An evaluation of HLA cross-reactive group matching on graft survival in deceased donor kidney recipients.

Since September 20, 1999, our organ procurement organization (OPO) serving an ethnically diverse local distribution area has allocated kidneys using a cross-reactive group (CREG)-based variance. This variance awards 7 points for 0-CREG,0-DR mismatches and 6 points for 0-A,B mismatches in addition to points given for waiting time (3) and panel-reactive antibodies (PRA) > or = 80% (3). Previously, we have shown that awarding points for 0-CREG,0-DR mismatches in kidney allocation improves the access to HLA-matched transplants for racial groups, especially for the black race. In this study, we evaluated if there are outcome benefits as well. One- and 3-year uncensored graft survival data and analyses for the influence of HLA mismatching on graft outcome in black and nonblack recipients were provided by Scientific Registry of Transplant Recipients (SRTR). Overall, 1-year graft survival was 87.4% and not significantly different for blacks (86.1%, n = 467) vs nonblacks (88.8%, n = 730); 3-year graft survival was 74.6% and significantly lower P = .0001 for blacks (68.5%, n = 480) vs nonblacks (78.4%, n = 765). No significant advantage was observed for either the black or nonblack recipients in any of the HLA-mismatched categories, including the 0-CREG,0-DR mismatch group. An HLA matching effect also was not seen when data were stratified for patients nonsensitized (PRA < or = 10%) and sensitized (PRA > 10%) at the time of transplantation, except for the improved graft survival in sensitized nonblack recipients of 0- A,B,DR-mismatched grafts. Of the patients who lost their grafts and returned to the waiting list for retransplantation, the 0-A,B,DR mismatched were the least sensitized group (6%, n = 16), and there was a trend for less sensitization in the 0-CREG,0-DR-mismatched group (33%, n = 9), compared to those with other HLA mismatches (68%, n = 137). Thus, based on 1-year and 3-year follow-up data, there are no apparent graft outcome benefits for either CREG matching or conventional HLA matching in our service area, except for sensitized nonblack recipients receiving 0-A,B,DR-mismatched grafts. Such benefits may become more apparent with longer follow-up.

Use of perfusion parameters in predicting outcomes of machine-preserved kidneys.

Perfusion parameters (PP) and early transplant outcome data from 332 consecutive ECD type kidneys machine preserved on the Waters RM-3 apparatus were reviewed and analyzed to examine the validity of using suboptimal PPs (renal resistance of .41-.60) as a criterion for discarding kidneys. Overall discard rate was 23.5%, with 55% of these having "poor" PP as part of reason for discard. PP analysis after 4 hours on the RM-3 is presented. This encompasses 280 kidneys with renal resistance .40. The PP-related discard rate in the renal resistance .41 to .60 kidneys was 51% versus 17% in the renal resistance

The pathogenesis of hyperchloremic metabolic acidosis associated with kidney transplantation.

The mechanism of persistent hyperchloremic metabolic acidosis developing after kidney transplantation was investigated in six patients. In five patients in whom acidosis failed to lower the urine pH below 5.5, an infusion of sodium sulfate also failed to lower the urine pH. Neutral phosphate infusion failed to increase the urine minus blood (U-B) carbon dioxide tension (pCO2) difference normally in these patients. This abnormal response to both maneuvers indicates the presence of a tubular defect for distal hydrogen ion secretion. In the remaining patient, spontaneous acidosis lowered the urine pH below 5.5 and increased the U-B pCO2 normally with the administration of phosphate, demonstrating that this patient's distal capacity for hydrogen secretion was intact. The plasma aldosterone level was low in this patient, and thus he had the acidification defect characteristic of aldosterone deficiency. Hyperkalemia developed in two patients; both were aldosterone-deficient, and they had a low fractional potassium excretion ion response to stimulation with sodium sulfate or acetazolamide. In all but one patient, who lost his kidney to accelerated rejection, chronic rejection developed. Homogeneous deposition of complement (C3) along the tubular basement membrane was found in three patients. Our data suggest that a secretory type of distal renal tubular acidosis can be an early sign of the immunologic process that leads to chronic rejection.

The relationship between flow cytometer crossmatch results and subsequent rejection episodes in cadaver renal allograft recipients.

Flow cytometry (FC) T and B cell crossmatches were done retrospectively for 38 cadaver renal transplant recipients (29 first and 9 retransplants--minimum follow-up 12 months) using both current pretransplant serum and peak-reactive sera. An increase in median fluorescence intensity (channel shift) and/or an increase in the number of donor T and/or B cells binding antibody in test sera occurred in 23 cases. These 23 patients experienced a greater number of reversible rejection episodes as compared with patients with negative FC crossmatches (65% vs. 33%), P = 0.031. Graft outcome, however, was not different in the two groups. Thus, a positive FC crossmatch allows for the detection of subliminal levels of donor presensitization and is associated with a greater number of rejection episodes. A positive FC crossmatch is not predictive of ultimate graft loss.

Removal of lymphocytotoxic antibodies by pretransplant immunoadsorption therapy in highly sensitized renal transplant recipients.

A high level of panel-reactive antibodies (PRA) in potential renal transplant recipients is associated with a long waiting time until transplantation and correlates inversely with graft outcome. We report our experience with the employment of immunoadsorption (IA) using a column composed to sepharose-bound staphylococcal protein A (which has a relatively selective affinity for binding IgG compared with other immunoglobulins) to decrease the PRA levels and expedite transplantation in 6 highly sensitized potential renal transplant recipients (1 primary and 5 awaiting second transplants). All patients had PRA levels of greater than or equal to 70% for a duration of 1 year prior to IA. Only patients with antibody specificity localized to 1 or 2 HLA A or B antigens were accepted for the study. IA procedures were performed on alternate days until a twofold decrease in antibody titer had occurred (maximum: 6 procedures). Repeat procedures were initiated if the HLA antibody titer returned to its baseline value. Intravenous cyclophosphamide (CY) (10 mg/kg/day every 3 weeks) and methylprednisolone (MP) (0.5 mg/kg/day) were provided as adjunctive immunosuppression until transplantation. A total of 44 immunoadsorption procedures were performed (27 primary and 17 repeat) with treatment of 2.49 +/- 0.02 plasma volumes per session. Serum IgG concentration decreased 95 +/- 3% and PRA activity decreased 75 +/- 16% after the primary treatment course. Four patients received cadaveric grafts within 3.7 +/- 1.2 months following the last IA procedure. Three grafts are functioning at 1 year, 8 months, and 8 weeks posttransplant. The remaining graft demonstrated primary nonfunction. All four patients had a past positive crossmatch using pre-IA sera with their respective donors. Patients not transplanted exhibited rapid resynthesis of IgG and a return of the PRA towards baseline levels within a few weeks after IA. We conclude that IA can effectively remove HLA antibodies and expedite graft availability in highly sensitized patients.

Evidence that HLA class II disparity is required for the induction of renal allograft enhancement by donor-specific blood transfusions in man.

We studied 46 living-related primary renal allograft recipients between June 1980 and Jan 1988 to determine if enhancement of allograft survival by donor specific transfusions requires a major histocompatibility complex mismatch between the blood/kidney donor and the recipient. Recipients were matched for a single HLA haplotype, but differed at various HLA loci on the unshared haplotype. DST (200 ml) was administered either 3 times at two-week intervals pretransplant (n = 17), or once 3-4 weeks pretransplant, together with oral azathioprine (1 mg/kg/day/28 days) (n = 29). Patients were followed for at least 1 year and all clinical rejection episodes were confirmed histologically. Enhanced graft survival by DST was defined as a rejection-free posttransplant course. Incompatibility for class II determinants on the unshared haplotype of donor had a beneficial effect. A significantly greater proportion of recipients had stable, rejection-free, allograft function if incompatible for the DR locus (80% vs. 44%, P = 0.012), for class II public determinants (100% vs. 58%, P = 0.013), or for at least one of the class II gene products (DR, DQ, class II public) (81% vs. 40%, P = 0.006). Graft loss occurred in 7 of 46 (15%); 6 of the 7 recipients were HLA class II-compatible with their blood/kidney donor. Mismatches for HLA class I private or public determinants and other factors known to affect graft outcome did not influence the results. We conclude that enhanced kidney allograft survival by DST may be predicated by factors within the MHC--specifically class II disparity. These observations also suggest that better HLA matching at the class II locus may account for the apparent "disappearance" of the transfusion effect in cadaver renal transplants in the cyclosporine era.

Immunopathological studies of the ruptured human renal allograft.

The immunopathology of five cases of spontaneous allograft rupture has been studied. All kidneys were edematous on exploration and routine histological sections showed interstitial edema and mononuclear cell infiltration characteristic of acute rejection. Immunofluorescence revealed, at most, scattered vascular deposition of IgM and mild mesangial C3 deposition. These findings are compared with findings in normal kidneys and kidneys which had been hyperacutely rejected. The normal kidney showed focal afferent arteriolar and proximal mesangial stalk deposition of C3 without IgM. The kidneys of patients with hyperacute rejection showed brilliant staining for fibrin and IgM in all arterial and arteriolar walls with lesser amounts of C3 and IgG; IgM and C3 were prominent in the glomerulus. These findings suggest that mechanisms other than circulating preformed antibodies are responsible for the pathogenesis of spontaneous allograft rupture.

Cytotoxic T-cell role in renal allograft rejection and regulation. Renal allograft infiltrating cytotoxic T-cell line with suppressor-inducer function.

We previously investigated the characteristics of renal allograft infiltrating T-cell lines that were propagated from biopsy and nephrectomy specimens designated as IG-Bip and IG-Neph, respectively, or analogous line designated IG-T-eff, which was generated by co-culturing pretransplant recipient blood with irradiated donor splenocytes (manuscript submitted). The recipient (IG) had no previous sensitization to donor mismatched HLA antigens (A2 and DR1). Phenotypically, all lines were of recipient origin and were CD3+, TCR alpha beta +, DR+. However IG-Bip line was low in CD4 (19%) and high in CD8 (50%), whereas IG-Neph and IG-T-eff lines had equal mixture of CD4+ (34%) and CD8+ (38%) subsets). Functionally, all three lines contained donor-specific CTLs. In the present report, we used the in vitro MLR to examine the possible utilization of these CTL lines as inducer cells to generate donor-specific Ts cells from recipient PBLs. Coculturing IG-PBL that was drawn before or after transplantation and immunosuppression with irradiated IG-T-eff or IG-Neph but not IG-Bip CTL lines, generated Ts cells. Ts cells were of recipient origin and were CD3+, CD8+, leu 11b+, CD28-, all characteristic of Ts-effector phenotype. Ts cells inhibited MLR response of recipient PBLs against donor or third-party stimulators that shared with the donor the mismatched HLA antigens. Ts suppression was more pronounced against early phase of MLR response and was not due to a shift in MLR kinetics or nonspecific soluble suppressor or cytotoxic products. These findings suggest that allograft infiltrating CTLs or their in vitro generated analogous line may modulate allograft rejection by acting as Ts inducers and that Ts induction was dependent on the presence of the CD4 subset within the Ts-inducer cells but was not dependent on renal transplantation or immunosuppression.

Parathyroid allotransplantation in the treatment of complicated idiopathic primary hypoparathyroidism.

Parathyroid allotransplantation was performed in a 25-year-old woman with idiopathic hypoparathyroidism that had been diagnosed at age 4 years. Long-term medical management of the primary condition with vitamin D and oral calcium supplementation was complicated by multiorgan calcinosis and renal failure. At the age of 21 years she received a successful cadaver renal allograft. Four years later she developed calcinosis cutis with widespread skin necrosis. Medical control of calcium and phosphate metabolism was unsatisfactory and the skin necrosis became progressive and life threatening. A parathyroid allograft that was performed with tissue from a parathyroid adenoma resulted in normalization of the serum calcium and phosphorus levels with arrest and subsequent healing of the skin necrosis. Later failure of the parathyroid allograft was followed by successful retransplantation of normal parathyroid tissue from a cadaver organ donor.

Partial splenic embolization, an alternative to splenectomy--results of a prospective, randomized study.

UNLABELLED: We conducted a prospective, randomized study comparing transcatheter partial splenic embolization (PSE) with splenectomy (SX) in 53 renal transplant candidates. An additional 112 PSE procedures were performed for various indications in 101 patients. STUDY RESULTS: A mean +/- SD of 65% +/- 16% of splenic mass was ablated in the PSE group. The early postoperative morbidity rate was similar in the two study groups, as was the duration of hospital stay. Abscess or rupture of the spleen were not encountered. Severe pancreatitis occurred only in the SX group. Renal transplantation was carried out in equivalent numbers in both groups, with a similar long-term (2.5 to 4.0 years) graft survival (60% versus 66%). No difference in long-term patient mortality was noted. Splenic "regeneration" occurred frequently after PSE. PSE experience exclusive of study: Embolization attempts failed in nine patients. Repeat PSE was performed in 11 of the 101 patients. Where hypersplenism was the primary indication, PSE resulted in significant improvement in the hematologic parameters. The incidence of serious complications was acceptably low. There were two late procedure-related deaths. Our conclusion from the study and the total experience of 137 PSE procedures is that PSE offers an acceptably safe alternative to SX in selected high-risk patients in whom both the surgical intervention and the resulting asplenic state carry a prohibitive risk.

Hepatic dysfunction during isoniazid chemoprophylaxis in renal allograft recipients.

Hepatitis is a frequent complication of dialysis and renal transplantation; therefore, the occurrence of drug hepatotoxicity is an additional important consideration in renal allograft recipients. Azathioprine, needed for immunosuppression, and isoniazid, used for antituberculous chemoprophylaxis, are both potentially hepatotoxic. A retrospective study of 119 patients who received 126 renal allografts was done to estimate the probable incidence of isoniazid-related hepatic dysfunction. All patients in this series were administered isoniazid chemoprophylaxis. Posttransplantation hepatitis developed in 13 patients. Circumstantial evidence supported a presumptive diagnosis of isoniazid hepatotoxicity in three recipients. We concluded that routine isoniazid chemoprophylaxis is not justified in renal allograft recipients based on the probability of hepatotoxicity as contrasted to the infrequent occurrence of tuberculosis.

Total parathyroidectomy and autotransplantation in secondary hyperparathyroidism.

Sixteen patients with chronic renal failure and symptomatic secondary hyperparathyroidism underwent total parathyroidectomy. Sixteen to 25 fragments of parathyroid tissue measuring 1 cu mm were autotransplanted into the brachioradial muscle. Evidence of "take" of the autotransplant was present in all patients, although four patients still have hypocalcemia and require calcium and vitamin D supplementation. Three patients have experienced late diminution of autotransplant function. Symptomatic improvement occurred promptly in 15 of the 16 patients. Two patients with persistently elevated parathormone levels were treated by partial excision of the implant, and one patient whose autograft functioned inadequately was successfully treated by implantation of cryopreserved autologous parathyroid tissue. Total parathyroidectomy with autotransplantation of parathyroid fragments to the forearm is the preferred surgical procedure for secondary hyperparathyroidism.

Digoxin-like immunoreactive substance in renal transplant patients.

Digoxin-like immunoreactive substance (DLIS) has been detected in several patient populations that were not receiving digoxin, including those patients with end-stage renal disease. The structure and physiologic significance of this compound are unknown, and the fate of DLIS after renal transplantation has not been studied. The authors prospectively evaluated 163 patients (not receiving digoxin) before and after transplantation for the presence of DLIS. Three different assays were used: radioimmunoassay (RIA), affinity mediated immunoassay (ACA), and fluorescence polarization immunoassay (TDX I). Depending on the assay method used, 11% (RIA), 6% (ACA), and 9% (TDX) of patients had detectable DLIS pretransplant. Using all 3 assays, a total of 34 patients (21%) were found to have DLIS. The mean serum digoxin concentration was 0.41 +/- 0.13 ng/mL (range: 0.2-1.2 ng/mL) and DLIS was detectable by greater than 1 assay method in seven patients. DLIS persisted longer in patients who had delayed allograft function (13.7 +/- 7 days) than in those who did not (3 +/- 1.9 days), P less than .05. In summary, detection of DLIS in renal transplant recipients appears to be an infrequent occurrence when using a single digoxin assay method. When detected, the concentration of DLIS is often below the usual therapeutic range for digoxin and disappears once allograft function is established. The authors conclude that the presence of DLIS is unlikely to be clinically significant in the renal transplant population.

Lipogenic activity and brown fat content of human perirenal adipose tissue.

The incorporation of 3H2O and/or 14C-glycerol into lipids and the specific activities of the enzymes acetyl CoA carboxylase and lipoprotein lipase were measured in the perirenal and subcutaneous adipose tissue of human subjects. The perirenal adipose tissue of younger subjects with higher brown adipocyte content had higher rates of lipogenesis and enzyme activities per gram tissue than the corresponding subcutaneous tissue. However, in individual specimens, the perirenal/subcutaneous ratios of all but one of the above parameters failed to show a correlation with the brown adipocyte content of the perirenal adipose tissue. One parameter, namely 3H2O incorporation into fatty acids per adipocyte, did relate to the brown adipocyte content of the perirenal adipose tissue in four normal-weight patients only.

Effect of a PGE-1 analogue on the survival of cardiac transplant rats.

Prostaglandins can be considered as soluble factors of cell-mediated immunity. Studies with animal models have shown that prostaglandins of the series E-1 (PGE-1) can modulate the lymphocyte response to alloantigens. The goal of this work was to evaluate the immunosuppressive effect of a PGE-1 analogue (Enisoprost) on cardiac allograft survival in rats. PGE-1 was given to groups of six rats with heterotopic cardiac transplant. Group 1 was the untreated control group. Group 2a received PGE-1 from 0 to 4 days after transplant and group 2b received PGE-1 from 7 days before transplant to 4 days after transplant. Group 3 was treated with donor-specific blood transfusions (DST) 7 days before transplant. Groups 4a, 4b, and 4c were treated with DST and PGE-1 (0 to 4 days, -7 to 0 days, and -7 to 4 days relative to transplant, respectively). Group 5 was treated with cyclosporine (CsA), groups 6a, 6b, and 6c received DST, CsA and PGE-1. Cardiac allograft survival of group 2a (PGE-1) was better than that of the control group (9.6 +/- 1.7 days vs. 6.6 +/- 1.9 days) X +/- SD; p < 0.05. Group 4a (DST+PGE-1) had better cardiac allograft survival than group 3 (DST) (20.0 +/- 14.3 days vs. 14.3 +/- 3.3 days, respectively; p < 0.05). Group 6a (DST+CsA+PGE-1) had a better graft survival than group 5 (CsA) but the difference was not significant (44.6 +/- 13 days vs. 37.5 +/- 19.5 days, respectively; p = 0.20).(ABSTRACT TRUNCATED AT 250 WORDS)

Orthotopic renal homotransplantation in a patient with thrombosis of the inferior vena cava.

Complete thrombosis of the infrarenal vena cava and the entire iliac venous system is a unique circumstance in a candidate for renal allotransplantation. This condition was created in a patient by the previous use of an inferior vena cava clip. The patient received a kidney transplant in the orthotopic intra-abdominal position, using his own renal vein for renovenous anastomosis. The usual method of urinary drainage was also modified. This approach to transplantation should be considered in the presence of partial clotting or occlusion in the distal vena cava or iliac venous system.

Erythrocythemia following renal transplantation: influence of diuretic therapy.

Post-transplant erythrocythemia (PTE) is a common finding in renal allograft recipients, although the etiology of this disorder has not been clearly established. We identified 22 patients (9.8%) with PTE from among 225 renal transplant recipients followed for an average of 5.5 years. To characterize possible predisposing factors and to study the clinical significance of PTE, these patients were compared with a control group matched for age, race, sex and etiology of renal failure. Plasma volume (PV) and red blood cell mass (RBCM) were measured in the majority of patients with PTE. Peripheral serum erythropoietin (Ep) levels were determined in the majority of patients in the control and PTE groups. PTE occurred an average of 11.4 months after transplantation. Risk factors for the development of PTE were pretransplant hypertension, retention of native kidneys, higher pretransplant hematocrit, and diuretic use for treatment of post transplant hypertension. Ep levels in the PTE and control groups were not significantly different. Twenty of the 22 patients with PTE were receiving concurrent diuretic therapy, and hematocrits fell to normal levels in all of these patients following cessation or dose reduction of diuretic. No other treatment of PTE was utilized, excluding the phlebotomy of a single unit of blood from one patient. No thromboembolic complications were noted during the follow-up period. We conclude that PTE is frequently induced by overzealous diuretic therapy for treatment of post-transplant hypertension. Discontinuation or reduction of diuretic therapy results in resolution of PTE in nearly all patients. From this experience we have developed an algorithm for the investigation and management of PTE.

Massive subcutaneous emphysema: an unusual presentation of jejunal perforation.

Massive diffuse subcutaneous emphysema resulting from perforation of the proximal jejunum is presented. Seventy-nine reported instances of subcutaneous emphysema of gastrointestinal origin were reviewed. Emphysema originating from the jejunum has not been previously reported. The colon (26 patients) and rectum (16 patients) were the more common sites of perforation. Perforations of the stomach and duodenum were found in 14 patients. The most common site for presentation of the subcutaneous air was the lower abdominal wall and thigh, and the more common causes were carcinoma of the colon and rectum and diverticulitis. The pathogenesis of emphysema in the patient described, as well as in the great majority of other patients, is from intraluminal gas rather than from gas-forming organisms. The air spreads along neurovascular bundles and other anatomic planes and may rapidly reach areas distant from the perforation. The recognition of these phenomena in the diagnosis of gastrointestinal perforation is important.

Anatomic abnormalities of cadaver kidneys procured for purposes of transplantation.

Over a 7-year period the authors studied the vascular and ureteric anomalies of kidneys procured from brain dead, heart-beating cadavers for the purposes of transplantation. Four hundred donors had a bilateral nephroureterectomy performed using an en-bloc technique, followed by fine anatomical dissection in cold saline slush solution. Thus, 800 kidneys were available for study. Single renal arteries were found in 72 per cent of the kidneys, with multiple arteries occurring in 28 per cent. The renal veins showed a more uniform anatomical pattern and were single in 92 per cent of instances. There were nine ureteral anomalies, all duplications, being just 1 per cent of the total number studied. Sex, race, and blood group of the donor did not significantly influence the number of anomalies seen. In sum, anatomical variants were noted in 197 (49.3%) donors, 69 (17.3%) with bilateral anomalies and 128 (32.0%) with unilateral anomalies. A knowledge of these anatomical variants will allow surgeons responsible for organ procurement to proceed with caution and so prevent wastage of cadaver kidneys due to technical misadventures.

The spectrum of peritonitis in renal transplant recipients.

Peritonitis in immunosuppressed renal transplant recipients continues to be associated with a high mortality. Twenty-four patients with intraperitoneal infections were identified in 542 consecutive renal transplant recipients over a period of 15 years (4.4%). Sixteen of the 24 (66.6%) died as a result of these infections. Transplant wound sepsis and the complications and surgery of gastrointestinal diseases accounted for the majority of instances. During the period 1980-1983 only four cases occurred with no episodes being due to wound complications. Symptoms and signs were vague and nonspecific, and in three patients the diagnosis was made only at autopsy. Surgery aimed to eliminate the septic focus with the drainage of abscesses and the avoidance of large bowel anastomoses. In 22 patients, a polymicrobial flora was obtained from the contaminated peritoneal cavity, with an average of 2.25 organisms per patient. These data suggest that the prohibitive mortality of peritonitis in renal transplant recipients may be lowered by prophylactic gastrointestinal surgery prior to transplantation, as well as by measures designed to lower the incidence of transplant wound sepsis. Peritoneal lavage, computed tomography, and laparotomy in the face of an undiagnosed source for sepsis may be warranted in these high-risk patients.