William E. Harmon

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.

Regulatory CD25+ T Cells in Human Kidney Transplant Recipients

Recent evidence suggests that a population of professional regulatory cells, which limit immune responsiveness, exist in rodents and healthy human subjects. However, their role in disease states remains unclear. A proportion of renal transplant recipients do not demonstrate in vitro reactivity toward their mismatched donor-derived HLA-DR antigens; it was therefore hypothesized that this may be due to such regulatory cells. A cohort of 23 renal transplant recipients was studied at a single institution. In patients with no history of acute rejection, 6 (40%) of 15 demonstrated regulation toward the mismatched HLA-DR allopeptides by CD25(+) cells. By contrast, only one (12.5%) in eight of those with a history of acute rejection demonstrated regulation. Interestingly, if the patient assays were stratified according to initial in vitro immune responsiveness toward the mismatched allopeptides, 8 (47.1%) of 17 of patient assays with low allopeptide responsiveness (alloreactive T cell frequencies less than 60/million) demonstrated regulation of indirect pathway alloresponses by CD25(+) cells, whereas 0 of 8 with higher responses (frequencies greater than 60/million) demonstrated no such regulation (P < 0.05 by chi(2) test). The regulatory cells are present in the circulation as early as 3 mo after transplantation and persist for a number of years, despite conventional immunosuppression. Furthermore, induction treatment with anti-IL-2R mAb did not prevent the development of these regulatory CD25(+) cells. Data from two patients suggest that these cells may also play a role in preventing epitope shifting, implicated in the ongoing immune activation contributing to chronic rejection, and that loss of regulation in a given patient may precede an episode of rejection.

Evaluation of living renal donors: The current practice of US transplant centers

To examine practice patterns regarding how living donors are evaluated and selected in the U.S., a survey was sent to all 231 United Network of Organ Sharing (UNOS)-approved transplant centers. Respondents from 75% of centers completed the questionnaire, all of whom utilize living donors for renal transplantation. Although the use of living-unrelated donors is also widely accepted (in 92% of centers), only 31% of responding centers performed such transplants in 1992, indicating a discrepancy between acceptance and actual practice. Morbidity (0.23%) and mortality (0.03%) of kidney donation continue to be low. The long-term risk of renal insufficiency in kidney donors appears to be similar to, or lower than, that in the general population. There is substantial variability in how potential donors are evaluated and what they are told regarding the risk involved in renal donation. There is also variability in exclusion criteria such as the acceptance of older donors (>55 years old); those with borderline-to-mild hypertension, and those with borderline low glomerular filtration rate. Larger centers tended to be less rigid in their exclusion criteria compared with smaller centers. While our results indicate widespread acceptance and use of living donors, they also highlight the need for future studies to examine the efficacy of tests used in the evaluation process and to determine the long-term risks of renal donation.

Hemoglobin Carbamylation in Uremia

CHROMATOGRAPHY of hemolysates of red cells resolves four minor hemoglobin components from the main hemoglobin A (HbA) fraction. These minor components — HbA1a1, HbA1a2, HbAlb, and HbA1c — collectiv...

Cytotoxic lymphocyte gene expression in peripheral blood leukocytes correlates with rejecting renal allografts.

BACKGROUND We have shown previously that heightened expression of the cytotoxic lymphocyte (CL) effector genes perforin (P), granzyme B (GB), and Fas ligand (FasL), is closely correlated with acute allograft rejection, particularly when two or more target genes are up-regulated. METHODS We used quantitative reverse transcription-polymerase chain reaction to analyze CL gene expression from peripheral blood leukocytes (PBLs) and renal allograft biopsies in 31 paired samples of PBLs and renal tissue from 25 renal allograft recipients. Our aims were (1) to determine whether the expression of CL gene expression in PBLs correlates with expression of these genes in renal allograft biopsy tissue and (2) to determine whether CL gene expression in PBLs correlates with the histological diagnosis. RESULTS Coordinate gene expression in PBLs and acutely rejecting allografts was found in 9/11 (82%) for P, 07/11 (64%) for GB, and 10/11 (91%) for FasL. Coordinate absence was found in 15/20 (75%) for P, 17/20 (85%) for GB, and 16/20 (80%) for FasL in nonrejecting allografts. Furthermore, up-regulation of any two genes in PBLs correlated with pathological diagnosis of rejection with excellent positive (100%) and negative (95%) predictive values. CONCLUSION Coordinate CL gene expression in PBLs and the allograft is usually detected. CL gene expression in PBLs is closely associated with a pathologic diagnosis of rejection. CL gene expression in PBLs may serve as a noninvasive method of monitoring for renal allograft rejection.

Risk factors for posttransplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).

Background. Posttransplant lymphoproliferative disorder (PTLD) is an important complication of transplantation. The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database has documented 56 cases of PTLD, the largest such series to date. Methods. We analyzed the available longitudinal and multicenter data in the NAPRTCS database to evaluate the demographic and therapeutic risk factors and the temporal trends for PTLD in children after renal transplantation. Results. The overall incidence of PTLD was 1.2% of all patients or 298/100,000 posttransplantation years of follow-up. However, this incidence increased from 254/100,000 years between 1987 and 1991 to 395/100,000 years from 1992 onwards. In the same periods, the time to PTLD decreased from a median of 356 days (range 64–3048) to a median of 190 days (range 42–944). PTLD occurred with greater frequency in white children (P =0.003) and in cadaver donor transplants (P =0.019), but there was no significant predilection for gender, younger children (0–5 years), or primary diagnosis. No significant difference was found in the use of anti–T-cell antibodies or in doses of CsA, azathioprine, or prednisone at 1 month, 6 months, and 1 year. Between 1996 and 1997, 69 patients were initiated with tacrolimus. Eight cases of PTLD were identified in these recipients to date (prevalence rate 11.5%), compared with 46/4084 (1.1%) where cyclosporine was used (P <0.0001). Conclusions. There is a trend towards increasing incidence and earlier occurrence of PTLD in the pediatric renal transplant population. White race and cadaver donor sources are risk factors not reported before. Continued monitoring of tacrolimus immunosuppression is important.

Post‐Transplant Infections Now Exceed Acute Rejection as Cause for Hospitalization: A Report of the NAPRTCS

Newer immunosuppressive agents have dramatically reduced the rates of acute graft rejection (AR) over the last decade but may have exacerbated the problem of post‐transplant infections (PTI). We analyzed data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) to determine the risks of hospitalization from PTI vs. AR in the years 1987–2000. For patients transplanted in 1987, the AR‐associated hospitalization rate exceeded the equivalent hospitalization rate for PTI at both early (1–6 months) and later time points (6–24 months). In contrast, for patients transplanted in the year 2000, the PTI‐associated hospitalization rate was twice that for AR‐associated hospitalization during each time period. During the first two years post‐transplant, rates of AR hospitalization trended significantly downwards (p < 0.001) while rates of PTI‐associated hospitalization stayed constant. In the 6–24‐month time period post‐transplant, the risk of bacterial and viral infection‐related hospitalization rose significantly from 1987 to 2000 (p < 0.001 for trend by transplant year). We conclude that the causes of hospitalization at all times up to 24 months post‐transplant, including the critical early 6 months, have shifted away from AR to PTI.

The 1989 report of the North American Pediatric Renal Transplant Cooperative Study - This report is prepared under the auspices of the scientific advisory committee of the North American Pediatric Renal Transplant Cooperative Study

This report of the North American Pediatric Transplant Cooperative Study summarizes data contributed by 57 participating centers on 754 children with 761 transplants from 1 January 1989 to 16 February 1989. Data collection was initiated in October 1987 and follow-up of all patients is ongoing. Transplant frequency increased with age; 24% of the patients were less than 5 years, with 7% being under 2 years. Common frequent diagnoses were: aplastic/dysplastic kidneys (18%), obstructive uropathy (16%), and focal segmental glomerulosclerosis (12%). Preemptive transplant, i.e., transplantation without prior maintenance dialysis, was performed in 21% of the patients. Dialytic modalities pretransplant were peritoneal dialysis in 42% and hemodialysis in 25%. Bilateral nephrectomy was reported in 29%. Live-donor sources accounted for 42% of the transplants. Among cadaveric donors, 41% of the donors were under 11 years old. During the first post-transplant month, maintenance therapy was used similarly for live-donor and cadaver source transplants, with prednisone, cyclosporine, and azathioprine used in 93%, 83%, and 81%, respectively. Triple therapy with prednisone, cyclosporine, and azathioprine was used in 78%, 75%, and 75% of functioning cadaver source transplants at 6 months, 12 months, and 18 months as opposed to 60%, 63%, and 54% for live-donor procedures, with single-drug therapy being uncommon. Rehospitalization during months 1–5 occurred in 62% of the patients, with treatment of rejection and infection being the main causes. Additionally, 9% were hospitalized for hypertension. During months 6–12 and 12–17, 30% and 28% of the patients with functioning grafts were rehospitalized. Times to first rejection differed significantly for cadaver and live-donor transplants. The median time to the first rejection was 36 days for cadaver transplants and 156 days for live-donor transplants. Overall, 57% of treated rejections were completely reversible although the complete reversal rate decreased to 37% for four or more rejections. One hundred and fifty-two graft failures had occurred at the time of writing, with a 1-year graft survival estimate of 0.88 for live-donor and 0.71 for cadaver source transplants. In addition to donor source, recipient age is a significant prognostic factor for graft survival. Among cadaver donors, decreasing donor age is associated with a decreasing probability of graft survival. Thirty-five deaths have occurred; 16 attributed to infection and 19 to other causes. The current 1-year survival estimate is 0.94. There have been 9 malignancies.

The Report of a National Conference on the Wait List for Kidney Transplantation

In March, 2002, over 100 members of the transplant community assembled in Philadelphia for a meeting designed to address problems associated with the growing number of patients seeking kidney transplantation and added to the waiting list each year. The meeting included representatives of nine US organizations with interests in these issues. Participants divided into work groups addressing access to the waiting list, assigning priority on the list, list management, and identifying appropriate candidates for expanded criteria donor kidneys. Each work group outlined problems and potential remedies within each area. This report summarized the issues and recommendations regarding the waiting list for kidney transplantation addressed in the Philadelphia meeting.

Cyclosporin A inhibits CD40 ligand expression in T lymphocytes.

The ligand for CD40 is expressed on activated T lymphocytes and delivers contact-dependent activation signals to B lymphocytes. The mechanisms regulating CD40 ligand gene expression are largely unknown. Optimal expression of CD40 ligand required activation of protein kinase C and a rise in intracellular calcium concentration. CD40 ligand expression was inhibited by pretreatment of T cells with cyclosporin A. Cyclosporin A analogues inhibited CD40 ligand expression with a potency mirroring the ability of each compound to inhibit calcineurin activity, indicating that calcineurin plays a key role in CD40 ligand gene expression. Cyclosporin A inhibited IL-4-driven CD40 ligand-dependent IgE isotype switching in PBMC but did not inhibit IgE synthesis induced by CD40 mAb plus IL-4. PBMC derived from transplant patients receiving cyclosporin A failed to express CD40 ligand upon stimulation. These results suggest that patients receiving cyclosporin A may be deficient in CD40 ligand-dependent T cell help.