to meals in controlling hyperphosphatemia in dialysis patients.

Phosphate binder compounds contribute to the control of hyperphosphatemia in hemodialysis (HD) patients. However, the most effective schedule of administration of phosphate binders in relation to meals is not well documented. We examined the effectiveness of aluminum hydroxide intake as the sole phosphate binder in relation to meals. Eighty-five patients on regular HD (45 male, 40 female), age 21-72 years, with a duration of 6-216 months HD participated in the study. In all patients, phosphate binders were discontinued for a one month period. Thereafter, and according to the protocol, all patients were advised to take aluminum hydroxide [Al(OH)3 ] 30 min before, during and 30 min after meals for 3 periods of one month each, in a random order. One month washout period preceded the periods of Al(OH)3 ingestion. When Al(OH)3 was administered 30 min prior to the meals, serum phosphate decreased by 7.0% (0.59 mg/dL), while when administrated with or 30 min after meals, it decreased statistically significantly by 28.5% (2.08 mg/dL), and 16% (1.29 mg/dL) respectively. Our results suggest that the efficacy of Al(OH)3 to bind phosphate salts and thus to prevent the hyperphosphatemia in HD patients is higher when this drug is taken with meals.

Serum potassium and acid-base parameters in severe dialysis-associated hyperglycemia treated with insulin therapy.

We analyzed the changes in serum potassium concentration ([K]) and acid-base parameters in 43 episodes of dialysis-associated hyperglycemia (serum glucose level > 33.3 mmol/L), 22 of which were characterized as diabetic ketoacidosis (DKA) and the remaining 21 as nonketotic hyperglycemia (NKH). All episodes were treated with insulin therapy only. Age, gender, initial and final serum values of glucose, sodium, chloride, tonicity and osmolality did not differ between DKA and NKH. At presentation, serum values of [K] (DKA 6.2 +/- 1.3 mmol/L; NKH 5.2 +/- 1.5 mmol/L) and anion gap [AG] (DKA 27.2 +/- 6.4 mEq/L; NKH 15.4 +/- 3.5 mEq/L) were higher in DKA, whereas serum total carbon dioxide content [TCO2 ] (DKA 12.0 +/- 4.6 mmol/L; NKH 22.5 +/- 3.1 mmol/L), arterial blood pH (DKA 7.15 +/- 0.09; NKH 7.43 +/- 0.07) and arterial blood PaCO2 (DKA 26.2 +/- 12.3 mm Hg; NKH 34.5 +/- 6.7 mm Hg) were higher in NKH. At the end of insulin treatment, serum values of [K] (DKA 4.0 +/- 0.7 mmol/L, NKH 4.0 +/- 0.5 mmol/L), [AG] (DKA 16.3 +/- 5.4 mEq/L, NKH 14.9 +/- 3.0 mEq/L), [TCO2 ] (DKA 23.5 +/- 5.0 mmol/L, NKH 24.1 +/- 4.2 mmol/L), arterial blood pH (DKA 7.42 +/- 0.09, NKH 7.51 +/- 0.14) and arterial blood PaCO2 (DKA 31.8 +/- 6.7 mm Hg, NKH 34.2 +/- 8.3 mm Hg) did not differ between the two groups. Linear regression of the decrease in serum [K] value during treatment, (Delta[K]), on the presenting serum [K] concentration,([K]2 ), was: DKA, Delta[K] = 2.78 - 0.81 x [K]2 , r = -0.85, p < 0.001; NKH, Delta[K] = 2.44 - 0.71 x [K]2 , r = -0.90, p < 0.001. The slopes of the regressions were not significantly different. Stepwise logistic regression including both DKA and NKH cases identified the presenting serum [K] level and the change in serum [TCO2 ] value during treatment as the predictors of Delta[K] (R2 = 0.81). Hyperkalemia is a feature of severe hyperglycemia (DKA or NKH) occurring in patients on dialysis. Insulin administration brings about correction of DKA and return of serum [K] concentration to the normal range in the majority of the hyperglycemic episodes without the need for other measures. The initial serum [K] value and the change in serum [TCO2 ] level during treatment influence the decrease in serum [K] value during treatment of dialysis-associated hyperglycemia with insulin.

Serum tonicity, extracellular volume and clinical manifestations in symptomatic dialysis-associated hyperglycemia treated only with insulin.

The absence of osmotic diuresis modifies the effects of hyperglycemia on body fluids in patients with advanced renal failure. To determine the relationship between clinical manifestations and abnormalities in tonicity and extracellular volume in such patients, we analyzed 43 episodes of severe dialysis-associated hyperglycemia (serum glucose exceeding 600 mg/dL) treated only with insulin. The main manifestations were dyspnea in 22 cases (pulmonary edema in 19), nausea and vomiting in 15, coma in 13 and seizures in 3, while 5 patients had no symptoms. Treatment with insulin resulted in a decrease in serum glucose value from 913 +/- 197 mg/dL to 170 +/- 78 mg/dL, an increase in serum sodium level from 125 +/- 5 to 136 +/- 5 mmol/L, and a fall in calculated serum tonicity value from 300 +/- 13 to 282 +/- 11 mmol/kg (all at p < 0.001). The ratio of the change in serum sodium level over change in serum glucose concentration was -1.50 +/- 0.22 mmol/L per 100 mg/dL. The percent increase in extracellular volume secondary to hyperglycemia developing from the prior euglycemic state and calculated from changes in serum sodium and chloride concentrations, was 10.9% +/- 4.6% (1.5% +/- 0.6% per 100 mg/dL increase in serum glucose level). All clinical manifestations dissipated after correction of hyperglycemia in 42 patients. One woman developed during treatment a fatal myocardial infarction. Dialysis patients with severe hyperglycemia may develop symptoms as a result of hypertonicity and extracellular expansion. Insulin alone may be sufficient treatment for these symptoms. The changes in serum tonicity and electrolytes during treatment are consistent with theoretical predictions.

Novel PKD1 deletions and missense variants in a cohort of Hellenic polycystic kidney disease families.

The autosomal dominant form of polycystic kidney disease is a very frequent genetically heterogeneous inherited condition affecting approximately 1 : 1000 individuals of the Caucasian population. The main symptom is the formation of fluid-filled cysts in the kidneys, which grow progressively in size and number with age, and leading to end-stage renal failure in approximately 50% of patients by age 60. About 85% of cases are caused by mutations in the PKD1 gene on chromosome 16p13.3, which encodes for polycystin-1, a membranous glycoprotein with 4302 amino acids and multiple domains. Mutation detection is still a challenge owing to various sequence characteristics that prevent easy PCR amplification and sequencing. Here we attempted a systematic screening of part of the duplicated region of the gene in a large cohort of 53 Hellenic families with the use of single-strand conformation polymorphism analysis of exons 16-34. Our analysis revealed eight most probably disease causing mutations, five deletions and three single amino acid substitutions, in the REJ domain of the protein. In one family, a 3-bp and an 8-bp deletion in exons 20 and 21 respectively, were co-inherited on the same PKD1 chromosome, causing disease in the mother and three sons. Interestingly we did not find any termination codon defects, so common in the unique part of the PKD1 gene. In the same cohort we identified 11 polymorphic sequence variants, four of which resulted in amino acid variations. This supports the notion that the PKD1 gene may be prone to mutagenesis, justifying the relatively high prevalence of polycystic kidney disease.

Individual renal function in polycystic kidney disease: a follow-up study.

PURPOSE: This study was undertaken to determine individual renal function in patients with autosomal dominant polycystic kidney disease (ADPKD). MATERIALS AND METHODS: The authors initially examined (study t1) 25 patients with ADPKD (12 female, 13 male; ages 18 to 68 years). The serum creatinine concentration and glomerular filtration rate, measured by Tc-99m DTPA, were 1.5 +/- 0.56 mg/dl and 65.7 +/- 31 ml.minute-1.1.73 m2, respectively. Thirteen patients had a follow-up study (t2) 2 years after their initial evaluations. Individual renal function was assessed on Tc-99m DMSA renal scans. RESULTS: The mean (+/- SD) difference between left kidney DMSA (DMSA-L) and right kidney DMSA (DMSA-R) was 7.04 % +/- 16.48%. In 20 patients (80%), the left kidney had a lower percentage contribution to the total renal function compared with the right kidney. When the results of the two studies were compared, deterioration in renal function was noted. In the t1 study, the mean serum creatinine concentration and glomerular filtration rate were 1.7 mg/dl and 67.02 ml.minute-1.1.73 m2 respectively, and in the t2 study these values were 2.01 mg/dl and 57.15 ml.minute-1.1.73 m2, respectively. No difference, however, was found in individual renal function in the two studies. CONCLUSIONS: In patients with ADPKD, the percentage contribution of each kidney to total renal function is not equal and remains stable during the progression of renal failure.

Evaluation of five methods for determining low-density lipoprotein cholesterol (LDL-C) in hemodialysis patients(1).

OBJECTIVES: Current recommendations for the management of dyslipidemia are largely based on the concentration of LDL-C. Most clinical laboratories estimate the concentration of LDL-C by the recommended routine method, the equation of Friedewald, in specimens from fasting subjects and with TG concentrations < 4.52 mmol/L. Because of the limitations of the Friedewald calculation, direct methods for an accurate quantification of LDL-C are needed. DESIGN AND METHODS: In the present study we evaluated the accuracy of the following 5 different procedures for LDL-C in 98 patients on hemodialysis: the Friedewald equation, where LDL-C is calculated from HDL-C, measured either by the precipitation procedure with dextran sulfate-Mg(2+) (Method 1), or by a direct HDL-C assay (Method 2), the Direct LDL assay (Method 3), the homogeneous N-geneous LDL assay (Method 4) and the calculated LDL-C values deriving from the ApoB based equation: 0.41TC - 0.32TG + 1.70ApoB - 0.27, (Clin Chem 1997;43:808-815) (Method 5). RESULTS: All five LDL-C methods were found to be in good agreement with ultracentrifugation/dextran sulfate-Mg(2+) precipitation with the coefficients of correlation of the assays to ranging between 0.93-0.95. However, significant differences in the mean values and biases vs. the reference method were observed. The Friedewald equation and the Direct assay were less affected by high LDL-C levels, and they presented higher sensitivity and higher negative predictive value. The N-geneous assay and the ApoB derived calculation were less affected by high triglyceride levels, and they presented higher specificity and higher positive predictive value. At the diagnostic LDL-C level of 3.37 mmol/L, both Friedewald calculations correctly classified 82/92 patients; Direct assay 86/98; N-geneous assay 88/98; and ApoB derived calculation 88/98. At the diagnostic LDL-C level of 2.98 mmol/L, Friedewald calculations (Method 1 and Method 2) correctly classified 82/92 and 81/92 patients, respectively; Direct assay (LDL-3) 87/98; N-geneous assay (LDL-4) 91/98; and ApoB derived calculation (LDL-5) 91/98. CONCLUSIONS: Among hemodialysis patients, who commonly present "average" LDL-C concentrations and high TG levels, the N-geneous assay and the apoB derived calculation seem to yield more acceptable results for the estimation of LDL-C.

Mechanisms of hyponatraemia in alcohol patients.

Hyponatraemia is commonly reported in chronic alcoholic patients. However, the underlying pathogenetic mechanisms are not well delineated. In the current study, we analysed the possible pathophysiological mechanisms of hyponatraemia in a group of alcoholic patients (n = 127) admitted to our hospital for causes related to alcohol misuse. Hyponatraemia (serum sodium <134 mmol/l) was found in 22 patients (17.3%). The most common cause of hyponatraemia in our cohort was hypovolaemia (12 patients); pseudohyponatraemia was diagnosed in six patients with alcohol-induced severe hypertriglyceridaemia. It is of interest that two patients fulfilled the criteria of the so-called 'beer potomania' syndrome, while in two others, hyponatraemia was due to reset osmostat or to cerebral salt wasting syndrome, not previously described in alcoholic patients. It is concluded that hyponatraemia is a frequently observed electrolyte disorder in hospitalized alcoholic patients and is related to various pathophysiological mechanisms.