Acute Antibody-Mediated Rejection in Kidney Transplant Based on the 2013 Banff Criteria: Single-Center Experience in Uruguay.

BACKGROUND: Acute antibody-mediated rejection (AMR) diagnosis criteria have changed in recent consensus of Banff, with current evidence of C4d-negative AMR. Our objective was to evaluate incidence of AMR in renal transplantation according to Banff 2013 criteria and to examine the histological features and outcome. METHODS: This retrospective study involved all kidney transplants with histological diagnosis of acute rejection (AR) at our center between 2000 and 2014. All the biopsies with AR were re-assessed by a nephro-pathologist and classified by use of the Banff 2013 criteria. RESULTS: Of 205 kidney transplants, biopsy-proven AR was diagnosed in 25 cases (12%). Re-assessing them according to Banff 2013 criteria, AMR was diagnosed in 17 (8.3%) and represented 68% of the confirmed rejections. AMR diagnosis was performed on day 23 ± 26, with median of 11 days. From the 17 cases, 7 had concomitant T-cell-mediated rejection. All cases presented endothelial edema and acute tubular necrosis. Glomerulitis was found in 12 cases and capillaritis in 14. In 3, associated thrombotic micro-angiopathy (TMA) was found. Intimal and transmural arteritis was evidenced in 5 and 1 patient. In 2, transplant glomerulopathy was present. Seven of the 10 biopsies with C4d staining in the peri-tubular capillaries were positive. Twelve cases received plasmapheresis, 6 received gamma-globulin, and 6 received rituximab. After administration of anti-AMR therapy, 16 cases recovered renal function, reaching a serum creatinine level of 1.5 ± 0.6 mg %. Graft survival at 1 year was lower in the AMR group versus patients without AMR (81.9% vs 98.9%, log-rank test, P < .001). Risk factors for AMR were re-transplant (30% vs 7%, P = .02), HLA-DR mismatch (1.06 ± 0.65 vs 0.7 ± 0.6, P = .03), panel-reactive antibody (28% ± 33 vs 6.2 ± 13, P = .00), and delayed graft function (82% vs 30%, P = .00). CONCLUSIONS: Adapting the new Banff 2013 criteria increased the sensitivity of the diagnosis of ARM. Regarding our data, despite an adequate response to the therapy, it resulted in a worse graft survival by the first year of renal transplant.

First 1500 Kidney Transplants at the Institute of Nephrology and Urology in Uruguay: Analysis of the Results.

BACKGROUND: The Institute of Nephrology and Urology (INU) has performed 75% of kidney transplantations (KT) in Uruguay during its 35 years of activity, with 90.6% from cadaveric donors. We investigated the risk factors (RF) for delayed graft function (DGF) and patient and graft survival (SV). METHODS: We analyzed retrospectively the characteristics and evolution of 1500 KT performed by INU until December 2014. The incidence of DGF and RF for patient and graft SV were analyzed in 4 eras, according to the year that KT was performed. RESULTS: The number of KT per year has progressively increased until reaching 40 KT per million population in 2006, with a decrease of the living donor KT (LDKT) rate. The age of the donors (D) and recipients (R) as well as the time on dialysis (TOD) have progressively increased over the different eras. Five hundred twenty-five R (35%) presented with DGF. The RF for DGF were the age of the R and the D, the TOD, the DDKT, and the warm ischemia time (WIT). In the DDKT group, the cold ischemia time and "died of stroke" were added factors. The death-censored graft SV at 1, 5, 10, and 15 years were 90%, 76%, 62%, and 49%, respectively. They improved as from era I, the patient SV being 92%, 83%, and 75% at 1, 5, and 10 years, in era I; 98%, 93%, and 86% in era II; 98%, 92%, and 83% in era III; and 95% and 90% at 1 and 5 years in era IV (P < .001). The graft SV over the same periods was 76%, 58%, and 40% in era I; 88%, 68%, and 52% in era II; 93%, 81%, and 70% in era III; and 93% and 85% at 1 and 5 years in era IV (P < .0001). The RF for patient SV were diabetes mellitus, era I, lower albuminemia, older age or TOD, and DGF. For kidney SV, the era, the age of the R, TOD, DGF, and D older than 60 years were RF associated with a worse evolution. In DDKT, the RF for the graft SV were the era, younger age of the R, and DGF. The group with the worst graft SV was the one made up of children and adolescents. CONCLUSIONS: Our results relating to patient and graft SV are acceptable and comparable to those mentioned on large records such as the OPNT/SRTR and the Collaborative Transplant Study. This has been the case, even though we have transplanted increasingly aged patients, with increasingly aged donors, or donors with associated pathology. The risk factors that we found both for DGF and SV have also been pointed out by other authors. The validity of some findings has the limitation of being from a retrospective analysis; hence, they should be corroborated by a prospective study.

Successful Pregnancies in Kidney Transplant Recipients: Experience of the National Kidney Transplant Program From Uruguay.

BACKGROUND: Renal transplantation increases the possibilities of pregnancy in women of reproductive age. The course of pregnancy was analyzed retrospectively in patients with kidney or kidney-pancreas transplant, surveying maternal-fetal or renal graft complications and the relation with pre-pregnancy renal function. METHODS: A cohort that includes all the kidney transplant recipients who went through pregnancy in Uruguay in a period of 28 years is described. Forty pregnancies in 32 patients were registered; the average time between the kidney transplant and the beginning of the gestation period was 47 months. From the total gestations, 10 abortions, 1 neonatal death, and 1 fetal demise were registered. From the remaining pregnancies, we highlight prematurity (18/29) and low birth weight (14/21). Twenty-nine in 30 pregnancies ended in cesarean section; in 8 of 30, pre-eclampsia diagnosis was performed. Acute rejection was diagnosed in 2 of 30 pregnancies, both undergoing their first post-transplant year. RESULTS: Two patients required dialysis throughout the pregnancy because of progress into severe renal insufficiency. Higher obstetric perinatal morbidity and renal function deterioration was related to lower pre-pregnancy glomerular filtration rate (GFR). CONCLUSIONS: A successful pregnancy is possible in transplant recipients, yet there are risks of prematurity, low birth weight, and abortion. A lower GFR before pregnancy was associated with poorer maternal and perinatal results as shown in the different series.

Development of the National Kidney Transplantation Program in Uruguay.

The first kidney transplantation (KT) in Uruguay was performed in 1969. We report the rates of KT and survival of patients and grafts up to December 2014. The country has a surface of 176,215 km(2) and a population of 3,286,314 inhabitants (18.6 inhabitants per km(2)). Till December 31, 2014, 1,940 KT have been performed in Uruguay (41.8 pmp that year); 90.4% of them were from cadaveric donors (CD). Median age of recipients (R) was 44 ± 14 years; R older than 55 years increased from 0 to 27% during the period. Our pre-emptive KT program started in 2007. Optimal donors (D) decreased from 65.2% to 35.5%, and D older than 45 years old increased from 9% to 37%. Trauma as cause of death decreased from 49% to 32% and stroke as cause of death increased from 25% to 39%. Patient survival rates at 1, 5, and 8 years were 93%, 87%, and 78%, respectively for KT performed between 1980 and 1989; they were 98%, 93%, and 89%, respectively, for KT performed between 1990 and1999; they were 97%, 91%, and 90%, respectively, for KT performed between 2000 and 2010. In December 2013, there were 1098 patients pmp in renal replacement therapy, 758 pmp in dialysis, and 340 pmp (30.9%) with a functioning graft. Our national KT program is mainly based (90.6%) on cadaveric donation. Epidemiological changes in the characteristics of R and D followed the changes in aging that occurred in the general population and the dialysis population. The survival rates from patients and kidneys are similar to those reported by the European and the American registries.

Preemptive kidney transplantation--a team experience in Uruguay.

Kidney transplantation is the best treatment for end-stage chronic renal disease. In Uruguay, the prevalence of patients on dialysis is 757 patients per millon inhabitants, plus 316 alive with a functioning renal graft. We install a preemptive renal transplantation program. Twenty-five patients received grafts without dialysis from 2004 to 2013, 5 receiving their 2nd transplantation and 17 from cadaveric donors, with 7.4 ± 7.7 months in the waiting list. At 24 months, patients' survival rate was 100% and the grafts' 97%, with a serum creatinine of 1.4 ± 0.6 mg%. The developed programs of dialysis and renal health care contributed install our preemptive kidney transplantation. Kidney transplantation should be proposed to selected patients with chronic renal failure as primary therapy of substitution of renal function.

Descriptive retrospective comparative study between two brands of mycophenolate mofetil used in Uruguay: innovator versus generic (Suprimun).

BACKGROUND: According to our experience, survival of cadaveric renal graft in 5 years increased from 63% as of the introduction of cyclosporine to 73% after azathioprine was substituted with mycophenolate mofetil (MMF) in 1997. Until 2003, the innovator mycophenolate mofetil (IMMF) (Cellcept; Roche) was used. In 2003, Laboratorios Clausen introduced in Uruguay a generic MMF (GMMF) (Suprimun/Micoflavin/Myclausen; Laboratorios Clausen) with previous bioequivalence studies. Since then, every health care provider administers one of these types of MMF available on the market to its renal transplant (RT) patients. METHODS: We compared the evolution of 2 groups of patients and their grafts, those treated with GMMF or with IMMF. This was a descriptive, retrospective, nonrandomized, comparative study that involved all transplant patients in a center from January 2005 to June 2010 from 2 different health care providers which administered GMMF or IMMF uninterruptedly. Patients were older than 18 years, underwent their first RT and received triple immunosuppressive regime with calcineurin inhibitor (CNI), corticoids, and MMF, and completed ≥6 months of post-RT evolution. RESULTS: The GMMF group included 29 patients and the IMMF group 23. Patients from both groups had no significant differences (NS) regarding age, sex, diabetes, hepatitis C virus (HCV), recipient hypertension, donor type (living or cadaveric, sex, age, cause of death), or mismatch degree. There were no material differences regarding antibody induction, CNI type, day of diuresis, or function recovery percentage. Statistically different results were reported for time in dialysis (6.1 ± 0.7 y in IMMF vs 3.8 ± 0.5 y in GMMF) and cadaveric donor cold ischemia time (989 ± 205 min vs 851 ± 219 min, respectively). For IMMF and GMMF, respectively, clinical acute rejection was 40.9% and 31% and creatinine over 3, 6, 12, 24, 36, and 48 months, respectively, was (mg%): 1.65 ± 0.12, 1.66 ± 0.15, 1.43 ± 0.10, 1.44 ± 0.12, 1.49 ± 0.18, and 1.41 ± 0.17 and 1.50 ± 0.08, 1.41 ± 0.07, 1.63 ± 0.26, 1.31 ± 0.08, 1.26 ± 0.09, and 1.21 ± 0.10, with 22/28, 22/28, 22/28, 22/26, 19/20, 17/11, and 15/9 patients under follow-up (NS). Patient survival over 3, 6, 12, and 18 months, respectively, was 94%, 94%, 94%, and 94% and 96%, 96%, 96%, and 96%, and graft survival was 94%, 89%, 89%, and 89% and 96%, 93%, 93%, and 93% for IMMF and GMMF, respectively (NS). Dosing adjustment frequency and substitution with mycophenolate sodium was similar for both groups. CONCLUSIONS: With the results of this preliminary study we can not reach any final conclusion regarding assistance practice. From both groups, which involved similar baseline variables except for time in dialysis and cold ischemia (both greater in IMMF), we could gather a similar graft and patient evolution. New prospective, randomized, double-blind studies involving an adequate number of patients will help to determine the efficacy of GMMF in renal transplantation.

Clinical spectrum of cutaneous manifestations in renal and renopancreatic recipients in two centers in Uruguay.

Uruguay, with a total population of 3,345,000 inhabitants, is the Latin American country with the second highest number of renal replacement therapies. Long-term immunosuppressant therapy is essential for graft survival but results in reduced immunosurveillance, leading to an increased risk of complications. A variety of dermatological manifestations and a large increase in nonmelanoma skin cancers have been reported in this population. The purpose of this study was to evaluate the frequency and clinical spectrum of cutaneous manifestations in renal and renopancreatic recipients in 2 reference centers in Uruguay. Two hundred and six renal or renopancreatic recipients between 21 and 77 years old were evaluated between September 2009 and September 2011. A total of 206 dermatoses were observed; 60% of the patients had at least 1 cutaneous manifestation. The most frequent dermatoses were cutaneous side effects due to immunosuppressive treatment (40.6%), followed by infections (26.1%), miscellaneous causes (18.9%), and malignant and premalignant lesions (14.4%). Transplant recipients represent a high-risk dermatological population. Physicians in transplant units should be aware of the importance of dermatological screening in order to promote early detection of skin cancer.

Behavioral effects of endogenous or exogenous estradiol and progesterone on cocaine sensitization in female rats.

Cocaine sensitization is a marker for some facets of addiction, is greater in female rats, and may be influenced by their sex hormones. We compared the modulatory effects of endogenous or exogenous estradiol and progesterone on cocaine-induced behavioral sensitization in 106 female rats. Ovariectomized female rats received progesterone (0.5 mg/mL), estradiol (0.05 mg/mL), progesterone plus estradiol, or the oil vehicle. Sham-operated control females received oil. Control and acute subgroups received injections of saline, while the repeated group received cocaine (15 mg/kg, ip) for 8 days. After 10 days, the acute and repeated groups received a challenge dose of cocaine, after which locomotion and stereotypy were monitored. The estrous cycle phase was evaluated and blood was collected to verify hormone levels. Repeated cocaine treatment induced overall behavioral sensitization in female rats, with increased locomotion and stereotypies. In detailed analysis, ovariectomized rats showed no locomotor sensitization; however, the sensitization of stereotypies was maintained. Only females with endogenous estradiol and progesterone demonstrated increased locomotor activity after cocaine challenge. Estradiol replacement enhanced stereotyped behaviors after repeated cocaine administration. Cocaine sensitization of stereotyped behaviors in female rats was reduced after progesterone replacement, either alone or concomitant with estradiol. The behavioral responses (locomotion and stereotypy) to cocaine were affected differently, depending on whether the female hormones were of an endogenous or exogenous origin. Therefore, hormonal cycling appears to be an important factor in the sensitization of females. Although estradiol increases the risk of cocaine sensitization, progesterone warrants further study as a pharmacological treatment in the prevention of psychostimulant abuse.

Behavioral effects of endogenous or exogenous estradiol and progesterone on cocaine sensitization in female rats

Cocaine sensitization is a marker for some facets of addiction, is greater in female rats, and may be influenced by their sex hormones. We compared the modulatory effects of endogenous or exogenous estradiol and progesterone on cocaine-induced behavioral sensitization in 106 female rats. Ovariectomized female rats received progesterone (0.5 mg/mL), estradiol (0.05 mg/mL), progesterone plus estradiol, or the oil vehicle. Sham-operated control females received oil. Control and acute subgroups received injections of saline, while the repeated group received cocaine (15 mg/kg, ip) for 8 days. After 10 days, the acute and repeated groups received a challenge dose of cocaine, after which locomotion and stereotypy were monitored. The estrous cycle phase was evaluated and blood was collected to verify hormone levels. Repeated cocaine treatment induced overall behavioral sensitization in female rats, with increased locomotion and stereotypies. In detailed analysis, ovariectomized rats showed no locomotor sensitization; however, the sensitization of stereotypies was maintained. Only females with endogenous estradiol and progesterone demonstrated increased locomotor activity after cocaine challenge. Estradiol replacement enhanced stereotyped behaviors after repeated cocaine administration. Cocaine sensitization of stereotyped behaviors in female rats was reduced after progesterone replacement, either alone or concomitant with estradiol. The behavioral responses (locomotion and stereotypy) to cocaine were affected differently, depending on whether the female hormones were of an endogenous or exogenous origin. Therefore, hormonal cycling appears to be an important factor in the sensitization of females. Although estradiol increases the risk of cocaine sensitization, progesterone warrants further study as a pharmacological treatment in the prevention of psychostimulant abuse.

Cutaneous manifestations in 100 renal and reno-pancreatic recipients of Uruguay.

Uruguay is the second country of Latin America in prevalence of renal replacement therapies, including functioning kidney allografts. Long-term immunosuppressive therapy is essential for adequate graft function, but results in reduced immunosurveillance leading to an increased risk of complications such as infections and malignancies. A variety of cutaneous manifestations as well as an increase in non-melanoma skin cancers have been reported in this population. The objective of this study was to evaluate the frequency and clinical spectrum of cutaneous manifestations in renal and reno-pancreatic recipients in Uruguay. One hundred renal or reno-pancreatic recipients aged between 21- and 77-years-old were evaluated between September 2009 and September 2010. A total of 104 dermatoses were observed; 68% of the patients had at least one cutaneous manifestation. The most frequent dermatoses were cutaneous side effects due to immunosuppressive treatment (43.3%), followed by infections (27.9%), miscellaneous causes (22.1%), as well as malignant and premalignant lesions (6.7%). This is the first study evaluating dermatological complications in organ transplant recipients in our country. Most of the patients had at least one dermatological manifestation of immunosuppression, including a malignant or pre-malignant lesion, highlighting that this is a high-risk dermatological population. Cancer is one of the most important causes of death in recipients with functioning grafts. Its prevention is a major goal in the care of transplant recipients. Physicians in transplant units should be aware of the importance of dermatological screening and skin cancer surveillance.

Cardiovascular disease and/or elderly donors in renal transplantation: the outcome of grafts and patients.

Kidney transplant programs nowadays increasingly use elderly, hypertensive and cardiac disease donors (expanded criteria donors). The impact of these donors on patient and graft outcome was investigated in our transplant population. Among 257 consecutive cadaveric kidney transplants, 56 were from expanded criteria donors. The frequency of anuria, delayed graft function, and the days of renal failure were higher using organs from the expanded criteria donor group. Serum creatinine was higher in this group, although the statistical significance disappeared at 36 months. There were no significant differences in graft or patient survival during the first 3 years. The use of expanded criteria donors should not be discouraged, but recipient selection and immunosuppression use should be adapted and cold ischemia minimized.

[Ischemic cadiopathy in patients undergoing chronic hemodialysis]. / Cardiopatía isquémica en pacientes en hemodiálisis crónica.

UNLABELLED: We report a retrospective study of patients on chronic hemodialysis in whom a diagnosis of ischemic heart disease had been established. We compared the findings on coronary cineangiography and the treatment (medical only, surgical revascularisation [CABG] and percutaneous transluminal coronary angioplasty [PTCA]) with the early and late evolution. From a population of 2,287 patients on chronic hemodialysis treatment during the 5 year period 1994-1999, 83 patients who underwent coronary cineangiography after starting dialysis were selected. Their mean age was 63 +/- 9.4 (39-80) and the mean time on hemodialysis was 6 years (6 months-19 years). RESULTS: 65 patients (78%) had severe coronary lesions, 40% of whom had three vessel disease. 14 patients had medical treatment only (group 1), 23 had CABG (group 2) and 28 PTCA (group 3). Mortality within 30 days of intervention was 13% in group 2 and 21.4% in group 3. Global survival at two years was 82% in group 2 and 69% in group 3. Survival without angina at 6 and 24 months were 69% and 46% in group 2 and 55% and 22% in group 3 respectively. Survival without acute myocardial infarction at 6 and 24 months was 95% and 95% in group 2 and 89% and 64% in group 3. Data analysis using Cox proportional risk model showed that PTCA posed a higher risk of angina and death than CABG. CONCLUSION: Surgery yielded better early and later results than angioplasty even in those patients with severe coronary artery disease.

Frequency, Type and Associated Diseases of Bacteria and Virus in The Oropharynx of Children Born to Human Immunodeficiency Virus-Infected Mothers.

HIV-infected children are more likely than other children to develop pneumonia, which in these children is often recurrent or persistent. The main reservoir of the major pathogens is the nasopharynx, but to date no data has been published on the frequency and biologic characteristics of S.pneumoniae, H.influenzae and respiratory viruses found in the upper respiratory tract of children born to human immunodeficiency virus-infected mothers. To document these aspects, 105 children was monitored by pharyngeal swab (PS) and nasopahryngeal aspirates (NPA) who attended an outpatient clinic for HIV-infection evaluation. Bacterial identification was performed by standard procedures. Serotype, biotype and beta-lactamase production was investigated in H.influenzae isolates. S.pneumoniae serotypes were recognized by "quellung" and the susceptibility to 4 antibiotics was assessed. Respiratory syncytial viruses, parainfluenza, influenza A and B, and adenoviruses were diagnosed by indirect immunofluorescence and/or viral isolation in cell cultures. Twenty-nine children were identified as infected by HIV as a result of maternal-child transmission. Seventy children born to HIV-positive mothers but who were not HIV-infected served as controls. Of 269 PS, 110 110 S. pneumoniae and 92 H.influenzae were identified. Also 31 viruses were detected in 188 NPA. After stratifying by age no differences were observed in the frequency of bacterial colonization or in the presence of viruses in the upper respiratory tract of the two groups. Some biologic characteristics of the agents were noteworthy such as the frequency of colonization by S.pneumoniae serotype 14, the predominance of H.influenzae biotype I and the high frequency of viruses in NPA of asymptomatic children. Of note, although colonization frequencies were similar, children presenting with acute respiratory illness (ARI) were more likely to have bacteria isolated if they also had HIV-infection than if they were HIV-negative. It is concluded that HIV-infection in infants as a result of maternal virus transmission have a similar frequency of bacteria and virus colonization of their respiratory tract, but a higher frequency of ARI and perhaps a higher frequency of types of bacteria with special characteristics.