Sexual acquisition of HIV infection after solid organ transplantation: Late presentation and potentially fatal complications.

INTRODUCTION: While the growing knowledge on HIV among solid organ transplant recipients (SOT) is limited to either pretransplant infection or allograft transmission, there are only sparse reports describing HIV-infection after transplantation through sexual route, the primary mode of transmission in the general population. METHODS: From two different centers, we report nine new cases of HIV infection in SOT recipients attributed to sexual acquisition: eight cases of kidney-transplant recipients and one heart-transplant recipient. FINDINGS: There were nine cases of post-transplant HIV-infection detected among 14 526 transplants performed 1998 to 2015. In 6/9 cases, infection was contracted 5 years after SOT. All but one patient had stable allograft function under immunosuppressive therapy. The main trigger to diagnosis was late CMV disease and sexually transmitted diseases; five patients had CDC-stage 3 HIV infection. In 7/9 patients, virologic response and CD4 recovery were achieved within 3 months after starting antiretroviral therapy (ART). After an average of 3.6 years post diagnosis, 5/9 patients remained alive with well-controlled infection and functioning allograft. CONCLUSION: Sexual acquisition of HIV infection after SOT represents a difficult challenge, as it may occur in any kind of transplant and at any time. The course of infection resembles that of the general population, with life-threatening infectious complications, but good response to ART. Assessment of lifestyle and risk behavior is paramount, as indications may be not disclosed without direct questioning.

Renal transplantation in human immunodeficiency virus-infected recipients: a case-control study from the Brazilian experience.

BACKGROUND: Highly active antiretroviral therapy has turned human immunodeficiency virus (HIV)-infected patients with end-stage renal disease into suitable candidates for renal transplantation. We present the Brazilian experience with kidney transplantation in HIV-infected recipients observed in a multicenter study. METHODS: HIV-infected kidney transplant recipients and matched controls were evaluated for the incidence of delayed graft function (DGF), acute rejection (AR), infections, graft function, and survival of patients and renal grafts. RESULTS: Fifty-three HIV-infected recipients and 106 controls were enrolled. Baseline characteristics were similar, but a higher frequency of pre-transplant positivity for hepatitis C virus and cytomegalovirus infections was found in the HIV group. Immunosuppressive regimens did not differ, but a trend was observed toward lower use of anti-thymocyte globulin in the group of HIV-infected recipients (P = 0.079). The HIV-positive recipient group presented a higher incidence of treated AR (P = 0.036) and DGF (P = 0.044). Chronic Kidney Disease Epidemiology Collaboration estimated that glomerular filtration rate was similar at 6 months (P = 0.374) and at 12 months (P = 0.957). The median number of infections per patient was higher in the HIV-infected group (P = 0.018). The 1-year patient survival (P < 0.001) and graft survival (P = 0.004) were lower, but acceptable, in the group of HIV-infected patients. CONCLUSIONS: In the Brazilian experience, despite somewhat inferior outcomes, kidney transplantation is an adequate therapy for selected HIV-infected recipients.

Long-term exposure to belatacept in recipients of extended criteria donor kidneys.

Patients in the BENEFIT-EXT study received extended criteria donor kidneys and a more intensive (MI) or less intensive (LI) belatacept immunosuppression regimen, or cyclosporine A (CsA). Patients who remained on assigned therapy through year 3 were eligible to enter a long-term extension (LTE) study. Three hundred four patients entered the LTE (n = 104 MI; n = 113 LI; n = 87 CsA), and 260 continued treatment through year 5 (n = 91 MI; n = 100 LI; n = 69 CsA). Twenty patients died during the LTE (n = 5 MI; n = 9 LI; n = 6 CsA), and eight experienced graft loss (n = 2 MI; n = 1 LI; n = 5 CsA). Three patients experienced an acute rejection episode (n = 2 MI; n = 1 LI). The incidence rate of serious adverse events, viral infections and fungal infections was similar across groups during the LTE. There were four cases of posttransplant lymphoproliferative disorder (PTLD) from the beginning of the LTE to year 5 (n = 3 LI; n = 1 CsA); two of three PTLD cases in the LI group were in patients who were seronegative for Epstein-Barr virus (EBV(-)) at transplantation. Mean ± SD calculated GFR at year 5 was 55.9 ± 17.5 (MI), 59.0 ± 29.1 (LI) and 44.6 ± 16.4 (CsA) mL/min/1.73 m(2) . Continued treatment with belatacept was associated with a consistent safety profile and sustained improvement in renal function versus CsA over time.

Planned randomized conversion from tacrolimus to sirolimus-based immunosuppressive regimen in de novo kidney transplant recipients.

Planned conversion from tacrolimus to sirolimus was evaluated in de novo kidney transplant recipients. In this multicenter, randomized, open-label study, 297 patients were initially treated with tacrolimus, mycophenolate sodium and prednisone. Of the 283 patients reaching 3 months, 97 were converted to sirolimus (SRL), 107 were maintained on tacrolimus (TAC) and 79 were patients receiving TAC without criteria to undergo intervention at month 3 (TACex). The primary objective was to show superior estimated glomerular filtration rate (eGFR) in the SRL group at month 24. Of the 258 patients who completed 24 months, 91 (94%) were in the SRL group, 101 (94%) in the TAC group and 66 (84%) in the TACex group. In the intention-to-treat population there were no differences in eGFR (66.2 ± 25.3 vs. 70.7 ± 25.1, p = 0.817) or in the severity of chronic sclerosing lesions scores in 24-month protocol biopsies. Higher mean urinary protein-to-creatinine ratio (0.36 ± 0.69 vs. 0.15 ± 0.53, p = 0.03) and higher incidence of treated acute rejection between months 3-24 (13.4% vs. 4.7%, p = 0.047) were observed in SRL compared to TAC group. In this population planned conversion from TAC to SRL 3 months after kidney transplantation was not associated with improved renal function at 24 months.

Safety profile comparing azathioprine and mycophenolate in kidney transplant recipients receiving tacrolimus and corticosteroids.

BACKGROUND: Debate is increasing on whether mycophenolic acid (MPA) provides survival benefits comparable to azathioprine (AZA) after renal transplantation. METHODS: This retrospective cohort study compared safety and efficacy of AZA (n = 662) vs. MPA (n = 267) in low-immunologic-risk kidney transplant recipients (KTR) receiving tacrolimus (TAC) and steroids between 1998 and 2007. Primary outcomes were treatment discontinuation and infection. Secondary endpoints included survival free from biopsy-proven acute rejection, graft loss, death, and renal function. RESULTS: The 5-year survival free of treatment discontinuation was higher in the MPA compared to the AZA group (74.1% vs. 60.3%, P < 0.001). MPA was discontinued exclusively because of adverse events (16.4%), while AZA was discontinued primarily for lack of efficacy (21.2%). In univariable analysis, MPA was associated with higher incidence of total (561.5 vs. 667.5 episodes/1000 person-year, P < 0.001), bacterial (167 vs. 158 episodes/1000 person-years, P = 0.001), and viral infections (83.2 vs. 100.4 episodes/1000 person-years, P = 0.001), but this association was not confirmed in multivariable analysis. Over 29% of viral infections in the AZA group occurred after conversion to MPA. A high incidence of tuberculosis was observed (2.9 episodes/1000 person-years) with a higher incidence (but not a statistically significant difference) in the AZA group. No significant differences were found in patient survival (90% vs. 89%, P = 0.78) or graft survival (81% vs. 77.7%, P = 0.08), but infection accounted for >50% of all deaths. CONCLUSION: The type of antimetabolite, AZA or MPA, was not independently associated with any safety or efficacy outcome 5 years after transplantation, suggesting that AZA is still a viable option for low-risk KTR receiving TAC and steroids.

Three-year outcomes from BENEFIT-EXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys.

Recipients of extended-criteria donor (ECD) kidneys have poorer long-term outcomes compared to standard-criteria donor kidney recipients. We report 3-year outcomes from a randomized, phase III study in recipients of de novo ECD kidneys (n = 543) assigned (1:1:1) to either a more intensive (MI) or less intensive (LI) belatacept regimen, or cyclosporine. Three hundred twenty-three patients completed treatment by year 3. Patient survival with a functioning graft was comparable between groups (80% in MI, 82% in LI, 80% in cyclosporine). Mean calculated GFR (cGFR) was 11 mL/min higher in belatacept-treated versus cyclosporine-treated patients (42.7 in MI, 42.2 in LI, 31.5 mL/min in cyclosporine). More cyclosporine-treated patients (44%) progressed to GFR <30 mL/min (chronic kidney disease [CKD] stage 4/5) than belatacept-treated patients (27-30%). Acute rejection rates were similar between groups. Posttransplant lymphoproliferative disorder (PTLD) occurrence was higher in belatacept-treated patients (two in MI, three in LI), most of which occurred during the first 18 months; four additional cases (3 in LI, 1 in cyclosporine) occurred after 3 years. Tuberculosis was reported in two MI, four LI and no cyclosporine patients. In conclusion, at 3 years after transplantation, immunosuppression with belatacept resulted in similar patient survival, graft survival and acute rejection, with better renal function compared with cyclosporine. As previously reported, PTLD and tuberculosis were the principal safety findings associated with belatacept in this study population.

The emerging role of Brazil in clinical trial conduct for transplantation.

Brazil is a country with over 190 000 000 inhabitants and a health system composed of a large public, government managed system. Between 1999 and 2010 the number of deceased donors increased by 161%, from 3.8 to 9.9 pmp, and the number of solid organ transplants increased by 121%, from 2891 to 6402. This growth was a consequence of the creation of a well-organized national transplant program. Government funding, decentralization and educational investment in transplant coordinators and related professional were decisive. In 2009 Brazil was the second largest country in the absolute number of kidney transplants (n = 4259). There are significant region disparities in performance which are mainly due to the development status. Improvements in transplant and research regulations resulted in an increasing participation of Brazilian transplant centers in multicenter trials, reaching over 44 studies during the last 11 years. Brazilian centers have been involved in clinical trials using everolimus, sirolimus, fingolimod, mycophenolate mofetyl, mycophenolate sodium, tacrolimus modified-release, sotrastaurin, belatacept, JAK3 inhibitor CP690,550 and valganciclovir. The still increasing number of transplants performed every year along with more efficient regulatory and sanitary analysis, organized clinical research programs and reduction in region performance disparities will eventually increase even more the participation of Brazil in trials worldwide.

Extreme subcutaneous, intramuscular and inhaled insulin resistance treated by pancreas transplantation alone.

Diabetes mellitus with resistance to insulin administered subcutaneously or intramuscularly (DRIASM) is a rare syndrome and is usually treated with continuous intravenous insulin infusion. We present here two cases of DRIASM in 16 and 18 years female patients that were submitted to pancreas transplantation alone (PTA). Both were diagnosed with type 1 diabetes as young children and had labile glycemic control with recurrent episodes of diabetic ketoacidosis. They had prolonged periods of hospitalization and complications related to their central venous access. Exocrine and endocrine drainages were in the bladder and systemic, respectively. Both presented immediate graft function. In patient 1, enteric conversion was necessary due to reflux pancreatitis. Patient 2 developed mild postoperative hyperglycemia in spite of having normal pancreas allograft biopsy and that was attributed to her immunosuppressive regimen. Patient 1 died 9 months after PTA from septic shock related to pneumonia. In 8 months of follow-up, Patient 2 presented optimal glycemic control without the use of antidiabetic agents. In conclusion, PTA may be an alternative treatment for DRIASM patients.

What is the impact of surgical site infection on graft function in kidney transplant recipients?

The impact of surgical site infections (SSIs) on graft function in kidney transplant recipients is controversial. We conducted a matched case-control study (1:1 ratio) between April 2001 and December 2004 in a Brazilian cohort of kidney transplant recipients. The epidemiological and clinical characteristics of SSIs were described based on chart review. The impact on graft function was assessed by comparing serum creatinine measurements and creatinine clearance up to 18 months after transplantation with analysis of variance model. Among 1939 kidney transplants, 120 patients with 145 SSIs were enrolled. Most wound infections were superficial (73.1%). The mortality rate was 0.8%. No impact on graft function was detected. In conclusion, accurate identification of SSIs may have resulted in shorter hospitalization periods, but they had no impact on graft function up to 18 months post transplantation.

Serum levels of YKL-40 and hyaluronic acid as noninvasive markers of liver fibrosis in haemodialysis patients with chronic hepatitis C virus infection.

Hepatitis C virus (HCV) infection is highly prevalent among end-stage renal disease (ESRD) patients undergoing haemodialysis and it is an important cause of morbidity and mortality in this population. The aim of this study was to evaluate the diagnostic value of YKL-40 and hyaluronic acid (HA) as noninvasive markers of liver fibrosis in 185 ESRD HCV-infected patients. Significant liver fibrosis was defined as METAVIR F2, F3 or F4 stages. Significant fibrosis was observed in 45 patients (24%). By univariate analysis, higher levels of YKL-40, HA, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) as well as reduced platelet count were associated with fibrosis. However, by multivariate analysis, only AST (P = 0.001), platelet count (P = 0.004) and HA (P = 0.042) were independently associated with significant fibrosis. For the prediction of significant fibrosis, the areas under receiver operating characterictic curve (AUROC) of the regression model (0.798) was significantly higher than the AUROC of YKL-40 (0.607) and HA (0.650). No difference was noted between the AUROC of the regression model and AST to platelet ratio index (APRI) (0.787). Values <8.38 of the regression model showed a negative predictive value of 94% and scores >or=9.6 exhibited a positive predictive value of 65%. If biopsy indication was restricted to scores in the intermediate range of the regression model, it could have been correctly avoided in 61% of the cases. In conclusion, APRI and a model based on AST, platelet count and HA showed better accuracy than YKL-40 and HA (when used solely) for the prediction of significant fibrosis in ESRD HCV-infected patients.

Exploratory calcineurin inhibitor-free regimens in living-related kidney transplant recipients.

Chronic allograft nephropathy is among the major causes of graft loss even in low-risk kidney transplant recipients and correlates with acute nephrotoxic events during the first year post-transplant. Therefore, calcineurin inhibitor-free regimens may improve patient and graft survival among recipients of living-related kidney transplants. To confirm this hypothesis, we evaluated the efficacy and safety of two calcineurin inhibitor-free regimens in 92 low-risk recipients of one-haplotype living-related kidney transplants. Immunosuppression consisted of tacrolimus, azathioprine and prednisone (group I, GI, N = 38), 2 doses of daclizumab, mycophenolate mofetil (MMF), and prednisone (GII, N = 33) and 2 doses of daclizumab, MMF, sirolimus and prednisone (GIII, N = 21). At 12 months, treatment failure (biopsy-confirmed acute rejection, graft loss or death) was higher in GII compared to GIII and GI (54.5 vs 24.0 vs 13.1%, P < 0.01, respectively). In patients of black ethnicity the incidence of acute rejection was 25 vs 83.3 vs 20% (P = 0.055), respectively. Patient and graft survival was comparable. There were no differences in mean creatinine or calculated creatinine clearance at 12 months. Overall incidence of post-transplant diabetes mellitus (3.3%) and cytomegalovirus disease (4.3%) was similar in all groups. Further development of effective calcineurin inhibitor-free regimens should exclude patients of black ethnicity and may need full-induction therapy, perhaps with depleting agents, and concentration-controlled use of sirolimus and MMF.

Worse renal transplant outcomes observed among Afro-Brazilian patients on prospective registry data of 2461 renal transplants at least 1 year follow-up.

We present prospective registry data of 2461 (live donor = 1753 and deceased donor = 08) renal transplants performed between 1999 and 2003. All subjects were followed for more than 1 year after transplantation and most were treated with a calcineurin inhibitor and azathioprine. Afro-Brazilian, white, and mixed patients constituted 11% (272), 67.1% (1651), and 14.9% (367) of the population respectively. Mean dialysis time was 42.3 +/- 32.9 months and delayed graft function, occurred in more than 60%. Three-year patient survival rates were 96.3%, 92.8%, and 86.7% for living-related, living-unrelated, and deceased donors, respectively. Corresponding 3-year graft survival rates were 87.3%, 82.1%, and 71.3% and functional graft survival rates were 90.2%, 88.8%, and 81.5%. The poorer transplant outcome observed among Afro-Brazilian patients has been mainly attributed to differences in absorption of cyclosporine, tacrolimus, and mycophenolate mofetil.

Deceased organ donation in Brazil: how can we improve?

METHODS: We retrospectively analyzed the registry data from one organ procurement organization obtained between January 1 and December 31, 2005. RESULTS: Among the 378 potential deceased donors, 182 (48.2%) were lost, mainly due to clinical conditions (27%) or cardiac arrest (19.3%). Of the remaining 196 (51.8%) potential donors, family consent was obtained in 94 cases (48%). Family refusal was higher for potential donors aged between 18 and 59 years (70%). Of the 94 donors, 72 (77%) had their organs harvested. Cardiac arrest before harvesting (56.5%) and positive viral serology (26%) were the main reasons for further losses. The mean donor age was 40 years and 51% were men. Causes of death were cerebral vascular accidents (55.5%), cranium encephalic traumas (29%), and gun shot wounds (8%). The rate of organ donation was 100% for kidneys and livers, 96% for hearts, 86% for pancreatas, 76% for lungs, and 74% for corneas. After assessment of organ viability, 94% of corneas, 91% of kidneys, and 88% of livers were transplanted, but only 52% of pancreata and 42% of hearts. The most frequent causes of discarded organs were age and concomitant donor infection. CONCLUSION: Areas for potential improvements are: (1) earlier identification and adequate maintenance of potential donors; (2) campaigns for organ donation; and (3) careful evaluation of donated organs and selection of a suitable population to increase utilization of expanded criteria organs.

Thymoglobulin and rate of infectious complications after transplantation.

UNLABELLED: Thymoglobulin is used as an induction agent in kidney transplantation, but the optimal dose is not well established. However, its use may be associated with increased infectious complications after transplantation. METHODS: This retrospective study of 61 high-risk renal recipients of transplants from deceased donors performed between June 2001 and April 2004 included patients treated with thymoglobulin. Patients were divided into two groups according to the total thymoglobulin dose (G1, n = 30, <7 mg/kg; G2, n = 31, >7 mg/kg) and followed for at least 1 year. RESULTS: Mean recipient age was 43 +/- 14 years; 41% were males; 63% non-Whites. Mean cold ischemia time was 26.3 +/- 7 hours. Mean PRA was 23% (0-100%). Second transplantation was performed in 18 (29.5%) patients. Mean donor age was 42.1 +/- 16 years, and 59% had a cerebral vascular accident as the cause of death. Patient- and death-censored graft survival at 12 months were 86% and 88%, respectively. There were 149 infectious episodes among 47 (78%) patients. The incidence of infection was 1.7 +/- 0.24 infections per patient per year in G1 (lower dose) vs 3.12 +/- 0.23 in G2 (P < .001). Bacterial (0.66 +/- 1.0 vs 1.48 +/- 1.26 infections per patient per year, P = .009) and viral infections (0.9 +/- 0.71 vs 1.41 +/- 0.71; P = .006) were more frequent in the higher dose group. CONCLUSION: This study suggested that a greater number of infectious episodes were present when the total dose of thymoglobulin was higher than 7 mg/kg.

Melanized fungal infections in kidney transplant recipients: contributions to optimize clinical management.

OBJECTIVES: This is a retrospective and observational study addressing clinical and therapeutic aspects of melanized fungal infections in kidney transplant recipients. METHODS: We retrospectively reviewed medical records of all patients admitted between January 1996 and December 2013 in a single institution who developed infections by melanized fungi. RESULTS: We reported on 56 patients aged between 30 and 74 years with phaeohyphomycosis or chromoblastomycosis (0.54 cases per 100 kidney transplants). The median time to diagnosis post-transplant was 31.2 months. Thirty-four (60.8%) infections were reported in deceased donor recipients. Fifty-one cases of phaeohyphomycosis were restricted to subcutaneous tissues, followed by two cases with pneumonia and one with brain involvement. Most dermatological lesions were represented by cysts (23/51; 45.1%) or nodules (9/51; 17.9%). Exophiala spp. (34.2%) followed by Alternaria spp. (7.9%) were the most frequent pathogens. Graft loss and death occurred in two patients and one patient, respectively. Regarding episodes of subcutaneous phaeohyphomycosis, a complete surgical excision without antifungal therapy was possible in 21 of 51 (41.2%) patients. Long periods of itraconazole were required to treat the other 30 (58.8%) episodes of subcutaneous disease. All four cases of chromoblastomycosis were treated only with antifungal therapy. CONCLUSIONS: Melanized fungal infections should be considered in the differential diagnosis of all chronic skin lesions in transplant recipients. It is suggested that the impact of these infections on graft function and mortality is low. The reduction in immunosuppression should be limited to severely ill patients.

Relationship of cyclosporin and sirolimus blood concentrations regarding the incidence and severity of hyperlipidemia after kidney transplantation.

The influence of drug concentrations on the development of persistent posttransplant hyperlipidemia was investigated in 82 patients who received cyclosporin A (CsA) and prednisone plus sirolimus (SRL) (52) or azathioprine (AZA) (30) during the first year after transplantation. Blood levels of CsA and SRL, daily doses of AZA and prednisone, and cholesterol, triglyceride, and glucose concentrations were determined during each visit (pretransplant and 30, 60, 90, 120, 180, and 360 days posttransplant). Persistent hyperlipidemia was defined as one-year average steady-state cholesterol (CavCHOL) or triglyceride (CavTG) concentrations above 240 and 200 mg/dL, respectively. Mean cholesterol and triglyceride concentrations increased after transplantation (P < 0.01) and were higher in patients receiving SRL compared to AZA (P < 0.001). Patients receiving SRL showed a significantly higher number of cholesterol (> 229 or > 274 mg/dL) and triglyceride (> 198 or > 282 mg/dL) determinations in the upper interquartile ranges. CsA and SRL interquartile ranges correlated with cholesterol concentrations (P = 0.001) whereas only SRL interquartile ranges correlated with triglyceride concentrations (P < 0.0001). Only pretransplant cholesterol concentration > 205 mg/dL was independently associated with development of persistent hypercholesterolemia (CavCHOL > 240 mg/dL, relative risk (RR) = 20, CI 3.8-104.6, P = 0.0004) whereas pretransplant triglyceride concentration > 150 mg/dL (RR = 7.2, CI 1.6-32.4, P = 0.01) or > 211 mg/dL (RR = 19.8, CI 3.6-107.9, P = 0.0006) and use of SRL (RR = 3, CI 1.0-8.8, P = 0.0049) were independently associated with development of persistent hypertriglyceridemia (CavTG > 200 mg/dL). Persistent hypercholesterolemia was more frequent among patients with higher pretransplant cholesterol concentrations and was dependent on both CsA and SRL concentrations. Persistent hypertriglyceridemia was more frequent among patients with higher pretransplant triglyceride concentrations and was dependent on SRL concentrations.

Severe hyperkalemic type 4 renal tubular acidosis after kidney transplantation: a case report.

BACKGROUND: Hyperkalemia after transplantation is a common event, occurring in up to 70% of patients. It is usually asymptomatic but sometimes manifests as muscle weakness or cardiac arrhythmias. METHODS: Case report. RESULTS: At 102 days after a second cadaveric kidney transplantation, a 15-year-old boy, was admitted to the emergency room with severe muscle weakness. His examinations showed a serum potassium of 9.8 mEq/L; blood pH 7.1; serum bicarbonate 7.6 mmol/L; and creatinine 2.5 mg/dL. He was initially treated with sodium bicarbonate, calcium gluconate, and furosemide. Subsequent investigation showed hyperchloremic metabolic acidosis, urinary pH <5.5, positive urinary anion gap, reduced transtubular potassium gradient (TTKG, 1.5) and low levels of aldosterone (0.7 ng/mL), suggesting the presence of type 4 renal tubular acidosis (RTA). Other causes of hyperkalemia were excluded in the present case. Serum levels of potassium returned to normal when fludrocortisone was added to the bicarbonate supplementation. This case of severe hyperkalemic secondary to type 4 RTA after kidney transplantation only responded to the combination of alkali and mineralocorticoid therapies.

Initial response to immunosuppressive and renoprotective treatment in posttransplant glomerulonephritis.

UNLABELLED: The current studies on posttransplant glomerulonephritis (PTxGN) do not establish when, how, or how long we must treat these patients. This study sought to compare the initial response to immunosuppressive treatment and renoprotection in PTxGN. PATIENTS AND METHODS: This prospective study was performed in 23 patients with a histological diagnosis of PTxGN. RESULTS: Mean follow-up was 12 months (3-18); 91% received immunosuppressants, and 56.5% just renoprotective drugs. The best results (reduction of serum creatinine [SCr] and proteinuria) with immunosuppression were observed in patients with recurrent membranous PTxGN using the scheme of Ponticelli (IV + PO corticosteroid [CS] + PO cyclophosphamide [CPP]). A similar response was also seen in subjects with recurrent or de novo focal glomerulosclerosis treated with PO CS or CPP, except when the initial SCr > 2.5 mg/dL. In de novo IgA nephropathy, reduction of proteinuria occurred with use of PO CS, with or without CPP, but without improvement in SCr. Patients with recurrent or de novo crescentic PTxGN used renoprotective drugs and always immunosuppressants. In this group, good results were seen with IV + PO CS, with or without CPP, when there was less than 50% of glomeruli with crescents, or more than 50% with crescents but an initial SCr < 2.5 mg/dL. CONCLUSION: Immunosuppression seemed to give a better initial response than renoprotection in cases of membranous, IgA, and focal segmental glomulerulosclerosis PTxGN. Patients with an initial SCr > or = 2.5 mg/dL displayed worse outcomes.

Conversion from azathioprine to mycophenolate mofetil followed by calcineurin inhibitor minimization or elimination in patients with chronic allograft dysfunction.

UNLABELLED: The purpose of this study was to evaluate the effects of the conversion from azathioprine (AZA) to mycophenolate mofetil (MMF) followed by calcineurin inhibitor (CNI) elimination or minimization in patients with progressive chronic allograft dysfunction (CAD). METHODS: Between November 6, 1999 and February 12, 2003, 169 patients receiving CNI/AZA/prednisone (153 CsA; 14 tacrolimus) were included in this study. Demographics, immunosuppression, graft function, hematology, and biochemistry were obtained before (-6, -3, and -1 month) and 1, 3, 6, 9 and 12 months after and at last follow-up visit after conversion. RESULTS: Mean age was 34 +/- 12 years, 66% males, 51% Caucasian, and 72% living allograft recipients. Mean follow-up times before and after conversion were 32.4 and 19.4 months; 10 patients completed 3 years of follow-up. CNI elimination was performed in 39% and minimization in 61% of patients. Overall there was significantly improved graft function at 1 year after conversion (2.6 +/- 1.0 vs 2.1 +/- 0.6 mg/dL, P = .038). The slopes of the regression lines of 1/Cr vs time were significantly improved from preconversion to after conversion (-0.026 vs +0.007 mg(-1)/dL per day(-1), P = .001). There was a significant decrease in mean systolic (141 +/- 21 vs 135 +/- 22 mm Hg, P = .015) and diastolic (89 +/- 15 vs 84 +/- 14 mm Hg, P = .005) blood pressure values at 1 year. There were four episodes of acute rejection (Banff IA) treated with steroids. Three years after conversion, patient and graft survivals were 95% and 79%, respectively. One patient developed posttransplant lymphoproliferative disease. CONCLUSION: Among patients with CAD, conversion from AZA to MMF followed by CNI minimization or elimination was a safe and effective strategy to preserve or improve graft function.

Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients.

FTY720 is a new and effective immunosuppressive agent, which produces peripheral blood lymphopenia through a lymphocyte homing effect. We investigated the relationship between the dose of FTY720 or blood concentration (pharmacokinetics, PK) and peripheral lymphopenia (pharmacodynamics, PD) in 23 kidney transplant recipients randomized to receive FTY720 (0.25-2.5 mg/day) or mofetil mycophenolate (2 mg/day) in combination with cyclosporine and steroids. FTY720 dose, blood concentrations and lymphocyte counts were determined weekly before and 4 to 12 weeks after transplantation. The effect of PD was calculated as the absolute lymphocyte count or its reductions. PK/PD modeling was used to find the best-fit model. Mean FTY720 concentrations were 0.36 +/- 0.05 (0.25 mg), 0.73 +/- 0.12 (0.5 mg), 3.26 +/- 0.51 (1 mg), and 7.15 +/- 1.41 ng/ml (2.5 mg) between 4 and 12 weeks after transplantation. FTY720 PK was linear with dose (r(2) = 0.98) and showed low inter- and intra-individual variability. FTY720 produced a dose-dependent increase in mean percent reduction of peripheral lymphocyte counts (38 vs 42 vs 56 vs 77, P < 0.01, respectively). The simple Emax model [E = (Emax * C)/(C + EC50)] was the best-fit PK/PD modeling for FTY720 dose (Emax = 87.8 +/- 5.3% and ED50 = 0.48 +/- 0.08 mg, r(2) = 0.94) or concentration (Emax = 78.3 +/- 2.9% and EC50 = 0.59 +/- 0.09 ng/ml, r(2) = 0.89) vs effect (% reduction in peripheral lymphocytes). FTY720 PK/PD is dose dependent and follows an Emax model (EC50 = 0.5 mg or 0.6 ng/ml). Using lymphopenia as an FTY720 PD surrogate marker, high % reductions (~80%) in peripheral lymphocytes are required to achieve best efficacy to prevent acute allograft rejection.