Survival Benefit From Kidney Transplantation Using Kidneys From Deceased Donors Aged ≥75 Years: A Time-Dependent Analysis.

Patients with end-stage renal disease have longer survival after kidney transplantation than they would by remaining on dialysis; however, outcome with kidneys from donors aged ≥75 years and the survival of recipients of these organs compared with their dialysis counterparts with the same probability of obtaining an organ is unknown. In a longitudinal mortality study, 2040 patients on dialysis were placed on a waiting list, and 389 of them received a first transplant from a deceased donor aged ≥75 years. The adjusted risk of death and survival were calculated by non-proportional hazards analysis with being transplanted as a time-dependent effect. Projected years of life since placement on the waiting list was almost twofold higher for transplanted patients. Nonproportional adjusted risk of death after transplantation was 0.44 (95% confidence interval [CI] 0.61-0.32; p < 0.001) in comparison with those that remained on dialysis. Stratifying by age, adjusted hazard ratios for death were 0.17 (95% CI 0.47-0.06; p = 0.001) for those aged <65 years, 0.56 (95% CI 0.92-0.34; p = 0.022) for those aged 65-69 years and 0.82 (95% CI 1.28-0.52; p = 0.389) for those aged ≥70 years. Although kidney transplantation from elderly deceased donors is associated with reduced graft survival, transplanted patients have lower mortality than those remaining on dialysis.

De novo kidney transplant recipients need higher doses of Advagraf compared with Prograf to get therapeutic levels.

INTRODUCTION: Advagraf is a new modified-release once-daily formulation of tacrolimus with a similar efficacy and safety profile to twice-daily tacrolimus (Prograf) according to clinical trials. Few data are published about its use in clinical practice, outside of sponsored clinical trials. We compared efficacy and basic pharmacokinetics of once-daily and twice-daily tacrolimus in de novo renal transplantation. METHODS: The Advagraf group included 26 de novo renal cases who had received initial immunosuppression with once-daily tacrolimus (0.2 mg/kg from day 1 posttransplantation) combined with mycophenolic acid, steroids, and anti-CD25 monoclonal antibodies (2 doses). We compared them with a Prograf group of 26 transplants performed immediately before, who received equivalent immunosuppression with twice-daily tacrolimus (0.2 mg/kg from day 1). RESULTS: We did not observe significant differences between groups in demographics, efficacy, and basic pharmacokinetics, namely, tacrolimus trough levels at 7, 15, 30, 60, or 90 days. We found that recipients on Advagraf needed significantly higher tacrolimus doses per kg up to 6 months post-transplantation than those on Prograf: 0.16 vs 0.11; 0.14 vs 0.08; and 0.12 vs 0.08 mg/kg at 1, 3, and 6 months. No patient suffered severe liver dysfunction. There were no differences between groups in the administration of drugs interacting with CYP3A4 or prokinetics, which could alter tacrolimus pharmacokinetics. CONCLUSIONS: Among de novo renal cases, the new once-daily formulation of tacrolimus offered a similar short-term efficacy profile as the twice-daily tacrolimus. But it was necessary to use up to a 50% higher dose of Advagraf than Prograf to achieve similar trough levels during the first 6 months.

Endothelial progenitor cells are reduced in refractory hypertension.

Circulating endothelial progenitor cells (EPCs) play a key role in the maintenance of endothelial homoeostasis and promote vascular repair. They may also be of predictive value for cardiovascular events. Reduced EPC number and functional activity have been associated with several cardiovascular risk factors, but their relationship with hypertension remains unclear. The objective of this study was to investigate if number and function of circulating EPCs are reduced in patients with refractory hypertension (RHT). Circulating EPCs (CD34+ CD133+/CD45+) were isolated from peripheral blood by flow cytometry in 39 RHT and 30 normotensive controls. EPC number was also determined in vitro after 7 days in culture. After age adjustment, EPC concentration was significantly reduced in RHT as compared with controls (mean (95% CI), 33.8 (18.1-49.6) vs 69.1 (50.7-87.5) EPCs per 10(5) peripheral mononuclear cells (MNCs), respectively; P=0.014). After in vitro culture, EPCs were also reduced in patients as compared with controls (mean (95% CI), 142.3 (49.5-235.0) vs 611.0 (480.2-741.8) EPCs per field, respectively, P<0.001). In multiple linear regression analysis, circulating EPCs were significantly reduced by 56.3% in RHT as compared with control (P=0.006), independently of all other known risk factors. Moreover, RHT had a high independent predictive value for lower EPC proliferation. The number of EPCs per field was reduced by 76.7% in RHT with respect to controls (P<0.001). In summary, the number of circulating EPCs after culture is reduced in patients with RHT, which may be related to the increased rate of endothelial dysfunction, atherosclerotic disease and cardiovascular events observed in this population.

ACE2 inhibition worsens glomerular injury in association with increased ACE expression in streptozotocin-induced diabetic mice.

Angiotensin converting enzyme 2 (ACE2) is localized to the glomerular epithelial cells. Since ACE2 promotes the degradation of angiotensin II, a decrease in ACE2 activity could lead to the development of glomerular injury. We gave a specific ACE2 inhibitor, MLN-4760, for 4 weeks to mice rendered diabetic with streptozotocin. The urinary albumin/creatinine ratio was increased along with expansion of the glomerular matrix in diabetic mice treated with the inhibitor compared to the vehicle-treated mice. Glomerular staining of ACE was increased in the diabetic group and was further significantly increased in the diabetic group treated with MLN-4760. In renal vessels, ACE expression was also increased in the diabetic mice and, again, further increased in those diabetic mice treated with the ACE2 inhibitor. Our study shows that chronic pharmacologic ACE2 inhibition worsens glomerular injury in streptozotocin-induced diabetic mice in association with increased ACE expression.

Dynamics of infestation of cattle and pasture by gastrointestinal nematodes in an Atlantic temperate environment.

The objective of the present study was to determine the dynamics of infestation of cattle and pasture by gastrointestinal nematodes in a mild humid environment in northwestern Spain. For this, infestation of pasture by free-living stages (L3), dynamics of faecal egg output, blood pepsinogen levels and worm burden in slaughtered animals were quantified. The results showed a high degree of annual variability, which was dependent on weather conditions. The seasons were clearly defined in the study area, with mild humid winters and relatively dry summers registered throughout the years of the study. Infestation of pasture by larvae varied from year to year, peaking during August in the first year, between August and December in the second year, and during October in the third year. The annual variation was mainly due to weather conditions, particularly the amount of rain in summer. The patterns of faecal egg output were similar in the first and third grazing seasons, with maximum levels observed in May/June; however, in the second year, the peak was reached in October. Blood pepsinogen levels increased from pasture turnout (March/April) until the end of the grazing season (November/December), reaching maximum values from August/September onwards. The nematode parasite species identified at necropsy were Ostertagia osteragi, O. lyrata, Cooperia oncophora, C. macmasteri, C. punctata and Trichuris ovis, with O. ostertagi and C. oncophora predominating. In faecal cultures, the following genera were also identified: Haemonchus, Trichostrongylus, Nematodirus, Bunostomum, Oesophagostomum and Strongyloides. There was a significant correlation (r=0.97, P<0.01) between worm burden (Ostertagia spp.) and pasture infestation (Ostertagia L3) 3 weeks prior to slaughter of the calves, and also between blood pepsinogen levels and pasture infestation by Ostertagia L3 (r=0.33, P<0.02). Correlations between worm burden and faecal egg output and between blood pepsinogen level and faecal egg output were not significant. The results obtained in the present study confirm that there is annual variability in the time-course of nematodosis in cattle, and demonstrate the importance of weather, particularly summer rainfall, in an Atlantic temperate environment.

Recurrence of IgA nephropathy and Henoch-Schönlein purpura after kidney transplantation: risk factors and graft survival.

BACKGROUND: IgA nephropathy (IgA) is one of the most common glomerulonephritis. Renal transplantation is the treatment of choice for patients with ESRD due to any kind of glomerulopathy, including IgA and Henoch-Schönlein purpura nephritis (H-SP), but original disease recurrence is now the third most frequent cause of allograft loss. METHODS: Eighty-seven cases of glomerulonephritis as the original disease were divided in two groups: group A--37 affected with 31 IgA and 6 H-SP; and group B--50 with other glomerulopathies. We compared patient and graft survivals at 5 years. To assess the presence of IgA or H-SP recurrence in group A patients, we performed an allograft biopsy in the presence of microhematuria, proteinuria, or an increased plasma creatinine. Known risk factors influencing recurrence rate were also analyzed. RESULTS: Five-year patient (97% vs 95%) and graft survivals (81% vs 78%) were not significantly different between groups A and B. Patients with crescentic glomerulonephritis (CGN) at the moment of diagnosis of IgA or H-SP showed a 5-year graft survival of 71% in contrast with 100% graft survival among those with mesangial or focal and segmental glomerulosclerosis pattern (P = .03). Histological recurrence was diagnosed in eight patients: six IgA and two H-SP. Women (P = .013) and a good HLA match (P = .029) were significantly associated with the risk of recurrence. CONCLUSIONS: When compared with other glomerulonephritis patients, with IgA or S-HP showed similar 5-year graft and patient survivals. Nevertheless, graft survival was shorter among patients with crescentic glomerulonephritis at the moment of diagnosis. Thus, the disease prognosis after grafting may be linked to the initial histological aggressiveness. Women and those patients transplanted with a good HLA match were prone to develop disease recurrence with a tendency toward a lower 5-year graft survival.

Ambulatory blood pressure monitoring in renal transplant patients: modifiable parameters after active antihypertensive treatment.

BACKGROUND: Hypertension (HT) accounts for nearly 60% to 80% of renal transplant patients (RT). It is one of the most important risk factors for cardiovascular diseases and may cause chronic graft dysfunction. Therefore, it is important to accurately detect and treat HT. We aimed to evaluate the changes in ambulatory blood pressure monitoring (ABPM) parameters among hypertensive RT after active treatment compared with baseline values. METHODS: Thirty seven RT (25 men, 12 women, aged 49.4 +/- 11.2 year) diagnosed with mild to moderate HT underwent 24-hour ABPM after a 4-week washout period (W0). For the 23 RT with confirmed HT of a second 24-hour ABPM was recorded after 4 weeks of treatment with doxazosin GITS (-4 mg once daily in the morning), a new formulation of an alpha1-receptor inhibitor (W4). Nondippers were considered when mean blood pressure (BP) showed a < or = 10% reduction during sleep. Statistical analyses included Saphiro-Wilks test, Student t test, and ANOVA. RESULTS: After active treatment systolic, diastolic, and mean BP (SBP, DBP, MBP) significantly decreased during diurnal and 24 hours but not the nocturnal period. No significant change was observed for heart rate nor for pulse pressure during any period. The prevalence dippers increased from 0% to 17% after treatment. After placebo administration 8 among 37 RT with HT diagnosed according to casual BP remained hypertensive at nighttime (but not at daytime) according to 24-hour ABPM. CONCLUSIONS: Diurnal and 24-hour periods of ABPM showed significant changes in SBP, DBP, and MBP after active treatment with doxazosin GITS. No significant BP changes were observed in the nocturnal period or in dipper status. Further studies using ABPM must be undertaken to determine the optimal dosage and time of administration of antihypertensive drugs in RT.

[Accelerated arterial hypertension in a young male]. / Hipertensión arterial maligna en un adulto joven.

Hypertensive crises are situations when arterial hypertension shows its immediate damaging potential, and in such circumstance, antihypertensive therapy provides its life-saving effectiveness. Among these situations are hypertensive emergencies, hypertensive urgencies, hypertensive encephalopathy, and also accelerated-malignant hypertension characterised by the presence of grade 3 or grade 4 Keith-Wagener retinopathy and numerous complications (acute renal failure, heart failure, haemorrhagic brain stroke or acute coronary events). Despite of antihypertensive therapy, the mortality rate of accelerated-malignant hypertension is about 25% after the 5th year. We present the case of a thirty-three years old male, with a five-year history of non-treated hypertension, who develops accelerated- hypertension with heart failure, microangiopathic haemolytic anaemia and renal failure that requires renal replacement therapy. After a strict control of blood pressure; initially using parenteral agents such as Solinitrin and Urapidil, followed by angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-adrenergic receptor blockers, calcium channel blockers and Hydralazine, the patient partially recovers his renal function, resulting in the withdrawal of haemodialysis.

Use of cyclosporine in renal transplantation.

The first cyclosporine trials in renal transplantation began in Cambridge in 1978. Between 1982 and 1985 several large multicenter trials and the reports from large series of patients evidenced that cyclosporine was a major advance in the prevention of acute rejection episodes and in improving short-term and long-term graft survival. Cyclosporine also showed the capacity to mitigate immunologic risk factors, HLA mismatching, and lack of pretransplant transfusions. However, cyclosporine has the serious defect of being nephrotoxic. Induction therapy with OKT3, polyclonal antibodies, and more recently with anti IL-2R monoclonal antibodies allowed the delay of introduction cyclosporine in patients showing posttransplant graft dysfunction. Other relatively unsuccessful attempts for overcoming cyclosporine nephrotoxicity were made before the association of new xenobiotics such as mycophenolate mofetil or sirolimus permitted cyclosporine doses to be reduced. These combinations reduce acute rejection incidence to below 20%, with its consequent positive impact on long-term graft outcome and also allow a safer steroid sparing and withdrawal early posttransplantation. Also, the association of cyclosporine with other new compounds such as the lymphocyte homing FTY20 or the peripheral lymphocyte-depleting Campath-1-IgG is currently under clinical investigation. Cyclosporine's future place is yet to be established in the new era of immunosuppression.

Hipertensión arterial maligna en un adulto joven / Accelerated arterial hypertension in a Young male

Las crisis hipertensivas suponen la situación donde la hipertensión arterial (HTA) muestra, de manera más inmediata, su potencial lesivo y así mismo la circunstancia en que el tratamiento hipotensor obtiene una efectividad mayor. Entre estas situaciones encontramos la emergencia, la urgencia y la encefalopatía hipertensivas y también la HTA maligna acelerada caracterizada por la presencia de retinopatía hipertensiva grado III o IV y acompañada de numerosas complicaciones (fracaso renal agudo, fallo cardíaco, accidente vascular cerebral hemorrágico o cardiopatía isquémica) que condicionan una mortalidad, a pesar del tratamiento hipotensor, del 25% a los cinco años. Presentamos el caso de un varón de 33 años de edad, hipertenso de cinco años de evolución sin tratamiento posterior, que desarrolla HTA maligna acompañada de insuficiencia cardíaca, anemia hemolítica microangiopática y fracaso renal que obliga a iniciar terapia renal sustitutiva. Tras un exhaustivo control tensional, inicialmente con agentes parenterales como la solinitrina y el urapidilo, y posteriormente con inhibidores de la enzima de conversión de la angiotensina (IECAs), antagonistas de los receptores de la angiotensina II (ARAII), betabloqueantes, calcioantagonistas e hidralacina, el paciente recupera parcialmente la función renal con abandono de la hemodiálisis (AU)

Hypertensive crises are situations when arterial hypertension shows its immediate damaging potential, and in such circumstance, antihypertensive therapy provides its life-saving effectiveness. Among these situations are hypertensive emergencies, hypertensive urgencies, hypertensive encephalopathy, and also accelerated-malignant hypertension characterised by the presence of grade 3 or grade 4 Keith-Wagener retinopathy and numerous complications (acute renal failure, heart failure, haemorrhagic brain stroke or acute coronary events). Despite of antihypertensive therapy, the mortality rate of accelerated-malignant hypertension is about 25% after the 5th year. We present the case of a thirty-three years old male, with a five-year history of non-treated hypertension, who develops accelerated- hypertension with heart failure, microangiopathic haemolytic anaemia and renal failure that requires renal replacement therapy. After a strict control of blood pressure; initially using parenteral agents such as Solinitrin and Urapidil, followed by angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-adrenergic receptor blockers, calcium channel blockers and Hydralazine, the patient partially recovers his renal function, resulting in the withdrawal of haemodialysis (AU)

Posttransplant lymphoproliferative disease: treatment and outcome in renal transplant recipients.

UNLABELLED: Posttransplant lymphoproliferative disorders (PTLD) are a heterogeneous group of lymphoid diseases that occur after solid organ and bone marrow transplantation. We performed a retrospective study to assess the incidence, response to treatment, and patient and graft survival after PTLD. PATIENTS: Between January 1980 and December 2002, 1.96% (n=10) of 509 renal transplant recipients developed PTLD. Seventy percent were men. Mean age was 40 years (range 21-65). They were classified into four groups based upon the type of PTLD: group I, early lesion (n=1); group II, polymorphic PTLD (n=1); group III, monomorphic PTLD (n=7) including five non-Hodgkin lymphoma [NHL] and two Burkitt (BL); and group IV, Hodgkin lymphoma (HL) (n=1). The mean time from transplantation to diagnosis was 77 months (range 4-138). Although only 20% of cases were early presentation, Epstein-Barr virus (EBV) was found in the tumor cells of seven cases. Treatment was individualized according to PTLD type: for group I, immunosuppression reduction (IR); group II, IR plus acyclovir; group III, withdrawal or IR plus chemotherapy and/or surgery in all but one patient who was also treated with anti-CD20 monoclonal antibody and radiotherapy. Interferon was also used in one patient. For group IV, treatment was IR plus radiotherapy. RESULTS: A complete response was achieved in nine cases (90%) with one recurrence. Three patients returned to dialysis. One patient with BL died. CONCLUSIONS: The incidence of PTLD in our center was 1.96%. Patient survival after PTLD was 90%, with 60% maintaining allograft function. Individualized treatment according to extension, histology, and location is mandatory to obtain a high survival rate.

Efficacy and safety of doxazosin GITS in hypertensive renal transplant patients: comparison of 8 and 4 mg.

BACKGROUND: Hypertension (HT), a prevalent complication in renal transplant patient (RT), must be accurately treated because cardiovascular disease is the leading cause of death and of chronic graft dysfunction. Sympathetic activity may contribute to HT in RT, yielding the rationale to suspect that doxazosin, an alpha1-adrenergic receptor inhibitor, may lower blood pressure (BP). The aim of this study was to evaluate the efficacy and safety of doxazosin GITS (4 and 8 mg) in RT. METHODS: Twenty-three hypertensive RT received doxazosin 4 mg once daily for 4 weeks (W4) followed by a 4-week washout (W0) and 17/23 treated with doxazosin 8 mg for 4 more weeks (W8) due to persistent HT. All patients underwent 24-hour ambulatory blood pressure monitoring (ABPM) after W0, W4, and W8. Laboratory tests were performed, adverse events recorded, and prostatic symptomatology examined. Statistical analysis included Saphiro-Wilks, Student t, ANOVA, Wilcoxon, or Friedman tests. RESULTS: The systolic, diastolic, and mean BP were significantly lowered at W4 in awake (P<.001) and 24 hour period (P<.005) but not sleep recordings. Doxazosin 8 mg had no significant additional effect to lower BP at any period. Normotension was reached in 13% and 21.7% of patients at W4 and W8, respectively. Palpitations were the only reported adverse event after treatment (incidence similar to placebo). There was no significant change in the laboratory values. CONCLUSIONS: Doxazosin (-4 mg) effectively decreased BP in awake and 24-hour periods without a significant improvement during sleep. A double dose of the drug added little benefit. Optimal BP was reached by an insufficient number of patients. Doxazosin proved to have a good tolerance and safe profile. This results suggest that doxazosin should be considered a good add-on treatment to other antihypertensive drugs in RT.

Reflex sympathetic dystrophy syndrome of the lower limbs in a renal transplant patient treated with tacrolimus.

BACKGROUND: Recently, a previously unrecognized posttransplant syndrome known as reflex sympathetic dystrophy syndrome of the lower limbs has emerged in patients receiving cyclosporine as immunosuppression. We describe herein this complication observed in a patient treated with tacrolimus after kidney transplantation. METHODS: A 49-year-old man received a kidney transplant from a cadaver donor and was treated with tacrolimus. Three months later, the patient complained of severe pain in the lower limbs that affected both knees and ankles. Bone scintigraphy and magnetic resonance were consistent with reflex sympathetic dystrophy syndrome. RESULTS: Laboratory tests that included creatinine, glomerular filtration rate, calcium, phosphate, urate, alkaline phosphatase, and parathormone were normal or near normal. Tacrolimus levels were around 13 microg/ml. Clinical improvement appeared slowly and spontaneously during the following 3 months, without appreciable changes in the tacrolimus level. CONCLUSIONS: In kidney transplant patients, tacrolimus could be a risk factor for the development of a reflex sympathetic dystrophy syndrome.