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PubMed1996

Routine early biopsy of allografts with delayed function: correlation of histopathology and transplant outcome.

Approximately 25-30% or our cadaveric renal transplant recipients have required post-transplant dialysis. In an attempt to discern the etiology, routine biopsies were performed 7-10 d post-transplant and repeated weekly. All patients received a triple-therapy cyclosporine-based regimen with (N = 61) or without (N = 10) antilymphocyte induction. Rejection was classified as 'early' when it appeared on the first biopsy (8.9 +/- 0.3 d), 'delayed' when it appeared only on the second biopsy (17.9 +/- 1.0 d) and persistent when present on both biopsies. Adequate biopsy material was obtained from 71 patients who provided a total of 117 biopsies. Acute tubular necrosis was the most common finding (50%) in the first biopsy, while rejection occurred in 30% of biopsies. Rejection on the first biopsy was strongly associated with primary nonfunction (PNF) (8 of 21 vs. 1 of 40, p < or = 0.0001). In contrast, eight patients without rejection on Biopsy 1 developed delayed rejection on Biopsy 2; only one was associated with PNF. DGF persisted beyond the second week in 38 patients; 17 (38%) of which had rejection. Nine patients had persistent rejection 55% of whom experienced PNF compared to 6% without persistent rejection (p < or = 0.001). The occurrence of early rejection was associated with pretransplant peak PRA levels > 50% (p < or = 0.01). Graft survival for all patients was 79% and 65% at 1 and 2 yr. Rejection influenced 1-yr graft survival for patients with persistent rejection who had 55% incidence of primary nonfunction and 1- and 2-yr graft survival rates of 42% and 37%. These data indicate that early biopsies are useful in unmasking rejection during DGF and at predicting primary nonfunction. Based on these data we recommend the routine utilization of biopsies for all patients with DGF.

Adult↗
PubMed2003

Delayed graft function may not adversely affect short-term renal allograft outcome.

INTRODUCTION: Delayed graft function (DGF) is commonly believed to adversely impact both short- and long-term renal allograft function. Because immunosuppressive therapy is commonly altered after DGF is identified, retrospective analyses are difficult to interpret. We therefore prospectively sought to examine the natural history of DGF in a controlled patient population under identical immunosuppressive protocols. METHODS: Adult patients undergoing cadaveric renal transplantation were treated with sequential triple drug immunotherapy. High-dose steroids were administered in the operating room and rapidly tapered to 20 mg prednisone by post-operative day (POD) 6. Cyclosporine (CsA) microemulsion was begun on POD 1, and dosed asymmetrically at 12-h intervals to reach a daytime Cav of 650 ng/mL (utilizing 2-h and 6-h levels), while PM doses were adjusted to an AM trough of 300 ng/mL. Mycophenolate (1000 mg q12 h) was added on POD 3 in most patients and discontinued after 3 months. No induction agents were used. All patients were followed for at least 6 months. RESULTS: Sixty consecutive patients received 64 allografts (four double grafts). In all, 17 patients required dialysis and were considered to have DGF. Eight of these patients received marginal organs turned down by at least one other centre. Cold ischaemia time was significantly longer in patients with DGF (24 h vs. 19 h, P < 0.01) All patients were treated as planned and there were no major protocol violations. One patient had primary non-function and was excluded from analysis. CsA trough and Cav values were similar between groups. Mean serum creatinine levels (mg/mL) fell more slowly in patients with DGF but there was no significant difference by 3 months (1.7 vs. 1.5) and the creatinine clearance was not significantly different between the groups after 1 year (71 cm3/min in DGF vs. 61 cm3/min, P = 0.13). Our data demonstrate that alterations in routine immunosuppressive strategies may not be necessary to achieve equivalent outcomes in patients with DGF.

Adult↗
PubMed1997

Delayed graft function: risk factors and implications for renal allograft survival.

Delayed graft function (DGF) may be associated with diminished kidney allograft survival. We studied the risk factors that lead to nonimmediate function of a renal allograft and the consequences of DGF on short- and long-term renal transplant survival. Data from the U.S. Renal Data System were used to measure the relationships among cold ischemia time, delayed graft function, acute rejection, and graft survival in 37,216 primary cadaveric renal transplants (1985-1992). These relationships were investigated using the unconditional logistic and Cox multivariate regression methods. Cold ischemia time was strongly associated with DGF, with a 23% increase in the risk of DGF for every 6 hr of cold ischemia (P<0.001). Acute transplant rejection occurred more frequently in grafts with delayed function (37% vs. 20%; odds ratio=2.25, P=0.001). DGF was independently predictive of 5-year graft loss (relative risk=1.53, P<0.001). The presence of both early acute rejection and DGF portended a dismal 5-year graft survival rate of 35%. Zero-HLA mismatch conferred a 10-15% improvement in 1- and 5-year graft survival regardless of early functional status of the allograft. However, the 5-year graft survival rate in HLA-mismatched kidneys without DGF was significantly higher than that of zero-mismatched kidneys with DGF (63% vs. 51%; P<0.001). DGF independently portends a significant reduction in short- and long-term graft survival. Delayed function and early rejection episodes exerted an additive adverse effect on allograft survival. The deleterious impact of delayed function is comparatively more severe than that of poor HLA matching.

Adult↗
PubMedDate not supplied

Renal transplantation and secondary hyperparathyroidism.

Secondary hyperparathyroidism (2'HPT) improves after renal transplantation (RTx) along with recovered function of the renal allograft. However, normal renal function does not last long due to rejection, drug-induced nephrotoxic nepthropathy, or recurrence of post-transplant glomerulonephritis. Therefore, improved calcium and phosphate metabolism, and parathyroid function after RTx fluctuate in accordance with the function of the renal allograft. In cases with severe 2'HPT, parathyroidectomy should be performed before RTx because hypercalcemia due to secondary or tertiary hyperparathyroidism aggravates the renal allograft function. In the follow-up of mild 2'HPT after RTx, hypercalcemia and vascular calcification should be monitored carefully by serum parathyroid hormone, calcium and phosphate concentrations, alkaline phosphatase activity, and bone X-ray film. If serum calcium level exceeds 12 mg/dl, parathyroidectomy (PTx) should be performed to prevent the acceleration of vascular calcification. Total PTx with forearm allograft is a preferred surgical procedure for 2'HPT even after RTx.

Cholecalciferol↗
PubMed1993

Extended survival and function of peripheral nerve allografts after cessation of long-term cyclosporin administration in rats.

To determine whether survival and function of peripheral nerve allografts are possible after cessation of long-term cyclosporin (CsA) treatment, we grafted 4.25 cm Lewis rat peripheral nerve allografts (n = 22) into tibial nerve gaps in recipient brown Norway rats. Allograft groups received CsA (15 mg/kg) subcutaneously every day for 20 days and then biweekly for either 5 or 8 months after transplantation. The control group, brown Norway rats with isografts from brown Norway donor rats (n = 2), also received identical CsA treatment. Semimonthly electrophysiologic studies were done from postoperative week 13 until the animals were killed (up to 79 weeks). The corresponding CsA levels in the nerve and blood were recorded from cessation of CsA up to 58 weeks after surgery. No electrophysiologic signs of rejection were observed in any of the 22 allograft recipients treated with CsA for up to 8 months or in 17 of the 22 observed for up to 58 weeks after cessation of CsA. Overall, 5 of 22 allografts were rejected in the first 8 weeks after discontinuation of CsA. Signs of rejection occurred only in the 5-month treatment group and followed the large initial drop in CsA blood level (from 1010 ng/ml to < 25 ng/ml) that occurred within the first 6 weeks after CsA cessation. The two isograft controls demonstrated no electrophysiologic signs of rejection up to 58 weeks after surgery. Peripheral nerve allografts in the rat can regenerate and function on long-term CsA; after cessation of CsA, they can function for extended periods of time without signs of rejection if trace amounts of CsA are present.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed2005

Risk factors for delayed kidney function and impact of delayed function on patient and graft survival in adult graft recipients.

The influence of delayed kidney graft function on allograft outcome is described controversially in the literature. The aim of the study was to evaluate possible risk factors for delayed graft function (DGF) and investigate the impact of DGF on short- and long-term renal allograft function. Two groups were formed: the first one consisted of patients who gained immediate graft function (IGF) (n = 64) after transplantation and the second group included patients with DGF (n = 31; with at least one dialysis needed in first week after transplantation). The DGF group had a statistically significant longer duration on dialyses prior to transplantation (DGF 54 vs. IGF 33 months; p < 0.05), on average more frequently a re-transplantation (DGF 1.7 vs. IGF 1.3; p < 0.01), a longer re-anastomosis time (DGF 52.9 vs. 44.2 min; p < 0.01), a lower systolic (DGF 136 +/-24 mmHg vs. IGF 158 +/- 25; p < 0.001) and diastolic blood pressure (DGF 78 +/- 14 vs. IGF 89 +/- 16 mmHg; p < 0.01) at admission to the hospital and a higher serum (S)-creatinine at discharge (DGF 2.5 +/- 1.6 vs. IGF 1.6 +/- 0.4 mg/dL; p < 0.01). Prior to transplantation the DGF group had more often advanced vascular diseases (DGF 29.0 vs. IGF 12.5%; p < 0.01) and these patients incurred more frequently new ones during the next 3 yr after transplantation (DGF 22.6 vs. IGF 6.3%; p < 0.001). After 3 yr the graft survival tended to be lower in the DGF group (DGF 74.2 vs. IGF 84.4%; NS), but this difference was not statistically significant.

Adult↗
PubMed1991

Influence of time from donor death to graft harvest on conduit function of cryopreserved aortic allografts in lambs.

We examined the influence of time from donor death to graft harvest on conduit function of aortic allografts in the thoracic aortic position in 18 lambs (mean weight, 11.4 kg). Five grafts were harvested immediately after donor death (fresh), seven at 24 hours, and six at 48 hours following cadaver storage at 4 degrees C. All grafts were treated with antibiotics and were stored by cryopreservation. All animals were catheterized postoperatively and at 3, 6, 9, and 12 months. One animal in the 24-hour group developed an allograft aneurysm, and another one died from a ruptured allograft; one graft in the fresh group occluded by nine months. No animal, however, in the 48-hour group either developed an aneurysm or occluded. There was in fact minimal change in graft diameter over time (p greater than 0.05), while the native aorta grew appropriately (greater than 50%, p less than 0.01). Forty-eight hour delay from donor death to graft harvest did not have significant effect on conduit function. This information may expand the donor pool for allografts.

Animals↗
PubMed1999

Complete loss of functional smooth muscle cells precedes vascular remodeling in rat aorta allografts.

BACKGROUND: The functional consequences of vascular remodeling in rat aorta allografts were studied at different times after transplantation (Tx). METHODS: At days 1, 3, 7, 14, 28, and 56 after Tx, rat aorta allografts (Dark Agouti [DA]-to-Lewis) were mounted as isolated organs, and their contractile properties tested with phenylephrine, KCl, or endothelin-1. Controls were native DA-aortae and DA-syngeneic grafts. Changes in alpha smooth muscle actin and morphology were assessed by immunoblotting and histology. RESULTS: PostTx syngeneic grafts presented similar functional and morphological properties to native aortae. In allografts, no morphological changes was detected at day 7 after Tx, but phenylephrine-induced vasoconstriction was reduced by 60%. Signs of medial smooth muscle cell (SMC) loss and adventitial inflammation were observed at day 14 after Tx, without neointima formation. A complete loss of contractile property was observed at day 28 after Tx in association with a 75% decrease in alpha-SMC actin, severe adventitial inflammation, and reduced medial cellularity. At this time, neointima was restricted to both edges of allografts. At day 56 after Tx, allografts were also not functional and exhibited neointima on their entire length. All these changes were prevented by treating recipients with cyclosporine (7.5 mg/kg/day). CONCLUSION: These results indicate that, after Tx, the contractile property of rat aorta allografts is altered before manifest vascular remodeling. Because this can be prevented by cyclosporine, it most likely reflects an acute rejection of SMC. These results also show that vascular graft dysfunction can be used to monitor the development of rejection in the rat aorta allograft model.

Actins↗
PubMed1993

Longitudinal study of in vitro CD4+ T helper cell function in recently transplanted renal allograft patients undergoing tapering of their immunosuppressive drugs.

Three distinct T helper activation pathways contribute to interleukin-2 production by human peripheral blood mononuclear cells following in vitro stimulation with HLA alloantigens in a mixed lymphocyte reaction. These pathways involve both CD4+ and CD8+ T helper cells, as well as self and allogeneic antigen-presenting cells. The pathways are differentially susceptible to cyclosporine in vitro, with the CD4+ T helper cell and selfAPC (CD4 approximately sAPC) pathway being the most sensitive. Furthermore, these pathways are differentially susceptible to immunosuppressive drugs in renal allograft patients, and by functional analysis of these pathways we have identified patients who are at increased risk for rejection of their kidney allografts. The present report provides a longitudinal study of the functional T helper cell status of recently transplanted renal allograft recipients undergoing tapering of their immunosuppressive drugs by testing the ability of recipient PBMC to generate IL-2 in response to pathway-specific stimuli. This study provides evidence that IL-2 generation by T helper pathways is dynamic, fluctuating independently of the commonly followed clinical parameters used to assess graft function and degree of immunosuppression. Significantly, the function of the CD4 approximately sAPC activation pathway correlates with risk of acute rejection. As such, we suggest that periodic assessment of pathway specific T helper function is a more sensitive index for the detection of subtherapeutic dosing of immunosuppressives--and, in particular, for assessing cyclosporine maintenance requirements. Monitoring of pathway specific activity with appropriate cyclosporine dosing adjustments might prevent the initiation of the rejection process and reduce a major source of late graft failure.

Adult↗
PubMed2005

[Effect of ciclosporin A on the organogenesis and function of embryonic metanephroi allografted into adult rats].

OBJECTIVE: To evaluate the effect of ciclosporin A (CsA) on the organogenesis and function of embryonic metanephroi allografted into adult rats. METHODS: The whole metanephroi from the 15, 16 and 17 embryonic day-old (E15, E16, E17) embryos of Sprague-Dawley (SD) rat were allografted into the omenta of SD adult rats with their left kidneys resected, which were divided into 2 categories: 3 CsA-treated groups of 10 rats (E15CsASD, E16CsASD, and E17CsASD) and 3 non-CsA-treated groups of 10 rats (E15SD, E16SD, and E17SD). Thirty SD rats without kidney resection were divided into 6 equal groups and underwent allografting embryonic metanephroi in the same manner as mentioned above. The E15 metanephroi of Lewis rats were allografted into the omenta of Thirty adult Brown Norway (BN) rats with one kidney resected. Were divided into 6 equal groups, received allografting of embryonic metanephroi, and injected with CsA of normal saline in the manner as mentioned above (E15CsABN and E15BN). Two to 4 weeks after implantation, the metanephroi allografted in host rats were removed for histopathological examination or anastomosed for renal function measurement 4 weeks later. RESULTS: (1) Four weeks after implantation, the E17SD and E16SD metanephroi showed signs of acute rejection as hypercellular glomeruli and mononuclear cell infiltration in the interstitium. The E16CsASD and E17CsASD metanephroi formed mature nephrons and collecting ducts with few lymphocytic infiltrates. After CsA was discontinued, the E16CsASD and E17CsASD metanephroi were rejected fully within 21 days. (2) 4 weeks after implantation, the E15SD metanephroi were enlarged, became vascularized, and developed mature tubules and glomeruli; however, they were rejected by 100 days after implantation. The E15 Lewis metanephroi were fully rejected within two weeks in the BN adult rats. With CsA administrated, the E15 Lewis metanephroi developed normal mature nephrons and collecting ducts within the adult BN rats. If CsA was discontinued, the E15CsABN metanephroi were rejected. (3) The E15CsASD metanephroi had significantly lower values of wet weight (P = 0.006) and higher values of creatinine clearances (P = 0.007) than the E15SD metanephros transplants, but were identical to those of the E16CsASD metanephroi (P = 0.948, P = 0.840). (4) The metanephroi did not grow or differentiate in the rats without host kidney resection. CONCLUSIONS: (1) Cyclosporin A may suppress graft rejection, thus normalizing the growth and function of fetal metanephroi in the omenta of host rats. (2) A variety of factors affect the growth and development of allografted metanephroi, whereas rejection remains the major one.

Animals↗
PubMed1998

Clinical and histopathologic examination of renal allografts treated with tacrolimus (FK506) for at least one year.

BACKGROUND: We clinically and pathologically analyzed renal allografts from 1 9 renal transplant patients treated with tacrolimus (FK506) for more than 1 year. METHODS: Twenty-six renal allograft biopsy specimens from 1 9 renal transplant patients who underwent transplantations between 1991 and 1993 were evaluated. Thirteen biopsies were performed from stable functioning renal allografts with informed consent (nonepisode biopsy) and the other 13 were from dysfunctional renal allografts with a clinical indication for biopsy (episode biopsy). RESULTS: The main pathologic diagnoses (some overlap) were acute rejection (AR; n = 4), chronic rejection (CR; n=5), AR+CR (n =4), recurrent IgA nephropathy (n =5), normal findings (n =2), minimal-type chronic FK506 nephropathy (n = 9), and mild-type FK506 nephropathy (n = 11). Of the nonepisode biopsies, 7 and 4 biopsies showed minimal-type and mild-type chronic FK506 nephropathy, respectively. Chronic FK506 nephropathy consisted of rough and foamy tubular vacuolization (5 biopsies), arteriolopathy (angiodegeneration of the arteriolar wall; 20 biopsies), focal segmental glomerulosclerosis (4 biopsies) and the striped form of interstitial fibrosis (11 biopsies). The serum creatinine levels of patients in the mild-type chronic FK506 nephropathy group, which included 7 episode biopsies, were statistically higher than those in the minimum-type chronic FK506-nephropathy group (P< 0.001). CONCLUSIONS: This study demonstrates that chronic FK506 nephropathy consists primarily of arteriolopathy manifesting as insudative hyalinosis of the arteriolar wall, and suggests that mild-type chronic FK506 nephropathy is a condition which may lead to deterioration of renal allograft function.

Adult↗