Screening a living kidney donor for polycystic kidney disease using heavily T2-weighted MRI.

Autosomal dominant polycystic kidney disease (ADPKD) accounts for approximately 8% of those awaiting renal transplantation. Living related kidney donors for these patients require screening for ADPKD, most commonly by ultrasonography. Ultrasound has a negative predictive value (NPV) of 100% in patients aged older than 30 years, but only 96% for donors aged 20 to 30 years. This case shows that heavily T2-weighted magnetic resonance imaging (HT2MRI) may be a more sensitive screening method for ADPKD in younger kidney donors. Despite a normal screening ultrasound result, a kidney donor with a family history of ADPKD was found to have renal cysts intraoperatively, and the transplantation was canceled. Afterward, the donor was imaged with HT2MRI. In addition, the mathematical relationship between sensitivity, specificity, and NPV for ADPKD screening tests was derived. After the canceled transplantation, a second ultrasound still could not identify renal cysts. However, HT2MRI showed multiple small ( approximately 3-mm) cysts in both kidneys and a 2.5-cm cyst on the right kidney. Mathematical analysis showed that the NPV of a screening test for ADPKD was most closely related to sensitivity and that only tests with 100% sensitivity would have a 100% NPV. We conclude that ultrasound is not a sufficiently sensitive screening test for ADPKD in younger living related renal donors. HT2MRI has improved sensitivity and may be the best screening test for ADPKD in this population.

Sonography: a useful tool to detect the mechanical causes of renal transplant dysfunction.

PURPOSE: The purpose of this study was to evaluate the utility of sonography in distinguishing between mechanical and nonmechanical causes for renal transplant dysfunction. METHODS: We reviewed all ultrasound examination reports (n = 286) for 63 consecutive patients who received 64 renal transplants. We assessed the sensitivity and specificity of different degrees of hydronephrosis (mild, moderate, or severe) in detecting urinary tract obstruction; different volumes of new or increasing peritransplant fluid in detecting urine leaks; different total volumes of peritransplant fluid in predicting significant compression of the transplant; and Doppler vascular criteria for predicting arterial and venous occlusion. RESULTS: All mechanical complications were detected (100% sensitivity) with specificities of 91.9% for ureteral obstruction (criterion, moderate hydronephrosis), 83.4% for urine leaks (criterion, any new fluid or any increase), 91.4% for fluid collections that compressed the transplant (criterion, > 100 ml), and 100% for vascular occlusion (criteria, no flow for arterial occlusion; no venous flow and reversal of arterial flow during diastole for venous occlusion). CONCLUSIONS: Sonography is very useful in distinguishing between mechanical and nonmechanical causes for renal transplant dysfunction. It has high sensitivity and acceptable specificity in this setting.

Tolerance induction permits the development of graft-versus-host disease: donor-mediated attack following small bowel transplantation in mixed chimeras.

The induction of tolerance to organ allografts would eliminate acute and chronic rejection as well as the need for nonspecific immunosuppression. We have shown that tolerance induced through the creation of mixed allogeneic bone marrow chimeras allows for the long-term engraftment of cardiac and small bowel allografts across strong multiple major histocompatibility barriers. The possibility that tolerance might render the host susceptible to graft-versus-host disease (GVHD) has not been investigated in this or other models of tolerance. To test this possibility chimeras were created by transplantation of T-cell depleted ACI and Lewis bone marrow into lethally irradiated Lewis rats. Chimerism was determined post bone marrow transplant (BMTx) by flow cytometry of lymphocytes from reconstituted animals. ACI/Lew chimeras (ALC), Lewis/ACI F1 (LACF1), and Lewis (LEW) rats all received heterotopic ACI vascularized small bowel grafts. A second group of chimeras received small bowel grafts from ACI rats pretreated with low dose irradiation to eliminate T-cells from the graft. LEW-->LEW small bowel isografts were also performed. Animals were examined for evidence of GVHD by clinical signs and histologic examination of biopsied tissues. GVHD was quantified using the popliteal lymph node enlargement assay. All LACF1 rats developed severe lethal GVHD following ACI small bowel transplant. Bone marrow chimeras, ALC (n = 6), developed fatal GVHD in a similar fashion after receiving a small bowel transplant. LEW-->LEW isografts and chimeras receiving bowel from irradiated ACI rats survived long term without GVHD while ACI-->LEW allogeneic transplants all underwent acute rejection. GVHD or its absence was confirmed histologically. Popliteal lymph node enlargement indices reflected the presence of GVHD in the chimeras (1.87) and LACF1 (5.4) receiving allografts, but not in isografts or chimeras receiving irradiated allogeneic transplants. Analysis of cytokines in the tongues of rats undergoing GVHD showed elaboration of Th1 type proinflammatory cytokines which was not seen in isografted rats or rats receiving preirradiated small bowel. These results demonstrate that tolerance induction through mixed chimerism results in susceptibility to small bowel induced GVHD. Preirradiating the donor bowel prior to SBTx can prevent GVHD.

Urine leaks in renal transplant patients. Diagnostic usefulness of sonography and renography.

We evaluated the utility of sonography and nuclear medicine renography in the detection of urine leaks in 57 renal transplant patients. Sonography and renography were equally sensitive in detecting leaks. But renography was more specific and therefore accurate (p < 0.0001) in detecting leaks. Urine leaks should be considered on sonography, which is often the first imaging study ordered in evaluating renal transplants, with new or increasing peritransplant fluid collections. Leaks should be confirmed by renography before performing additional invasive radiologic or surgical procedures.

An examination of the renal transplant evaluation process focusing on cost and the reasons for patient exclusion.

A medical evaluation of prospective renal transplant recipients is performed to identify conditions that may exclude patients from transplantation because of unacceptable risks. Protocols for evaluating potential transplant candidates are available, but there is little information about reasons for excluding patients from transplantation. To assess the effectiveness and cost of our renal transplant-recipient evaluation process, we retrospectively reviewed patients excluded from renal transplantation between January 1993 and December 1995 to categorize the reasons for exclusion. We also examined the costs of the evaluation. The study group included all adults referred for kidney-only transplantation during the study period who were excluded from transplantation (n=125). Demographics of the 160 patients with end-stage renal disease (ESRD) who underwent renal transplantation during the study period were also examined. Compared with the patients who underwent transplantation, the excluded patients were older (48+/-14 v 43+/-12 years; P=0.006) and more likely to be women (66 of 125 patients; 53% v 57 of 160 patients; 36%; P=0.005) and diabetic (59 of 125 patients; 47% v 30 of 160 patients; 19%; P=0.005). The most common reason for excluding patients was medical contraindication (46%), followed by patient declined (25%), obesity (10%, defined as a body mass index [BMI] > or = 35), patient death (6%), and insurance/financial (5%). The medical reasons for exclusion were heart disease (38%), noncompliance (28%), miscellaneous (22%), and cancer (12%). Tests performed after the initial evaluation included cardiac testing (stress thallium or echocardiography and coronary angiography) in 50 patients, Doppler studies of the lower extremities in 28 patients, and hepatitis C polymerase chain reaction (PCR) or recombinant immunoblot assay (RIBA) assays in 8 patients. The cost of standard pretransplantation blood work for selected tests (ABO blood group typing, HLA, hepatitis B and C, and cytomegalovirus) was $709. Deferring such routine pretransplantation blood work until after the patient education session and history and physical examinations by nephrology and surgery in the 31 patients (25%) who declined transplantation at the initial visit would have resulted in considerable savings. Our evaluation process now includes prereferral information on a prospective recipient's medical problems, height and weight, and basic screening laboratory tests. This protocol has resulted in a more efficient and cost-effective evaluation process. Further examination of the cost-effectiveness of the transplant evaluation process is warranted.

Tolerance induction by intrathymic inoculation prevents chronic renal allograft rejection.

BACKGROUND: These experiments investigated the ability of the donor-specific unresponsiveness created by the intrathymic inoculation of donor alloantigen to effectively prevent chronic rejection in an established rat model of chronic renal allograft rejection. METHODS: Three study groups were examined: (1) Allograft controls--F-344 rats received a Lewis renal allograft plus 10 days of low-dose cyclosporine (CsA); (2) isograft controls--F-344 rats received an F-344 renal isograft and low-dose CsA; (3) experimental group--F-344 rats received a T-cell depleted syngeneic bone marrow transplant and intrathymic injection of Lewis bone marrow. Twenty-one days after bone marrow transplant, these animals received a Lewis renal allograft. RESULTS: Allograft controls demonstrated severe parenchymal fibrosis; isograft controls and intrathymic (IT) animals failed to develop this lesion. Immunohistochemical analysis revealed increased CD4+ T cells infiltrating the cortex of the allograft controls. Cytokine interferon-gamma and interleukin-2 transcripts were strongly positive in allograft controls and were absent from isograft controls and IT allografts as determined by reverse transcriptase-polymerase chain reaction. Analysis of tolerant grafts by flow microfluorimetry and genomic DNA amplification could not detect chimerism to a level of < 0.1%. CONCLUSION: IT inoculation of donor alloantigen can confer long-term unresponsiveness and prevent the development of the characteristic lesions of chronic rejection.

Use of intraoperative ultrasonography during hepatic transplantation.

The aim of this study was to evaluate if intraoperative vascular ultrasonography is of clinical value in the perioperative management of hepatic transplant patients. Fifteen intraoperative ultrasonographic examinations were performed on 13 patients (five female, eight male) during transplantation. These patients had clinically suspected vascular compromise. Among the 13 patients studied intraoperatively, five were correctly diagnosed as having hemodynamically significant vascular compromise. Of the intraoperative vascular sonographic examinations, the results of 13 were in concordance with the surgical impression as to whether further intervention was necessary or if the procedure could be terminated. Intraoperative sonography demonstrates potential to be of aid to the surgeon in recognition of vascular compromise.

Graft versus host disease in rats made tolerant for organ allografts.

Tolerance for organ allografts would eliminate acute and chronic rejection as well as the need for nonspecific immunosuppression. A potential hazard of tolerance is the susceptibility to graft vs host disease (GVHD) due to unresponsiveness to alloantigen. This study sought to determine if our model of tolerance induction results in susceptibility to GVHD. Chimeras were created by transplantation of T-cell depleted ACI and Lewis bone marrow into lethally irradiated Lewis rats. Chimerism was determined post-BMTx by flow cytometric analysis of recipient spleens for the presence of ACI cells. ACI/Lew chimeras (ALC), animals that reconstituted only with syngeneic (Lewis) marrow (so-called failed chimeras), and ACI/Lew F1 (LACF1) hybrid rats were all given 200 x 10(6) ACI splenocytes i.v. Animals were examined for evidence of GVHD. GVHD was quantified using the popliteal lymph node enlargement assay. All LACF1 (n = 6) rats developed severe lethal GVHD following ACI splenocyte injection. Similarly, ALC (n = 6) developed fatal GVHD. Animals that reconstituted only with syngeneic Lewis marrow (failed chimeras) showed no signs of illness. GVHD was confirmed histologically and immunohistochemically. Failed chimeras receiving ACI splenocyte challenge showed no evidence of GVHD histologically. Popliteal lymph node enlargement indices reflected the presence of GVHD in the chimeras and hybrids but not in the failed chimeras. We conclude that tolerance induction by mixed chimerism results in susceptibility to GVHD if enough donor lymphoid tissue is given to the host at the time of organ transplant. Animals that are not mixed chimeras (failed bone marrow transplant) rejected the allogeneic splenocytes as evidenced by their lack of disease. Tolerance may therefore make the host defenseless against fatal GVHD.

The hyperventilation of cirrhosis: progesterone and estradiol effects.

Progesterone and estradiol are metabolized in the liver and are elevated in patients with cirrhosis. Progesterone stimulates ventilation by activating progesterone receptors in the central nervous system; estradiol may facilitate progesterone's actions by increasing progesterone receptors. This study evaluated whether progesterone and estradiol contribute to the respiratory alkalosis common in cirrhotic patients. Arterial blood gases and progesterone and estradiol levels were obtained in 50 patients with cirrhosis. Multiple linear regression revealed a statistically significant correlation between PaCO2 and progesterone and estradiol (r = .54, P < .05). Patients with severe hyperventilation (PaCO2 < or = 30 mm Hg) had statistically higher levels of progesterone and estradiol than did patients with mild hyperventilation (30 < PaCO2 < or = 35) or normal ventilation (PaCO2 > 35) (P < .05). Although the progesterone levels were two orders of magnitude lower than those associated with hyperventilation in pregnant patients, the increased ventilatory effect may be because of the altered blood-brain barrier (BBB) present in cirrhotic patients. Progesterone and estradiol appear to contribute to the hyperventilation in cirrhotic patients.

Hyaluronate levels in donor organ washout effluents: a simple and predictive parameter of graft viability.

The principal cause of primary non-function in orthotopic liver transplantation is thought to be preservation injury to the microvasculature. We, therefore, evaluated if effluent levels of hyaluronate, whose uptake is an endothelial cell marker, could predict early graft function and ultimate graft outcome in orthotopic liver transplantation. A total of 102 cases were studied in two phases. In the first phase, we attempted to determine if a correlation existed between effluent hyaluronate levels, early graft function and ultimate graft outcome. This phase of the study was also used to determine hypothetical cut-off values for hyaluronate which could discriminate between good and bad livers. Thirty-two livers orthotopically transplanted to randomly selected primary recipients were studied. After varying periods of static cold storage (4 degrees C) in University of Wisconsin solution, the livers were reinfused with cold (4 degrees C) lactated Ringer's solution. The first 50 ml of the reperfusion effluent was collected from the infrahepatic vena cava. Effluent samples were analyzed for hyaluronate. Linear regression analysis demonstrated a significant correlation between effluent hyaluronate levels and post-operative aspartate and alanine aminotransferase levels (p < 0.001 for both). Logistic regression demonstrated a highly significant correlation (p = 0.0056) between effluent hyaluronate levels and ultimate graft outcome. Generation of Receiver Characteristics Curves indicated that a level between 400 and 430 micrograms.l-1 could possibly discriminate between good livers and those at risk of early graft failure. The authenticity of this hyaluronate cut-off level was further confirmed in the second phase of the study where 70 consecutive primary crossmatch-negative transplants were performed. A highly significant difference was observed in peak aspartate and alanine aminotransferase levels in the first week (p < 0.0006 and p < 0.0005, respectively) between livers with effluent hyaluronate levels < or = 400 micrograms.l-1 and livers with hyaluronate levels higher than 400 micrograms.l-1. Logistic regression revealed a highly significant correlation between effluent hyaluronate levels and graft success (p = 0.0001). Since hyaluronate uptake by the microvascular endothelial cell is significantly greater than production, high hyaluronate effluent levels in failed livers would be due to decreased hyaluronate uptake by the injured microvascular endothelial cell. We therefore conclude that effluent hyaluronate levels may prove to be a reliable preoperative test to assess early graft function and outcome in clinical orthotopic liver transplantation.

Immunoglobulin G lymphocytotoxic antibodies in clinical liver transplantation: studies toward further defining their significance.

Twenty-two consecutive liver allograft recipients, who tested positive for immunoglobulin G (IgG) lymphocytotoxicity were subjected to pretransplantation and posttransplantation immunologic monitoring of anti-donor IgG lymphocytotoxic antibody titers, total hemolytic complement activity (CH100), circulating immune complexes (CIC), and platelet counts in an effort to improve our understanding of the preformed antibody state in clinical hepatic transplantation. Ten contemporaneous liver transplant recipients whose crossmatch results were negative and who experienced severe hepatocellular damage early after transplantation were included as controls. Crossmatch test results were negative 1 day after transplantation and during the 1 month follow-up remained negative in 14 of 22 (64%) sensitized recipients, most of whom had relatively low (< or = 1:16) anti-donor IgG antibody titers before transplantation. After transplantation, this group and the control group experienced no thrombocytopenia, no increase of CIC, and a gradual increase in CH100 activity that reached normal levels within 1 week. A strong negative correlation between prothrombin time (PT) and CH100 activity in these groups of patients suggested that changes in CH100 activity (P < .0005) were tightly linked to liver synthetic function. In contrast, the crossmatch test results remained positive after transplantation in 8 of 22 (36%) sensitized recipients, all of whom had relatively high (> 1:32 to 1024) pretransplantation titers of anti-donor IgG antibodies. After transplantation these patients developed a syndrome that was characterized by decreased CH100 activity and increased CIC compared with pretransplantation levels and refractory thrombocytopenia that was associated with a 50% allograft failure rate because of biopsy-proven humoral and acute (cellular) rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

Liver transplantation for HBV-related disease under immunosuppression with tacrolimus: an experience with 78 consecutive cases.

Hepatitis B viral liver disease (HBVLD) is a major worldwide health problem. It is estimated over 300 million people have had hepatitis B virus infection and that one-third of these have chronic HBVLD. Little effective therapy exists for HBVLD even though high dose interferon (IFN) has been advocated. For those who either are untreated or do not respond to IFN, HBVLD is steadily progressive and orthotopic liver transplantation (OLTx) is the only available therapy. Until quite recently, all OLTx recipients received cyclosporine (CyA) and prednisone. The consequence of OLTx for HBV disease in individuals immunosuppressed with tacrolimus has not previously been reported. A total of 78 consecutive patients with HBV-related liver diseases who were transplanted between January 1, 1990, and December 31, 1991, and treated with tacrolimus were studied. The clinical records of these patients were reviewed retrospectively. HBV disease recurrence was documented with serologic and histologic methods. As of April 1, 1993, 57 of 78 (73%) of the patients were still alive. Thirty-one of the alive patients have documented HBV recurrence. Eighteen of these 31 patients, however, have normal liver function. With a median follow-up of 24 months, 8 patients (10.9%) have died of recurrent HBVLD. Seven of 8 patients, who preoperatively were HBeAg+, developed recurrence and 4 of these patients have already died of recurrence. Patients who were HBsAg+ rarely recurred (1 of 16 patients). The use of HBIG did not prevent recurrence.(ABSTRACT TRUNCATED AT 250 WORDS)

Experience with liver and kidney allografts from non-heart-beating donors.

Given the shortage of cadaveric organs, we began a study utilizing NHBD for OLTx and KTx. There were 24 NHBD between January 1989 and September 1993. These donors were divided into 2 groups: uncontrolled NHBD (G1) (n = 14) were patients whose organs were recovered following a period of CPR; and controlled NHBD (G2) (n = 10) were patients whose organs were procured after sustaining cardiopulmonary arrest (CA) following extubation in an operating room setting. Eight kidneys and 5 livers were discarded because of macroscopic or biopsy findings. In G1, 22/27 (81.5%) kidneys were transplanted; 14/22 (64%) developed ATN; 20/22 (95%) recipients were off dialysis at the time of discharge. With a mean follow-up of 32.7 +/- 21.1 months, sixteen (73%) kidneys are still functioning, with a mean serum creatinine of 1.7 +/- 0.6 mg/dl. The one-year actuarial patient and graft survivals are 95% and 86%. In G2, 17/20 (85%) kidneys were transplanted; 13/17 (76%) kidneys experienced ATN. All patients were off dialysis by the time of discharge. With a mean follow-up of 17.6 +/- 15.4 months, twelve (70%) kidneys are still functioning, with a mean serum creatinine of 2.5 +/- 2.1 mg/dl. The one-year actuarial patient and graft survivals are 94% and 82%, respectively. In G1, 6/10 (60%) livers were transplanted; 3/6 (50%) livers functioned, the other 3 patients required ReOLTx in the first week postoperatively because of PNF (n = 2) and inadequate portal flow (n = 1). Two functioning livers were lost due to HAT (n = 1) and CMV hepatitis (n = 1). In G2, 6/7 (85.7%) livers were transplanted. All the livers (100%) functioned. 2 patients required ReOLTx for HAT at 0.9 and 1.0 months. Both patients eventually died. One patient with a functioning liver died 2 months post OLTx. The remaining 3 patients are alive and well at 27 months of follow-up. This study shows that the procurement of kidneys from both uncontrolled and controlled NHBD leads to acceptable graft function despite a high incidence of ATN. The function of liver allografts is adequate in the controlled NHBD but suboptimal in the uncontrolled NHBD, with a high rate of PNF.

Single-center experience with primary orthotopic liver transplantation with FK 506 immunosuppression.

OBJECTIVE: The efficacy for primary orthotopic liver transplantation of a new immunosuppressive agent, FK 506 (tacrolimus, Prograf, Fujisawa USA, Deerfield, IL), was determined. SUMMARY BACKGROUND DATA: After 3 years of preclinical research, a clinical trial of FK 506 for orthotopic liver transplantation was begun in February 1989, first as a rescue therapy for patients with intractable rejection with conventional immunosuppression, then as a primary drug. METHODS: Between August 1989 and December 1993, 1391 recipients (1188 adult and 203 pediatric) of primary liver allografts were treated with FK 506 from the outset. Results from these patients were analyzed and compared with those of 1212 historical control patients (971 adult and 241 pediatric) given cyclosporine-based immunosuppression. RESULTS: Actuarial survival at 4 years was 86.2% with FK 506 versus 65.5% with cyclosporine in the pediatric patients (p < 0.0000) and 71.4% versus 65.5% in the adults (p < 0.0005). The need for retransplantation was reduced significantly for FK 506 patients. Four-year graft survival was 77.0% with FK 506 versus 48.4% with cyclosporine in the pediatric patients (p < 0.0000), and 61.9% with FK 506 versus 51.4% with cyclosporine in the adult recipients (p < 0.0000). Regression analysis revealed that reduction in mortality or graft loss from uncontrollable rejection, sepsis, technical failure, and recurrent original liver disease were responsible for the improved results with FK 506 therapy. CONCLUSIONS: FK 506 is a potent and superior immunosuppressive agent for orthotopic liver transplantation.