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PubMed2000

Outcomes of simultaneous kidney-pancreas transplantation in African-American recipients: a case-control study.

INTRODUCTION: Previous studies have suggested that African-American (AA) ethnicity is a risk factor for rejection and graft loss after kidney transplantation. However, little data is available regarding outcomes after simultaneous kidney pancreas transplantation (SKPT) in AA recipients. The objective of this study was to compare the outcomes of SKPT in AA patients to matched Caucasian patients as controls. METHODS: From January 1996 to September 1999, we performed 79 SKPTs, including 10 in AA recipients. Ten Caucasian controls were selected and matched for age, gender, weight, timing and technique of transplantation, and immunosuppressive regimen. Clinical outcomes were collected and compared between the two groups. RESULTS: The two groups were well matched for donor and recipient demographic, immunologic and transplant characteristics, including 2 patients in each group with type 2 diabetes. All patients received tacrolimus (TAC), mycophenolate mofetil (MMF) and steroids, and about half in each group received antibody induction therapy. Patient survival was 100% in both groups with a mean follow-up of 18 months (range 6 47). Kidney and pancreas graft survival rates were both 80% in the AA and 100% in the Caucasian groups, respectively (p = 0.14). All but one kidney (in the AA group) and all pancreas grafts experienced immediate function. There were two immunologic kidney and two immunologic pancreas graft losses in the AA group. No grafts were lost due to technical problems. The mean length of initial hospital stay was 16 d in the AA group compared to 10 d in the Caucasian group (p = 0.07). The AA group had a slight increase in the number of readmissions (mean 2.2 AA vs. 1.6 Caucasian, p = 0.08). The incidence of biopsy-proven pancreas acute rejection was significantly higher in the AA group (50%) compared to the Caucasian group (10%) (p = 0.05). The incidence of either kidney or pancreas acute rejection was also higher in the AA group (60% AA vs. 20% Caucasian, p = 0.06). TAC levels were comparable at specific times after transplantation, al-though there was a trend toward higher doses of TAC in the AA group to achieve therapeutic levels. The incidences of relaparotomy (30% AA vs. 20% Caucasian) and major infection (40% AA vs. 60% Caucasian) were similar between groups. Renal and pancreas allograft functions were comparable between groups at specific times after transplantation. CONCLUSIONS: These results suggest that SKPT in AA recipients may be associated with a higher incidence of rejection and immunologic graft loss compared to matched Caucasian controls.

Adult↗

PubMed1998

Human hepatocytes produce an isoform of FAS that inhibits apoptosis.

BACKGROUND: Fas (Apo-1/CD95), a member of the tumor necrosis factor receptor family, can mediate apoptosis when engaged by its ligand or by anti-Fas antibody. Fas is expressed by cells of the immune system and by some nonlymphoid tissues. Numerous studies have suggested that the Fas pathway may play a role in the rejection of allografts. Functional, soluble forms of the Fas receptor are produced by activated peripheral blood mononuclear cells and some transformed cell lines. The purpose of this study was to determine if soluble variants of Fas are produced in the liver and to determine if blockade of the Fas pathway, by liver-derived soluble Fas, inhibits Fas-mediated apoptosis. METHODS: Liver and purified hepatocyte specimens were analyzed for Fas transcripts by reverse transcriptase-polymerase chain reaction with primers that span the transmembrane region of the molecule. Bile and cell lysates were analyzed for soluble Fas by specific enzyme-linked immunosorbent assay. Lysates were prepared from normal liver and hepatocytes and utilized to block Fas-mediated apoptosis of Jurkat cells as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and flow cytometry. RESULTS: A variant form of Fas is abundantly expressed in normal liver and purified hepatocytes. This variant form of Fas is expressed in all normal liver specimens but only in half of the liver specimens obtained during allograft rejection. The levels of soluble Fas diminish in patients undergoing liver allograft rejection in contrast to patients with stable grafts. Importantly, a soluble form of Fas is produced in the liver by hepatocytes and can specifically inhibit Fas-mediated apoptosis. CONCLUSION: These data raise the possibility that soluble Fas, produced by hepatocytes, may influence the immune response by blocking Fas-mediated apoptosis and, thus, may have a role in liver transplantation.

Apoptosis↗

PubMed2001

Long-term outcomes in simultaneous kidney-pancreas transplant recipients with portal-enteric versus systemic-bladder drainage.

We retrospectively reviewed long-term outcomes in simultaneous kidney-pancreas transplant (SKPT) recipients with portal-enteric (P-E) versus systemic-bladder (S-B) drainage. Forty-five patients were alive with functioning grafts 1 year after SKPT and were followed up for a minimum of 3 years (mean, 5.9 years), including 26 patients with P-E drainage and 19 patients with S-B drainage. Recipient demographic and transplant characteristics were similar between the two groups. In both groups, hospital admissions decreased significantly with increasing time after SKPT, although significantly fewer readmissions occurred in the first year in the P-E than the S-B group. The most common reason for readmission in both groups was infection, followed by miscellaneous, surgical, and immunologic morbidity. The incidence of readmission for dehydration was significantly less in the P-E group (P < 0.01). Mean systolic and diastolic blood pressures were similar between groups, although the number of antihypertensive medications was significantly less in the S-B group. Although fasting C-peptide levels were significantly greater in the S-B group, the two groups were similar with regard to carbohydrate (fasting serum glucose, hemoglobin A(1c)) and lipid (total cholesterol) metabolism. Renal and pancreas allograft functions were similar between the two groups. At 1 year post-SKPT, stabilization in most diabetic complications was reported. Four quality-of-life surveys that provided 29 scores were completed 6 to 24 months (mean, 18.5 months) after SKPT. Improved quality of life was reported in all but one of the scales, with many dimensions showing significant improvements. At 3 years after SKPT, no activity limitation was reported in 76% of patients with P-E drainage versus 53% with S-B drainage (P = 0.11). Five-year actual patient, kidney, and pancreas graft survival rates after P-E versus S-B drainage are 92% and 84%, 81% and 79%, and 88% and 74%, respectively (P = not significant). SKPT with P-E drainage is a safe and effective method to treat advanced diabetic nephropathy and is associated with decreasing morbidity, improving rehabilitation and quality of life, and stablizing metabolic function over time. The long-term prognosis after the first year is excellent and at least similar to the results achieved with S-B drainage.

Adult↗

PubMed1995

A COL4A3 gene mutation and post-transplant anti-alpha 3(IV) collagen alloantibodies in Alport syndrome.

The X-linked Alport syndrome is associated with mutations and deletions in COL4A5 gene, one of six genes which constitute the alpha-chains of type IV collagen in basement membranes. The autosomal recessive form of Alport syndrome is characterized by mutations and deletions in the COL4A3 and COL4A4 genes. A fraction of Alport patients who undergo renal transplantation develop anti-glomerular basement membrane (GBM) nephritis, which results in loss of the renal allograft function. Recently, the target for alloantibodies from an X-linked Alport patient with complete COL4A5 gene deletion was determined to be the alpha 3 chain of type IV collagen. The present study characterized the post-transplant alloantibodies from an autosomal recessive Alport patient with anti-GBM glomerulonephritis and a COL4A3 gene mutation which predicted a loss of 85% of the alpha 3(IV) NC1 domain. The specificity of these new antibodies were studied using glomerular basement membrane constituents and recombinant type IV collagen domains. The results establish the target for the alloantibodies from an autosomal recessive Alport patient with COL4A3 deletion as principally the alpha 3(IV) collagen chain, similar to the post-transplant alloantibodies from X-linked Alport patients with COL4A5 gene deletions. The absence of alpha 3(IV) chain in the GBM of patients with both these forms of Alport syndrome, due either to a failure of synthesis or a failure of assembly, presumably leads to a loss of immunologic tolerance for the alpha 3(IV) NC1 domain in transplanted allografts.

Antibody Specificity↗

PubMed2003

Pregnancy outcome in liver transplant recipients.

OBJECTIVE: To evaluate pregnancy course, complications, and outcomes in liver transplant recipients. METHODS: We conducted a retrospective review of 38 pregnancies conceived between 1992 and 2002 in 29 women who underwent liver transplantation at Mount Sinai Medical Center. RESULTS: The most common primary liver disease was autoimmune hepatitis. All patients were on immunosuppressive regimens that included cyclosporine A or tacrolimus. There were four spontaneous first-trimester abortions and ten first-trimester terminations for worsening liver function. The interval from transplantation to pregnancy was shorter in the group that had abortions and terminations (24.4 +/- 24.3 months) as compared with the group that had live births (47.8 +/- 28.7 months), P =.02. There were 24 live births to 20 patients. The mean gestational age at delivery was 36.4 weeks, and the mean birth weight was 2762 g. Pregnancy complications included preeclampsia (20.8%), chronic hypertension (20.8%), hemolysis, elevated liver enzymes, low platelets syndrome (8.3%), creatinine 1.3 mg/dL or more (25.0%), anemia (33.3%), diabetes (37.5%), cesarean delivery (45.8%), preterm birth less than 37 weeks (29.2%), intrauterine growth restriction (16.7%), and biopsy-proven graft rejection during pregnancy (16.7%). There were no intrauterine or neonatal deaths. All 5-minute Apgar scores were greater than 7. Four minor congenital anomalies were noted. Before 1997, there were five maternal deaths, 10-54 months after pregnancy. Pregnancy complications in our population were more common in those patients who delivered from 1992 to 1997 than in those who delivered from 1998 to 2002. CONCLUSION: Pregnancy planned at least 2 years after liver transplantation with stable allograft function can have excellent maternal and neonatal outcome.

Abortion, Spontaneous↗

PubMedDate not supplied

Effects of combination of cyclosporine with losartan or enalapril on kidney function in uremic rats.

Long-term treatment with cyclosporine in solid organ transplantation has been shown to be associated with the development of hypertension and nephrotoxicity. Angiotensin-converting enzyme inhibitors have well-known nephroprotective properties and may prevent cyclosporine A (CYA)-induced hypertension. Angiotensin receptor 1 antagonists have similar properties. The purpose of this study was to investigate if losartan or enalapril could be administered with CYA to reduce its nephrotoxic effect in uremic rats. The studies were performed on the following groups of rats: group I--control; group II--control rats + losartan; group III--control rats + CYA; group IV uremic rats; group V--uremic rats + losartan; group VI--uremic rats + CYA; group VII--uremic rats + losartan + CYA, group VIII--control rats + enalapril; group IX--control rats + enalapril + CYA; group X - uremic rats + enalapril; group XI--uremic rats + enalapril + CYA. Pretreatment with CYA, losartan or enalapril in uremic rats resulted in a significant increase in urea and creatinine levels and a decrease in hematocrit. The same effect was observed when uremic rats were given CYA + losartan or CYA + enalapril. Pretreatment with losartan was associated with the increase in the level of CYA much higher than with CYA treatment alone. Similarly, pretreatment with enalapril resulted in a significant increase in CYA concentration in both groups of rats given CYA: uremic and non-uremic. Results of our study show that the treatment with cyclosporine and a combination of losartan or enalapril results in an increase in creatinine and urea levels and a decrease in hematocrit. Therefore, physicians should exercise caution, when they give losartan and enalapril to kidney allograft recipients treated with cyclosporine, particularly with impaired allograft function.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1987

Proper donor selection for heart-lung transplantation. The Stanford experience.

Clinical cardiopulmonary transplantation is currently limited by the availability of suitable heart-lung donors. Distant graft procurement, with pretreatment, of the donor by intravenous prostaglandin E1 and cooling of the graft with pulmonary artery perfusion, is now clinically established and should increase the number of available donors. Between March 1981 and September 1986, 40 heart-lung transplantations were performed. The characteristics of the donor pool were analyzed. Gram stain of the donor tracheal aspirate revealed gram-positive bacteria in 80% and gram-negative organisms in 35%. Yeast was present on stain in 25% of the patients. Donor arterial oxygen tension was less than 100 torr inspired oxygen concentration 40%) repeatedly in one patient; this recipient died of lung failure at operation. Severe deterioration of allograft lung function was seen in 11 (27.5%) recipients. The causes of deterioration were substantial postoperative bleeding in six patients, sepsis in two, and acute rejection, poor lung function, and allograft heart failure in one patient each. HLA-A locus mismatch, poor donor alveolar-capillary gas exchange, tracheal colonization with heavy polymorphonuclear cells, and heavy bacteria and fungus resulted in increased operative mortality. Donor pretreatment with prostaglandin E1 was associated with improved survival. Recipient selection, emphasizing adequate liver function and absence of previous thoracic operation, careful surgical technique with minimal bleeding, and brief perfusion time were factors associated with improved survival. Early morbidity and mortality were principally related to recipient risk factors, and the strict criteria observed for selection of heart-lung donors were valid. The importance of appropriate recipient selection is underscored.

Adolescent↗

PubMedDate not supplied

Angiotensin-converting enzyme genotype is a predictive factor in the peak panel-reactive antibody response.

The presence of a high panel-reactive antibody (PRA) level represents an independent risk factor for early graft failure and chronic allograft dysfunction. It has also been reported that patients with the ACE-DD and AGT-AA genotypes display poorer chronic allograft function. We investigated the effects of gene polymorphisms of the renin angiotensin system (RAS) on anti-HLA antibody production among renal transplant candidates. Genotyping was performed on 133 dialysis patients for the ACE (I/D) and AGT (M235T) as well as the type 1 (A1166C) and type 2 (A1223G) angiotensin II receptor genes. Patients with a peak PRA >/= 30% were considered to be positive for anti-HLA antibody (40.6% of 133 patients). Genetic polymorphisms of the RAS were not associated with anti-HLA antibody production at this PRA level. Another analysis comparing the 29 patients with a peak PRA >/=50% with the 104 patients with a peak PRA <50% showed that previous transplants, the presence of ACE-DD genotype, history of blood transfusions, and dialysis duration were all associated with the high levels of antibody production by univariant analysis. A multivariate analysis using a logistic regression model revealed previous transplants, the presence of ACE-DD genotype, and history of blood transfusions to be predictors of anti-HLA antibody production. The ACE-DD genotype is an important risk factor for higher PRA levels. This study suggests that genetic control of RAS activity correlates with production of anti-HLA antibodies, possibly explaining the relationship to chronic allograft outcome.

Adolescent↗

PubMed2000

Pharmacologic graft protection without donor pretreatment in liver transplantation from non-heart-beating donors.

BACKGROUND: Non-heart-beating donors (NHBDs) are considered potential sources of transplant organs in an effort to alleviate the problem of donor shortage in clinical liver transplantation. We investigated the possibility of pharmacologic protection of hepatic allograft function from NHBDs without donor pretreatment. METHODS: Orthotopic liver transplantation was performed using pigs. In donors, cardiac arrest was induced by stopping the respirator. Forty-five minutes after cessation of the respirator, the liver was flushed with cold lactated Ringer's solution including heparin and with the University of Wisconsin (UW) solution, and then preserved for 8 hr at 4 degrees C in the UW solution. The pigs were divided into two groups: a control group and a treated group. In the treated group, an endothelin antagonist TAK-044 was added to the UW solutions (10 mg/L), and TAK-044 (10 mg/kg body weight) and a platelet activating factor antagonist E5880 (0.3 mg/kg body weight) were also administered to the recipients. RESULTS: TAK-044 and E5880 treatment significantly increased the 7-day survival rate of the recipients (100% vs. 17%, P<0.05). In the treated group, portal venous pressure immediately after reperfusion of the graft was significantly lower than in the control group, and postoperative increase in serum concentrations of glutamic oxaloacetic transaminase and total bilirubin was attenuated. Moreover, the energy charge and adenosine triphosphate concentration of the liver were rapidly restored after reperfusion. CONCLUSIONS: Pharmacologic modulation with TAK-044 and E5880 avoiding donor pretreatment can improve the viability of hepatic allografts procured from NHBDs.

Animals↗

PubMed2001

Involvement of platelet-derived growth factor and histocompatibility of DRB 1 in chronic renal allograft nephropathy.

BACKGROUND: The role of activated T cells in graft arteriosclerosis, which is observed in chronic renal allograft nephropathy, and the involvement of major histocompatibility complex (MHC) incompatibility remain to be determined. We examined the effect of T lymphocytes that were obtained from renal transplant patients undergoing chronic rejection treated with cyclosporine (CsA) on platelet-derived growth factor (PDGF)-induced proliferation of cultured human vascular smooth muscle cells (SMC) and compared the proliferation activity of T lymphocytes with MHC incompatibility, especially DRB 1 mismatch. METHODS: Renal transplant patients with continued allograft function, who survived more than 1 year after transplantation, were recruited. Chronic rejection was documented by graft-biopsy findings together with increasing serum creatinine levels (10-20% per year). After the incubation of supernatant (conditioning medium) of cultured T cells from CsA-treated renal transplant patients with chronic rejection (n=18) and with normal renal function (n=14) as control, normal subjects (n=11) and chronic hemodialysis (HD) patients (n=5) with cultured SMC in the presence or absence of PDGF, DNA synthesis (3H-thymidine uptake) of SMC was examined. The in vitro effects of CsA on DNA synthesis of cultured SMC were also evaluated. RESULTS: The supernatant of cultured T cells from renal transplant patients with chronic rejection stimulated PDGF-induced DNA synthesis of SMC in a dose-dependent manner, showing significant enhancement as compared with control transplant patients, normal subjects, and chronic HD patients. The supernatant itself did not significantly stimulate DNA synthesis of SMC. No significant in vitro stimulation of CsA on DNA synthesis was observed. The supernatant of T cells obtained from recipients undergoing chronic rejection with two DRB 1 mismatches showed significantly higher enhanced activity of PDGF-induced DNA synthesis than the supernatant from those recipients without mismatch of DRB 1. On the other hand, no significant correlation of the enhanced activity by T cell supernatant to HLA A and B mismatch numbers was observed. CONCLUSIONS: Growth factor-promoting factors(s) derived from activated T cells associated with MHC class II DR expression, which promotes PDGF-induced proliferation of SMC, exists in renal transplant patients with chronic renal allograft nephropathy, and is probably involved in arteriosclerosis of the graft kidney.

Adult↗

PubMed2002

Can a transplanted living donor kidney function equivalently to its native partner?

Early renal functional adaptation was examined in 81 haploidentical donor and recipient pairs, as well as long-term stability of glomerular filtration rate (GFR) in 78 recipients. GFR was determined pre- and 1 month postnephrectomy in donors and 1 month post-transplant and yearly thereafter in recipients. Compensatory increase in filtration (CIF) of transplanted and native kidneys was calculated using donor pretransplant GFR: [CIF= (GFR at 1 month/donor prenephrectomy GFR) x 100]. Annual rates of change in GFR were estimated using within-patient linear regression analysis (slopes). Recipients without rejection (n = 62) and their donors had similar early GFR and CIF. Those with acute rejection (n = 19) had significantly lower GFR and CIF than their donors (61 +/- 16 mL/min/1.73 m2 and 57 +/- 14% vs. 75 +/- 11 and 69 +/- 9; p = 0.01 and p < 0.001). Recipients without cyclosporine (n = 52) had 1 month GFR and CIF of 70 +/- 14 and 67 +/- 14 vs. 72 +/- 11 and 69 +/- 11 for their donors. Those with cyclosporine (n = 29) had 1 month GFR and CIF of 64 +/- 14 and 62 +/- 16 vs. 69 +/- 12 and 67 +/- 11 for their donors (p = 0.15 and 0.16). Comparison of median (25th, 75th) rates of change of GFR with and without acute rejection or cyclosporine did not demonstrate significant effects of either on stability of allograft function, although there was a trend towards greater loss of GFR in cyclosporine-treated patients [-1.1 (-2.5, 0.8) vs. 0.0 (-1.8, 1.2) mL/min/1.73 m2/year, p = 0.47]. We conclude that, in the absence of rejection, the transplanted kidney maintains the same capacity for functional adaptation as its native partner. Therapy with cyclosporine does not significantly inhibit early physiological adaptation of renal transplants.

Cyclosporine↗

PubMed2004

Improved clinical outcomes in Chinese renal allograft recipients receiving lower dose immunosuppressants.

BACKGROUND: The application of potent immunosuppressants has decreased the incidence of acute rejection and increased short- and long-term graft survival; however, these drugs cause a variety of complications. In China, many transplant centers have adopted the immunosuppressive protocols based on the white population, neglecting the differences between the races. The purpose of this study was to explore a suitable immunosuppressive regimen for Chinese renal allograft recipients. METHODS: Two hundred cadaveric renal allograft recipients who underwent transplantation between July 1999 and October 2001 were observed. Before October 2000, 104 recipients received the conventional dose of immunosuppressants; thereafter, 96 recipients received lower dose treatment. Doses of immunosuppressive agents, the incidence of acute rejection and pulmonary infection, and patient and graft survival rates were compared between the two groups. RESULTS: Doses of mycophenolate mofetil (MMF) and cyclosporine A (CsA) administered in the conventional dose group were significantly higher than in the lower dose group at 3 months posttransplant, as was prednisone at 6 months posttransplant. The incidence of acute rejection and subclinical rejection that was biopsy-proven or diagnosed by clinical manifestations was 17.3% and 19.8%, respectively, in the conventional dose group and the lower dose group within the first 6 months, and no significant difference was noted (P=0.55). The incidence of pulmonary infection, especially severe infection, was much higher in the conventional treatment group (40.1% and 26.9%, respectively) than that in the lower dose group (11.5% and 5.2%, respectively), and the differences were statistically significant (P<0.001). The corresponding 1-year survival rate of patients was 87.4% and 97.9% (P<0.01), and that of renal grafts was 85.5% and 96.9% (P<0.01), for patients receiving conventional dose and lower dose immunosuppressive drugs, respectively. The rate of death with a functioning allograft caused by infection in the conventional dose group was significantly higher than that in the lower dose group (12.5% vs. 0%, P<0.01). CONCLUSIONS: The regimen of lower dose MMF, CsA, and prednisone in combination can significantly reduce the incidence of pulmonary infection, especially severe pulmonary infection, without increasing the incidence and severity of allograft rejection.

Adult↗

PubMed2004

Molecular markers in subclinical acute rejection of renal transplants.

In this study, we evaluated the expression of molecular markers of acute rejection in protocol biopsies of patients with and without subclinical acute rejection (SAR). Protocol biopsies were performed at 2 months (n = 21) and 12 months (n = 14) after kidney transplantation in patients with stable allograft function. After biopsy tissue RNA isolation, reverse transcription and polymerase chain reaction (RT-PCR) for the glyceraldehyde 3-phospate dehydrogenase (GAPDH), perforin, granzyme B and Fas ligand genes were performed. The Banff 97 classification was used for histological diagnosis. Creatinine concentrations at 2 months were significantly higher in patients with SAR (1.46 +/- 0.27 x 1.18 +/- 0.24; p < 0.02). Perforin transcripts were found in 15 biopsy specimens, 10 of which had histological signs of SAR (p = 0.06). Granzyme B expression was found in 10 specimens, nine of which had SAR (p < 0.01). Fas ligand was expressed in seven specimens, and six of them were classified as SAR (p < 0.01). Perforin expression had the highest sensitivity (81%) for the diagnosis of SAR. Granzyme B and Fas ligand had specificity of 90%. At 12 months, there was no significant difference in creatinine concentrations for patients with and without previous SAR (1.63 +/- 0.57 x 1.28 +/- 0.31; p = 0.10). Molecular analysis revealed that there was no statistically significant difference in the expression of perforin and granzyme B in patients with and without SAR. Fas ligand expression was observed in five samples, four of which had histological signs of SAR (p = 0.03). At 12 months, perforin expression had the highest sensitivity (83%), and Fas ligand, the highest specificity (88%) for the diagnosis of SAR. We concluded that the expression of genes that encode proteins involved in the cytolytic attack against the allograft is increased in kidneys with SAR. These findings support the understanding that SAR is an active immune process potentially deleterious to renal allografts.

Acute Disease↗

PubMed2003

A prospective, randomized, clinical trial of intraoperative versus postoperative Thymoglobulin in adult cadaveric renal transplant recipients.

BACKGROUND: Delayed graft function (DGF) is frequently observed in recipients of cadaveric renal transplants. Previous retrospective or nonrandomized studies have suggested that intraoperative administration of polyclonal antithymocyte preparations may reduce the incidence of DGF, possibly by decreasing ischemia-reperfusion injury. METHODS: We performed a prospective randomized study of Thymoglobulin induction therapy in adult cadaveric renal transplant recipients. Between January 2001 and January 2002, 58 adult cadaveric renal transplant recipients were randomized to receive intraoperative or postoperative Thymoglobulin induction therapy. Three to six doses of Thymoglobulin (1 mg/kg/dose) were administered during the first week posttransplant. Baseline immunosuppression consisted of tacrolimus (54 of 58) or cyclosporine A (4 of 58), steroids, and mycophenolate mofetil. DGF was defined by the requirement for hemodialysis within the first week posttransplant. RESULTS: There were no significant differences between the two groups in recipient demographics, donor age, cold ischemia time, or total number of doses of Thymoglobulin administered. Intraoperative Thymoglobulin administration was associated with significantly less DGF and a lower mean serum creatinine on postoperative days 10 and 14 (P<0.05). Posttransplant length of stay was also significantly shorter for the intraoperative Thymoglobulin patient group. The acute rejection rate was also lower in the intraoperative treatment group but this did not achieve statistical significance. There was no difference in the incidence of cytomegalovirus disease between the two groups. CONCLUSIONS: The results of this study indicate that intraoperative Thymoglobulin administration, in adult cadaveric renal transplant recipients, is associated with a significant decrease in DGF, better early allograft function in the first month posttransplant, and a decreased posttransplant hospital length of stay.

Acute Disease↗

PubMed2001

Pneumoperitoneum upregulates preproendothelin-1 messenger RNA.

BACKGROUND: Laparoscopic pneumoperitoneum has been shown to decrease glomerular filtration rate (GFR) and urine volume (UV). Endothelin-1 (ET-1), a potent renal vasoconstrictor, has been implicated. The purpose of this study was to determine renal function, ET-1 gene expression, and peptide localization in kidneys subjected to CO2 pneumoperitoneum. METHODS: Experiments were performed in three groups of anesthetized Sprague-Dawley rats in which GFR and UV were measured before, during, and after insufflation. In the first group (n = 8), pneumoperitoneum (10 mmHg) was established for 30 min. The second group (n = 4) underwent a sham operation without pneumoperitoneum. In the final group (n = 4), kidneys were obtained from normal control animals without any prior surgical instrumentation. PreproET-1 (ppET-1) mRNA levels were measured by reverse transcription-polymerase chain reaction (RT-PCR). The ET-1 peptide was localized within kidneys by immunohistochemistry (IHC). RESULTS: Pneumoperitoneum caused a significant (p < 0.05) 87% decrease in GFR and a 79% decrease in UV from baseline, with a return to baseline values after desufflation. RT-PCR showed a significant (p < 0.05) increase in expression of ppET-1 mRNA in the laparoscopic group; it was 3.52 +/- 0.33 densitometric units (DU), as compared to 0.35 +/- 0.06 DU and 0.57 +/- 0.12 DU in the control and sham groups, respectively. IHC showed enhanced expression of the ET-1 peptide in the vascular endothelium and proximal tubular cells of the laparoscopic group compared to the control and sham groups. CONCLUSION: Pneumoperitoneum induces ET-1 gene and peptide upregulation in the kidney. Expression of ET-1 is increased in the renal vasculature and proximal tubular cells. The elevation of ET-1 and its localization may account for some of the renal dysfunction observed during pneumoperitoneum. This suggests that antagonism of ET-1 may be beneficial in patients with renal impairment undergoing prolonged laparoscopic procedures or in protecting allograft function during and after living donor nephrectomy.

Animals↗

PubMed1999

Lung allograft dysfunction correlates with gamma-interferon gene expression in bronchoalveolar lavage.

BACKGROUND: Preceding episodes of acute cellular rejection (ACR) may predispose lung allografts to the subsequent development of irreversible dysfunction or bronchiolitis obliterans syndrome (BOS). Other histologic patterns such as bronchiolitis obliterans with organizing pneumonia (BOOP), organizing pneumonia, lymphocytic bronchiolitis and diffuse alveolar damage (DAD) may also adversely affect allograft function. We have previously reported the predominant expression of Th1 cytokines (IL-2 and interferon gamma) in rejecting and Th2 (IL-10) in a tolerant model of rat lung transplantation. Here we correlate the "Th1/Th2 paradigm" in clinical lung transplantation with histologic findings and assess the effect on serial spirometric function. METHODS: We examined the mRNA expression of IL-2, interferon gamma, IL-10 and ICAM-1 in 53 bronchoalveolar lavage (BAL) specimens from 23 lung transplant (LT) recipients utilizing qualitative "nested" reverse transcriptase polymerase chain reaction (RT-PCR). We also measured IgG1 and IgG2 levels in 44 BAL specimens by ELISA. The mRNA expression for cytokines, ICAM-1 and the IgG2/IgG1 ratios were correlated with the presence or absence of ACR and alternate "histologic patterns". Serial spirometry were analyzed for the 2-3 month interval before bronchoscopic (FOB) assessment to derive "baseline" forced expiratory volume-one second (FEV1) values. The change in FEV1 coincident with (deltaFEV1 pre) and for the 2-3 month interval subsequent to (deltaFEV1 post) FOB were expressed relative to "baseline" spirometric indexes. RESULTS: Detection of mRNA for interferon gamma and ICAM-1 correlated significantly with ACR, whereas IL-2 and IL-10 expression did not correlate. IL-10 was virtually "ubiquitous" in most BAL samples irrespective of the presence or absence of ACR. The highest correlation was observed with interferon gamma for acute cellular rejection whereupon the sensitivity was 77.7%, specificity 87.7%, positive predictive value 73.6% and negative predictive value 88.2%, although for ICAM-1 these values were 75%, 65.7%, 50.0% and 85.0%, respectively. Nevertheless, 4 of 5 episodes of respiratory tract infection (bacterial, CMV, Aspergillus spp.) were similarly associated with cytokine mRNA. The ratios of IgG2 to IgG1, a reflection of Th1/Th2 influence, were not statistically different when analyzed for the presence or absence of ACR (0.91+/-0.53 vs. 1.02+/-0.70, respectively; p = NS). By analysis of FEV1 trends, expression of interferon gamma was associated with a greater and persistent decrement (deltaFEV1 pre: -0.265+/-0.78 liters, and post: -0.236+/-0.1161; mean +/- SE) than ACR in the absence of interferon gamma expression (+0.158 +/- +0.065 and +0.236+/-0.007 liters, respectively) (Student-Newman-Keuls, p<.05). CONCLUSION: Our findings suggest that interferon gamma mRNA expression and ICAM-1 may be valuable in both the diagnosis and prognosis for lung allograft ACR. IL-10, a Th2 cytokine, was locally expressed both in the presence and absence of ACR. Expression of mRNA for interferon y in BAL and, to a lesser extent ICAM-1, were associated with increased lung allograft dysfunction. Whether BAL cytokine "immunosurveillance" would complement or possibly supplant a specific "histologic pattern" and thereby direct different therapies after lung transplantation, may be potentially rewarding areas of further investigation.

Acute Disease↗

PubMed1991

Cyclosporine's effect on functional reserve in the renal allograft.

Thirteen renal allograft recipients (6 patients on cyclosporine/7 patients on azathioprine) participated in a short-term oral protein-loading study to determine the effect of cyclosporine on an allograft's functional reserve. The baseline glomerular filtration rate of the two groups were similar (52 +/- 18 ml/min/1.73 m2 for the azathioprine/conventional therapy (CT) group and 47 +/- 12 ml/min/1.73 m2 for the cyclosporine (CsA) group), as were the baseline effective renal plasma flows (218 +/- 78 ml/min/1.73 m2 and 222 +/- 75 ml/min/1.73 m2, respectively). At 3 hr following the protein load there was an increase in GFR to 66 +/- 28 ml/min/1.73 m2 in the CT group. The GFR (39 +/- 8 ml/min/1.73 m2) of the CsA group at this time was unchanged. The responses in ERPF were similar. No significant difference was found between the two groups baseline RAA profiles (4.7 +/- 3.3 ng/ml/hr (CT) and 4.7 +/- 1.7 ng/ml/hr [CsA]), or those at the third hour (8.1 +/- 8.3 ng/ml/hr (CT) and 3.5 +/- 1.9 ng/ml/hr [CsA]). The data in this study indicate that CsA alters the renal allograft's response to a protein meal. This difference may be related to an altered vasodilatory response. This altered vascular reactivity may be mediated through renin activation and/or other hemodynamic regulators such as prostaglandins.

Adult↗

PubMed1978

Relationship of renal transplantation to hypertension in end-stage renal failure.

The relationship of renal transplantation to new onset or persistence of previously established hypertension was analyzed in 164 transplant recipients in whom the renal allograft functioned for six months or longer. Of the 164, thirty-seven (23%) had normal blood pressure and 127 (77%) were hypertensive prior to transplantation. Following transplantation 83 patients (51%) were normotensive; high blood pressure was found in 81 (49%). Posttransplant hypertension could not be correlated with the recipient's original renal disease, age, sex, renal donor source, donor age, or maintenance dose of prednisone. More normotensive paients had undergone prior binephrectomy when compared with the hypertensive group (P less than .05). Mean serum creatinine levels was higher (2.0 mg/dl) in hypertensives than in normotensives (1.54 mg/dl) (P greater than .05). Selective renal veins' renin measurements in patients with severe hypertension were not helpful in predicting the beneficial effects of either bilateral nephrectomy or surgical correction of transplant renal artery stenosis.

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