Renal dopaminergic system activity in the rat remnant kidney
Institute of Pharmacology & Therapeutics, Faculty of Medicine, Porto, Portugal.
Nephron Exp Nephrol. 2005; 99(2): 46-55
BACKGROUND: Renal dopamine exerts natriuretic and diuretic effects by activating D1-like receptors. Uninephrectomy results in increased renal dopaminergic activity and dopamine-sensitive enhanced natriuresis. METHODS: The present study evaluated renal adaptations in sodium handling and the role of dopamine in rats submitted to (3/4) nephrectomy: right nephrectomy and excision of both poles of the left kidney ((3/4)nx rats). RESULTS: Two weeks after surgery the absolute urinary levels of dopamine were markedly reduced in (3/4)nx rats whereas the urinary dopamine excretion per % of residual nephrons was significantly increased in the remnant kidney of (3/4)nx rats. The V(max) values for renal aromatic L-amino acid decarboxylase, the enzyme responsible for the synthesis of renal dopamine, were decreased in (3/4)nx rats. Renal catechol-O-methyltransferase activity, the enzyme responsible for the methylation of dopamine, was increased in (3/4)nx rats whereas the renal activities of monoamine oxidases A and B did not differ between (3/4)nx and Sham animals. Volume expansion (5% body weight) resulted in similar natriuretic responses in (3/4)nx and Sham rats. During D1 antagonist administration (Sch-23390, 30 microg x h(-1) x kg(-1)) the natriuretic response to volume expansion was reduced in (3/4)nx rats more pronouncedly than in Sham animals. CONCLUSION: The decrease in absolute renal dopamine output in (3/4)nx rats is related with reduced renal synthesis and enhanced O-methylation of the amine. However, this is accompanied in (3/4)nx rats by increased renal dopamine excretion per residual nephrons and dopamine-sensitive enhanced natriuresis. Copyright (c) 2005 S. Karger AG, Basel.
PMID: 15627800 [PubMed - in process]
Salt sensitivity of blood pressure in patients with psoriasis on ciclosporin therapy
Department of Dermatology, Hospital S. Joao, Portugal.
Br J Dermatol. 2005; 152(4): 773-6
BACKGROUND: Hypertension is one of the main side-effects of long-term therapy with ciclosporin. However, the influence of salt intake on the 24-h mean blood pressure of patients with psoriasis treated with ciclosporin is not known. OBJECTIVES: To evaluate, in patients with psoriasis, the sodium sensitivity of the ciclosporin-induced rise in blood pressure. METHODS: The 24-h ambulatory blood pressure was evaluated in 13 patients with psoriasis (age range 20-57 years) in two phases, before (phase I) and after the completion of 4 months of therapy with ciclosporin 3 mg kg(-1) daily (phase II). In both phases, the patients were studied in conditions of low sodium (LS) intake followed by a high sodium (HS) diet.
RESULTS: Twenty-four-hour mean +/- SD blood pressure during LS and HS intake was, respectively, 86.3 +/- 1.6 mmHg and 85.5 +/- 1.8 mmHg during phase I, and 88.5 +/- 1.5 mmHg and 91.8 +/- 2.2 mmHg (P < 0.001 vs. phase I, HS; P < 0.05 vs. phase II, LS) during phase II. The median (interquartile range) sodium sensitivity index was greater during phase II than during phase I: - 0.0028 (- 0.0071 to 0.0009) vs. 0.0065 (- 0.0055 to 0.0258) (P < 0.02). The plasma levels and the daily urinary excretion of noradrenaline did not differ between phases I and II.
CONCLUSIONS: The ciclosporin-induced rise in blood pressure is sodium sensitive. It is also suggested that sympathetic activation is not involved in the pathogenesis of ciclosporin-induced rise in blood pressure.
PMID: 15840112 [PubMed - in process]
Longitudinal membrane function in functionally anuric patients treated with APD: data from EAPOS on the effects of glucose and icodextrin prescription
North Staffordshire Hospital, Stoke on Trent, UK; Charing Cross Hospital, London, UK. Simon.Davies1@compuserve.com
Kidney Int. 2005; 67(4): 1609-15
BACKGROUND: Peritoneal dialysis is associated with changes in membrane function that can lead eventually to ultrafiltration (UF) failure. Factors driving these changes are thought to include hypertonic glucose exposure, but previously reported associations are confounded by the presence of residual renal function. METHODS: Longitudinal membrane function (solute transport and UF capacity) were measured annually in a prospective cohort of 177 functionally anuric patients as part of the European Automated Peritoneal Dialysis Outcomes Study (EAPOS). Subgroup analysis was performed according to glucose exposure and icodextrin use at baseline.
RESULTS: The whole cohort experienced an increase in solute transport and reduction in UF capacity at 12 and 24 months that could not be explained by informative censoring. These changes were accelerated and more severe in patients using either 2.27% or 3.86% glucose, or those not using icodextrin at baseline. These differences could not be explained by age, comorbidity score, previous time spent on renal replacement, differential dropout from the study, peritonitis rates, or, by definition, residual renal function. Patients using icodextrin at baseline had worse membrane function and were more likely to be diabetic. There was an association between membrane function changes and achieved 24-hour ultrafiltration over the 2-year study period.
CONCLUSION: Anuric automated peritoneal dialysis (APD) patients experience significant detrimental changes in membrane function over a relatively short time period. Glucose appears to enhance these changes independent of residual renal function. Icodextrin use in these circumstances is associated with less deterioration in membrane function.
PMID: 15780118 [PubMed - indexed for MEDLINE]
A novel heterozygous missense mutation in the UMOD gene responsible for Familial Juvenile Hyperuricemic Nephropathy
KBMC Medical Genetics 2005; 6: 5
Familial Juvenile Hyperuricemic Nephropathy is an autosomal dominant nephropathy, characterized by decreased urate excretion and progressive interstitial nephritis. Mutations in the uromodulin coding UMOD gene have been found responsible for the disease in some families.
We here describe a novel heterozygous p.K307T mutation in an affected female with hyperuricemia, renal cysts and renal failure. The proband's only son is also affected and the mutation was found to segregate with the disease.
This mutation is the fourth reported in exon 5. Initial studies identified a mutation clustering in exon 4 and it has been recommended that sequencing this exon alone should be the first diagnostic test in patients with chronic interstitial nephritis with gout or hyperuricemia. However, regarding the increasing number of mutations being reported in exon 5, we now suggest that sequencing exon 5 should also be performed.
Bone Alkaline Phosphatase besides Intact Parathyroid Hormone in Hemodialysis Patients ? Any Advantage?
Hemodial – Centro de Hemodiálise de Vila Franca de Xira, Vila Franca de Xira , Portugal
Nephron Clin Pract 2005; 101: 122-127
Blunted renal dopaminergic system activity in puromycin aminonucleoside-induced nephrotic syndrome
Institute of Pharmacology and Therapeutics, Faculty of Medicine, 4200-319, Porto, Portugal.
Nephrol Dial Transplant. 2005; 21(2): 314-23
Background. A primary tubular sodium handling abnormality has been implicated in the edema formation of nephrotic syndrome. Dopamine synthesized by renal proximal tubules behaves as an endogenous natriuretic hormone by activating D1-like receptors as a paracrine/autocrine substance. Methods. We examined the time courses of the urinary excretion of sodium, protein and dopamine in puromycin aminonucleoside (PAN)-treated and control rats. The rats were sacrificed during greatest sodium retention (day 7) as well as during negative sodium balance (day 14) for the evaluation of renal aromatic L-amino acid decarboxylase (AADC) activity, the enzyme responsible for the synthesis of renal dopamine. Also, the influence of volume expansion (VE) and the effects of the D1-like agonist fenoldopam (10 microg/kg bw/min) on natriuresis and on proximal tubular Na(+),K(+)-ATPase activity were examined on day 7. Results. The daily urinary excretion of dopamine was decreased in PAN-treated rats, from day 5 and beyond. This was accompanied by a marked decrease in the renal AADC activity, on days 7 and 14. During VE, the fenoldopam-induced decrease in proximal tubular Na(+),K(+)-ATPase activity was more pronounced in PAN-treated rats than in controls. However, the urinary sodium excretion during fenoldopam infusion was markedly increased in control rats but was not altered in PAN-treated animals.
Conclusion. PAN nephrosis is associated with a blunted renal dopaminergic system activity which may contribute to enhance the proximal tubular Na(+),K(+)-ATPase activity. However, the lack of renal dopamine appears not to be related with the overall renal sodium retention in a state of proteinuria.
PMID: 16204272 [PubMed - as supplied by publisher]
Jejunal dopamine and Na,K+-ATPase activity in nephrotic syndrome
Institute of Pharmacology and Therapeutics, Faculty of Medicine, Porto, Portugal.
Am J Nephrol. 2005; 25(4): 382-92
BACKGROUND: The occurrence of complementary functions in sodium transport between the intestine and the kidney was suggested to occur when the renal function is immature or compromised and jejunal dopamine has been implicated in this renal-intestinal cross-talk. The jejunal sodium transport was not previously evaluated in the nephrotic syndrome. METHODS: We examined the jejunal Na(+),K(+)-ATPase activity and the role of dopamine in puromycin aminonucleoside (PAN) and HgCl(2)-induced nephrotic syndrome rat models.
RESULTS: In both nephrotic syndrome rat models, the jejunal Na(+),K(+)-ATPase activity was reduced during greatest sodium retention and ascites accumulation (PAN nephrosis, day 7; HgCl(2) nephrosis, day 14), whereas during enhanced sodium excretion and ascites mobilization the jejunal Na(+),K(+)-ATPase activity was increased in HgCl(2) nephrosis (day 21) and was similar to controls in PAN nephrosis (day 14). In both PAN- and HgCl(2)-induced nephrosis, the jejunal aromatic L-amino acid decarboxylase (AADC) activity, the enzyme responsible for the synthesis of jejunal dopamine, did not differ from controls. In addition, the jejunal Na(+),K(+)-ATPase activity was not sensitive to inhibition by dopamine (1 microM) in both experimental groups throughout the study.
CONCLUSIONS: In the nephrotic syndrome the jejunal Na(+),K(+)-ATPase activity may respond in a compensatory way to changes in extracellular volume, through dopamine-independent mechanisms. Copyright 2005 S. Karger AG, Basel.
PMID: 16088079 [PubMed - in process]
Sequential body composition analysis by bioimpedance early post-kidney transplantation
Nephrology Department, S Joao Hospital, Porto, Portugal.
Transpl Int. 2005; 18(5): 541-7
Summary Background: While chronic renal failure patients present disturbed body water composition, few studies have been done on its behavior following kidney grafting (Tx). We report the changes associated with a successful Tx on body composition evaluated by bioelectrical impedance analysis (BIA). Methods: Twelve Tx (seven males, five females) were studied. The BIA was assessed before Tx, at month 1 and at month 3 post-Tx. Total body water (TBW), extracellular water (ECW), intracellular water (ICW), Na:K exchange rate (Nae:Ke) and phase angle (PA) were studied. An healthy group and a HD group were evaluated three times in a year interval. Results: Comparing before Tx with month 1 post-Tx, TBW, ECW and Nae:Ke increased, while ICW and PA decreased significantly. Comparing month 1 with month 3 post-Tx, ECW decreased, while ICW and PA increased. On comparing month 1 post-Tx with the healthy group, Nae:Ke was greater and PA was lower at month 1. Conclusions: The BIA showed that the different body water compartments of Tx recipients quickly match the constitution of normal individuals, overcoming drug therapy side effects.
PMID: 15819802 [PubMed - in process]
Humoral immune response after kidney transplantation is enhanced by acute rejection and urological obstruction and is down-regulated by mycophenolate mofetil treatment
Unidade de Investigacao e Desenvolvimento de Nefrologia, Faculty of Medicine of University of Porto, Portugal. firstname.lastname@example.org
Transpl Int. 2005; 18(11): 1286-91
The anti-allograft immune response may have a cellular and a humoral component. Lymphocytotoxic antibodies (Ab) and anti-human leucocyte antigen (HLA) Ab present before kidney transplantation carry an enhanced risk of acute rejection. Current immunosuppressive drugs act predominantly upon the cellular immune pathway which may leave unopposed the humoral mechanisms of anti-allograft response. We studied the production of lymphocytotoxic Ab and anti-HLA Ab after kidney transplantation under different drug therapies. Two hundred and sixty-four consecutive kidney transplant recipients treated with different immunosuppressive drugs, either stable and or with previous acute rejection or acute urologic obstruction, entered this study. Lymphocytotoxic Ab and anti-HLA Ab were evaluated by complement-dependent cytotoxicity and by ELISA. Ab donor-specificity was determined by flow cytometry. Both lymphocytotoxic Ab and anti-HLA Ab were significantly increased in acute rejection whatever the immunosuppressive regimen and almost significantly in urologic obstruction treated with azathioprine (AZA) groups. The presence of antidonor-specific Ab was associated with a significantly higher rate of graft loss. Mycophenolate mofetil (MMF) therapy significantly down-regulated Ab synthesis in all patients groups when compared with AZA. The development of humoral antidonor response post-transplantation is associated with a dismal graft prognosis. This is the first report that acute urologic obstruction may be followed by unspecific lymphocytotoxic and anti-HLA Ab synthesis, surmising that a protracted obstruction may promote renal fibrosis through antibody mediation. The significant down-regulation of the humoral response by MMF when compared with AZA may herald a lower risk to mount a chronic rejection process.
PMID: 16221160 [PubMed - in process]
Nutritional status and body composition evolution in early post-renal transplantation: is there a female advantage?
Nephrology Department, S Joao Hospital, Porto, Portugal. email@example.com
Transplant Proc. 2005; 37(6): 2765-70
OBJECTIVE: Chronic renal failure is associated with metabolic derangements, affecting proteins, amino acids, and lipids. Usually these patients follow a restricted diet. Kidney transplant patients enjoy a recovery of renal function, but their therapeutics may entail significant changes in general metabolism. We compare the anthropometric results during the first 3 months after successful transplant for male and female patients versus a healthy group.
METHODS: Eighteen patients (11 men and 7 women) were studied. Anthropometry was assessed before and at month 1 and month 3 posttransplant including body weight (Wt), body mass index (BMI), triceps (TSF), biceps (BSF), subscapular (SCSF), and suprailiac skinfolds (SISF), midarm circumference (MAC), midarm muscle circumference (MAMC), corrected arm muscle area (CT.AMA), total body muscle mass (MM), body density (D), fat mass (FM), and fat-free mass (FFM). The healthy group was evaluated three times in the first year. RESULTS: Pretransplant men showed lower Wt, BMI, TSF, BSF, SCSF, SISF, MAC, MAMC, CT.AMA, MM, FM and FFM than controls, while women displayed no differences from controls. By the third month, men showed only a partial recovery and women higher TSF and SCSF than controls.
CONCLUSIONS: Uremic men before transplant displayed undernutrition indices. During the first 3 months posttransplant men showed an incomplete recovery of anthropometric parameters. Quite differently, women started close to normal and had significantly increased body weight and fat content posttransplant. We suggest that nutritional requirements post-kidney grafting may be significantly different among male compared to female patients.
PMID: 16182805 [PubMed - in process]
Impact of homocysteinemia on long-term renal transplant survival
Department of Nephrology, Santo Antonio Hospital, Porto, Portugal. firstname.lastname@example.org
Transplant Proc. 2005; 37(6): 2784-8
AIM: We prospectively followed a cohort of 202 renal transplant recipients for 5 years to examine the impact of fasting homocysteinemia on long-term patient and renal allograft survival.
METHODS: Cox proportional hazards regression analysis was used to identify independent predictors of all-cause mortality and graft loss. RESULTS: Hyperhomocysteinemia (tHcy >15 micromol/L) was present in 48.7% of the 202 patients, predominantly among men (55.8%) as opposed to women (37.1%). At the end of the follow-up period, 13 (6.4%) patients had died including 10 from cardiovascular disease, and 23 had (11.4%) had lost their grafts. Patient death with a functioning allograft was the most prevalent cause of graft loss (13 recipients). Levels of tHcy were higher among patients who died than among survivors (median 23.9 vs 14.3 micromol/L; P = .005). Median tHcy concentration was also higher among the patients who had lost their allografts than those who did not (median 19.0 vs 14.1 micromol/L; P = .001). In a Cox regression model including gender, serum creatinine concentration, transplant duration, traditional cardiovascular risk factors, and associated conditions, such as past cardiovascular disease, only tHcy concentration (ln) (HR = 5.50; 95% CI, 1.56 to 19.36; P = .008) and age at transplantation (HR = 1.07; 95% CI, 1.02 to 1.13; P = .01) were independent predictors of patient survival. After censoring data for patient death, tHcy concentration was not a risk factor for graft loss.
CONCLUSIONS: This prospective study shows that tHcy concentration is a significant predictor of mortality, but not of graft loss, after censoring data for patient death.
PMID: 16182810 [PubMed - in process]
Conversion to sirolimus in a population of kidney and kidney-pancreas transplant recipients
Department of Nephrology, Hospital Geral de Santo Antonio, Oporto, Portugal.
Transplant Proc. 2005; 37(6): 2777-80
INTRODUCTION: Calcineurin inhibitors (CI) are associated with nephrotoxicity that might reduce long-term graft survival. We report our experience with sirolimus (SRL) conversion among a population of kidney and kidney pancreas transplant recipients. METHODS: Thirty transplant recipients (6 women, 24 men; age 41 +/- 10.5 years old) were converted to SRL therapy at 25.97 +/- 32.5 months after transplantation. Indications for conversion were: intolerance to mycophenolate mofetil (n = 13), diabetes mellitus (n = 3), CI nephrotoxicity (n = 11), CI nephrotoxicity with chronic allograft rejection (n = 2), and side effects of azathioprine (n = 1). Follow-up after conversion is 3 to 45 months.
RESULTS: No significant changes were observed in the 3 months postconversion in renal function, hematological profile, and mean arterial blood pressure. In contrast there was a significant increase in cholesterol values (pre: 198.7 +/- 49.4, versus post 221.2 +/- 60.8, P = .018). At a follow-up of 15.2 +/- 9.9 months after conversion two patients (6.7%) died with functioning allograft (one because of infection and one to myocardial infarct) three kidney allografts (10.7%) have been lost: two chronic rejection; one infection. In two patients SRL therapy was discontinued (one infection, one refractory edema). Neither significant change in renal function nor episodes of acute rejection were observed.
CONCLUSIONS: Conversion to SRL was safe. There was no deterioration in renal function nor episodes of acute rejection. There was a significant increase in cholesterol values after conversion. The size of the sample and the time of follow-up may have determined our results.
PMID: 16182808 [PubMed - in process]
Immunosuppression with antithymocyte globulin in renal transplantation: better long-term graft survival.
Nephrology Department, Hospital Santo Antonio, Porto, Portugal. email@example.com
Transplant Proc. 2005; 37(6): 2755-8
We analyzed the impact of antithymocyte globulin (ATG) in renal transplantation. We retrospectively studied 1217 recipients performed from July 83 to December 03. ATG-Fresenius-S (ATG-F) was used for induction therapy in 492 patients (40.4%; group I) and compared with group II, 725 patients (59.6%), without antilymphocyte induction. Groups were comparable in terms of recipient gender and race distribution; time on dialysis; cause of renal disease; number of human leukocyte antigen (HLA) mismatches; donor age, gender, and creatinine; and cold ischemia time. Patients with ATG-F were younger (35.8 +/- 13.8 vs 38.9 +/- 12.5 years, P < .001), more frequently hypersensitized (10% vs 3%, P < .001), and had more second transplants (15.7% vs 5.8%, P < .001). The incidence of acute rejection episodes was lower among ATG-F patients (23.6% vs 32.1%, P = .004). Admission time and incidence of delayed graft function (DGF) were similar in the two groups. Graft survival at 1, 5, 10, and 15 years was 88.9%, 80.7%, 71.3%, and 64.9% in group I and 86.4%, 77.4%, 60.7%, and 48.4% in group II (P = .003). The difference in patient survival over the same follow-up did not reach statistical significance. Multivariate analysis showed that the risk of graft failure was higher for those who did not receive ATG-F (HR = 1.51; 95% CI, 1.14 to 2.00; P = .004). Donor age and DGF were also independent predictors of graft failure. Our results showed a better long-term graft survival among patients who received ATG-F, despite their higher immunological risk. The absence of induction with ATG-F, donor age, and DGF were independent risk factors for graft failure.
PMID: 16182802 [PubMed - in process]
Evaluation of pre-implantation kidney biopsies: comparison of Banff criteria to a morphometric approach
Department of Nephrology, Hospital Universitari de Bellvitge, Barcelona, Spain.
Kidney Int. 2005 Apr;67(4):1595-600.
BACKGROUND: Donor glomerulosclerosis, interstitial fibrosis, and fibrous intimal thickening correlate with graft outcome. We evaluate chronic lesions in donor biopsies according to Banff criteria and with a morphometric technique to ascertain their predictive value on graft outcome.
METHODS: We evaluated 77 cadaveric donor biopsies according to Banff criteria. Glomerulosclerosis was expressed as the percentage of global sclerotic glomeruli. The following morphometric parameters were obtained: cortical interstitial volume fraction (Vvint/c), cortical glomerular volume fraction (Vvglom/c), mean glomerular volume (Vg), mean and maximal intimal arterial volume fraction (Vvintima/art), and Vvintima/art of the largest artery. We evaluated the correlation of histologic lesions with delayed graft function, 3 months' glomerular filtration rate (GFR), and death-censored graft survival. RESULTS: Multivariate logistic regression showed that delayed graft function was associated with cv score [relative risk (RR) 4.2 and 95% CI 1.1 to 16.0) and glomerulosclerosis (RR 1.06 and 95% CI 1.01 to 1.13). Stepwise regression showed that Vvint/c and glomerulosclerosis were independent predictors of 3 months' GFR (R= 0.62, P= 0.0001). Repeated analysis not considering morphometric parameters showed that glomerulosclerosis, cv score and ci score were independent predictors of 3 months' GFR (R= 0.64, P= 0.0001). A donor chronic damage score was generated considering glomerulosclerosis, cv score and ci score. This score after adjusting for clinical variables was associated with 3 months' GFR (R= 0.71, P < 0.0001) and death-censored graft survival (RR 2.2 and 95% CI 1.3 to 3.7).
CONCLUSION: Combined evaluation of donor glomerulosclerosis, chronic vascular and interstitial damage according to Banff criteria allows a precise prediction of graft outcome. Morphometric evaluation of donor biopsies does not improve the predictive value of semiquantitative grading.
PMID: 15780116 [PubMed - indexed for MEDLINE]