Factors and outcome in BK virus nephropathy in a Hispanic kidney transplant population.

UNLABELLED: BK virus nephropathy (BKVN) is an increasingly recognized cause of kidney allograft loss and is thought to be related to the newer, more potent immunosuppressive agents. Conflicting information has been reported on risk factors for BK infection. PURPOSE: To determine incidence, associated factors, and outcome of BKVN in our kidney transplant population in order to improve identification and management. METHODS: Kidney transplants from January 2000 to December 2005 were retrospectively reviewed. Data were collected for patients with biopsy-proven BKVN including age, sex, body mass index (BMI), etiology of renal failure, other medical diseases, donor type, surgical complications, rejection and infection, time to diagnosis, induction, immunosuppressive and antiviral therapy, and clinical outcome. A control group of patients matched for sex, age, type of graft, etiology of kidney disease, and BMI, was established for comparison. STUDY GROUP: During this period, 20 (4%) of 497 transplanted patients were diagnosed with BKVN. Thirteen (65%) were males, 8 (40%) were young adults (ages 21-40), and 18 (90%) received grafts from cadaveric donors (P=0.05). Twelve (60%) had hypertensive renal disease, 2 (10%) also had diabetes, and 16 (80%) had a BMI >25 (P=0.01). Lymphoceles occurred in 5 patients (25%). Mean creatinine level at diagnosis was 2.7 mg/dL and mean time to diagnosis was 23 months. Ten patients (50%) had leukopenia at or within a year before biopsy (P=0.001). Viruses other than BK occurred in 9 patients: varicella zoster virus in 3, cytomegalovirus in 2, herpes simplex virus in 1, molluscum contagiosum in 1, Epstein-Barr virus in 1, and human papillomavirus in 1. Eighteen patients (90%) had related rejection (P= 0.001) and 4 (20%) suffered allograft loss (P= 0.001). Basiliximab (living donors) and anti-thymocyte globulin (cadaver donors) were given for induction. All patients were on triple therapy; 15 on prednisone and sirolimus, with either tacrolimus in 8, cyclosporine in 4, mycophenolate in 1, or mycophenolate and tacrolimus in 2. The other 5 received prednisone with tacrolimus and mycophenolate. Graft loss occurred in 2 patients on tacrolimus and mycophenolate, 1 patient on tacrolimus and sirolimus, and 1 patient on cyclosporine and sirolimus. Immunosuppression was decreased in all patients. Two were given cidofovir for 6 months and had stable creatinine levels at the end of the study. Records were reviewed until April 2007. There were no deaths in this cohort. CONTROL GROUP: The number of rejections experienced by patients with BKV was much higher (P<0.0001), but the rate of graft loss was similar between the 2 groups (P=0.19). Viral co-infection was more frequent in patients with BKV (P=0.04). No episodes of leukopenia were reported for any of the patients in the control group (P=0.001). Immunosuppression with tacrolimus and sirolimus was more frequent in the BKV group, but this was not statistically significant (P=0.18, 0.28, respectively). The number of lymphoceles was larger in patients with BKV, but the difference was not statistically significant (P=0.35). CONCLUSION: BKVN is present in our transplant population and results in a high rate of allograft rejection with varying rates of graft loss. Associated factors were deceased donor and immunosuppression with potent agents, particularly tacrolimus and sirolimus. We also found a higher frequency of obesity, viral co-infection, and leukopenia. Routine screening and timely biopsy could prove cost-effective and significantly reduce morbidity.

A 16-fold increase in organ donation in a Hispanic population.

UNLABELLED: Organ transplantation as a substitute for diseased organs in end-stage organ failure has led to a worldwide increase in this treatment modality, but donation has not kept pace with the demand, despite scientific, social, and government efforts. For many years, Hispanic donation in Puerto Rico was meager and lagged behind major centers in North America and Europe. Studies signaled mostly cultural factors in this limited donation. We report a 16-fold increase in organ donation with the development of a formal procurement organization tailored to a local culture. METHODS: The 30-year, 1400-transplant experience of the Puerto Rico Transplant Center was divided in three periods: 1977 through 1893, the latter signaling the approval of a transplant law; 1984 through 1995, signaling the commencement of a formal organ procurement organization; and 1996 through 2006. The subset of 2001 to 2006 was used in an additional calculation against 1984 to 1995. RESULTS: The comparison of the mean deceased donors from 1984 to 1995 with 1998 to 2006 shows a 12-fold increase; and the last 6 years versus 1984 to 1995, a 16.8-fold increase. CONCLUSION: Cultural and educational obstacles in a given country may be overridden by aggressive administrative and educational approaches and strategic planning tailored to local realities, with improvement in organ transplantation.

Study of factors that affect complications after renal transplantation.

There are no multifactorial studies of complications after renal transplant in the Hispanic population. The objective of this study was to identify which factors are associated with the development of complications after renal transplantation. This retrospective study was performed on all patients transplanted in the Puerto Rico Transplant Program during 2002. Independent variables included preoperative albumin, white blood cell (WBC) count, hemoglobin, creatinine, weight, height, body mass index (BMI), type of dialysis, time on dialysis, and urine production after transplant. Dependent parameters included posttransplant diuresis, wound infection, wound dehiscence, lymphoceles, acute tubular necrosis, length of stay, postoperative weight, graft survival, and patient survival. Data were analyzed with parametric and nonparametric techniques using STAT 200 software. Sixty-four patients were included in the study: 37 male, 27 female. No significant differences in complication rate or length of stay were found with age, preoperative albumin, WBC count, hemoglobin, creatinine, weight, height, dialysis modality, and donor type. Significant factors included type of dialysis, time on dialysis, and BMI. Preoperative albumin if > 3 was not a prognostic indicator for the development of surgical complications following renal transplantation. Only preoperative weight, BMI, and dialysis duration were significant factors in the development of postoperative complications and prolonged hospital stay in this sample Hispanic transplant population. These data are important in formulating selection, education, and transplant management policy.

The fate of organs refused locally and transplanted elsewhere.

UNLABELLED: The number of kidney allografts procured from deceased donors has been fairly constant in the past few years, while organs from living donors steadily increase. In our program, existing protocols refused some kidneys which were subsequently accepted and transplanted at other hospitals. Thus, a review of our criteria to accept kidneys became necessary. METHODS: We studied the outcome of all kidneys refused by us but transplanted in other programs between 2002 and 2004. The data analyzed included ID no. donor, transplant center, procurement date, donor age, ischemic times, recipient alive or dead, creatinine level (when it was offered), initial function, hypertension, diabetes mellitus, biopsy, reason why the kidney was not accepted in our program, kidney functioning or lost, and cause of graft failure. The chi-square, Fisher, and t tests were used to analyze our data; P values of <.05 were regarded as significant. RESULTS: Originally 137, we excluded kidneys exported due to mandatory sharing (26 of 137 = 18.97%) and multiorgan placement (10 of 137 = 7.3%). Thus, 101 kidneys were not accepted by us because they did not meet the existing criteria of our program, but were accepted elsewhere. Reasons for nonacceptance were divided into donor quality, donor social history, donor age, donor size/weight, positive serological test, as well as organ preservation time, organ anatomical damage, elevated creatinine, abnormal urinalysis, abnormal biopsy, and decreased urine output. Donor issues were 66 of 101 (65.3%) with a graft loss of 13.6%, and organ issues were 35 of 101 (34.7%) with a graft loss of 66.6%. Donor quality totaled 24 of 66 (36.4%) and donor social history totaled 20 of 66 (30.3%); these were the most common causes for kidney nonacceptance related to donor issues. Reasons related to organ quality included elevated creatinine (15 of 35 = 42.9%; graft loss, 46.6%), and abnormal biopsy (9 of 35 = 25.7%; graft loss, 11.1%) and organ anatomical damage (4 of 35 = 11.4%; graft loss, 75%) (P = .42). Graft loss was more frequent with creatinine levels above 2.4 mg/dL (P < .001, RR gf = 1.5). Long-term fate of these 101 kidneys transplanted elsewhere: 82 (81.2%) were still working while 19 (18.8%) were lost. The causes of graft loss were renal artery thrombosis (42.1%), renal venous thrombosis (26.3%), death for other reasons (15.8%), graft never worked (10.5%), and ESRD (5.7%). The results suggest that the criteria for refusal related to donor issues, including hypertension, diabetes mellitus, donor age and donor size, should be revised owing to the low percentage of graft loss. Other donor issues such as positive serological test and donor social history (drug use, alcoholism) represent a serious potential risk for the health of recipients; for this reason, considering these persons as possible donors is very difficult irrespective of the graft outcome. Kidney refusals related to organ issues (especially elevated creatinine and anatomical damage) due to the very high percentage of graft loss should be considered high risk and probably be excluded. The increase in the demand of kidneys to be transplanted is a very important reason for a continuous and systematic review of donor exclusion criteria in every transplant program. The results presented here have helped us to improve both our outcomes and utilizations based on scientific evidence.

HLA is not predictive of posttransplant diabetes mellitus.

AIMS: New-onset posttransplant diabetes mellitus (PTDM) is a frequent complication of kidney transplantation. The goal of this study was to identify if the tendency to develop PTDM was associated to the HLA, as is seen in the general population. METHODS: A retrospective study was made of 525 patients who underwent renal transplantation between 1997 and 2004. They were divided into three categories depending on the diabetic status before and after kidney transplantation. The HLA profile of each patient was identified for class 1 and class 2 antigens including HLA-A, HLA-B, and DR-R. Antigen frequencies were calculated and gene frequencies derived. These were compared among the three groups and with the published data for the Puerto Rico population. Other variables studied included weight, age, gender, and family history. RESULTS: Seventy-two of 526 (13.7%) were diabetic before transplantation; 92/453 (20.3%) developed PTDM after kidney transplantation. Pretransplant diabetics showed a higher incidence of A3 (0.1102 vs 0.0869 vs 0.0361), DR4 (0.3334 vs 0.1932 vs 0.2124), and DR-13 (0.1835 vs 0.1115 vs 0.1175) than nondiabetics and the normal Puerto Rican population. Posttransplant diabetics showed a higher A3 (0.1154) and a higher DR3 (0.0675 vs 0.0295 vs 0.0022) than nondiabetics and normal population. CONCLUSION: PTDM was not associated statistically with the HLA in this group of transplant recipients, although A3 and DR3 were higher. Patients with the phenotype that is related to diabetes in the normal population did not have a higher incidence of diabetes in this series.

Assessing the risk of infection and rejection in Hispanic renal transplant recipients by means of an adenosine triphosphate release assay.

INTRODUCTION: Because of the necessary immunosuppression, transplant recipients have a high risk of infection. Conversely, underimmunosuppression carries with it the risk of rejection. It would be quite useful to have a test that could differentiate between infection and rejection in renal transplant patients and better still, to predict which patients are at risk of complications. A new assay, which measures adenosine triphosphate (ATP) synthesis by CD4+ T cells in response to stimulation by phytohemagglutinine (Immuknow assay, Cylex, Inc) is undergoing clinical evaluations. Preliminary investigations suggest that this test could be useful to assess and predict the immune status of patients with other conditions. METHODS: We examined the records of all patients who received a kidney transplant in our program between August 2004 and January 2005. Of 64 patients, 58 had pretransplant and posttransplant ATP level determinations. We searched for associations between ATP levels and immunosuppression type, doses, and levels; creatinine levels; white blood cell count; tissue typing; preformed antibodies; as well as ATP levels on infection and rejection, and changes in ATP levels with time. Chi-square, Fisher, t test, analysis of variance (ANOVA), and relative risks were used for analysis of data. RESULTS: There was no relation between ATP levels and immunosuppression type, doses, or levels; creatinine levels; white blood cell counts; HLA; and panel-reactive antibody (P > 0.05). However, patients with moderate or high pretransplant ATP levels had more rejection episodes (8/10) while patients with ATP levels in the low immune response had more infections (6/11) (P < .001; relative risk [RR] for rejection = 1.2; RR for infection = 4.4). The mean ATP levels for rejection was 423.3 ng/mL versus 268.45 ng/mL for infection and 277.15 ng/mL for no events (ANOVA, P = .0145). Although acute rejections occurred mostly above 300, this was not significant (P = .059; RR = 0.9). Infections were more frequent with ATP under 300 (RR = 7.3) and severe infection (endocarditis, meningitis, peritoneal abscesses, pneumonia, etc) were more frequent under 200 (P < .001). Comparing pretransplant with posttransplant values at the second week an increase correlated with rejection (P < .001, RR = 15.3), while a decrease did not correlate with the infection (P = .845, RR = 1.4). Patients who received antirejection treatment had a decrease in their ATP levels at 5 days (P = .002). CONCLUSION: This ATP release assays helpful in determining the risk of developing infection or rejection, as well as follow-up in the response to therapy.

A marked increase in organ donation in Puerto Rico.

During its first years of existence, the Puerto Rico Transplant Program barely reached 18 to 20 renal transplants per year. A brain death amendment to the law improved the numbers but only to a stable thirty/year. Polls and studies showed that, although people knew about transplantation and expressed willingness to donate, the powerful emotional grief reaction, as well as a peculiar decision-making process, all militated against effective donation. In 1995, LifeLink of Puerto Rico was created as part of the very successful LifeLink Foundation of Tampa, staffed by local professionals. Cadaveric donation increased exponentially by 1227% and in 2004, 22.4 donors per million population were recovered, up from 1.5, one of the steepest growth curves in the United States. As a result, kidney transplantation increased, a cardiac transplant program was inaugurated, a pancreas transplant program has started, and liver will follow. The success is the result of well-trained, culturally sensitive coordinators and requestors; continuous education to the public, hospitals, administrators, neurospecialists, and critical care units; hospital development; implementation of federal law; and a sensitive approach the deceased donor family, and not only to the waiting list patients. The results demonstrate that organizational and educational factors can override cultural obstacles.

Results of living-related kidney transplantation in Puerto Rico.

A total of 103 kidney transplantations from living-related donors were performed in the Puerto Rico Kidney Transplant Program between January 1977 and June 1984. The majority of these patients were male, 76% were between 21 and 50 years of age, 33% were indigent, and 38% were either black or of mixed race. Rigid exclusion criteria were established in the selection of kidney donors. All donor operations were at least 2-antigen-compatible. Surgical technique and posttransplant management were standard, except that in 1980 the immunosuppressive policy was changed as follows: posttransplant prednisone was very rapidly tapered to 20 mg/day at two weeks after transplantation and antilymphocyte globulin was used to treat all rejections. The overall 3-year patient survival for the 7 1/2 years is 91.6%, but after 1980 it increased to 98% perhaps a reflection of the changes in immunosuppressive policy. Eight of ten deaths were due to sepsis, most of them related to rejection treatment. The 3-year kidney survival was 77%. All kidney losses were due to rejection. A low incidence of urological complications is reported. There were no technical losses. A relatively low incidence of cancer is reported. Cutaneous mycosis is highly prevalent in our patients, but systemic fungi are virtually absent.

Cold ischemia and outcome in 17,937 cadaveric kidney transplants.

To determine if cold preservation time continues to affect renal transplant outcome, prospectively collected data from 17,937 cadaveric renal transplants performed between 1982 and 1991 were analyzed. Cold preservation intervals of 1-16, 16-32, 32-48, and greater than 48 hr were studied by multi- and univariate methods for two time periods: 1982-1989 (n = 13,800) and 1990-1991 (n = 4137). The functional one-year graft survival for kidneys stored over different intervals was significantly different (P < 0.001) only for the 1982-1989 epoch: one-year allograft survival ranged from 76% (1-16), to 72% (16-32 and 32-48) to 74% (> 48) hr. One-year graft survival ranged from 81 to 83% for the four preservation times in 1990 through 1991 (P = NS). Overall actuarial graft survival was 76% (74% prior to 1990, and 82% after 1990). Factors significantly (P < 0.0001) affecting kidney transplant outcome before and after 1990 were delayed graft function (DGF): n = 4232, 65% one-year graft survival; retransplant status: n = 3029, 67% one-year graft survival; and HLA match at three or more loci: n = 6067, 79% one-year graft survival. While DGF occurred more often with prolonged preservation, kidneys with DGF had similar survival regardless of preservation duration. Before 1990, pretransplant transfusion was associated with better and black recipient race with worse outcome; neither transfusion nor recipient race had any effect after 1990. Patients receiving kidneys preserved for longer periods demonstrate one-year graft survival comparable to kidneys preserved for shorter periods. Prolonged cold ischemic time should no longer be a principal reason for considering organ discard.

A reversed jejunal segment interposition as feeding gastrostomy.

Permanent feeding gastrostomies are needed for prolonged alimentation in some patients with foregut obstruction. The usual gastric flap or tube may be limited in patients with previous gastric surgery or with a small stomach. In these patients, interposition of a short, vascularized jejunal segment between the anterior wall of the stomach and the outside may be valuable. Periodic intubation is easy. Tested initially in dogs and then applied to selected patients, we have not seen ulcers, regurgitation, soiling, pain, or other complications.

Successful renal vein reconstruction with a polytetrafluoroethylene vascular graft in kidney transplantation.

Very frequently, technical difficulties make renal transplantation difficult and, on occasion, impossible. Problems with short renal veins are a classic example. We have successfully repaired two exceedingly short donor renal veins of equal size using two short polytetrafluoroethylene vascular grafts interposed between the renal veins and the recipient's iliac vein. So far, the kidney has functioned normally except for one minor episode of rejection.

Low incidence of urologic complications after renal transplantation.

The incidence of urologic complications after renal transplantation has been reported to range from less than 1 to 10 percent. They are still a significant source of morbidity and mortality. We report on 111 kidney transplants performed at the San Juan Veterans Administration Hospital in 85 of whom urinary continuity was restored with a Politano-Lead-better ureteroneocystostomy, 23 with the Lich-Grégoir operation, and 3 with extravesical urinary, diversions. Important factors included meticulous attention to details during ureter manipulation, the use of prophylactic antibiotics, unabsorbable sutures in the closure of the muscular part of the bladder wall and infrequent use of drains. This resulted in a low rate of complications which included early ureteral obstruction (3.6 percent), late ureteral obstruction (1.8 percent), lithiasis (1.8 percent), urinary extravasation (0.9 percent), and ureteropelvic necrosis. No kidneys or patients were lost to technical complications, and no deep wound infections were observed. Our experience demonstrates the beneficial effects of a low complication rate on patient and graft loss.

Pretransplant predictors in renal transplantation.

We have prospectively studied the predictive value of three tests commonly used in transplant units (mixed lymphocyte culture, phytohemagglutinin-induced transformation, and skin testing with recall antigens), and their correlation with rejection and kidney loss. Thirty-five transplant recipients provided complete data for analysis. The results of mixed lymphocyte culture reactivity, phytohemagglutinin-induced transformation, and skin reactivity to recall antigens were similar and did not predict or discriminate between the patients that had few or many rejections, nor between those that kept or lost their allografts. Nonetheless, patients with a very high mixed lymphocyte culture stimulation index (above 3) had higher morbidity and mortality than those with a nonreactive mixed lymphocyte culture. Pretransplant mixed lymphocyte culture may give more important information than nonspecific immunologic tests regarding allograft outcome.

Histamine and sympathetic blockade in septic shock.

The relative roles of endogenously released histamine and the sympathetic nervous system in septic shock were indirectly studied by blocking each one separately. Antihistamines in doses of 3-10 mg/kg prevented severe blood pressure drops and improved urinary output in groups treated before and after shock. Release of histamine seems to be important at least in the pathogenesis of early septic shock, although analysis of blood pressure pattern and survival implicates additional factors in late shock. Epidural block in combination with E. coli injection was detrimental, producing severe hypotension and even immediate death. Neural sympathetic tone is essential to survival in shock.

Glycerol and methylprednisolone in lung contusion.

An experimental model was developed in dogs that quantifies the amount of pulmonary trauma produced. The severity of thoracic trauma is related to mortality and to a presence or absence of bilateral pulmonary injury. Bilateral injury represents severe trauma, consistently alters blood gases and is associated with significant mortality when untreated. Both methylprednisolone and glycerol exerted beneficial effects on mortality from bilateral pulmonary contusion, and glycerol altered the blood gas pattern towards normal. Glycerol has been utilized extensively clinically to reverse the adverse effects of cerebral edema. It may prove to be of similar value when pulmonary injury is an important factor.

Protective effect of steroids on liver ischemia.

Occlusion of the afferent liver circulation for variable periods of time would be advantageous to temporarily control bleeding from profound lacerations or during extensive resections. Because of its low tolerance to ischemia we attempted to protect the liver with steroids during inflow occlusion. Total hepatic ischemia was produced in rabbits by ligating the portal triad and gastrohepatic ligament for 30 minutes. A 10 per cent survival was obtained in untreated controls whereas pre-treatment with methylprednisolone improved survival to 100 per cent. Methylprednisolone injection after occlusion improved survival only to 57 per cent. There were profound pathohistologic and electron microscopic changes in untreated controls. In animals treated with methylprednisolone either before or after occlusion changes were minimal or absent. This treatment was used in four trauma patients in whom occlusion of the liver inflow was carried out for various periods of time. Even though no significant statement can be made from such small group, the early postoperative course was remarkably smooth and stable. Methylprednisoline protects the liver during warm ischemia, especially if given before occlusion, and decreases the mortality from this maneuver in experimental animals.

Inhibition of lymphocyte capping by fatty acids in mouse and man.

Lipid-enriched diets have been related to a high cancer incidence in experimental animals for many years, and more recently, to assorted defects on the immune response. We investigated the effect of incubating human or murine (C3H/HEJ) lymphocytes with saturated (16:0) and unsaturated (18:1, 18:2, 18:3, 20:4) fatty acids (12 micrograms for each 10(7) cells), on the ability to cap with antihuman or antimouse anti-IgM, mu-chain specific antibody. Capping was also tested in obese (ob/ob, C57BL/6J) mice. Capping at 30 and 60 min was reduced by fatty acid incubation to 10-30% of control values in humans (p less than .001), and to 30% of control values in mice (p less than .01), regardless of degree of unsaturation. ob/ob capped normally. A lymphocyte membrane effect caused by fatty acids is observed in these experiments. Whether this is related to the dysimmunity caused by lipid diets cannot be assessed from our data, especially since all fatty acids, regardless of unsaturation, reduced the capping phenomenon.

Ethical dilemmas: transplantation in prisoners and the mentally disabled.

The particular case of organ transplantation in prisoners and the mentally disabled gives rise to discussions within the context of several aspects of bioethics. After medical and legal aspects are considered, the most important problem relates to the allocation of scarce resources to subsets of patients that are viewed differently from other citizens. The legal and basic rights of these individuals are discussed, as is the validity of social worth as a criterion of access to this treatment care modality. The respective roles of the physician and of society are considered to be distinct from each other.

The endothelium and early immune activation: new perspective and interactions.

Far from being just a membrane for the passive transport of cells, molecules, and water between blood vessels and their interstitium or a passive target for humoral immunological reactions, the endothelium is now being viewed as an active modulator of both normal physiological homeostasis and the early inflammatory response. The repertoire of receptors and mediators produced by endothelial cells overlap those traditionally assigned to the immune system. This new paradigm together with the changes caused by brain death in the cadaver donor have far-reaching repercussions on how rejection is conceived, while opening new venues for its prevention. The respective theoretical roles of the neuro-endocrine-immunological axis and of syndecans are highlighted.

The immunoregulatory role of cholesterol and other lipids: a hypothesis.

Membrane lipids play an important role in cellular responses to exogenous signals. In immunocompetent lymphocytes, marked changes in the concentrations of membrane lipids occur following cell-antigen interaction. These changes lead to an increase in membrane fluidity, thus facilitating the microaggregation of receptor-antigen complexes. This event constitutes the inductive signal for lymphocytes. Lipid profile alterations leading to increased concentration of membrane cholesterol, of polyunsaturated lipids, or of both, bring about a decrease in membrane fluidity. The latter interferes with receptor displacement preventing delivery of an inductive signal to the responding cell. Interference with microaggregation is readily brought about in interactions involving low affinity antigens, such as tumoral antigens. We postulate that in hyperlipidemic and hypercholesterolemic states there is decreased immune responsiveness to weak antigens due to the aformentioned lipid profile alterations in the membranes of immunocompetent cells. The manner in which an increase in the concentration of the lipids mentioned can lead to decreased immune responsiveness and hence to an increased incidence of malignancies in hyperlipidemic and hypercholesterolemic states is the hypothesis presented in this paper.