Sodium Excretion Pattern at 1 Year After Kidney Transplantation and High Blood Pressure.

BACKGROUND: High blood pressure (BP) after kidney transplantation decreases graft and patient survival. There is a causal relationship between high salt intake and increased BP in the general population, but the role of salt intake on post-transplant hypertension remains controversial. The aims of our study were to determine the pattern of salt intake in the first year post-transplantation and its influence on BP in our kidney transplant population. MATERIAL AND METHODS: We selected 270 deceased-donor kidney transplant recipients with graft survival longer than 1 year and at least 1 adequate 24-h urinary sodium excretion measurement at the first year visit in order to be included in the analysis. RESULTS: Some 87.0% patients had a sodium excretion (mean 165±73 mmol/day) higher than recommended. Male and younger recipients with a high body mass index had a higher sodium excretion. Among other variables, sodium excretion was independently related to higher systolic (b 3.529 per 100 mmol/day, 95%CI 0.725-6.334, p=0.014) and diastolic (b 1.866 per 100 mmol/day, 95%CI 0.237-3.496, p=0.025) BP. CONCLUSIONS: A high percentage of kidney transplant recipients have salt intake higher than recommended, contributing to increased BP. Measurement of 24-h urinary sodium excretion identifies non-compliant kidney transplant recipients who need intervention to improve BP control and graft outcome.

Cystatin C and albuminuria as predictors of long-term allograft outcomes in kidney transplant recipients.

Although cystatin C (Cys) and albuminuria (Alb) are predictors of end-stage renal disease in the general population, there are limited data about the performance of these markers alone or combined with respect to the prediction of the kidney transplant outcome. We assessed the ability of one-yr creatinine (Cr), MDRD equation, Cys, Hoek equation, Alb, the logarithm of albuminuria (LogAlb), and two products of these variables for predicting death-censored graft loss (DCGL) in 127 kidney transplant recipients. Mean follow-up time was 5.6 ± 1.7 yr. During this time, 18 patients developed DCGL. The area under the receiver operating characteristic curve for DCGL ranged from 71.1% to 85.4%, with Cys*LogAlb being the best predictor. Cys-based variables and variables combining LogAlb and renal function estimates have better discrimination ability than Cr-based variables alone. After multivariate analysis, quartiles of all one-yr variables (except of Cr and MDRD) were independent predictors for DCGL. Predictors combining Alb and a Cr- or Cys-based estimate of renal function performed better than those markers alone to predict DCGL. Cys-based predictors performed better than Cr-based predictors. Using a double-marker in kidney transplantation, it is possible to identify the highest risk group in which to prioritize specialty care.

Microbiological profile of peritoneal dialysis peritonitis and predictors of hospitalization.

Peritonitis, the major complication of peritoneal dialysis (PD), is associated with high morbidity and mortality. It is a major cause of hospitalization and transfer to hemodialysis. In the present study, we aimed to identify predictors of hospitalization in PD-related peritonitis and to examine its microbiology profile over time in our unit to determine the best therapeutic approach. We studied all peritonitis episodes that occurred in a 6-year period (January 1, 2004, to December 31, 2009), evaluating whether adequate treatment could be delivered on an outpatient basis. During the study period, 411 patients were on PD, and 229 peritonitis episodes were recorded in 91 patients. Peritonitis were treated according to unit protocol. The average hospital stay was 11.6 +/- 6.6 days. We observed an increase of Streptococcus (to 19.4% from 7.7%) and a stabilization of coagulase-negative Staphylococcus, S. epidermidis, and S. aureus (from 9.5%, 22.6%, and 3.2% to 7.7%, 30.8%, and 3.8% respectively) peritonitis episodes. The main risk factors for hospitalization were fungal infection, poor 72-hour outcome, inability to perform self-care, and age greater than 80 years. We observed a decline in the incidence of peritonitis, and despite changes in its microbiology profile, no loss of sensitivity to antibiotics used was observed.

Heterogeneity of induction therapy in Spain: changing patterns according to year, centre, indications and results.

Background. The use of induction drugs has increased markedly over the last 15 years in the USA, but there are few data about their use in other countries. Moreover, there are not enough data about when they are indicated and their long-term effects. The aim of our study was to know the rates of use and the drugs used as induction therapy, in which patients they were prescribed and the long-term graft survival effect in Spain.Methods. We conducted a retrospective cohort study with adult patients (4861) receiving a kidney allograft in Spain over four different years (1990, 1994, 1998 and 2002) with a functioning graft at the end of the first post-transplant year. Induction therapy was defined as when the patient received polyclonal antibodies, OKT3 monoclonal antibodies or anti-CD25 monoclonal antibodies.Results. From 1990 to 2002, the use of induction therapy in Spain changed, with a progressive reduction in the use of OKT3 and an increasing use of anti-CD25 antibodies. There were great differences in the rate of induction use from one centre to another, although with a common trend to greater use at each centre. Induction therapy was mainly prescribed in patients with a higher rejection risk (higher panel reactive antibody (PRA) titres and mismatches and re-transplants) and in older and diabetic recipients. Lastly, patients who were treated with induction therapy had significant higher allograft survival than those who did not (P value = 0.035).Conclusions. The use of induction therapy in Spain has changed, with an increasing use of monoclonal antibodies in recent years. Induction therapy has a protective role in long-term graft survival.

Calcium-mediated parathyroid hormone release changes in patients treated with the calcimimetic agent cinacalcet.

BACKGROUND: The parathyroid-calcium (Ca(2+)-PTH) curve expresses modulation of parathyroid hormone (PTH) secretion by the parathyroid gland as a function of changing extracellular Ca(2+) concentration. Patients with hyperparathyroidism (HPT) show a rightward shift of the curve compared with controls, suggesting a reduced sensitivity of parathyroid cells to Ca(2+). Increasing the sensitivity of the parathyroid gland to extracellular Ca(2+) by manipulation of the Ca(2+)-sensing receptor (CaR) may have therapeutic potential. Calcimimetics allosterically modify CaR and render it more sensitive to extracellular Ca(2+), accounting for the simultaneous reduction of Ca(2+) and PTH seen in most patients. METHODS: The Ca(2+)-PTH curve was evaluated in 10 haemodialysis patients, with baseline intact PTH levels >300 pg/ml in two haemodialysis sessions, one before and the other after (range, 9-22 weeks) cinacalcet treatment. In each session a 2-h low-dialysate Ca(2+) concentration was used to induce hypocalcaemia and maximally stimulate PTH secretion, followed immediately by a 2-h high-dialysate Ca(2+) concentration to induce hypercalcaemia and maximally inhibit PTH secretion. RESULTS: Significant decreases in ionized Ca(2+) and intact PTH were observed following cinacalcet treatment. Cinacalcet treatment also led to a decrease in the set point for Ca(2+) and to a leftward shift of the Ca(2+)-PTH curve. Significant differences were present in all segments of the Ca(2+)-PTH curves. CONCLUSION: The pathological rightward shift of the Ca(2+)-PTH curve seen in many HPT patients may be reversed by cinacalcet treatment.

Intracellular ATP concentrations of CD4 cells in kidney transplant patients with and without infection.

In the field of organ transplantation, overimmunosuppression is associated with severe side effects, such as infection, drug toxicity, and cancer, whereas underimmunosuppression is associated with acute rejection. Intracellular adenosine triphosphate (iATP) concentration following CD4 cell activation provides an assessment of cellular immune function to help monitor the immune status of immunosuppressed patients. This assay has shown to be the first post-transplant test related not only to the risk of acute rejection but also with the appearance of infection. The aim of our study was to compare the iATP concentrations of CD4 cells between healthy adults and kidney transplant recipients from a European population, analyzing the differences according to transplant clinical status. Samples from 81 kidney transplant patients who were admitted to our hospital over a nine-month period were drawn. T-cell activation was measured by determining the increase of iATP from CD4 cells. Results were compared with patient clinical status (rejection, infection, and stability). Three patients suffered an acute rejection episode and they were not included in the analysis (mean iATP concentration 247 +/- 87 ng/mL). iATP concentrations differed significantly between stable and infected patients (313 +/- 193 vs. 197 +/- 114 ng/mL; p = 0.008). iATP concentration values were not related to the length of admission, age, peak and current panel reactive antibodies, mismatches, leukocytes, weight, creatinine, days after transplantation and blood levels of cyclosporin, tacrolimus, and sirolimus. This assay measures global immune responses of CD4 T cells from a whole-blood sample, allowing for the assessment of the impact of immuno- suppressive drugs and of the patient's underlying clinical conditions. This assay identifies transplant patients at risk for infection or rejection, providing information which can guide immunosuppressive therapy.

Impact of treatment with calcimimetics on hyperparathyroidism and vascular mineralization.

Soft tissue calcification that involves primarily the medial portion of the arterial vasculature is a widely recognized and common complication of chronic kidney disease Vascular calcification (VC) causes increased arterial stiffness and contributes to the high cardiovascular mortality and morbidity in dialysis patients. The pathogenesis of VC is complex and includes factors that promote calcification and others that inhibit calcification. Studies in dialysis patients have shown a correlation between VC and a number of uremia-related factors. Overall, abnormalities in calcium and phosphate metabolism, such as hyperphosphatemia and a raised serum calcium-phosphorus product traditionally have been thought of as important determinants in patients with chronic renal failure. Common therapeutic interventions in secondary hyperparathyroidism have come under scrutiny for associations with the development of VC. Calcimimetics provide a means of controlling serum levels of parathyroid hormone in secondary hyperparathyroidism without increasing the calcium-phosphorus product and, more important, may lower the risk for VC in these patients.

New-onset diabetes after kidney transplantation: risk factors.

New-onset diabetes after transplantation (NODAT) contributes to the risk for cardiovascular disease and infection, reducing graft and patient survival. For improvement of the outcome of kidney transplant recipients, it is of great interest to know precisely the risk factors that contribute to NODAT development. Nonmodifiable risk factors for development of NODAT are age, race, genetic background, family history of diabetes, and previous glucose intolerance. Modifiable risk factors are obesity and overweight, hepatitis C virus and cytomegalovirus infections, and immunosuppressive drugs. Both steroids and calcineurin inhibitors influence the appearance of NODAT, whereas the role of sirolimus in glucose metabolism currently is controversial.

Calcineurin inhibitors, but not rapamycin, reduce percentages of CD4+CD25+FOXP3+ regulatory T cells in renal transplant recipients.

BACKGROUND: Immunosuppression in renal transplantation, although manageable in the short-term, is a major hurdle for long-term graft survival. Recently, increased frequencies of CD4CD25 regulatory T cells (Tregs) have been described as an additional mechanism that induces alloimmune tolerance. METHODS: We assessed 64 renal transplant recipients with stable renal function for at least one year. Patients were divided into two groups according to the immunosuppression they were receiving at the moment of the study: one consisted of patients receiving rapamycin (Rapa) but not calcineurin inhibitors (CNI), and the other group received CNI but not Rapa. The Rapa group was further divided into three subgroups according to their previous experience with CNI: CNI-free, CNI withdrawal, and CNI conversion. Frequencies of blood Tregs were studied by flow cytometry after staining with monoclonal antibodies specific for different markers of Tregs. RESULTS: Frequencies of CD4 T cells with regulatory phenotype and function were significantly decreased in peripheral blood of renal transplant patients receiving CNI compared with those receiving Rapa. This effect was independent of an early exposure to CNI because the CNI-free patients in the Rapa group showed similar frequencies of Tregs to the CNI withdrawal and CNI conversion groups. CONCLUSIONS: CNI, but not Rapa, induce a decrease of circulating Tregs in stable renal transplant recipients. Thus, Rapa might be further explored in strategies using preservation of Tregs for transplant tolerance. Furthermore, quantification of blood Tregs may be a suitable tool to identify renal transplant recipients who may be candidates for reduced immunosuppression.

The renal benefits of a healthy lifestyle.

Over the next decade, the number of patients with end-stage renal disease requiring treatment by dialysis may double, and even developed nations will have difficulty coping with this alarming increase. There is an urgent need to highlight the importance of modifiable risk factors as a basis for treatment strategies to prevent the development and progression of chronic kidney disease (CKD). This should include active extension of our current understanding of a healthy lifestyle.

Evolution of tacrolimus blood levels and concentration-dose ratios in patients who develop new onset diabetes mellitus after kidney transplantation.

New onset diabetes mellitus (NODM) affects kidney transplantation outcome. Several risk factors, including immunosuppressive drug levels, are related with NODM development. This analysis evaluates the incidence and risk factors of NODM in kidney transplant patients receiving tacrolimus, taking into account 6-month blood levels and concentration-dose ratios (CDRs). Seventy-six patients under tacrolimus therapy who received a cadaveric renal transplant in our centre and with graft survival higher than 1 year were included in the study. NODM was defined as two fasting plasma glucose values > or =126 mg/dl or symptoms of diabetes plus casual plasma glucose concentrations > or =200 mg/dl throughout the first year. We examined previously reported variables related with NODM development. The incidence of NODM at 12 months was 27.6%. Risk factors for NODM included older age, higher first tacrolimus level, higher body mass index and lower first year weight gain. In multivariate analysis, the first year occurrence of NODM was significantly determined by the first tacrolimus blood level >20 ng/ml and age older than 50 years. CDR remains significantly higher in NODM throughout the 6 months. Older age and a high first tacrolimus blood level are associated with the development of NODM during the first year after kidney transplantation. NODM patients show higher CDR during the first 6 months.

Effects of weight loss after biliopancreatic diversion on metabolism and cardiovascular profile.

BACKGROUND: Obesity is associated with increased prevalence of cardiovascular risk factors. Biliopancreatic diversion (BPD) for morbid obesity has been reported to produce anemia and malnutrition in short-term follow-up. The aim of our study was to analyze the effect of weight reduction on cardiovascular profile, renal function and nutritional status. METHODS: 35 morbidly obese patients underwent BPD. We analyzed the presence of cardiovascular risk factors, renal status, proteinuria and nutritional status before and 1 year after BPD. RESULTS: Excess weight loss was 67% at 1 year after BPD. All cardiovascular risk factors (hypertension, diabetes, hyperlipidemia) improved during follow-up. We could not find any relevant signs of malnutrition in the patients. Microalbuminuria decreased and proteinuria disappeared after weight loss. We observed less urinary calcium and citrate excretion, with an increase in oxaluria, but these changes did not increase the incidence of renal stones. CONCLUSIONS: BPD was followed by improved cardiovascular profile and a lower pro-inflammatory state. BPD did not produce significant malnutrition, anemia or renal stone disease.

Creatinine reduction ratio on post-transplant day two as criterion in defining delayed graft function.

Delayed graft function (DGF) is a common complication after renal transplant, affecting its outcome. A common definition of DGF is the need for dialysis within the first week of transplantation, but this criterion has its drawbacks. We tried to validate an earlier and better defined parameter of DGF based on the creatinine reduction ratio on post-transplant day 2 (CRR2). We analyzed the clinical charts of 291 cadaver kidney recipients to compare the outcome of patients with immediate graft function (IGF), dialyzed patients (D-DGF) and nondialyzed CRR2-defined DGF patients (ND-DGF) and to identify risk factors for D-DGF and ND-DGF. Creatinine reduction ratio on post-transplant day 2 correlates significantly with renal function during the first year. Patients with IGF have significantly better renal function throughout the first year and better graft survival than patients with D-DGF and ND-DGF, while we found no differences either in renal function from days 30-365 or in graft survival between D-DGF and ND-DGF patients. Defining DGF by CRR2 allows an objective and quantitative diagnosis after transplantation and can help to improve post-transplant management. Creatinine reduction ratio on post-transplant day 2 correlates with renal function throughout the first year. The worse survival in the ND-DGF group is an important finding and a major advantage of the CRR2 criterion.

Evaluation of the potential protective effect of 21-aminosteroid U-74389G on liver injury induced by reduced and prolonged partial hepatic ischaemia reperfusion in rats.

The protective effect of the 21-aminosteroid U-74389G was studied in an experimental model of partial ischaemia reperfusion liver injury. Previous studies have proven the remarkable potency of 21-aminosteroids to prevent oxidant-induced cell injury in vitro and in vivo. However, the capability of these compounds to limit oxidative injury in clinical trials has been considered to be less certain. The potential protective effect exerted by U-74389G on reduced and prolonged models of ischaemia reperfusion liver injury was studied in male rats subjected to 75 min. of segmentary hepatic ischaemia followed by 1 or 24 hr of reperfusion. Liver injury was evaluated by measuring serum levels of liver enzymes and by histopathological studies. The oxidative status of liver cells was measured by evaluating the levels of liver lipid peroxidation products such as malondialdehyde and the levels of reduced glutathione. Our results lead us to think that treatment with U-74389G (6 mg/kg) does not bring about any protective effect neither in the levels of transaminases nor in the percentage of hepatocellular necrosis and cellular infiltration observed in any reperfusion-period groups. In fact and in contrast with our expectations, U-74389G seemed to increase enzyme release. Furthermore, at the dose used, this 21-aminosteroid is not capable of inhibiting the lipoperoxidation processes, although it induced an important increase of GSH levels at any time-period of reperfusion. This last finding seem to suggest that U-74389G could increase the resistance to oxidant-induced liver tissue damage. However, our results show that, at the dose used, this compound did not exert any protective effect on liver tissue, thus explaining, at least partially, the absence of beneficial effects on the part of these compounds in clinical trials carried out to limit organ injury in transplants.

Acute rejection in the elderly recipient: influence of age in the outcome of kidney transplantation.

Since the immune response in older recipients is weaker they should be less likely to reject a transplanted organ and should need less aggressive immunosuppressive treatment. Our aim was to record the incidence and severity of episodes of acute rejection (AR), estimate the influence of these events on graft survival of elderly recipients (> or = 60) and to compare these with that in younger ones. We performed 363 kidney transplants between 1/94 and 12/98, and recorded clinical and immunological data, incidence-severity of AR and cause of graft loss. Patients were divided into two groups, according to the age at transplantation: A (<60, n = 281/77.4%) and B (> 60, n = 82/22.6%). The percentage of aging recipients and mean age of donors and recipients increased throughout the period. Although the incidence of ATN was higher in the older group (29% vs.19%, p < 0.0001) the number of graft biopsies was equal in both groups. The incidence of AR was similar, 33.4% vs. 26.8%, pNS. The number of AR episodes per patient was 0.44 and 0.41 respectively. The severity of AR was: Banff grade I: A (40.3%)/B (45.7%) pNS; grade II: A (44.1%)/B (48.57) pNS; grade III: A (15.5%)/B (5.7%) pNS. Younger recipients presented a higher level of panel-reactive antibodies (PRA) (4.3% vs. 2.07%, p = 0.01). One-yearpatient survival was 96%/91% (p < 0.05) and graft survival was 81%/78% (pNS) respectively. The age of recipient does not seem to have influenced the incidence-severity of AR or the graft survival. Thus immunosuppression should be individualized for each patient and should not depend on the age at transplantation.

Past, present and future of erythropoietin use in the elderly.

More than a decade has passed since the first patient with end-stage renal failure was treated with erythropoietin (EPO) and more than 85% of patients now receive this therapy. In the year 2002 more than 60% of dialysis patients will be elderly, and the treatment of anemia will be more complex due to the aditional causes: folate, iron and vitamin deficiency in this population. Correction of anemia with EPO brings about partial regression of left ventricular hypertrophy and some data suggest that such treatment reduces cardiovascular mortality in patients without advance cardiac disease. Normalization of hematocrit with EPO increases oxygen supply to the brain tissue with improvement in brain function. The improvement in the ability to recognize, discriminate and hold stimuli in memory for difficult tasks is particularly important for elderly people. No differences have been noted in the incidence of clotting of vascular access in patients treated with EPO compared with hemodialysis patients not so treated. Also no one has demostrated that treatment with EPO accelerates renal decline in patients with progressive renal insufficiency. In elderly people with anemia secondary to advanced renal failure, EPO therapy improves physical, cognitive and sexual function, and health related quality of life.