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.

Counting of lymphocyte subpopulations using standard versus low-dose antiCD3 monoclonal antibody treatment.

The monoclonal anti-CD3 antibody is used as part of prophylaxis and also in treatment of rejection. In the present article we analyzed changes in different lymphocyte subpopulations after anti-CD3 treatment. T lymphocytes were decreased under anti-CD3 antibody administration, with a simultaneous increase in B lymphocytes but no changes in natural killer (NK)cells. No differences were found between patients administered anti-CD3 antibody (Ab) at 5 versus 2.5 mg/d. It is uncertain whether these changes may be implicated in the lack of response or in the prophylactic effects of anti-CD3 Ab.

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.

[Chronic dialysis in Uruguay: mortality trends from 1981 to 1998]]. / Diálisis crónica en Uruguay: evolución de la mortalidad entre 1981 y 1998.

Uruguay is a developing country with 3.16 million inhabitants. Chronic dialysis treatment (CDT) expanded after the creation of a National Fund of Resources in 1980 who receives contribution from all inhabitants to finance, among others, the CDT and renal transplantation. During the 1981-1998 period, about 4,819 patients were treatment, 2,365 patients had died, 454 were transplanted and 51 patients were lost to follow-up due to change in residence. At the start of the treatment, mean age was 57.0 +/- 17.7 years, 37% were 65 or older than 65 year old, 61.3% were male and 98% of patients were white persons. The most common diseases responsible for End Stage Renal Disease were: hypertension (22%), chronic glomerulonephritis (19%) and diabetic nephropathy (15%). In 1998, there were 44 dialysis units in the country (13.6 units per million population--pmp), 100% of them had water treatment (reverse osmosis 96.8%) and reuse dialyzer. The most frequent causes of death were: cardiovascular and infection. In this paper, eighteen years of the mortality time course of CDT are analyzed. Annual mortality rate was expressed as deaths per 1,000 patients years at risk (M/1,000). The indirect standardization method was applied to adjust the mortality rate. Two populations were used as standard: the 1996 population of USRDS to adjust for age, sex, race and nephropathy and the 1996 Uruguayan general population to adjust for age. Standardized mortality rate (SMR) for each year was obtained dividing observed deaths by expected deaths. From 1981 to 1998, the incident population increased from 32 to 133 patients per million populations and the prevalent population from 28 to 639 pmp. There was a simultaneously increase in the prevalence of diabetic patients and of patients older than 65 years. The annual mortality rate decreased from 249 to 138 deaths per 1,000 patient years (M/1,000). The standardized mortality (SM) with the USRDS population as standard decreased from 452 in 1981 to 132 in 1998 and the SMR from 2.07 to 0.60. The SMR with the Uruguayan general population decreased from 17 to 4. In conclusion, these results are similar with those observed in developed countries. There has been a decrease both in the gross and the standardized mortality ratio in the period of observation.

Comparison of survival for haemodialysis patients vs renal transplant recipients treated in Uruguay.

BACKGROUND: Our aim was to compare survival among renal transplant recipients and haemodialysis patients treated in Uruguay. METHODS: All the patients transplanted in Uruguay (n=460) and all the patients who started haemodialysis (HD) in three centres in Uruguay (n=695) from 01 January 1981 to 31 December 1998 were included. Overall survival, adjusted survival and survival of the patients in the low-risk group were compared for HD patients and renal transplant recipients. Diabetic and non-diabetic patients were considered independently. The low-risk group was defined by the absence of any significant risk factor related to mortality on the Cox proportional hazard regression model (age more than 55 years at start of HD, previous history of diabetes, heart disease, cancer, and smoking habit). The significant variables were also used to adjust the survival curve. RESULTS: Overall survival was significantly greater in renal transplant recipients (P<0.0001). One-, five- and ten-year survival rates were 95.2, 88.0 and 78.8% for renal transplant recipients and 90.6, 62.7 and 39.8% for HD patients. In non-diabetic patients, adjusted survival rates (for age, heart disease, cancer, and smoking habit) were similar in renal transplant recipients and HD patients (P=0.8713). In the low-risk group as well, significant differences in survival between renal transplant recipients (n=289) and HD patients (n=134) were not observed (P=0.2312). Ten-year survival rates were 82.6 and 87.9% respectively. In diabetic patients 5-year survival rates adjusted for heart disease, smoking habit, and chronic pulmonary disease were 89.2% for renal transplant recipients and 40.9% for HD patients (P=0. 0168) The relative risk of haemodialysis patients related to renal graft recipients was 2.85 (1.21-6.75). CONCLUSIONS: We conclude that when the outcome is adjusted to co-morbid factors there is no difference between renal transplant recipients and haemodialysis patients survival in non-diabetic patients, while renal transplantation gives better survival rates than haemodialysis in diabetic patients.

[Heat syndrome: the first 7 cases in Granada]. / Golpe de calor: primeras siete observaciones en Granada.

We present the seven first cases with heatstroke in Granada provinces. Six patients were elderly man with passive heatstroke, the other was a young adult with active heatstroke. The clinic picture was evident: fever, hiperpnea, anhidrosis and mental impairment; there was not peculiar biochemic sign though the prognosis depended of the development of tubular kidney failure. We expose the main phisiopathologic therapeutic measure.