Evaluation of MDRD4, CKD-EPI, BIS-1, and modified Cockcroft-Gault equations to estimate glomerular filtration rate in the elderly renal-transplanted recipients.

Equations to estimate glomerular filtration rate (eGFR) were developed in patients using the variables age, body weight, and serum creatinine, which may be different in the elderly. Elderly renal transplant patients (EG; n=70; mean age 65 ± 4 y) who measured plasma 51 Cr-EDTA-Clearance (mGFR) had mGFR compared to eGFR obtained by the Cockcroft-Gault corrected by body surface area (CG-BSA), the modification of diet in renal disease (MDRD-4), the Berlin Initiative Study (BIS-1), and the chronic kidney disease epidemiology collaboration (CKD-EPI). Results were validated using a cohort of 43, of the 70 elderly recipients, who performed a second 51 Cr-EDTA-Clearance. Mean mGFR was 47 ± 16 mL/min/1.73 m2 and statistically lower than eGFR by MDRD (52 ± 19, P=.001) and BIS-1 (51 ± 13, P=.007) but not different from the CG-BSA (47 ± 15) and CKD-EPI (49 ± 18). The CKD-EPI and CG-BSA presented the lowest bias but only CKD-EPI also showed the highest 30% and 10% accuracy. The same findings were repeated in the validation set. For a cohort of elderly recipients ≥65 years (n=35, 68 ± 3y), the CKD-EPI performed better with the lowest bias (0 ± 12 mL/min/1.73 m2 ) and best 30% and 10% accuracy. The CKD-EPI equation is a valuable tool to monitor GFR in the elderly RTx recipients.

Treatment of subcutaneous phaeohyphomycosis and prospective follow-up of 17 kidney transplant recipients.

BACKGROUND: Subcutaneous phaeohyphomycosis in solid organ recipients may have an adverse outcome. OBJECTIVE: We sought to describe the disease course, treatment, and outcome of allograft function in kidney transplant recipients with phaeohyphomycosis. METHODS: Seventeen patients were followed for a mean period of 25.4 months to analyze the clinical response to treatment. RESULTS: There was no treatment failure or relapsing disease among 12 patients who completed treatment. Two patients were still in treatment with disease remission. One patient discontinued the study during treatment with partial remission, one died after finishing treatment with disease remission, and one was dropped from the study because contact was lost. Immunosuppressive regimens were not changed. Two of 17 patients had a significant reduction in allograft function. LIMITATIONS: The follow-up time was short and the number of patients was small. CONCLUSIONS: The outcome of phaeohyphomycosis in kidney transplant recipients was favorable with minimal impact on renal allograft function.

Aging and End Stage Renal Disease Cause A Decrease in Absolute Circulating Lymphocyte Counts with A Shift to A Memory Profile and Diverge in Treg Population.

There is a growing number of elderly kidney transplant (Ktx) recipients. Elderly recipients present lower acute rejection rates but higher incidence of infection and malignancies. Aging per se seems to result in a shift to memory profile and chronic kidney disease (CKD) in premature immunological aging. Understanding aging and CKD effects on the immune system can improve elderly Ktx immunosuppression. We analyzed the effects of aging and CKD in the immune system, comparing healthy adults (HAd) (n=14, 26±2y), healthy elderly (HEld) (n=15, 79±7y), end stage renal disease (ESRD) adults (EnAd) (n=18, 36±7y) and ESRD elderly (EnEld) (n=31, 65±3y) prior to Ktx regarding their naïve, memory and regulatory T and B peripheral lymphocytes. Aging and ESRD presented additive effect decreasing absolute numbers of B and T-lymphocytes, affecting memory, naive and regulatory subsets without synergic effect. Both resulted in higher percentages of T memory subsets and opposing effects on regulatory T (TREG) subsets, higher percentage in aging and lower in ESRD. Combined effect of aging and ESRD also resulted in higher regulatory B cell percentages. In addition to global lymphopenia and TCD4+ memory shift in both aging and ESRD, aging shifts to an immunoregulatory profile, inducing a increase in TREG percentages, contrasting with ESRD that decreases TREGs. Differential immunosuppression regimens for elderly Ktx may be required. (ClinicalTrials.gov number: NTC01631058).

Longitudinal Pharmacokinetics of Everolimus When Combined With Low-level of Tacrolimus in Elderly Renal Transplant Recipients.

BACKGROUND: Although the proportion of elderly patients among renal transplant recipients has increased, pharmacokinetic (PK) studies of immunosuppressants rarely include older patients. METHODS: We studied 12-hour everolimus (EVL) PK in 16 elderly renal transplant recipients (all whites; 10 men; mean age, 64 ± 2 years (61-71 years), in 4 separate timepoints (at 7, 30, 60, and 150 days) after EVL introduction, corresponding to a mean postrenal transplantation day: PK1 (43 ± 4 days), PK2 (65 ± 7 days), PK3 (106 ± 17 days), and PK4 (206 ± 40 days). Patients received EVL (target trough level (Ctrough, 3-8 ng/mL), prednisone, and tacrolimus (TCL) (target Ctrough, 2-5 ng/mL). RESULTS: Mean TCL-Ctrough was 7.2 ± 3.8, 4.9 ± 2.2, 4.9 ± 2.2, and 4.5 ± 1.2 ng/mL at PK1, PK2, PK3, and PK4, respectively. There were no differences among timepoints for mean EVL daily dose (data shown as PK3) (3.5 ± 1.3 mg/d), Ctrough (4.7 ± 2.5 ng/mL), AUC0-12h (106 ± 51 ng/h per mL), Caverage (8.8 ± 4.2 ng/mL), Cmax (19.2 ± 9.7 ng/mL), apparent Half-life (11.7 ± 4.2 hours), estimated total body clearance (0.39 ± 0.27 L/h), or fluctuation (166 ± 65%). Also, none of those PK parameters differed statistically when adjusted for body weight. EVL-Ctrough showed a very high correlation (r = 0.849) with AUC0-12h. CONCLUSIONS: Our data indicate that elderly renal transplant recipients starting EVL 1 month after transplantation along with a steady-state TCL level, present stable EVL-PK parameters without significant changes in dose or exposure during the first 6 months after renal transplantation.

Longitudinal Pharmacokinetics of Tacrolimus in Elderly Compared With Younger Recipients in the First 6 Months After Renal Transplantation.

BACKGROUND: Elderly (Eld) (≥60 years) recipients are receiving renal transplants more frequently. The pharmacokinetics (PK) studies of immunosuppressive drugs in healthy volunteers, rarely, include old patients. METHODS: We studied 208 12-hour tacrolimus (TAC) PK (0, 20, 40, 60, 90, 120, 180, 240, 360, 480, 600, 720 min) in 44 Eld (65 ± 3 years) and compared the results with 31 younger controls (Ctrl) (35 ± 6 years) recipients, taking oral TAC/mycophenolate sodium (MPS)/prednisone, at 4 different timepoints: PK1 (8 ± 2 days; n = 72), PK2 (31 ± 4 days; n = 61), PK3 (63 ± 6 days; n = 44), and PK4 (185 ± 10 days; n = 31). Tacrolimus PK was measured by ultraperformance liquid chromatography coupled to a mass spectrometer repetition and noncompartmental PKs were analyzed using Phoenix WinNonlin. RESULTS: Mean TAC dose was lower in the Eld group than in Ctrl ones throughout timepoints either by total daily dose or adjusted (Adj) per body weight. Mean TAC trough level (Cmin), used to adjust daily dose, was not different between the 2 groups in all timepoints. AdjCmax and AdjTAC-area under the curve at dosing interval were both higher in the Eld compared to the Ctrl group in PKs1, 3, and 4. Estimated total body clearance normalized by dose and weight was lower in the Eld group compared with the Ctrl in all PKs and statistically lower at PKs 1 and 3. Similar to younger recipients TAC trough level has also a high correlation (R = 0.76) with area under the curve at dosing interval. CONCLUSIONS: These data indicate that Eld recipients have a lower TAC clearance and therefore need a lower TAC dose than younger recipients.

Noninvasive immune monitoring assessed by flow cytometry and real time RT-PCR in urine of renal transplantation recipients.

BACKGROUND: Monitoring recipient's alloreactivity has shown to be critical for limiting overimmunosuppression besides allowing preemptive treatment of acute rejection (AR). METHODS: Flow cytometry and real time RT-PCR were performed in urine of kidney transplant recipients with AR (n = 13) and compared with pyelonephritis (n = 10), chronic allograft nephropathy (n = 13), acute tubular necrosis (n = 13) and stable graft function (n = 11). Expression of CD3, CD4, CD8, HLA-DR, Fas-L, ICAM-1 and CD25 were assessed using flow cytometry. mRNA of perforin, granzyme B and Fas-L were quantified by real time RT-PCR. RESULTS: Frequencies of CD3+, HLA-DR+, Fas-L+, ICAM-1+ and CD25+ cells were significantly higher in AR group (p < 0.05). ROC curves showed sensitivity from 70% to 91% and specificity from 30% to 100%, whereas the highest sensitivity and specificity was 91% and 100% respectively, for Fas-L+ cells. Levels of mRNA of perforin, granzyme B and Fas-L were significantly augmented in AR, while the sensitivity and specificity ranged from 85% to 88% and from 55% to 100%, respectively. CONCLUSIONS: Analyses of immune activation markers by flow cytometry and real time RT-PCR are equally useful for noninvasive monitoring kidney allografts.

Frequency of Valpha24+Vbeta11+ NKT cells in peripheral blood of human kidney transplantation recipients.

There are still lacking data supporting a role for natural killer T (NKT) cells in the maintenance of human tissue-specific tolerance. We are interested to study NKT cell frequency in kidney transplant recipients and its correlation with graft function. Peripheral blood T cell receptors (TCR) Valpha24(+)Vbeta11(+) NKT cells were phenotyped according to CD4 and CD8 expression in normal controls (NC), in 10 years rejection-free cadaver kidney allografts maintained with minimal immunosuppression (long-term rejection free [LTRF]), in patients with acute rejection (AR) and in patients with acute tubular necrosis (ATN). Results were expressed as percentages of CD4(+)CD8(-) (CD4(+) NKT) or CD4(-)CD8(-) (double negative--DN NKT) Valpha24(+)Vbeta11(+) cells. The percentages of Valpha24(+)Vbeta11(+) cells were 0.09%, 0.14%, 0.02% and 0.09% on gated lymphocytes respectively in AR, ATN, LTRF and NC groups (p=0.263). DN NKT cells were more frequent in NC patients (52.11%) and less present in ATN patients (11.04%). In contrast, CD4(+) NKT (IL-4-producing NKT cells subset) was more frequent in AR (42.86%), and corresponded to almost 3 to 7 folds more what we obtained in the other groups. Although total Valpha24(+)Vbeta11(+) cells did not significantly differ among the groups, the lowest frequency was observed in the LTRF group. In conclusion, we observed that total number of NKT cells did not differ significantly among transplant patients when compared to normal controls, although specific-subsets seem to be more frequent in determined events.

Modulation of peripheral blood T-lymphocytes in kidney transplant recipients treated with low dose OKT3 therapy.

The immunosuppressive effect of OKT3 depends upon both T cell depletion and antigenic modulation of CD3 complex. To establish the effect of low doses of OKT3 on peripheral T lymphocytes, we analyzed 47 kidney transplant recipients receiving OKT3 for the first time. OKT3 was used as rescue therapy in 39 patients and as part of induction protocols in 8. The mean age of patients was 39+/-10 years, 30 were females and 9 were re-transplants. Half of them (51.1%) received kidney from cadaver donors. Among those receiving OKT3 as rescue therapy, 82% recovered graft function, including patients with severe BANFF-graded rejections. After the first dose of OKT3, it a pronounced T cell depletion was observed followed by an increase in CD4 and CD8 expression in CD3 negative T cells, supporting the idea that T cell modulation was present. In conclusion, low dose OKT3 was effective in treating severe allograft rejection by inducing a sustained TCR/CD3 down modulation without long-lasting T cell depletion.

Transplantation with kidneys retrieved from deceased donors with acute renal failure.

BACKGROUND: The discard rate of kidneys recovered from deceased donors with acute renal failure (ARF) is higher compared with those without ARF mainly due to the uncertainty regarding short-term and long-term outcomes. METHODS: We retrospectively analyzed 1-year patient, graft, and rejection-free survivals and renal function of transplantations performed with kidneys recovered from deceased donors with or without ARF, defined as serum creatinine level of more than 1.5 mg/dL. We performed multivariable analysis to evaluate whether ARF was an independent risk factor associated with inferior outcomes. RESULTS: Of a total of 1518 patients, 253 received kidneys from expanded-criteria donors (ECD; with ARF [n=116] and without ARF [n=137]) and 1265 from standard-criteria donors (SCD; with ARF [n=369] and without ARF [n=896]). The incidence of delayed graft function was higher in ECD (68.1% vs. 58.4%; P=0.072) and SCD (69.9% vs. 50.6%; P<0.001) recipients of kidneys with ARF compared with those without ARF, respectively. At 1 year, patient, graft, and rejection-free survivals were not statistically different in SCD or ECD recipients with or without ARF. Renal function at 1 year was similar in recipients of ECD (41.9±26.3 vs. 40.1±21.7 mL/min; P=0.565) or SCD (50.9±29.9 vs. 53.6±28.5 mL/min; P=0.131) kidneys with and without ARF, respectively. Compared with kidneys without ARF, receiving a kidney allograft with ARF was not associated with increased risk of death, graft lost, or inferior renal function 1 year after transplantation. CONCLUSION: In this cohort of patients, kidneys from deceased donors with ARF provided graft survival and renal function comparable with kidneys from donors without ARF 1 year after transplantation.

Clinical manifestations and evolution of infection by influenza A (H1N1) in kidney transplant recipients.

INTRODUCTION: The emergence of the pandemic outbreak of influenza A (H1N1) in April, 2009, represented a logistic challenge for public health. Although most infected patients presented clinical and evolutionary manifestations which were very similar to seasonal influenza, a significant number of individuals developed pneumonia and severe acute respiratory failure. The impact of influenza A (H1N1) in immunocompromised patients is not well established yet. METHODS: This study aimed to analyze the clinical presentations and evolution of influenza A (H1N1) in 19 kidney transplant recipients. Influenza A (H1N1) infection was confirmed by RT-PCR in all patients. Treatment included antiviral therapy with oseltamivir phosphate and antibiotics. RESULTS: The studied population was compounded mostly of white people (63%), males (79%), at a mean age of 38.6 ± 17 years and patients with at least one comorbidity (53%). Influenza A (H1N1) infection was identified 41.6 ± 49.6 months after transplantation. Common symptoms included cough (100%), fever (84%), dyspnea (79%), and myalgia (42%). Acute allograft dysfunction was observed in 42% of the patients. Five patients (26%) were admitted to the Intensive Care Unit, two (10%) required invasive ventilation support, and two (10%) required vasoactive drugs. Mortality rate was 10%. CONCLUSIONS: Acute renal allograft dysfunction was a common finding. Clinical, laboratory, and evolutionary characteristics were comparable to those in the general population.

Impact of delayed pancreatic graft function in simultaneous pancreas-kidney transplantation.

OBJECTIVE: Simultaneous pancreas-kidney transplantation is an effective treatment for patients with type 1 diabetes mellitus and end-stage chronic kidney disease. Delayed pancreatic graft function is a common and multifactor condition with significant impact in short-term outcome of simultaneous pancreas-kidney transplantations. The aim of this study was to analyze the impact of pancreatic delayed pancreatic graft function on simultaneous pancreas-kidney transplantation. METHODS: Donor and recipient's demographic data, percentage of panel reactivity, acute rejection incidence, and patient and grafts survivals were retrospectively analyzed in 180 SPKT performed between 2002 and 2007. RESULTS: The incidence of pancreatic delayed pancreatic graft function was 11%. Donors older than 45 years had significant risk of pancreatic delayed pancreatic graft function (OR 2.26; p < 0,05). Patients with pancreatic delayed pancreatic graft function had higher rates of acute renal rejection (47 versus 24%; p < 0.05), altered fasting plasma glucose (25 versus 5%; p < 0.05) and mean glycated hemoglobin (5.8 versus 5.4%; p < 0.05), than patients without pancreatic delayed pancreatic graft function at the end of the first year of follow up. There were no significant differences between patients with and without pancreatic delayed pancreatic graft function regarding patient survival (95 versus 88.7%; p = 0.38), pancreatic graft survival (90 versus 85.6%; p = 0.59) and renal graft survival (90 versus 87.2%; p = 0.70), respectively at the sample period of time. CONCLUSION: Pancreatic delayed pancreatic graft function had no significant impact in the short-term outcome of simultaneous pancreas-kidney transplantations. Although delayed pancreatic graft function had no impact on 1-year pancreas graft survival, it contributed to early pancreas graft dysfunction, as assessed by enhanced insulin and oral anti-diabetic drugs requirements.

Kidney transplantation in Brazil and its geographic disparity.

The Brazilian National Transplantation System coordinates and regulates perhaps the largest public transplantation program worldwide. Since its implementation in 1997, the number of kidney transplantations increased from 920 (5.8 pmp) in 1998, to 4,630 (24.1 pmp) in 2010. This growth was primarily due to the increased number of effective donors (from 1.8 pmp in 1998 to 9.3 pmp in 2010), with a corresponding increased number of kidneys transplanted from deceased donors (3.8 pmp in 1999 versus 9.9 pmp in 2010).The number of kidney transplantations from living donors has not increased significantly, from 1,065 (6.7 pmp) in 1998 to 1,641 (8.6 pmp) in 2010, either as a consequence of the observed increase in the deceased donor program or perhaps because of strict government regulations allowing only transplantations from related donors. From 2000 to 2009, the mean age of living donors increased from 40 to 45 years, while it increased from 33 to 41 years for deceased donors, of whom roughly 50% die of stroke. There are clear regional disparities in transplantation performance across the national regions. While the state of São Paulo is ranked first in organ donation and recovery (22.5 pmp), some states of the Northern region have much poorer performances. These disparities are directly related to different regional population densities, gross domestic product distribution, and number of trained transplantation physicians. The initial evaluation of the centers with robust outcomes indicates no clear differences in graft survival in comparison with centers in the USA and Europe. Ethnicity and time on dialysis, but not the type of immunosuppressive regimen, decisively influence the measured outcomes. Since the implementation of national clinical research regulations in 1996, Brazilian centers have participated in a number of national and international collaborative trials for the development of immunosuppressive regimens. Besides the challenge of reducing the regional disparities related to access to transplantation, further improvements can be obtained by the creation of a national registry of the outcomes of transplanted patients and living donors, and also by the promotion of clinical and experimental studies to better understand the transplantation-related immune response of the Brazilian population.

Steroid or tacrolimus withdrawal in renal transplant recipients using sirolimus.

BACKGROUND: Calcineurin inhibitor (CNI) and steroid (ST) withdrawal are strategies under investigation to reduce long-term toxicities associated with current immunosuppressive regimens. We conducted a single center, prospective trial comparing the efficacy and safety of CNI or ST withdrawal in kidney transplant recipients receiving sirolimus-based immunosuppressive regimen. METHODS: Forty-seven recipients of first renal transplant with non-HLA-identical living donors received sirolimus (SRL), tacrolimus (TAC), and ST without induction therapy and were randomized to undergo ST (TAC/SRL group, n = 24) or TAC (SRL/ST group, n = 21) withdrawal 3 months after transplantation. Primary efficacy and safety endpoints were the incidence of biopsy-confirmed acute rejection (BCAR) and renal function at 12 months. RESULTS: No differences were observed in the incidence of BCAR (4.2% vs. 9.5%), graft (95.8% vs. 95.6%), and patient (95.8% vs. 95.6%) survivals or in renal function (60 ± 11.5 vs. 63.4 ± 10.5 ml/min, P = 0.361). Higher mean cholesterol concentration was observed in the SRL/ST group (191.9 ± 63.3 vs. 241.6 ± 61.5 mg/dl, P = 0.019). Treatment discontinuation due to adverse events occurred in 12.5% of patients in TAC/SRL group and 21.7% in SRL/ST group. CONCLUSION: Within this short period of observation, our study was unable to detect any significant difference in major transplant outcomes comparing CNI and ST elimination strategies.

[Incidence of infectious complications and their risk factors in the first year after renal transplantation].

INTRODUCTION: Infectious complications significantly increase morbidity and mortality after renal transplantation. The immunosuppression used is the main risk factor and relates directly to the incidence and severity of infectious events. METHODS: This is a retrospective cohort study, which assessed the incidence of infections and their risk factors among 1,676 kidney transplant recipients during the first year of follow-up. RESULTS: Infectious events were observed in 821 (49%) patients. The mean number of infectious episodes among patients with at least one episode was 2.3 (1 -12). The most prevalent infectious complications were as follows: urinary tract infection (31.3%); cytomegalovirus infection (12%); surgical wound infection (10.3%); herpes virus infection (9.1%); pulmonary infection (5.2%); and bloodstream infection (4.3%). Cold ischemia time and the use of deceased donor grafts were important risk factors for infectious episodes. CONCLUSIONS: Infections are highly prevalent in the first year following transplantation. The main infectious complication was urinary tract infection.

One unit's experiences when establishing buttonhole technique, analysis of reasons for failure of procedure: a report.

The buttonhole technique of access of needle insertion into a single selected site in the arteriovenous fistula has proved to be a reliable alternative to older methods due to its overall low complication rates. Although the use of blunt needles improves the technique, the success rate of cannulation with these needles is difficult to predict. We analysed the short-term outcome of 16 patients receiving in-centre haemodialysis and compared clinical relevant parameters between patients with and without buttonhole technique failure. Our dialysis unit treats about 180 patients and is located in a tertiary hospital in Sao Paulo, Brazil. The variables as discussed in the paper were the same for both groups. The incidence of technique failure was 43.7%. Patients enrolled later in the study had a better buttonhole failure-free survival rates than patients enrolled at the beginning (p < 0.05). Patients' clinical characteristics did not predict the success rate of buttonhole tunnel tracks cannulation with blunt needles. This paper also reports on our successes and failures in buttonhole technique and gives some reasons and reflections for both.

[Overcoming limits with deceased donors: successful renal transplantations from a donor with serum creatinine of 13.1 mg/dL].

Non-expanded deceased donors with acute kidney failure can be a safe option to increase the number of kidneys for transplantation. Histological evaluation is fundamental to establish the functional prognosis of those grafts. Two kidney transplantations were performed from a young deceased donor with severe acute kidney failure and no structural change in the renal parenchyma. Both patients had postoperative delayed graft function, but one of them, who had good initial urinary volume, required no dialysis. Adequate renal function was present at day 30 after transplantation. Severe acute kidney failure in deceased donors is not an independent risk factor for short-term outcome of renal graft and should not be considered an absolute contraindication for transplantation.

[Alemtuzumab induction in kidney transplant recipients].

INTRODUCTION: Induction therapy has been used in sensitized patients, re-transplants, and in patients who have high risk to delayed graft function (DGF) after renal transplantation. METHODS: Retrospective study with aim to compare transplant endpoints between recipients of deceased donors which have received induction with alemtuzumab (n = 9) versus thymoglobulin (n = 18). Patients were matched for age, duration of dialysis treatment and cold ischemia time. RESULTS: There were no differences at demographic characteristics. All patients received kidney grafts from deceased donors and 67% of these donors met the expanded criteria. The incidence of DFG was similar in alemtuzumab and thymoglobulin groups, 55% and 56%. At 12 months, rates of rejection free survival (67% versus 89%, p = 0,13), graft survival (62,5% versus 76,6%; p = 0,73), graft with death censored (62,5% versus 76,6%; p = 0,82) and patient survival (83,3% versus 81,2%; p = 0,63) were similar between the two groups. Viral infections and renal function were similar between groups. At the end of the first month, alemtuzumab patients displayed a fewer lymphocyte number (135 ± 78 versus 263 ± 112 N/mm³, p < 0,05) followed by a more rapid recovery after 3 months (day 90: 683 ± 367 versus 282 ± 72 N/mm³; p < 0,05). Cost associated with alemtuzumab and thymoglobulin inductions therapies were R$ 1,388.00 and R$ 7,398.00. CONCLUSION: In this cohort of patients, alemtuzumab induction showed efficacy and safety comparable to thymoglobulin but with significant cost reduction.

Buttonhole, em casa de botão ou botoeira: uma técnica antiga redescoberta: [carta ao editor] / Buttonhole: an old technique rediscovered: [letter to the editor]

A presente carta ao Editor aborda os artigos de Silva et al. Õ e de Castro et al. ² que nos levam a dois tipos de comentários: o primeiro de ordem linguística, e o segundo referente a aspectos médicos.

The present letter to the Editor regards the articles by de Silva et al. Õ and de Castro et al. ² that lead us to two kinds of comments, the first refers to the language, and the second comment refers to the medical aspects.