Edgar L. Milford

Comparison of Mortality in All Patients on Dialysis, Patients on Dialysis Awaiting Transplantation, and Recipients of a First Cadaveric Transplant

BACKGROUND AND METHODS The extent to which renal allotransplantation - as compared with long-term dialysis - improves survival among patients with end-stage renal disease is controversial, because those selected for transplantation may have a lower base-line risk of death. In an attempt to distinguish the effects of patient selection from those of transplantation itself, we conducted a longitudinal study of mortality in 228,552 patients who were receiving long-term dialysis for end-stage renal disease. Of these patients, 46,164 were placed on a waiting list for transplantation, 23,275 of whom received a first cadaveric transplant between 1991 and 1997. The relative risk of death and survival were assessed with time-dependent nonproportional-hazards analysis, with adjustment for age, race, sex, cause of end-stage renal disease, geographic region, time from first treatment for end-stage renal disease to placement on the waiting list, and year of initial placement on the list. RESULTS Among the various subgroups, the standardized mortality ratio for the patients on dialysis who were awaiting transplantation (annual death rate, 6.3 per 100 patient-years) was 38 to 58 percent lower than that for all patients on dialysis (annual death rate, 16.1 per 100 patient-years). The relative risk of death during the first 2 weeks after transplantation was 2.8 times as high as that for patients on dialysis who had equal lengths of follow-up since placement on the waiting list, but at 18 months the risk was much lower (relative risk, 0.32; 95 percent confidence interval, 0.30 to 0.35; P<0.001). The likelihood of survival became equal in the two groups within 5 to 673 days after transplantation in all the subgroups of patients we examined. The long-term mortality rate was 48 to 82 percent lower among transplant recipients (annual death rate, 3.8 per 100 patient-years) than patients on the waiting list, with relatively larger benefits among patients who were 20 to 39 years old, white patients, and younger patients with diabetes. CONCLUSIONS Among patients with end-stage renal disease, healthier patients are placed on the waiting list for transplantation, and long-term survival is better among those on the waiting list who eventually undergo transplantation.

Use of Cytomegalovirus Immune Globulin to Prevent Cytomegalovirus Disease in Renal-Transplant Recipients

We undertook a prospective randomized trial to examine whether an intravenous cytomegalovirus (CMV) immune globulin would prevent primary CMV disease in renal-transplant recipients. Fifty-nine CMV-seronegative patients who received kidneys from donors who had antibodies against CMV were assigned to receive either intravenous CMV immune globulin or no treatment. The immune globulin was administered in multiple doses over the first four months after transplantation. The incidence of virologically confirmed CMV-associated syndromes was reduced from 60 percent in controls to 21 percent in recipients of CMV immune globulin (P less than 0.01). Fungal or parasitic superinfections were not seen in globulin recipients but occurred in 20 percent of controls (P = 0.05). Only 4 percent of globulin recipients had marked leukopenia (reflecting serious CMV disease), as compared with 37 percent of the controls (P less than 0.01). There was a concomitant but not statistically significant reduction in the incidence of CMV pneumonia (17 percent of controls as compared with 4 percent of globulin recipients). A significant reduction in serious CMV-associated disease was observed even when patients were stratified according to therapy for transplant rejection (P = 0.04). We observed no effect of immune globulin on rates of viral isolation or seroconversion, suggesting that treated patients often harbored the virus but that clinically evident disease was much less likely to develop in them. We conclude that CMV immune globulin provides effective prophylaxis in renal-transplant recipients at risk for primary CMV disease.

Transmission of Hepatitis C Virus by Organ Transplantation

BACKGROUND Liver disease is a frequent and major complication after organ transplantation. We sought to determine whether hepatitis C virus (HCV) is transmitted by organ transplantation and whether it causes post-transplantation liver disease. METHODS Serum samples from all cadaver organ donors to the New England Organ Bank between 1986 and 1990 were screened retrospectively for antibodies to HCV (anti-HCV) by enzyme-linked immunosorbent assay (ELISA). We reviewed the hospital records of all recipients of organs from anti-HCV-positive donors for evidence of liver disease. Serum samples from recipients obtained before transplantation and during follow-up were analyzed for anti-HCV. RESULTS Of 716 organ donors, 13 (1.8 percent) were positive for anti-HCV. Their organs (19 kidneys, 6 hearts, and 4 livers) went to 29 recipients. Non-A, non-B hepatitis developed after transplantation in 14 of the 29 (48 percent), for a prevalence 7.4 times the 6.5 percent prevalence after transplantation from untested donors that was previously reported by two institutions in the organ bank (P less than 0.0001). The liver disease began a mean of 3.8 months after transplantation and became chronic in 12 patients; the other 2 had subfulminant hepatic failure. Liver disease was more frequent in the patients who had received antilymphocyte preparations (P = 0.04). HCV was the cause of the post-transplantation liver disease in 12 of the 13 recipients (92 percent) for whom serum samples were available. Anti-HCV was detected by ELISA in eight and enzyme immunoassay in one; in three others, HCV RNA was detected by polymerase chain reaction in serum samples obtained after transplantation. CONCLUSIONS Organ transplantation can transmit hepatitis C. This raises serious questions about the continued acceptance of organs from donors positive for anti-HCV.

Nephron Underdosing: A Programmed Cause of Chronic Renal Allograft Failure

The findings cited in this report suggest that renal allograft survival might be improved by matching nephron supply to recipient needs (analogous to prescription dialysis based on Kt/V). Methods for assessing functional graft capacity (ie, nephron number, filtration, or total microvascular surface area) are needed. Graft weights might serve as a useful alternative until better indices are devised. Measures for defining and possibly reducing recipient demands are also needed to preserve graft performance. Where gross imbalances between nephron supply and recipient demand are not likely to be corrected over the long term by engraftment of a single kidney, consideration should be given to dual kidney transplantation, currently feasible only from cadaveric, but eventually from xenogeneic sources as well. The predicted longer survival and avoidance of premature return to end-stage renal disease with the transplantation of two kidneys in certain conditions could render this approach more rational, both in clinical and economic terms, than single kidney engraftment for those at greatest risk for shortened graft survival. The dosing of larger numbers of nephrons might also lessen the risk of coexistent hypertension and thereby reduce the magnitude and tempo of immune injury to the graft.

Impact of racial genetic polymorphism on the probability of finding an hla-matched donor

As successful organ or marrow transplantation correlates with the degree of HLA-compatibility between patient and donor, registries have been developed to facilitate matching. However, racial minority groups have a lower chance of finding a match. We evaluate the impact of the biology of racial genetic polymorphism upon the probability of finding an HLA match for patients of different racial groups. The National Marrow Donor Program has compiled the HLA types of 20,449 patients and 1,625,159 potential volunteer donors. These HLA types were used to estimate the probability of finding an HLA-matched donor for patients of different racial groups. We estimated the HLA haplotype frequencies for different races, and then determined the probability of finding matched donors, given several hypothetical registry sizes. We confirmed that patients of minority races searching the current National Marrow Donor Program registry have low probabilities of finding matches. This was only partly due to the smaller number of donors from these racial minorities, as the observation persisted even when hypothetical donor registry sizes were the same for all racial groups. We demonstrate that African-Americans are more polymorphic with respect to HLA, and are hence less likely to find donors at any given registry size. An increase in the recruitment of minority racial groups for organ and marrow donors will only partially alleviate the problem of equal access to HLA matches for patients belonging to racial minority groups. It will therefore be important to attempt to improve methods for transplantation using HLA-mismatched donors.

HLA gene and haplotype frequencies in the North American population: The National Marrow Donor Program donor registry

BACKGROUND As of May 1, 1995, the National Marrow Donor Program had a donor registry consisting of over 1.35 million HLA-typed volunteers recruited from most major cities and states in the United States. This registry represents the largest single HLA-typed pool of normal individuals in the world. METHODS We analyzed the HLA-A, -B, -DR locus phenotypes of the National Marrow Donor Program donors in order to estimate gene and haplotype frequencies for major racial groups of the United States: Caucasian American, Asian American, African American, Latin American, and Native American. The large size of the database allowed us to calculate the frequencies of relatively rare antigens and haplotypes with more accuracy than previous studies. RESULTS We observed 89,522 distinguishable HLA-A, -B phenotypes in 1,351,260 HLA-A, -B-typed donors and 302,867 distinguishable HLA-A, -B, -DR phenotypes in 406,503 HLA-A, -B, -DR-typed donors. Gene and haplotype frequencies differed remarkably among the five racial groups, with African Americans and Asian Americans having a large number of haplotypes that were specific to their racial groups, whereas Caucasian Americans, Latin Americans, and Native Americans shared a number of common haplotypes. CONCLUSIONS These data represent an important resource for investigators in the fields of transplantation and population genetics. The gene and haplotype frequencies can be used to aid clinicians in advising patients about the probability of finding a match within a specific ethnic group, or to determine donor recruitment goals and strategies. The information is also a valuable resource for individuals who are interested in population genetics, selection and evolution of polymorphic human genes, and HLA-disease association.

Dependence of antibody-mediated presentation of antigen on FcRn

The neonatal Fc receptor for IgG (FcRn) is a distant member of the MHC class I protein family. It binds IgG and albumin in a pH-dependent manner and protects these from catabolism by diverting them from a degradative fate in lysosomes. In addition, FcRn-mediated IgG transport across epithelial barriers is responsible for the transmission of IgG from mother to infant and can also enhance IgG-mediated antigen uptake across mucosal epithelia. We now show a previously undescribed role for FcRn in mediating the presentation of antigens by dendritic cells when antigens are present as a complex with antibody by uniquely directing multimeric immune complexes, but not monomeric IgG, to lysosomes.

Accelerated rejection of renal allografts from brain-dead donors.

ObjectiveTo define the potential influences of donor brain death on organs used for transplantation. Summary Background DataDonor brain death causes prompt upregulation of inflammatory mediators on peripheral organs. It is hypothesized that this antigen-independent insult may influence the rate and intensity of host alloresponsiveness after engraftment. MethodsThe rates of survival of unmodified Lew recipients sustained by kidney allografts from brain-dead, normal anesthetized, and anesthetized ventilated F344 donors were compared. Brain death was induced by gradually increasing intracranial pressure under electroencephalographic control. Tracheotomized brain-dead animals and anesthetized controls were mechanically ventilated for 6 hours before transplant nephrectomy. The rate and intensity of the acute rejection event were examined by histology, immunohistology, and reverse transcriptase–polymerase chain reaction. ResultsAnimals bearing kidneys from brain-dead donors died of renal failure secondary to acute rejection at a significantly faster rate than those from anesthetized living controls or anesthetized animals ventilated for 6 hours. Within 3 hours after placement and reperfusion of brain-dead donor grafts, significant neutrophil infiltration was observed, followed by increasing numbers of macrophages and T cells. mRNA of proinflammatory mediators detected in kidneys within 6 hours of brain death and upregulated even before transplantation increased thereafter and appeared to accelerate and amplify host alloresponsiveness, as manifested by the rapid expression of chemokines, cytokines, adhesion molecules, and major histocompatibility complex class II antigens in the engrafted organ. The process evolved in the controls less intensely and at a slower rate. ConclusionsDonor brain death is a significant risk factor for peripheral organs used for transplantation. The activated state of such organs appears to trigger host immune mechanisms that accelerate the process of acute rejection. The effects of this central injury may explain in part the less satisfactory performance of cadaver organs in human transplantation compared with those from living sources.

Human T and Natural Killer Cells Possess a Functional Renin-Angiotensin System: Further Mechanisms of Angiotensin II–Induced Inflammation

The renin-angiotensin system (RAS) plays an important role in the regulation of inflammation and in the progression of chronic kidney disease. Accumulation of inflammatory cells into the renal parenchyma has been a hallmark of chronic kidney disease; however, little is known concerning the presence and the function of RAS elements in T and natural killer (NK) cells. Here is reported a co-stimulatory effect of angiotensin II (AngII) by showing an augmentation of mitogen and anti-CD3-stimulated T and NK cell proliferation with AngII treatment. Angiotensinogen and AngI also generated the same effect, suggesting that NK and T cells have functional renin and angiotensin-converting enzyme activity. Indeed, they express renin, the renin receptor, angiotensinogen, and angiotensin-converting enzyme by mRNA analysis. Flow cytometric analysis and Western blot revealed angiotensin receptor 2 (AT(2)) expression in T and NK cells, whereas AT(1) expression was found in T and NK cells and monocytes by Western blot. These receptors were shown to be functional in calcium signaling, chemotaxis, and proliferation. However, AT(1) and AT(2) antagonists alone or in combination were unable to abrogate completely the effects of AngII, suggesting that another AngII receptor may also be functional in leukocytes. This is the first study to show that T and NK cells are fully equipped with RAS elements and are potentially capable of producing and delivering AngII to sites of inflammation. Because their chemotaxis is enhanced by AngII, this creates a potential inflammatory amplification system.

Donor-specific anti-HLA antibodies predict outcome in double umbilical cord blood transplantation

Using a uniform detection method for donor-specific anti-HLA antibodies (DSAs), we sought to determine the effect of preformed DSAs on outcomes in double umbilical cord blood transplantation. DSAs were associated with an increased incidence of graft failure (5.5% vs 18.2% vs 57.1% for none, single, or dual DSA positivity; P = .0001), prolongation of the time to neutrophil engraftment (21 vs 29 days for none vs any DSA; P = .04), and excess 100-day mortality or relapse (23.6% vs 36.4% vs 71.4% for none, single, or dual DSA positivity; P = .01). The intensity of DSA reactivity was correlated with graft failure (median of mean fluorescent intensity 17 650 vs 1 850; P = .039). There was inferior long-term progression-free and overall survival when comparing patients with DSAs against both umbilical cord blood units to those without DSAs (3-year progression-free survival, 0% vs 33.5%, P = .004; 3-year overall survival 0% vs 45.0%, P = .04). We conclude that identification of preformed DSAs in umbilical cord blood recipients should be performed and that the use of umbilical cord blood units where preformed host DSAs exist should be avoided.