Juan C. Scornik

The changing causes of graft loss and death after kidney transplantation.

Background. The results of kidney transplantation have improved markedly over the last three decades. Despite this, patients still lose grafts and die. We sought to determine whether the causes of graft loss and death have changed over the last 30 years. Methods. We reviewed patients who underwent transplantation or who died between January 1, 1970 and December 31, 1999. We compared the causes of graft loss or death for three decades: 1970 to 1979, 1980 to 1989, and 1990 to 1999. Results. From January 1, 1970 to December 31, 1999, we performed 2501 kidney transplantations in 2225 patients. For the three periods, 210, 588, and 383 patients lost their grafts, respectively. Graft survival increased substantially. Graft loss occurred later after transplantation, with 36.0% losing grafts in the first year during 1970 to 1970, 22.8% during 1980 to 1989, and 11.4% during 1990 to 1999. Death with a functioning graft increased from 23.8% for 1970 to 1979 to 37.5% for 1990 to 1999. Concomitantly, rejection as a cause of graft loss fell from 65.7% for 1970 to 1979 to 44.6% for 1990 to 1999. Approximately two thirds of the patients who died after transplantation died with a functioning graft and one third died after returning to dialysis. Cardiac disease as a cause of death increased from 9.6% for 1970 to 1979 to 30.3% for 1990 to 1999. Deaths from cancer and stroke also increased significantly over the three decades from 1.2% and 2.4%, respectively, for 1970 to 1979, to 13.2% and 8.0%, respectively, for 1990 to 1999. Conclusions. The causes of graft loss and death have changed over the last three decades. By better addressing the main causes of death, cardiac disease, and stroke with better prevention, graft loss due to death with a functioning graft will be reduced.

Enzyme-linked immunoassay for anti-HLA antibodies : an alternative to panel studies by lymphocytotoxicity

In order to provide a simple and specific assay for the detection and quantitation of IgG and IgM anti-HLA antibodies in sera, HLA antigens purified from a pool of 240 random donor platelets were used to develop a solid-phase enzyme-linked immunoassay (EIA). The reference values for identifying the presence of IgG or IgM anti-HLA antibodies were determined by assaying sera from 39 healthy individuals without prior HLA alloimmunization. The assay was evaluated by studying sera from 122 patients who had been characterized previously for panel reactive antibodies by the lymphocytotoxicity assay (LCA). A significant linear correlation between two assays was noted (r=0.8, P=0.0001). Further analyses of the data demonstrated that the newly developed EIA has 100% specificity and 95.3% sensitivity as compared with the LCA. Additional studies revealed that patients whose PRA increased zr decreased over time were in parallel with antibody levels measured by EIA. When the EIA was used to measure anti-HLA antibody titers, it was more sensitive than the LCA. Since the EIA is sensitive, specific, and technically less demanding, it should provide an useful alternative to reduce the number of the more laborious panel studies for monitoring anti-HLA antibody status in candidates for organ transplantation and recipients of blood transfusions.

Obesity does not portend a bad outcome for kidney transplant recipients.

Background. Kidney transplant programs may avoid transplantation in obese patients because of reports indicating that obese patients have poorer outcomes than do nonobese patients. We recently reviewed our experience. Methods. Patients receiving a kidney transplant between January 1, 1990 and December 31, 1999 were divided according to body mass index (BMI): group 1, BMI<25 (n=457); group 2, BMI≥25 and <30 (n=278); and group 3, BMI≥35 (n=98). Results. Cadaveric graft survival rates at 2 years were 85% for group 1, 88% for group 2, and 85% for group 3 (P>0.10). Cadaveric patient survival rates at 2 years were 92% for group 1, 91% for group 2, and 94% for group 3 (P>0.10). There were no differences in technical losses or in posttransplantation wound complications. Group 3 patients, however, did have a higher incidence of steroid‐induced posttransplantation diabetes mellitus than the other two groups (P<0.01). Conclusion. Obese transplant recipients have similar outcomes to nonobese patients.

Anti-CD20 monoclonal antibody (rituximab) therapy for acute cardiac humoral rejection: a case report.

Humoral or antibody-mediated rejection in cardiac transplant recipients is mediated by donor-specific cytotoxic antibodies and is histologically defined by linear deposits of immunoglobulin and complement in the myocardial capillaries. Antibody-mediated rejection often is accompanied by hemodynamic compromise and is associated with reduced long-term graft survival. Standard immunosuppression, designed to target T cell immune function, is largely ineffective against this B cell-driven process. Current treatment options for humoral rejection are limited by a lack of specific anti-B cell therapies. We present the case of a 50-year-old woman with hemodynamically significant humoral rejection resistant to steroids, cyclophos-phamide, and plasmapheresis who responded to the addition of anti-CD20 monoclonal antibody therapy (rituximab). One year posttransplant, the patient is rejection-free, with normal left ventricular systolic function and coronary arteries.

Poststreptococcal reactive arthritis: Clinical characteristics and association with HLA-DR alleles

OBJECTIVE To assess the relationship of poststreptococcal reactive arthritis (ReA) to other forms of ReA and rheumatic fever by comparing the frequency of HLA-B27 and DRB1 alleles in these diseases. METHODS The diagnosis of poststreptococcal ReA was established in 25 children seen in a pediatric rheumatology clinic. HLA-B27 and DRB1 genotyping was performed in 18 of the white American patients. The DRB1 genotyping results were compared with those in 33 patients with rheumatic fever and 190 normal individuals. RESULTS HLA-B27 was positive in 3 of the 18 poststreptococcal ReA patients, a frequency not different from that found in normal individuals. Compared with normal controls, the frequency of the DRB1*01 allele was higher in poststreptococcal ReA patients (odds ratio [OR] 2.7, P=0.044), while DRB1*16 was increased in patients with rheumatic fever (OR 4.3, P=0.028). CONCLUSION The association of poststreptococcal ReA with HLA-DRB1*01, but not with HLA-B27, suggests that its pathogenesis may be more similar to that of rheumatic fever than to that of ReA associated with enteric pathogens.

A lifetime versus a graft life approach redefines the importance of HLA matching in kidney transplant patients

Introduction. Human leukocyte antigen (HLA) matching has been de-emphasized in the allocation of renal allografts and further discounting is planned in the new United Network of Organ Sharing kidney allocation model. An unforeseen consequence of poorer matching could be increased sensitization for candidates pursuing retransplantation. Methods. We examined candidates listed in the United States from 1988 to 2007 from the Scientific Renal Transplant Registry (SRTR) database that were relisted after loss of a primary kidney transplant (n=15,980). The primary outcome was change in panel reactive antibody (PRA) from prior to recipients initial transplant to the subsequent listing. Absolute change in PRA levels were examined in general linear models and the likelihood of becoming newly sensitized in logistic models. Results. There was no appreciable change in PRA for patients receiving a first 0 HLA-A, -B, -DR, or 0 HLA-A, -B–mismatched kidney transplant; contrariwise, there was a significant increase in PRA by increasing HLA mismatch of the first transplant. Only 10% of patients became sensitized after a 0 HLA-A, -B–mismatched transplant, whereas the proportion rose up to 37% with increasing HLA mismatches. Other factors, notably younger age and African American race, also contributed to a higher PRA at relisting. Conclusions. Although there might be a limited impact of HLA matching on acute rejection and graft survival, many patients might be negatively impacted from poor HLA matching of their first kidney transplant when needing a second transplant. This might be particularly important in patients with a long life expectancy because of the high likelihood of needing a second transplant during their lifetime.

Hyperacute and acute kidney graft rejection due to antibodies against B cells

Because of the perception of its uncertain clinical significance, the B cell crossmatch is not universally performed before renal transplantation. Even though sporadic cases of hyperacute rejection associated with B cell antibodies have been reported, doubts remain in light of other studies suggesting no effect on graft survival. This report describes 4 cases of graft rejection (3 hyperacute and 1 acute) that occurred in patients with anti-B-cell antibodies specific against donor HLA-DR or DQ antigens. Absence of anti-donor class I antibodies was confirmed in all cases by 2-color flow cytometry. Strong evidence for an antibody-mediated mechanism was found in one patient with anti-class I and anti-class II antibodies in serum transplanted with a class II mismatched kidney. In this case, only anti-class II antibodies were recovered in the eluate of the nephrectomy specimen. These four cases were compiled from three different institutions over a four-year period, which confirms the infrequent occurrence of these events. While anti-class II antibodies may not always be detrimental for graft survival, these results also confirm that they have the potential to cause hyperacute or acute graft loss. We conclude that the information provided by the B cell crossmatch should be available at the time that a decision to proceed with a renal transplant is made.

Association between HLA phenotype and HLA concentration in plasma or platelets

To understand the relationship between HLA phenotype and plasma or platelet HLA better, concentrations of plasma and platelet HLA were measured in 215 individuals of known HLA phenotypes. Precise quantitation of HLA antigens was achieved by means of an enzyme-linked immunoassay using the W6/32 monoclonal antibody and purified HLA molecules. The mean plasma and platelet HLA concentrations were 2.04 +/- 1.67 micrograms/ml (+/- SD, n = 215) and 11.28 +/- 4.65 fg/cell (+/- SD, n = 213), respectively. Statistical analysis of associations between HLA phenotypes and plasma HLA revealed that the mean plasma HLA concentration of individuals with HLA-A23 or HLA-A24 was 1.4 (p less than 0.002) or 1.9 (p less than 0.001) times higher than those without these two HLA antigens. Furthermore, the mean plasma HLA concentration of individuals who have HLA-A26 was 25% less than those without HLA-A26 (p less than 0.05). In contrast, the only association between HLA phenotypes and HLA concentrations of platelets was observed in HLA-B7-positive individuals. The mean platelet HLA concentration of HLA-B7 individuals was 27% higher than those without HLA-B7 (p less than 0.005). This finding is in accordance with previous observations made on red blood cells. The results indicate that the HLA concentrations in plasma are regulated, at least in part, by genetic factors that are different from those regulating platelet HLA.

Value of Posttransplant Antibody Tests in the Evaluation of Patients with Renal Graft Dysfunction

Posttransplant HLA antibodies correlate with C4d positive rejection and decreased graft survival. However, the diagnostic value of various antibody tests in the management of patients presenting with graft dysfunction is uncertain. Whether all or some patients should be tested, how often, what antibodies to test for and how to interpret results in presensitized or transfused patients, are issues still unresolved. We tested for HLA and non‐HLA antibodies by flow cytometry assays in 103 consecutive patients with graft dysfunction. The results show that: (1) C4d positive rejection was diagnosed in 75% of patients who developed posttransplant HLA antibodies, but only in 2% in antibody negative patients. (2) The correlation existed for donor specific IgG antibodies but not for IgM or nondonor specific IgG antibodies. (3) Weak antibody reactivity required confirmation by alternative testing as there were false positive results. (4) Posttransplant transfusions did not induce de novo HLA antibodies. (5) Negative antibody results were unlikely to turn positive after several months of follow‐up. (6) Antibodies to the angiotensin II type 1 receptor, HLA‐DP and MICA did not correlate with C4d+ rejection. We conclude that testing for posttransplant HLA antibodies is critical in narrowing the diagnostic alternatives in patients with graft dysfunction.

The crossmatch in renal transplantation : evaluation of flow cytometry as a replacement for standard cytotoxicity

Flow cytometry (FC) is increasingly being used as a crossmatch procedure in addition to the standard complement-dependent cytotoxicity (CDC) test. In fact, FC offers a number of advantages over CDC and has the potential to become the primary crossmatch technique for cadaveric donor renal transplantation. We evaluated this possibility in 230 patients crossmatched by both CDC and FC. The results showed that when the T cell crossmatch was negative by FC it was always negative by CDC, and that when the T cell results were positive by CDC (IgM antibodies excluded) they were also positive by FC. As expected, a number of tests were T cell-positive by FC but negative by CDC. A T cell CDC crossmatch was more likely to be positive when FC was positive for both T and B cells and when FC results were quantitatively higher. However, FC was unable to consistently predict a positive, dithiothreitol-resistant B cell CDC crossmatch. A policy to transplant patients with negative FC results (70% of the patients evaluated) and not to transplant sensitized patients with FC+ T cell results (10%) would allow us to make a final decision with only FC in 80% of the cases. Actual graft survival was similar for nonsensitized first-transplant candidates with positive (83%) or all patients with negative (86%) FC results. We conclude that FC is sufficient to make a final decision in most cases. Wider utilization will require improvements in the ability of FC to measure B cell antibodies and to quantitate antibodies to T cells.