Biomedical subjects

J R Thistlethwaite

Publications and source records attributed to J R Thistlethwaite.

At least 19 recordsLinked to original sources

PubMed2006

Attitudes of minority patients with end-stage renal disease regarding ABO-incompatible list-paired exchanges.

A few transplant centers in the United States have implemented list-paired exchange programs that include both ABO-compatible and ABO-incompatible living-donor recipients. ABO-incompatible list-paired exchanges raise ethical concerns because they increase the total number of organs available but increase the waiting time for wait-list candidates of blood type O. In this manuscript, we explore attitudes of a convenience sample of minority patients with end-stage renal disease (ESRD) regarding living paired exchanges, ABO-compatible and ABO-incompatible list-paired exchanges and ABO-incompatible direct transplants. Data from 87 minority respondents were analyzed. Eighty-seven (100%) supported living paired exchanges and ABO-compatible list-paired exchanges. In contrast, only 50 of 85 (59%) respondents supported ABO-incompatible list-paired exchanges (p < 0.001), including half (12 of 24) of those with blood type O. Subjects were asked how much additional time it would be fair to ask wait-list candidates of blood type O to wait to implement ABO-incompatible list-paired exchanges. Forty percent (35 of 87) responded 'no additional time' and another 10% (9 of 87) responded 'one month or shorter'. Minority dialysis patients hold mixed opinions about the fairness of ABO-incompatible list-paired exchanges. If our findings are confirmed in a more diverse randomly selected sample, then the UNOS variances that permit these exchanges should be reconsidered.

ABO Blood-Group System↗

PubMed2001

Cutting edge: membrane lymphotoxin regulates CD8(+) T cell-mediated intestinal allograft rejection.

Blocking the CD28/B7 and/or CD154/CD40 costimulatory pathways promotes long-term allograft survival in many transplant models where CD4(+) T cells are necessary for rejection. When CD8(+) T cells are sufficient to mediate rejection, these approaches fail, resulting in costimulation blockade-resistant rejection. To address this problem we examined the role of lymphotoxin-related molecules in CD8(+) T cell-mediated rejection of murine intestinal allografts. Targeting membrane lymphotoxin by means of a fusion protein, mAb, or genetic mutation inhibited rejection of intestinal allografts by CD8(+) T cells. This effect was associated with decreased monokine induced by IFN-gamma (Mig) and secondary lymphoid chemokine (SLC) gene expression within allografts and spleens respectively. Blocking membrane lymphotoxin did not inhibit rejection mediated by CD4(+) T cells. Combining disruption of membrane lymphotoxin and treatment with CTLA4-Ig inhibited rejection in wild-type mice. These data demonstrate that membrane lymphotoxin is an important regulatory molecule for CD8(+) T cells mediating rejection and suggest a strategy to avoid costimulation blockade-resistant rejection.

Abatacept↗

PubMed2001

CD8 T cell-mediated rejection of intestinal allografts is resistant to inhibition of the CD40/CD154 costimulatory pathway.

BACKGROUND: Disruption of the CD40/CD154 pathway inhibits rejection in numerous models. The importance of this pathway on intestinal allograft rejection was examined in this study. METHODS: Intestinal grafts from B6C3F1 mice transplanted into C57BL/6 recipients were assessed histologically for rejection. RESULTS: The monoclonal antibody to CD154, MR1, failed to inhibit rejection in wild-type mice. Similarly, CD154-/- recipient mice rejected intestinal allografts. MR1 did inhibit early rejection in CD8-/- mice, but had no effect in CD4-/- recipients. All MR1-treated CD8-/- recipients eventually developed rejection. No benefit was observed when blockade of the CD40/CD154 pathway by MR1 was combined with blockade of the CD28/B7 pathway by mCTLA4Ig. CONCLUSIONS: These data suggest that CD4+ T cells mediating intestinal allograft rejection may be more dependent upon the CD40/CD154 pathway than CD8+ T cells. This finding highlights the importance of identifying agents that suppress CD8+ T cell-mediated rejection.

Animals↗

PubMed2001

Different mechanisms of cardiac allograft rejection in wildtype and CD28-deficient mice.

Although CD28 blockade results in long-term cardiac allograft survival in wildtype mice, CD28-deficient mice effectively reject heart allografts. This study compared the mechanisms of allogeneic responses in wildtype and CD28-deficient mice. Adoptive transfer of purified CD28-deficient T cells into transplanted nude mice resulted in graft rejection. However, this model demonstrated that the allogeneic T cell function was severely impaired when compared with wildtype T cells, despite similar survival kinetics. Cardiac allograft rejection depended on both CD4+ and CD8+ T cell subsets in CD28-deficient mice, whereas only CD4+ T cells were necessary in wildtype recipients. These results suggested that CD8+ T cells were more important in CD28-deficient than wildtype mice. In addition to the CD8+ T cell requirement, allograft rejection in CD28-deficient mice was dependent on a sustained presence of CD4+ T cells, whereas it only required the initial presence of CD4+ T cells in wildtype mice. Taken together, these data suggest that CD4+ T cells from CD28-deficient mice have impaired responses to alloantigen in vivo, thus requiring long-lasting cooperation with CD8+ T cell responses to facilitate graft rejection. These results may help to explain the failure to promote graft tolerance in some preclinical and clinical settings.

Abatacept↗

PubMed2001

The clinical and pathologic implications of plasmacytic infiltrates in percutaneous renal allograft biopsies.

Plasmacytic infiltrates in renal allograft biopsies are uncommon and morphologically distinctive lesions that may represent variants of acute rejection. This study sought significant clinical and pathologic determinants that might have influenced development of these lesions and assessed their prognostic significance. Renal allograft biopsies (n = 19), from 19 patients, with tubulointerstitial inflammatory infiltrates containing abundant plasma cells, composing 32 +/- 8% of the infiltrating mononuclear cells, were classified using Banff '97 criteria. Clonality of the infiltrates was determined by immunoperoxidase staining for kappa and lambda light chains and polymerase chain reaction for immunoglobulin heavy-chain gene rearrangements, using V(H) gene framework 3 and JH consensus primers. In situ hybridization for Epstein-Barr virus encoded RNA (EBER) was performed in 17 cases. The clinical features, histology, and outcome of these cases were compared with kidney allograft biopsies (n = 17) matched for time posttransplantation and type of rejection by Banff '97 criteria, with few plasma cells (7 +/- 5%). Sixteen of 19 biopsies (84%) with plasmacytic infiltrates had EBER-negative (in 14 cases tested) polyclonal plasma cell infiltrates that were classifiable as acute rejection (types 1A [4], 1B [10], and 2A [2]). These biopsies were obtained between 10 and 112 months posttransplantation. Graft loss from acute and/or chronic rejection was 50% at 1 year and 63% at 3 years, and the median time to graft failure was 4.5 months after biopsy. There was no significant difference in overall survival or time to graft failure compared with the controls. Three of 19 biopsies (16%) had EBER-negative polyclonal plasmacytic hyperplasia, mixed monoclonal and polyclonal polymorphous B cell hyperplasia, and monoclonal plasmacytoma-like posttransplantation lymphoproliferative disease (PTLD) and were obtained at 17 months, 12 weeks, and 7 years after transplantation, respectively. Graft nephrectomies were performed at 1, 19, and 5 months after biopsy, respectively. Plasmacytic infiltrates in renal allografts comprise a spectrum of lesions from acute rejection to PTLD, with a generally poor prognosis for long-term graft survival.

Adult↗

PubMed2000

Role of STAT4 and STAT6 signaling in allograft rejection and CTLA4-Ig-mediated tolerance.

STAT4(-/-) mice have impaired type 1 T cell differentiation, whereas STAT6(-/-) mice fail to generate type 2 responses. The role of type 1 and type 2 T cell differentiation in acute cardiac allograft rejection and in the induction of tolerance was examined in wild-type, STAT4(-/-), and STAT6(-/-) recipients. All recipients rejected the grafts promptly. Analysis of in situ cytokine gene expression in the allografts confirmed decreased levels of IFN-gamma in STAT4(-/-) recipients and undetectable levels of IL-4 and IL-5 in STAT6(-/-) mice. Blockade of the CD28/B7 costimulatory pathway prolonged cardiac graft survival for >100 days in 100% of wild-type and STAT4(-/-) mice. However, 14% of CTLA4-Ig-treated STAT6(-/-) mice rejected their grafts between 20 and 100 days. Moreover, of those animals followed past 100 days, 60% of the STAT6(-/-) mice rejected their grafts. Splenocytes harvested on day 145 posttransplant from CTLA4-Ig-treated rejecting STAT6(-/-) recipients were transfused into syngeneic SCID mice transplanted with donor or third party cardiac allografts. Both donor and third party grafts were rejected, indicating that the initial graft loss may be due to an immunological rejection. In contrast, when splenocytes from CTLA4-Ig-treated wild-type or nonrejecting STAT6(-/-) mice were transferred into SCID recipients, donor allografts were accepted, but third party hearts were rejected. Thus, long-term prolongation of cardiac allograft survival by CTLA4-Ig is STAT4-independent but, at least in part, STAT6-dependent. These data suggest that the balance of type 1 and type 2 T lymphocyte differentiation is not critical for acute rejection but influences the robust tolerance induced by CD28/B7 blockade in this model.

Abatacept↗

PubMed2000

Reduced acute rejection and superior 1-year renal allograft survival with basiliximab in patients with diabetes mellitus. The Global Simulect Study Group.

BACKGROUND: Renal allograft recipients with diabetes mellitus often demonstrate poorer clinical outcomes than nondiabetic patients. Basiliximab (Simulect), a chimeric anti-interleukin-2 receptor monoclonal antibody, reduced the incidence of acute rejection in renal allograft recipients in 2 multicenter, placebo-controlled, phase III trials. METHODS: An analysis of pooled results from the 2 trials was conducted to compare the efficacy and safety of basiliximab with placebo in renal transplant recipients with and without prior diabetes. Patients received either basiliximab (20 mg on day 0 and day 4 posttransplantation) or placebo in combination with cyclosporine for microemulsion (Neoral) and steroids. RESULTS: A total of 722 patients (150 diabetic, 572 nondiabetic) were eligible for intent-to-treat analysis. At 12 months, basiliximab as compared with placebo reduced the proportion of patients experiencing first acute rejection by 41% in diabetics (P<0.01) and by 29% in nondiabetics (P<0.001). Biopsy-confirmed rejection was reduced by 44% in diabetics (P<0.01) and by 26% in nondiabetics (P<0.01). The first acute rejection episode requiring augmented immunosuppression other than steroids was reduced by 49% in diabetics (P<0.01) and by 41% in nondiabetics (P<0.001); death, graft loss, or first rejection episode was reduced by 43% in diabetics (P=0.001) and by 22% in nondiabetics (P<0.01). Superior graft survival was maintained in diabetic recipients treated with basiliximab versus placebo (96% vs. 86%; P=0.022). There were no significant differences in safety between basiliximab and placebo in both diabetic and nondiabetic patients. CONCLUSIONS: Basiliximab is associated with a significant reduction in acute rejection and an excellent safety profile in renal transplant recipients with and without diabetes mellitus. Superior graft survival was evident in diabetic patients.

Acute Disease↗

PubMed2000

Combined liver and kidney transplantation in children.

BACKGROUND: Preexisting renal dysfunction has been reported to significantly increase the morbidity and mortality associated with orthotopic liver transplantation (OLT). OLT alone has been recommended for adults and children with end-stage liver disease and reversible causes of renal failure (i.e., hepatorenal syndrome), whereas combined liver and kidney transplantation (LKT) has been shown to be an effective treatment for adults with combined end-stage liver and kidney disease. The purpose of this study was to examine the role of LKT in children. METHODS: Between October of 1984 and 1997, 385 children less than 18 years of age underwent OLT at the University of Chicago. During this same time period 12 patients underwent LKT. Data were gathered by retrospective review of the patients medical records and by interviews conducted with the patients' families. RESULTS: Actuarial patient survival was comparable for children who underwent OLT alone and LKT (69% versus 67% at 5 years). All allograft losses in the LKT group were the result of patient death and occurred within the first 90 postoperative days. Factors associated with decreased patient survival included severity of illness as reflected by United Network of Organ Sharing status and LKT after failed OLT or cadaveric renal transplant. CONCLUSIONS: In children with concomitant endstage liver and kidney disease, LKT can be considered an effective therapeutic option in selected patients. Long-term patient survival in patients undergoing LKT is comparable to that of patients with normal renal function undergoing OLT alone.

Child↗

PubMed2000

Absence of host B7 expression is sufficient for long-term murine vascularized heart allograft survival.

CD28 antagonists have been shown to promote long-term graft survival and induce donor-specific tolerance. In this study, the role of CD28/B7 costimulation and the relative importance of host versus donor B7 expression in allograft rejection was assessed in a murine abdominal vascularized heterotopic heart transplant model. Wild-type, CD28-deficient, or B7-1/B7-2-deficient C57BL/6 (B6) mice were grafted with allogeneic wild type or B7-1/B7-2-deficient hearts. The results demonstrate allogeneic heart grafts survive long-term in mCTLA4Ig-treated B6 and untreated B7-1/B7-2-deficient B6 recipients but not CD28KO B6 mice. B7-1/B7-2KO B6 recipients treated with anti-CD28 (PV-1) or recombinant human IL-2 rejected the heart transplants indicating that these mice are immunologically competent to reject grafts if costimulatory signals are supplied or bypassed. Finally, there was no difference in rejection between normal animals transplanted with wild-type versus B7-1/B7-2-deficient hearts. These results support a critical role for B7-expressing host antigen presenting cells in the rejection of heart allografts in mice and differences among B7KO and CD28KO animals.

Animals↗

PubMed2000

Primary living-donor liver transplantation at the University of Chicago: technical aspects of the first 104 recipients.

OBJECTIVE: To evaluate the impact of technical modifications on living-donor liver transplants in children since their introduction in 1989. SUMMARY BACKGROUND DATA: Although more than 4,000 liver transplants are performed every year in the United States, only approximately 500 are performed in children. Living-donor liver transplantation has helped to alleviate the organ shortage for small children in need of liver transplantation. Few centers have amassed a sufficient number of cases to evaluate the impact of the different techniques used in pediatric living-donor liver transplantation. METHODS: From 1989 through 1997, 104 primary living-donor liver transplants were performed at the University of Chicago. Three phases of the living-donor liver transplant program can be defined based on the techniques of vascular reconstruction: phase 1, November 1989 to November 1994 (n = 78); phase 2, November 1994 to January 1996 (n = 6); and January 1996 to present (n = 20). The patients' charts were reviewed retrospectively. The incidence and type of vascular complications and patient and graft survival rates were analyzed. RESULTS: Although the demographics of the patients have not changed during the three phases of the living-donor liver transplant program, the outcomes have improved. Without the use of conduits, the incidence of portal vein complications has significantly decreased from 44% to 8%. The incidence of hepatic artery thrombosis has decreased from 22% to 0% with the use of microvascular techniques. The combined use of both techniques has led to a significant increase in graft survival, from 74% to 94%. CONCLUSIONS: The living-donor liver transplant recipient operation has undergone significant technical changes since its introduction in 1989. These changes have decreased the vascular complications associated with this type of graft. Avoiding the use of vascular conduits and performing microvascular hepatic artery anastomoses are the critical steps in improving graft survival.

Anastomosis, Surgical↗

PubMed1999

Evaluation of pre- and posttransplant donor-specific transfusion/cyclosporine A in non-HLA identical living donor kidney transplant recipients. Cooperative Clinical Trials in Transplantation Research Group.

BACKGROUND: The beneficial effects of donor specific transfusion (DST) have become controversial in the cyclosporine era. This study was performed to evaluate the potential benefits of a new protocol for administering DSTs in the perioperative period. METHODS: Non-HLA identical living donor kidney transplant recipients were randomized prospectively to control or to receive a DST 24 hr before transplant and 7-10 days posttransplant. All patients received similar immunosuppression according to protocol. RESULTS: The protocol had 212 evaluable patients (115 transfused and 97 control). There were no differences in 1- and 2-year graft and patient survival, causes of graft failure, incidence and types of infection, repeat hospitalization, or the ability to withdraw steroids. Immunological hyporesponsiveness (by mixed lymphocyte culture) occurred more frequently in transfused patients (18%) than controls (3%) (P = 0.04). Blood stored for > or =3 days was associated with fewer early rejections than blood stored < or =2 days. Overall, class II antigen mismatches were associated with more rejection episodes than class I antigen mismatches. However, transfused patients, but not control patients, with more class I antigen mismatches were more likely to have rejections. CONCLUSIONS: Administration of DSTs by the method described had no practical influence on patient or graft survival for up to 2 years. However, donor-specific hyporesponsiveness was more common in transfused patients (18 vs. 3%). Longer follow-up will be needed to determine whether DST will be associated with long-term benefit.

Blood Preservation↗

PubMed1999

Phase I trial of a humanized, Fc receptor nonbinding OKT3 antibody, huOKT3gamma1(Ala-Ala) in the treatment of acute renal allograft rejection.

BACKGROUND: HuOKT3gamma1(Ala-Ala) is a genetically-engineered derivative of the parental murine OKT3 monoclonal antibody, in which the six complementarity-determining regions have been grafted within a human IgG1 mAb, and whose C(H)2 region has been altered by site-directed mutagenesis to alter FcR-binding activity, thereby eliminating T cell activation properties. This report describes the results of a phase I trial of huOKT3gamma1(Ala-Ala) treatment of acute renal allograft rejection. METHODS: Acute renal allograft rejection in kidney and kidney-pancreas transplant recipients was treated with huOKT3gamma1(Ala-Ala). huOKT3gamma1(Ala-Ala) dosing consisted of daily 5- or 10-mg doses adjusted initially to achieve target levels of 1000 ng/ml. RESULTS: A total of seven patients, five kidney transplant and two kidney-pancreas transplant recipients, were treated with the monoclonal antibody for first rejection episodes. Corticosteroids (500 mg i.v. Solumedrol) were given 2 hr before the first huOKT3gamma1(Ala-Ala) dose only. Banff classification of treated rejections were the following: grade I, 1 patient, grade IIA, 1 patient, grade IIB, 4 patients, and grade III, 1 patient. Median time from transplant to rejection was 15 days, and median follow up 12 months (range 10-17 months). HuOKT3gamma1(Ala-Ala) therapy was given for 10.1+/-2.5 days, and mean total dose was 76+/-27 mg. Rejection was reversed in five of seven patients, and recurrent rejection was observed in one patient. Serum creatinine values peaked on day 1 of huOKT3gamma1(Ala-Ala) therapy, and thereafter demonstrated a progressive decline. Rejection reversal (return of creatinine to baseline) occurred at a median of 4 days and a mean of 4.1+/-2 days. Renal allograft biopsies obtained during huOKT3gamma1(Ala-Ala) therapy provided evidence of rapid rejection reversal. Patient and graft survival were both 100%. First dose reactions were minimal, and anti-OKT3 antibodies were not detected. Elevations in serum IL-10, but not IL-2 levels were observed after the first huOKT3gamma1(Ala-Ala) dose. Marked reductions in circulating CD2+, CD4+, and CD8+ T cells were observed after the first huOKT3gamma1(Ala-Ala) dose, followed by a slow progressive return of cell counts toward pretreatment values. Pharmacokinetic analysis revealed a half-life of 142+/-32 hr. CONCLUSIONS: HuOKT3gamma1(Ala-Ala) possesses the ability to reverse vigorous rejection episodes in kidney and kidney-pancreas transplant recipients, and in comparison to murine OKT3, possesses minimal first dose reactions and does not seem to induce antibodies that bind the OKT3 idiotype. These results support the conduct of additional clinical trials with the huOKT3gamma1(Ala-Ala) antibody.

Acute Disease↗

PubMed1999

Cutting edge: blockade of the CD28/B7 costimulatory pathway inhibits intestinal allograft rejection mediated by CD4+ but not CD8+ T cells.

The effect of blocking the CD28/B7 costimulatory pathway on intestinal allograft rejection was examined in mice. Murine CTLA4Ig failed to prevent the rejection of allografts transplanted into wild-type or CD4 knockout (KO) mice but did inhibit allograft rejection by CD8 KO recipients. This effect was associated with decreased intragraft mRNA for IFN-gamma and TNF-alpha and increased mRNA for IL-4 and IL-5. This altered pattern of cytokine production was not observed in allografts from murine CTLA4Ig-treated CD4 KO mice. These data demonstrate that blockade of the CD28/B7 pathway has different effects on intestinal allograft rejection mediated by CD4+ and CD8+ T cells and suggest that these T cell subsets have different costimulatory requirements in vivo. The results also suggest that the inhibition of CD4+ T cell-mediated allograft rejection by CTLA4Ig may be related to down-regulation of Th1 cytokines and/or up-regulation of Th2 cytokines.

Abatacept↗

PubMed1999

Induction, maintenance, and reversal of streptozotocin-induced insulin-dependent diabetes mellitus in the juvenile cynomolgus monkey (Macaca fascilularis).

BACKGROUND: Insulin-dependent diabetes mellitus (IDDM) is the second most prevalent chronic illness of children. Investigation of the treatment of IDDM is hindered by the lack of a reproducible and easily maintained non-human primate model of this disorder. METHODS: We induced IDDM in 11 juvenile cynomolgus monkeys after a single (150 mg/kg) intravenous injection of streptozotocin (STZ). All diabetic monkeys were treated with insulin twice daily, based on a sliding scale. Subcutaneous vascular access ports were surgically placed in each monkey to facilitate serial blood sampling and drug administration. Allogeneic pancreatic islet cells from unrelated donors were subsequently transplanted into the mesenteric circulation of all STZ-treated monkeys. RESULTS: Mild, transient nausea and vomiting occurred in all animals after STZ injection; however, no additional signs of toxicity occurred. Within 36 hr, all monkeys required twice daily administration of exogenous insulin to maintain a non-ketotic state. Serum C-peptide levels decreased from >1.2 ng/ml before STZ, to between 0.0 and 0.9 ng/ml after STZ, confirming islet cell destruction. Animals were maintained in an insulin-dependent state for up to 147 days without any observable clinical complications. Subcutaneous vascular access port patency was maintained up to 136 days with a single incidence of local infection. Islet cell transplantation resulted in normoglycemia within 24 hr. Serum C-peptide levels increased (range: 2-8 ng/ml) for 6 - 8 days in immune competent animals, and for 39-98 days after transplant in immunosuppressed monkeys. CONCLUSIONS: IDDM can be consistently induced and safely treated in juvenile cynomolgus monkeys. Chronic vascular access can be maintained with minimal supervision and complications. This model is appropriate for studies investigating potential treatments for IDDM including islet cell transplantation.

Animals↗

PubMed1999

The role of CD8 and CD4 T cells in intestinal allograft rejection: a comparison of monoclonal antibody-treated and knockout mice.

BACKGROUND: The relative contribution of CD8 and CD4 T cells to allograft rejection remains an unresolved issue. Experimental results suggest that the relative importance of these T-cell subsets may vary depending on the model used and the organ studied. We have previously shown that treatment of murine recipients of intestinal allografts with a depleting anti-CD8 or a depleting anti-CD4 monoclonal antibody (mAb) significantly inhibited allograft rejection. This study was undertaken to further examine the contribution of CD8 and CD4 T cells to the rejection of intestinal allografts. METHODS: Intestinal allografts from B6C3F1/J (C57BL/6 x C3H/HeJ) mice were transplanted into C57BL/6 recipients. Recipient groups included mice with an acquired deficiency in CD8 or CD4 T cells caused by treatment with depleting mAb or mice genetically deficient in CD8 or CD4 T cells as a result of disruption of the genes encoding major histocompatibility complex (MHC) class I, MHC class II, CD8, or CD4. In all cases, rejection was assessed histologically at predetermined time points. In some recipient groups, graft function was also assessed using a maltose absorption assay. RESULTS: Rejection, assessed between days 10 and 28 after transplantation, was significantly inhibited in mice deficient in CD8 or CD4 T cells after treatment with depleting mAb. In contrast, mice genetically deficient in either CD8 T cells (MHC class I or CD8 knockouts) or CD4 T cells (MHC class II or CD4 knockouts) rejected intestinal allografts promptly. Both histologic and functional evaluation of anti-CD8 mAb-treated mice on day 60 showed that the inhibition of rejection persisted even after the return of a substantial number of CD8 T cells. Although intestinal allografts from anti-CD8 mAb-treated mice displayed little to no evidence of rejection on day 60 after transplantation, these mice were able to reject both donor and third-party skin grafts. CONCLUSIONS: These results demonstrate that the inhibition of intestinal allograft rejection associated with mAb treatment is not attributable solely to depletion of CD8 or CD4 T cells. Furthermore, anti-CD8 mAb administration did not induce donor-specific tolerance or cause nonspecific immune suppression, as indicated by the skin-grafting experiments. Our findings suggest that at least some depleting mAbs mediate their protective effect on allograft rejection via an alternative mechanism such as the induction of a regulatory cell population(s).

Animals↗

PubMed1999

Drug-induced acute interstitial nephritis in renal allografts: histopathologic features and clinical course in six patients.

Drug-induced acute interstitial nephritis is a common cause of dysfunction in native kidneys, but is rarely reported in renal allografts. This report describes six renal transplant recipients with acute renal allograft dysfunction or delayed allograft function in whom a renal transplant biopsy showed histopathologic features of drug-induced interstitial nephritis with no diagnostic evidence of acute rejection, cyclosporine or tacrolimus nephrotoxicity, or other lesion that could account for the graft dysfunction. In five of the six patients, interstitial nephritis occurred within 4 weeks of transplantation. All the patients were receiving trimethaprim-sulfamethoxazole and/or other drugs associated with interstitial nephritis. After discontinuation of these drugs and short-term corticosteroid treatment, all patients showed improvement in renal function, although the time course of this improvement varied considerably, with three patients showing a return to baseline serum creatinine level within 2 weeks and two patients showing a gradual improvement over 8 weeks. Four of the five patients followed up for more than 1 year (range, 14 to 33 months) after the episode of interstitial nephritis had good allograft function (serum creatinine level </= 1.6 mg/dL) at most recent follow-up, with one patient who had graft loss because of severe rejection 7.5 months after the development of interstitial nephritis. These findings suggest drug-induced interstitial nephritis may be an infrequent cause of graft dysfunction in kidney transplant recipients. Drug-induced interstitial nephritis is a reversible lesion that should be considered in the differential diagnosis of acute renal allograft dysfunction.

Acute Disease↗

PubMed1999

Smooth muscle-specific actin levels in the urine of renal transplant recipients: correlation with cyclosporine or tacrolimus nephrotoxicity.

Cyclosporine A (CSA) and tacrolimus (FK506) are powerful immunosuppressive agents that have proven useful for antirejection therapy in patients with solid organ transplants, including kidney. However, both drugs are nephrotoxic, each producing similar histological patterns of injury to renal tubules and preglomerular arterioles, and this toxicity is a major cause of renal allograft dysfunction. A renal transplant biopsy presently represents the most reliable means of diagnosing nephrotoxicity caused by CSA or tacrolimus and distinguishing it from acute rejection. Because CSA and tacrolimus nephrotoxicity often involve arteriolar smooth muscle, whereas vascular smooth muscle is rarely involved in acute rejection, we investigated if the appearance of a smooth muscle-specific isoform of alpha-actin (SMA) in the urine of renal transplant recipients about to undergo a biopsy for graft dysfunction correlated with biopsy evidence of CSA or tacrolimus toxicity. Eighty-nine urine samples from 61 patients, plus 6 samples from healthy control subjects, were analyzed in a blinded manner by enzyme-linked immunosorbent assay using a specific anti-SMA monoclonal antibody. For the patient samples, the results of these assays were then correlated with the biopsy findings. Those 40 cases in which the biopsy showed evidence of CSA or tacrolimus nephrotoxicity had a significantly (P < 0.01) greater SMA level in the corresponding urine samples (0.089 +/- 0.126 microgram/mL; mean +/- SD) than the 49 cases without toxicity (0.018 +/- 0.027 microgram/mL) or 6 control subjects (0.003 +/- 0.007 microgram/mL), although there was considerable overlap of SMA values among these groups. The greatest SMA levels were seen in patients with CSA or tacrolimus nephrotoxicity that was likely to be relatively acute, namely those with thrombotic microangiopathy and those without previous biopsy evidence of toxicity. SMA levels correlated significantly with the estimated severity of arteriolopathy on biopsy. In patients with tubular but not arteriolar lesions of CSA or tacrolimus toxicity, the mean SMA level was not significantly greater than that in patients without toxicity. Urine SMA levels in patients with a biopsy specimen showing acute rejection were not significantly different from those in patients without rejection, and there was no correlation between urine SMA level and severity of rejection. Whereas the degree of overlap of SMA levels in patients with and without nephrotoxicity was far too great to consider this assay as a potential alternative to renal transplant biopsy for the diagnosis of nephrotoxicity, the assay may have potential as a marker for active arteriolar injury in renal transplant recipients and other patients receiving CSA or tacrolimus therapy.

Actins↗

PubMed1999

The relationship of untreated borderline infiltrates by the Banff criteria to acute rejection in renal allograft biopsies.

The relationship of borderline infiltrates to acute rejection by Banff criteria in renal allografts of patients receiving only maintenance immunosuppression is not clear. Renal allograft biopsies with borderline lesions that were not treated with additional anti-rejection therapy were retrospectively studied. Sixty-five such biopsies were identified from 50 patients, and their outcome was determined by serum creatinine and/or histologic findings in subsequent biopsies, up to 40 d after the initial biopsy. In addition to the borderline infiltrates, there was evidence of acute cyclosporine or tacrolimus toxicity (58%), acute tubular necrosis (12%), and urinary obstruction (12%). Forty-day follow-up after 30 (46%) biopsies revealed serum creatinine < 110% of baseline, and repeat biopsies were not indicated. In 17 (26%), the serum creatinine initially decreased, then increased, and follow-up biopsies showed acute rejection in nine. In 18 (28%), the creatinine remained elevated and follow-up biopsies revealed acute rejection in nine. The untreated borderline infiltrates were thus nonprogressive after 47 biopsies (72%) and progressed to histologic acute rejection after 18 (28%). When there was increasing or persistently elevated creatinine after the initial biopsy, 51% of cases (18 of 35) progressed to acute rejection. Infiltrates that progressed to rejection had more frequent glomerulitis (7 of 18 versus 3 of 47, P = 0.003) and Banff acute score indices (i+t+v+g) >2 (16 of 18 versus 29 of 47, P = 0.03). A majority (72%) of borderline infiltrates not given additional anti-rejection therapy did not progress to acute rejection over 40 d of follow-up, suggesting that conservative management of these lesions, at least in the short term, may be more appropriate than routine treatment as acute rejection.

Adolescent↗