Preliminary Screening Results of Fabry Disease in Kidney Transplantation Patients: A Single-Center Study.

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by the deficiency of alfa-galactosidase A (AGALA) and leads to progressive impairment of renal function in almost all male patients and in a significant proportion of female patients. FD is underdiagnosed or even misdiagnosed in patients undergoing kidney transplantation. We initiated a selective screening study for FD among kidney transplant patients in our center. In this study, 1095 male and female patients were included. Dried blood samples on Guthrie papers were used to analyze galactosidase A enzyme for male patients. Genetic analyses were performed in all female and male patients with low enzyme activity. In total, 648 female and 447 male patients with functioning grafts were evaluated. Among 1095 patients, 5 male patients had AGALA activity below threshold and 3 female patients had galactosidase alpha gene DNA variations. One male patient had a disease-causing mutation. The other 4 patients had polymorphisms causing low enzyme activity. All the 3 female patients had mutations that were associated with FD according to Human Gene Mutation Database (ID: CM025441). In contrast, these mutations were reported as unknown clinical significance in Clinvar (rs149391489). The patients with clinical findings suggesting FD were planned to be analyzed for Lyso Gb3. In our selective screening study, 8 variations were found among 1095 kidney transplantation patients, which needs further investigation to determine causes of FD. Clinical findings, physical examination, and family history are also necessary to evaluate the genetic changes as a mutation in this selected population.

Impact of Prophylaxis vs Pre-emptive Approach for Cytomegalovirus Infection in Kidney Transplant Recipients.

Cytomegalovirus (CMV) is the most common viral infection during the post-transplant period, and it is one of the major causes of morbidity and mortality in kidney transplantation. In this study, the incidence and impact of pre-emptive and prophylactic approaches and long-term effects on graft and patient survival of CMV infection were investigated. Among 493 adult kidney transplant recipients, pretransplant CMV IgG-negative patients and patients with a follow-up shorter than a month were excluded. The patients were divided into 2 groups: pre-emptive group (n = 187, regular screening and acyclovir 400 mg twice daily for 6 months), and prophylaxis group (n = 275, valganciclovir 450 mg/d for 3 months). The pre-emptive group was screened for CMV with either pp65 antigenemia or CMV DNA. There were 462 patients, and mean follow-up was 37.7 months. There were more CMV infections in the pre-emptive group than in the prophylaxis group (n = 56, 30.1% vs n = 12, 4.4%, respectively; P < .001). Late CMV infections were significantly more frequent in the prophylaxis group (10 of 12, 83.3%) than in the pre-emptive group (8 of 56, 14.3%, P < .001). In multivariate analysis, valganciclovir prophylaxis was associated with a lower CMV infection (relative risk [RR]: 0.18, 95% confidence interval [CI] 0.08 to 0.39, P < .001). Delayed graft function was the only independent risk factor for graft loss during the follow-up on multivariate Cox regression analysis (RR: 2.66, 95% GA 1.17 to 6.04, P = .02). Valganciclovir prophylaxis was more protective against CMV infection than the pre-emptive approach. Neither prophylaxis/pre-emptive approaches nor CMV infection had negative effect on graft and patient survival.

Impedance ratio: a novel marker and a powerful predictor of mortality in hemodialysis patients.

PURPOSE: Impedance ratio (Imp-R) obtained by multifrequency bioimpedance analysis (BIA) has been shown to be associated with volume and nutrition status. In this prospective study, the predictive role of Imp-R for mortality in hemodialysis (HD) patients was investigated. METHODS: Multifrequency (5-50-100-200 kHz) BIA was applied to 493 prevalent HD patients in March-April 2006. Imp-R was defined as the ratio of 200-5 kHz impedance values. Demographical, clinical and laboratory data at the time of the analysis were recorded. All-cause and cardiovascular (CV) mortality were assessed during 3 years of follow-up. RESULTS: Mean age was 57.7 ± 13.9 years, HD duration 52.1 ± 42.6 months and prevalence of diabetes 21.7 %. Imp-R was negatively correlated with nutritional markers including albumin, creatinine and hemoglobin levels. In addition, there was a positive correlation between Imp-R and age, ratio of extracellular water to total body water and high-sensitive C-reactive protein. Over a mean follow-up period of 27.9 ± 11.1 months, 93 deaths (52 from CV reasons) were observed. In the multivariate analysis, Imp-R was significantly associated with all-cause and CV mortality after adjustments [HR 1.13, 95 % CI (1.04-1.23); p = 0.004 and HR 1.15, 95 % CI (1.03-1.27); p = 0.01, respectively]. The risk of all-cause mortality was 3.4 times higher in the fourth quartile of Imp-R (>83.5 %) compared to the first Imp-R quartile (<78.8 %) as reference. Cutoff value of Imp-R for all-cause mortality was 82.0 % with a sensitivity of 65.5 % and specificity of 64 %. CONCLUSION: Impedance ratio measured by multifrequency in standardized conditions BIA is an independent and powerful predictor of both all-cause and CV mortality in hemodialysis patients.

The effect of immunosuppressive treatment on arterial stiffness and matrix Gla protein levels in renal transplant recipients.

INTRODUCTION: Arterial stiffness is a risk marker for cardiovascular events. In this study we aimed to compare the effect on calcineurin inhibitors (CNI) and mammalian Target of Rapamycine inhibitors (mTORi) on arterial stiffness in renal transplant patients. PATIENTS AND METHODS: 81 renal transplant patients under CNI-based or mTORi-based protocol for at least 6 months were included in the study. Arterial stiffness was measured by using the SphygmoCor device (AtCor Medical, Sydney, Australia). Vitamin K-dependent, calcification inhibitor matrix Gla protein (MGP) concentrations were quantified by ELISA methods (Biomedica, Vienna, Austria). RESULTS: 34 patients were on mTORi-based and 47 on CNI-based immunosuppression. Mean age was 37.9 ± 10.8 (18 - 71) years and 45% were female. Age, gender, graft functions and follow-up period of the groups were similar. Augmentation index was 15.2 ± 12.6% in CNI and 18.8 ± 14.0% in mTORi groups (p > 0.05). There was no difference regarding carotid-femoral pulse wave velocity between groups. Arterial stiffness was positively correlated with age, total cholesterol, LDL cholesterol, mean arterial pressure (MAP) and proteinuria. MGP levels were higher in the mTORi group but were not predictors for carotid-femoral pulse wave velocity. CONCLUSION: Rather than specific immunosuppressive drug effects, conventional risk factors, blood pressure and proteinuria are the most important predictors for arterial stiffness in renal transplant patients.

The acquisition time of infection: a determinant of the severity of hepatitis C virus-related liver disease in renal transplant patients.

BACKGROUND: The aim of this study was to compare the clinical and histopathological course of HCV infection acquired before and during or after renal transplantation. METHODS: According to HCV status, 197 RT patients were divided into three groups. At the time of RT, anti-HCV antibody was positive in 47 patients (pre-RT HCV group). In 27 patients, in whom anti-HCV negative at the time of RT, anti-HCV and/or HCV RNA was found to be positive following an ALT elevation episode after RT (post-RT HCV group). Both anti-HCV and HCV RNA were negative at all times in remaining 123 patients (control group). RESULTS: Liver biopsy was performed in 31 of 47 patients in pre-RT and 24 of 27 in post-RT HCV group after RT. Duration of follow-up was similar in all groups with a mean of 7.1 +/- 4.0 yr. Ascites and encephalopathy were seen in only post-RT HCV group (22%). Histological grade (6.5 +/- 2.7 vs. 4.1 +/- 1.4) and stage (2.0 +/- 1.5 vs. 0.8 +/- 0.8) was significantly severe in post-RT HCV group (p < 0.01). Three patients died due to liver failure in post-RT HCV group. CONCLUSIONS: HCV infection acquired during or after RT shows a severe and rapidly progressive clinicopathological course, which is significantly different from pre-transplant anti-HCV positive patients.

Is "zero-hour" biopsy of the transplanted kidney risky?

"Zero-hour" renal allograft biopsy provides valuable diagnostic information for comparison to subsequent kidney material. However, the invasive nature of the biopsy procedure tends to limit its widespread use in many centers. We undertook this retrospective study to examine the rate and clinical importance of complications in our series of patients routinely undergoing zero-hour biopsies performed between 1994 and 2001. Two hundred thirty-six zero-hour biopsies included only one sample performed with a 14G needle from lower posterior part of kidney by using a manual tru-cut technique. Doppler ultrasonography was performed after first 5 days. An average of 34 +/- 19 glomeruli were obtained in the biopsies. The biopsy specimens were adequate for diagnosis in 77% of the procedures. Ten (4%) patients experienced complications of intraparenchymal arteriovenous fistula (n = 4), which regressed spontaneously; perirenal hematoma (n = 4); intraparenchymal hematoma (n = 2); and a minimal perirenal collection (n = 41). We conclude that zero-hour biopsy is a safe diagnostic method. The rate of complications is low, as well as generally mild and self-limiting.

Intima media thickness as a predictor of atherosclerosis in renal transplantation.

It has been reported that an increase in carotid artery intima-media thickness (IMT), a sign of early atherosclerosis, has a predictive value for future cardiovascular (CV) events. There are limited data about IMT measurements in renal transplant patients who display a high rate of CV mortality. In this study carotid artery IMT was measured by high resolution B-mode ultrasonography in 102 randomly selected RT patients to assess the relationship between IMT and CV disease and risk factors. A positive correlation was found between IMT and age, triglyceride level, and hematocrit. IMT was significantly higher among patients who were diabetic (0.68 +/- 0.27 vs 0.50 +/- 0.2) or had CV disease (0.88 +/- 0.28 vs 0.53 +/- 0.21). An increased IMT was associated with a longer duration of ESRD, higher lipid level, lower serum albumin, and presence of previous CMV disease. CV disease was more frequent among patients with increased IMT. Considering its relation to CV risk factors, it is concluded that the measurement of carotid artery IMT is an easy, reliable and non-invasive method to be used to assess atherosclerotic disease in renal transplant patients.

Does enalapril prevent peritoneal fibrosis induced by hypertonic (3.86%) peritoneal dialysis solution?

OBJECTIVE: Peritoneal fibrosis (PF) is one of the most serious causes of failure in continuous ambulatory peritoneal dialysis (PD). Although the underlying mechanism responsible for the genesis of PF is still unknown, transforming growth factor beta (TGFbeta1) has been shown to be associated with PF. Angiotensin converting enzyme inhibitors have been shown to prevent the stimulating effect of growth factors. The aim of the present study was to investigate the effect of enalapril on peritoneal function and morphology in a rat model of experimental PF. METHODS: Twenty-one albino Wistar rats were divided into three groups: (1) the control group (C) received 10 mL isotonic saline intraperitoneally (i.p.), (2) the dextrose (Dx) group 10 mL 3.86% dextrose PD solution i.p., and (3) the enalapril-treated group (ENA) 10 cc 3.86% dextrose PD solution i.p. plus 100 mg/L enalapril in drinking water. After 4 weeks, a 1-hour peritoneal equilibration test was performed with 20 mL 2.27% dextrose PD solution. Dialysate-to-plasma urea ratio (D/P urea), glucose reabsorption (D1/D0 glucose), ultrafiltration (UF) volume, and levels of dialysate protein, TGFbeta1, and cancer antigen 125 (CA125) were determined. The parietal peritoneum was evaluated histologically by light microscopy. RESULTS: Administration of enalapril resulted in preserved UF (-0.2 +/- 0.7 mL vs 1.7 +/- 0.3 mL, p < 0.05), protein loss (2.3 +/- 0.5 g/L vs 1.6 +/- 0.2 g/L, p > 0.05), and peritoneal thickness (77 +/- 7 microns vs 38 +/- 5 microns, p < 0.001). D/P urea increased significantly in the Dx group (p< 0.05). Both higher levels of TGFbeta1 (undetectable vs 298 +/- 43 pg/mL, p < 0.001) and lower levels of CA125 in dialysate effluent (0.94 +/- 0.5 U/L vs 0.11 +/- 0.1 U/L, p > 0.05) were determined in the Dx group. CONCLUSION: These findings show that peritoneal morphology and function tests were dramatically deranged in the Dx group. The same properties were partially preserved in the ENA group. The production of TGFbeta1 was significantly reduced but peritoneal thickness was not completely inhibited. In conclusion, by inhibiting the production of TGFbeta1, enalapril can preserve peritoneal histology, peritoneal function, and remodeling of mesothelial cells.

Strict volume control normalizes hypertension in peritoneal dialysis patients.

The aim of this study is to investigate whether normal blood pressure (BP) can be achieved in patients with hypertension on continuous ambulatory peritoneal dialysis (CAPD) therapy by strict volume control without the use of antihypertensive drugs. Of the 78 patients in our center, 47 persons had hypertension and/or were on antihypertensive drug therapy. After discontinuing these drugs, a strong dietary salt restriction was imposed by repeatedly explaining the need for it to patients and families. If this approach did not result in sufficient BP decrease, ultrafiltration (UF) was added by increased use of hypertonic (3.86% glucose) peritoneal dialysis solution. Cardiothoracic index (CTI) on the chest radiograph was also used as a measure of volume control. With salt restriction alone or combined with UF, body weight decreased by a mean of 2.8 +/- 0.5 kg, and BP decreased from a mean of 158.2 +/- 17.0/95.7 +/- 10.3 to 119.7 +/- 16.0/77.9 +/- 9.7 mm Hg in 37 patients, accompanied by a decrease in CTI from 48.0% +/- 5.6% to 42.9% +/- 4.5%. In 19 patients who had residual renal function, 24-hour urine volume decreased to 28% of the pretreatment volume, accompanied by a mean decrease in Kt/V urea from 2.06 +/- 0.5 to 1.85 +/- 0.4. In 7 of the remaining patients who did not respond to the applied treatment, BP decreased from 158.8 +/- 23.2/111.6 +/- 9.8 to 113.5 +/- 14.3/76.4 +/- 6.2 mm Hg after administration of an angiotensin-converting enzyme (ACE) inhibitor. Their CTI was 41.2% +/- 1.3%, indicating the absence of hypervolemia. In 3 patients, the desired results could not be reached because of noncompliance. Our findings show that normal BP can be achieved by severe salt restriction combined with increased UF in the majority of CAPD patients. This is accompanied by a decrease in CTI from upper limits into the normal range, but also by a decrease in residual renal function and Kt/V index. In most of the remaining patients, normal BP can be reached by the use of ACE inhibitors.

How can we standardize peritoneal thickness measurements in experimental studies in rats?

OBJECTIVE: The various methods of measuring peritoneal thickness in experimental studies in rats have yielded conflicting results. Also, no standard method exists to assess histologic findings in peritoneal morphology. We therefore undertook the present study to create a reproducible and standard method for assessing rat peritoneal histology in experimental studies. METHODS: Parietal peritoneal samples from 61 Wistar albino rats were used in the study. Excepting the skin, the whole abdominal wall from each rat was cut two-dimensionally (longitudinally and horizontally), fixed in formalin, and processed routinely for light microscopy. Slides were divided into two groups according to the direction of the inner abdominal muscle fibers in the sections. Longitudinal and horizontal sections of abdominal muscle were evaluated. For every section, one histopathology image was captured from a light microscope to an IBM-compatible computer. Peritoneal thickness (mean of the maximum and the minimum) and submesothelial area (SMA) were drawn on the image. A computer program then automatically performed measurements. Two different measurement methods were compared, based on the same sections. RESULTS: The mean peritoneal thickness was 91 +/- 8 microm in the longitudinal sections and 75 +/- 7 microm in the horizontal sections (p < 0.05). Measurements of the SMA were found to be 47,762 +/- 4,374 microm2 for the longitudinal sections and 40,389 +/- 3,631 microm2 for the horizontal sections (p < 0.05). In both types of sections, a positive correlation (96% for longitudinal and 90% for horizontal) was found between the SMA and the peritoneal thickness (p < 0.01). The SMA measurements correlated significantly with functional properties [ratio of the dialysate concentration of glucose initially and after a 1-hour dwell (D1/D0 glucose), ultrafiltration, and protein loss; p < 0.01]. CONCLUSION: Peritoneal thickness can be measured as a mean of the minimum and maximum values. That measurement strongly correlates with submesothelial area. Both types of sections can be used, but the horizontal and longitudinal sections show systematic differences. All samples in a study should be taken using the same section pattern, either longitudinal or horizontal.

Treatment of hypertension in dialysis patients by ultrafiltration: role of cardiac dilatation and time factor.

We retrospectively analyzed the blood pressure (BP) and cardiothoracic index (CTi) of 67 hemodialysis patients with hypertension who could be followed up for at least 8 months. A new treatment policy was adopted, aimed at strict volume control. Dietary salt restriction was strongly emphasized. Ultrafiltration (UF) was applied during regular dialysis sessions and sometimes in additional sessions, as long as BP and CTi remained at greater than normal values. All antihypertensive drugs were discontinued at the beginning of treatment. Average BP decreased from 173 +/- 17/102 +/- 9 to 139 +/- 18/86 +/- 11 mm Hg after 6 months and to 118 +/- 12/73 +/- 6 mm Hg after 36 months. Corresponding values for CTi were 52% +/- 4%, 47% +/- 3%, and 42% +/- 4%, respectively. Conventional relatively short dialysis (three times weekly for at least 4 hours) can achieve normal BPs with prolonged effort in most patients, whereas improvement in heart condition facilitates this.