Severe vascular calcification and tumoral calcinosis in a family with hyperphosphatemia: a fibroblast growth factor 23 mutation identified by exome sequencing.

BACKGROUND: Tumoral calcinosis is an autosomal recessive disorder characterized by ectopic calcification and hyperphosphatemia. METHODS: We describe a family with tumoral calcinosis requiring amputations. The predominant metabolic anomaly identified in three affected family members was hyperphosphatemia. Biochemical and phenotypic analysis of 13 kindred members, together with exome analysis of 6 members, was performed. RESULTS: We identified a novel Q67K mutation in fibroblast growth factor 23 (FGF23), segregating with a null (deletion) allele on the other FGF23 homologue in three affected members. Affected siblings had high circulating plasma C-terminal FGF23 levels, but undetectable intact FGF23 or N-terminal FGF23, leading to loss of FGF23 function. CONCLUSIONS: This suggests that in human, as in experimental models, severe prolonged hyperphosphatemia may be sufficient to produce bone differentiation proteins in vascular cells, and vascular calcification severe enough to require amputation. Genetic modifiers may contribute to the phenotypic variation within and between families.

Patient and technique survival in continuous ambulatory peritoneal dialysis in a single center of the west of Mexico.

INTRODUCTION: In Mexico, CAPD survival has been analyzed in few studies from the center of the country. However, there are concerns that such results may not represent what occurs in other province centers of our country, particularly in our geographical area. AIM: To evaluate the patient and technique survival on CAPD of a single center of the west of Mexico, and compare them with other reported series. DESIGN: Retrospective cohort study. SETTING: Tertiary care, teaching hospital located in Guadalajara, Jalisco. PATIENTS: Patients from our CAPD program (1999-2002) were retrospectively studied. Interventions. Clinical and biochemical variables at the start of dialysis and at the end of the follow-up were recorded and considered in the analysis of risk factors. MAIN OUTCOME MEASURES: Endpoints were patient (alive, dead or lost to follow-up) and technique status at the end of the study (June 2002). RESULTS: 49 patients were included. Mean patient survival (+/- SE) was 3.32 +/- 0.22 years (CI 95%: 2.9-3.8 years). Patients in the present study were younger (39 +/- 17yrs), had larger body surface area (1.72 +/- 0.22 m2), lower hematocrit (25.4 +/- 5.2%), albumin (2.6 +/- 0.6g/dL), and cholesterol (173 +/- 44 mg/dL), and higher urea (300 +/- 93 mg/dL) and creatinine (14.9 +/- 5.6 mg/ dL) than those in other Mexican series. In univariate analysis, the following variables were associated (p < 0.05) to mortality: pre-dialysis age and creatinine clearance, and serum albumin and cholesterol at the end of follow-up. In multivariate analysis, only pre-dialysis creatinine clearance (RR 0.66, p = 0.03) and age (RR 1.08, p = 0.005) significantly predicted mortality. Mean technique survival was 2.83 +/- 0.24 years (CI 95%: 2.4-3.3). Pre-dialysis age (p < 0.05), peritonitis rate (p < 0.05), and serum phosphorus at the end of follow-up (p < 0.05) were associated with technique failure in univariate analysis, while in multivariate analysis, only pre-dialysis age (RR 1.07, p = 0.001) and peritonitis rate (RR 481, p < 0.0001) were technique failure predictors. CONCLUSIONS: Patients from this single center of the west of Mexico were younger, had higher body surface area and initiated peritoneal dialysis with a more deteriorated general status than patients reported in other Mexican series; in spite of the latter, patient and technique survival were not different. In our setting, pre-dialysis older age and lower CrCl significantly predicted mortality, while older predialysis age and higher peritonitis rate predicted technique failure.

End-stage renal disease and hepatitis C infection: comparison of alanine aminotransferase levels and liver histology in patients with and without renal damage.

BACKGROUND AND AIM: To what extent the serum levels of alanine aminotransferase (ALT) are related to histological characteristics of liver damage caused by hepatitis C virus (HCV) infection among patients with end-stage renal disease (ESRD) remains unclear. METHODS: Patients with a positive anti-HCV antibody titer confirmed by supplemental tests were evaluated by liver biopsy. We compared ALT levels in patients with and without renal damage, with similar histological grades and stages of inflammation and fibrosis. Results: Patients were divided into two groups: patients with ESRD (n = 25) and patients without ESRD renal damage (n = 39). RESULTS: The ALT level was 42.1 +/- 24.3 IU/L for the ESRD group, compared with 109.9 +/- 55.8 IU/L for the non-ESRD group (P < 0.001). Liver inflammation (modified Knodell grade) was 4.0 +/- 2.1 in the ESRD group versus 5.2 +/- 2.4 in the non- ESRD group; fibrosis (6-point scale) was 1.1 +/- 1.2 versus 1.7 +/- 1.5, respectively. CONCLUSIONS: Despite histological evidence of liver inflammation, ALT levels in the ESRD group were normal, while ALT levels were significantly higher in the non-ESRD group with similar levels of liver inflammation. In conclusion, ALT levels are not a useful indicator of HCV infection in patients with ESRD and liver biopsies should be recommended for kidney transplant candidates.

Drug-related hepatotoxicity in a renal transplant recipient with long-term survival and hepatitis C.

Drug-related hepatotoxicity is more common in renal transplant (RT) recipients with chronic liver disease because drug metabolism is not as efficient in these individuals. We describe a long-term survivor (30 years) of renal transplantation with hepatitis C virus (HCV) and drug-related hepatotoxicity. Our patient, a 26-year-old male, developed uremic syndrome in May 1976 and received a renal allograft from a related, living donor with an identical human leukocyte antigen genotype in August 1976. Maintenance immunosuppression treatment consisted of azathioprine (AZA) and prednisone. In 1993, the patient tested negative for HCV antibody v1.0 (anti-HCV). In 2000, the patient had elevated aminotransferases, which was attributed to pravastatin treatment. Remission of this abnormality was achieved once pravastatin was discontinued. In 2003, the patient again exhibited elevated levels of aminotransferases and AZA-related hepatotoxicity was suspected; therefore, AZA was discontinued and treatment with mycophenolate mofetil was initiated, which led to normal aminotransferase levels. The patient tested positive for anti-HCV v3.0 and HCV RNA and a liver biopsy showed chronic hepatitis with moderate activity. Currently, the patient's renal transplant and liver are functional. In conclusion, hepatotoxic drugs should be used with caution in renal transplant recipients and close monitoring of liver function in patients with chronic viral hepatitis is crucial.

Risk factors and incidence of posttransplant diabetes mellitus in Mexican kidney recipients.

BACKGROUND: Many risk factors are associated with the development of posttransplant diabetes mellitus (PTDM), which has adverse effects on graft and patient survival. We report the incidence and risk factors associated with the development of PTDM in Mexican kidney recipients. METHODS: In a retrospective cohort study, we included kidney transplants performed between January 1, 1994 and December 31, 2000; all patients were followed up for at least 1 year posttransplantation. PTDM was defined as fasting blood glucose >126 mg/dL on at least two occasions. Statistical analysis included estimation of crude relative risk (RR) with 95% confidence intervals (CI). Adjusted RR and 95% CI by logistic regression were used. RESULTS: We studied 522 kidney recipients. Fifty three (10.1%) cases of PTDM were identified in this cohort. Cumulative dosage of prednisone (PDN) >13 g (RR 7.6, 95% CI 1.5-16.3 p <0.0001) and the presence of >or=1 acute rejection episodes (RR 3.7, 95% CI 1.2-11.6 p <0.001 were independent risk factors associated with the development of PTDM. Obesity (RR 2.6, 95% CI 0.8-8.7, p = 0.083) and age range of 40-49 years (RR 2.0; 95% CI 0.6-7.2, p = 0.093) were identified as marginal risk factors. CONCLUSIONS: The incidence of PTDM in kidney recipients was 10.1% in our population. Cumulative PDN dosage and presence of >or=1 acute rejection episodes were independent risk factors for the development of PTDM. These results are consistent with prior studies of the diabetogenic effect of the PDN. The relationship between acute rejection and PTDM deserves further investigation in order to learn more about the role that inflammatory mechanisms may play in this association.

Can the inflammation markers of patients with high peritoneal permeability on continuous ambulatory peritoneal dialysis be reduced on nocturnal intermittent peritoneal dialysis?

BACKGROUND: Patients with high peritoneal permeability have the greatest degree of inflammation on continuous ambulatory peritoneal dialysis (CAPD), which may be associated with their higher mortality. Nocturnal intermittent peritoneal dialysis (NIPD; "dry day") may decrease inflammation by reducing the contact between dialysate and peritoneum and/or providing better fluid overload control. Therefore, the aims of this study were to determine and compare serum and dialysate concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) of patients with high or high-average peritoneal transport on CAPD, changed to NIPD, and ultimately to continuous cyclic peritoneal dialysis (CCPD). METHODS: Crossover clinical trial in 11 randomly selected patients. All subjects had been on CAPD and were changed to NIPD, and ultimately to CCPD (6.4 +/- 3.1 months after initiation of study). All patients used glucose-based dialysate. Evaluations of clinical and biochemical parameters, dialysis adequacy, and serum and dialysis inflammation markers were performed at baseline on CAPD, 7 - 14 days after changing to NIPD, 7 - 14 days after switching to CCPD, and after 1 year of follow-up. All patients used only 1.5% glucose dialysate during evaluation days. CRP was determined by nephelometry, and IL-6 and TNF-alpha by ELISA. RESULTS: Seven patients were high transporters and 4 high average. Ultrafiltration increased (p < 0.05) when patients changed from CAPD [0.38 L (-0.3 - 1.1 L)] to NIPD [2.64 L (0.7 - 4.7 L)]; it then decreased on CCPD [0.88 L (0.4 - 1.3 L) and at the end of study [0.65 L (0.3 - 1.0 L)]. This better fluid overload control was accompanied by decreased weight and systolic and diastolic blood pressure when patients changed from CAPD (89 +/- 13 kg, 160 +/- 23 and 97 +/-9 mmHg, respectively) to NIPD (86 +/- 17 kg, 145 +/- 14 and 86 +/- 9 mmHg, respectively), and increased weight and systolic and diastolic blood pressure on CCPD (85 +/- 15 kg, 143 +/-23 and 88 +/- 14 mmHg, respectively) and at the end of follow-up (87 +/- 16 kg, 155 +/- 24 and 89 +/- 12 mmHg, respectively). Median serum CRP decreased (p = 0.03), from 3.8 (1.6 - 8.5) mg/L on CAPD to 1.0 (0.4 - 4.4) mg/L on NIPD, but increased on CCPD [1.8 (1.3 - 21) mg/L] and at the end of the study [3.2 (0.3 - 8.2) mg/L]. Dialysate CRP decreased nonsignificantly, from 0.10 (0 - 0.5) mg/L on CAPD to 0 (0 - 0.03) mg/L on NIPD, to 0.01 (0 - 0.08) mg/L on CCPD, and to 0 (0 - 0) mg/L at final evaluation. Serum TNF-alpha concentration decreased, from 0.14 (0.04 - 0.6) pg/mL on CAPD to 0.01 (0 - 0.08) pg/mL on NIPD, and then increased to 0.06 (0 - 0.4) pg/mL on CCPD and to 0.11 (0 - 0.2) pg/mL at the end of the study; whereas dialysate TNF-alpha decreased, from 0.08 (0.03 - 0.2) pg/mL on CAPD to 0.04 (0 - 0.2) pg/mL on NIPD, and to 0 (0 - 0) pg/mL and 0 (0 - 0.05) pg/mL on CCPD and final evaluation respectively. Serum IL-6 decreased (p = 0.07), from 2.5 (2.0 - 4.2) pg/mL on CAPD to 1.0 (0.7 - 2.0) pg/mL on NIPD, and to 1.0 (0.8 - 2.9) pg/mL on CCPD and 1.0 (0.5 - 9.8) pg/mL at the end of the study; whereas dialysate levels remained similar on CAPD [8.0 (3.7 - 13) pg/mL] and NIPD [7.8 (5.1 - 23) pg/mL], and increased on CCPD [11.2 (9.5 - 19) pg/mL] and at final evaluation [11.2 (8.3 - 15) pg/mL]. CONCLUSIONS: NIPD significantly decreased serum CRP and displayed a trend to decrease TNF-alpha and IL-6 serum concentrations compared with CAPD; whereas CCPD tended to reverse these effects. These results did not appear to be due to decreased local peritoneal inflammation, but they could be associated with better control of fluid overload on NIPD. Thus, NIPD, as Long as the residual renal function allows it, may be useful in reducing the systemic inflammation of patients with high peritoneal membrane permeability.

The kidney transplant experience at Hospital de Especialidades, Centro Médico Nacional de Occidente, IMSS, Guadalajara México.

A total of 1,356 kidney transplants has been performed in the Hospital de Especialidades del Centro Médico Nacional de Occidente, IMSS, in Guadalajara Mexico, including 935 in the past 8 years. This represents an important increase of this activity in our country. Of the total transplants, 1,218 (90%) were from living donors and only 138 (10%) were from cadaveric donors, a number that we hope to increase. Most recipients were young adults, with an average age of 31 years old. The overall one-year graft and patient survival rates for living-donor kidney recipients were 90% and 82%, and for cadaveric kidney recipients they were 80% and 70%, respectively. Acute rejections occurred in 17% and chronic allograft nephropathy was diagnosed in 7% of our kidney transplant recipients. The main cause of patient death was infection, frequently invasive CMV. Cardiovascular complications were a relatively infrequent cause of death as has been seen in other international series. Hepatitis B and C have been widley studied. Hepatitis C is the most prevalent viral infection in our population. Both living and cadaveric donors in our series were young, which may explain the good results. We have had very few complications among living donors and no mortality. Two donors developed chronic renal insufficiency after the kidney donation (0.001%). This excellent safety record reflects the experience of our team. We hope to increase the number of cadaveric transplant donors with the renewed interest in enlarging the transplantation programs in Mexico while maintaining our high percentage of living donors in order to benefit more patients.

Risk factors for long-term graft loss in kidney transplantation: experience of a Mexican single-center.

BACKGROUND/AIM: There is not enough information regarding risk factors for renal graft loss in Mexico and Latin America. The aim of this study was to analyze risk factors associated with graft loss in our renal transplant (RT) population. METHODS: Clinical records of 326 patients with a first RT performed between August/76 and June/99 were reviewed. Clinical and laboratory variables were recorded, as well as the final patient and renal function status. STATISTICAL ANALYSIS: Survival analysis by Kaplan-Meier method; mortality risk by multivariate Cox's proportional hazard model. RESULTS: At the end of the study, 275 patients were alive, 30 were dead, 21 lost to follow-up; 65 patients (20%) had reinitiated dialysis. Patient survival at 1, 3, 5, 8, and 10 years was 92%, 86%, 81%, 77%, and 77%, respectively. Graft survival at 1, 3, 5, 8, and 10 years was 87%, 73%, 64%, 50%, and 47%, respectively. In the univariate analysis, the following were significantly associated (p < 0.05) with graft loss: acute rejection episodes, cadaveric donors, and HLA haplotype mismatches. In the multivariate analysis, only acute rejection (RR 2.12, p = 0.002) and a lower HLA haplotype matching (RR 0.37, p = 0.002) predicted graft loss. CONCLUSIONS: In Mexican population, graft survival was similar to the reported in developed countries. The main risk factors for long-term graft failure were acute rejection and HLA haplotype mismatching.

Evaluación de la función sexual y la fertilidad en pacientes con insuficiencia renal crónica tratados con hemodiálisis / Evaluation of sexual function and fertility in patients with chronic renal failure treated with hemodyalisis

Se evaluaron la función sexual y la fertilidad en 10 varones con insuficiencia renal crónica que se encontraban en tratamiento de hemodiálisis. La edad promedio de los pacientes fue de 30.9 años. La función sexual se valoró de manera subjetiva mediante una encuesta, y la fertilidad mediante tres espermatobioscopias y determinaciones de los niveles hormonales de LH, FSH, testosterona y prolactina. Se evaluaron también la función sexual y la fertilidad mediante la misma encuesta y tres espermatobioscopias, en un grupo testigo de 10 pacientes, para ser más objetivos en la valoración de los pacientes en estudio. Cinco pacientes se clasificaron como oligoastenozoospérmico, dos como oligozoospérmicos y tres como azoospérmicos. El índice sexual fue aceptable en la mayoría de los pacientes. El tiempo de evolución de la insuficiencia renal crónica fue de 37.9 meses. En conclusión, únicamente fecundos, con valores mínimos aceptables de espermatozoides por mililitro

Valoración comparativa del efecto antihipertensivo y metabólico de la combinación de hidroclorotiacida y amilorida, y de la clortalidona sola y con sales de potasio en pacientes con hipertensión arterial esencial / Antihypertesive and metabolic effect of hidrochlorothiazide-amiloride combination and chlorthalidone alone and with potassium salts in patients with essential hypertension

En 20 pacientes con hipertensión arterial esencial leve a moderada se valoró en forma comparativa el efecto antihipertensivo y metabólico de una combinación de 50 mg de hidroclorotiacida con 5 mg de amilorida con el obtenido tras la administración de clorotalidona sola y agregado sales de potasio por vía oral. Cada grupo se formó de 10 enfermos que recibieron indistintamente uno de los medicamentos durante tres meses. Al final del estudio se observó una disminución similar en la tensión arterial media en ambos grupos, con promedio de 25 mm Hg. Sin embargo, los pacientes que recibieron clorotalidona desarrollaron alcalosis y disminución sérica (4.6 + 0.1 a 3.5 + 0.1 mEg/L, p 0.01) e intraglobular de potasio (98 + 1 a 86 + 1.1 mEq/L, p 0.001). La administración oral de sales de potasio sólo originó incremento en la eliminación renal del electrólito, sin modificación del potasio en el suero o en el eritrocito. Los pacientes que recibieron hidroclorotiacida más amilorida no mostraron alteración electrolítica, lo que pone de manifiesto la eficiencia de la amilorida para prevenir esos efectos indeseables de los diuréticos tiacídicos