Intrarenal manometry in the diagnosis of acute rejection superimposed on acute tubular necrosis in renal transplantation

We used fine-needle intrarenal manometry as a guide for detection of acute rejection superimposed on protracted oliguric acute tubular necrosis occurring in the postoperative course of human renal transplantation. We followed intrarenal pressure (IRP) in 31 patients who received 32 renal transplants, 12 from living related donors and 20 from cadaveric donors. There were 19 rejection episodes and 10 episodes of transient cyclosporin A (CyA) nephrotoxicity. Nine patients had posttransplant acute renal failure. Levels of IRP (mmHg) in acute rejection were (mean +/- SD) 48.6 +/- 11.1, significantly higher (p less than 0.001) than the levels in CyA nephrotoxicity (28.2 +/- 5.21), acute tubular necrosis (24.5 +/- 5.5) and normal functioning grafts (26.4 +/- 6.63). Antirejection treatment was associated with return to normal of IRP after 10 days. Intrarenal manometry was performed routinely ever 2-3 days in patients who had postoperative acute renal failure. Increments in IRP were detected on the 7-10th postoperative day in 7 patients who had 10-25 days of post-transplant oliguria. Renal biopsy findings were compatible with acute rejection, and the patients responded to intravenous bolus of steroids. We suggest that fine-needle intrarenal manometry is a reliable test for the detection of acute rejection in circumstances when traditional parameters of altered renal function cannot be evaluated.     

The detection of renal allograft rejection by fine-needle intrarenal manometry

The causes of early renal allograft malfunction include rejection, acute tubular necrosis, cyclosporin nephrotoxicity and vascular complications. Fine-needle intrarenal manometry is a potential method of distinguishing rejection from the other causes of malfunction and has been used by Salaman and Griffin in patients' treated with cyclosporin. The technique involves inserting a fine-needle, which is connected to a specially designed manometer, into the substance of the transplant kidney. One hundred and six measurements of intrarenal pressure have been made in 28 patients immunosuppressed with either azathioprine and prednisolone or cyclosporin. Thirteen rejection episodes were identified and confirmed by biopsy. These were treated by pulse steroid (methylprednisolone) therapy. Seven episodes of cyclosporin toxicity were identified and there were fifteen episodes of acute tubular necrosis. The mean intrarenal pressure in the rejecting group was 52.8 mmHg compared with 22.3, 24.1 and 24.3 mmHg for the normal function, acute tubular necrosis and cyclosporin nephrotoxicity groups, respectively (P less than 0.01; Wilcoxon unpaired test). There were no differences within these groups related to the type of immunosuppression used. There were no clinical complications associated with the procedure. Thus in newly transplanted patients, fine-needle intrarenal manometry accurately identified rejection and distinguished it from normal function, acute tubular necrosis and cyclosporin nephrotoxicity in all the patients regardless of the immunosuppressants used.     

The use of fine-needle intrarenal manometry in the management of renal transplant patients receiving cyclosporine

The pressure inside a renal transplant can be measured by means of a fine (25-G) needle passed into the kidney, and we have shown previously that a rise in pressure to more than 40 mmHg commonly occurs during rejection episodes. A rise was not observed in patients with cyclosporine nephrotoxicity or acute tubular necrosis, so we have now used this test prospectively as part of our management of 37 patients undergoing renal transplantation. Fine needle intrarenal pressure was recorded weekly during the first three weeks after transplantation, with more frequent measures taken in patients with deteriorating or absent renal function. Treatment was dictated by the result of these tests. Deteriorating function in a kidney registering a normal pressure was diagnosed as cyclosporine nephrotoxicity and the dose of cyclosporine was reduced appropriately. A pressure reading in excess of 40 mmHg was regarded as rejection--and, after obtaining a conventional needle biopsy of the kidney, antirejection treatment was commenced immediately. Nineteen episodes of nephrotoxicity were confirmed and there was only one false-positive result. Twenty-eight of twenty-nine rejection episodes (observed in twenty-three patients) were associated with a significant rise in intrarenal pressure and were treated appropriately. In six patients who were oliguric at the time, as a result of posttransplant acute tubular necrosis, this rise in pressure was the first indication of rejection. A high pressure was recorded on the first day that the creatinine rose in two-thirds of the cases. In the remainder the pressure was seen to rise more slowly, particularly when the rejection was of the chronic vascular type and was occurring two months or more after transplantation. Fine-needle intrarenal manometry accurately identified rejection episodes in newly transplanted patients--and, because the results were unaffected by cyclosporine nephrotoxicity and acute tubular necrosis, the test was of most value in monitoring patients with these conditions.     

Urinary secretory immunoglobulin A in acute renal allograft rejection

Periodical determinations of the urinary secretory immunoglobulin A (S-IgA) excretion rate were performed in 12 cadaveric graft recipients. In five patients with primary functioning grafts the S-IgA excretion on the first postoperative day was 4.2 +/- 2.6 mg/g creatinine, decreasing to 1.8 +/- 1.2 mg/g creatinine (P less than 0.05) at the day of discharge. Acute tubular necrosis developed in the seven remaining patients. In this group the initial S-IgA excretion was 12.6 +/- 7.5 mg/g creatinine (P less than 0.05 compared to the former group), decreasing to 2.0 +/- 0.9 mg/g creatinine (P less than 0.05) at discharge. An acute rejection episode was observed in six patients. The S-IgA excretion increased from 3.0 +/- 1.5 mg/g creatinine 3-4 days before rejection to 6.4 +/- 3.1 mg/g creatinine (P less than 0.05) 1-2 days before rejection, and peaked at 14.0 +/- 8.6 mg/g creatinine (P less than 0.05) when the diagnosis of rejection was established and anti-rejection treatment was started. In three patients the initial steroid pulse therapy was not successful and S-IgA excretion further increased to 29.0 +/- 15.6 mg/g creatinine. After successful anti-rejection treatment, using steroids and OKT3, the S-IgA excretion decreased to 3.4 +/- 2.6 mg/g creatinine. In acute graft rejection, the elevated globulin synthesis by infiltrating plasma cells. In the early phase of rejection, dimeric IgA is the only immunoglobulin able to penetrate into the urine by transepithelial transport after binding to secretory component expressed on tubular epithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of renal grafts in patients with lupus nephritis as cause of end-stage renal disease

INTRODUCTION: Kidney transplantation is the best option in end-stage renal disease (ESRD). For many years patients affected with lupus nephritis have had poor graft results. However, this has been changing over recent years with the development of new immunosuppressive drugs and a better comprehension of the natural evolution of the entity. METHODS: We studied 20 patients with lupus nephritis who received 22 kidney grafts: 15 women and five men (n = 11) who were treated with cyclosporine or with tacrolimus (n = 11). Secondary immunosuppression included mycophenolate match (MMF) (n = 13) or azathioprine (n = 9). We analyzed human leukocyte antigen, cold ischemia time, acute tubular necrosis, creatinine, cholesterol, triglycerides, glucose, blood pressure, acute rejection episodes, immunosuppression, infections, disease recurrences, as well as graft and patient survival. RESULTS: After a mean cold ischemia time of 22 +/- 4 hours, nine patients displayed delayed graft function of an average duration 9 +/- 4 days. At 36 +/- 35 months nine grafts were lost: two due to acute rejection; five to chronic allograft nephropathy; and two to venous thrombosis. One patient died of hemorrhagic shock. There were five cytomegalovirus infections. Graft survival was dependent on the type of secondary immunosuppression, incidence of acute rejection episodes and occurrence of delayed graft function. CONCLUSIONS: We found no clinical recurrence of lupus nephritis after transplantation and a low incidence of complications, although there was a trend toward thrombosis. The presence of delayed graft function, episodes of acute rejection, and receiving azathioprine instead of MMF as secondary immunosuppression were associated with poorer graft survival.     

Limited value of 111-indium platelet scintigraphy in renal transplant patients receiving cyclosporine

Since the differential diagnosis between cyclosporine (CyA) nephrotoxicity and acute graft rejection is still a problem in clinical routine, we studied retrospectively the value of 111-indium (In) platelet scintigraphy in 53 patients immunosuppressed with CyA and prednisolone. Autologous platelets were labeled once per week. After daily gamma camera imaging, the platelet deposition in the graft was expressed as platelet-uptake ratio (PUR). The patients were monitored during the first 4-6 weeks after surgery. PUR values measured during an episode of graft dysfunction were compared to the histological diagnosis. The PUR of well-functioning and stable grafts measured 1.07 +/- 0.11 (mean +/- SD). The 111-In platelet scintigraphy failed to register acute interstitial rejection. The PUR values in episodes of chronic vascular rejection, of acute tubular necrosis due to prolonged ischemia times, of tubular CyA nephrotoxicity and of cytomegalovirus (CMV) infection did not differ from the PUR of well-functioning and stable grafts as well. The PUR was significantly increased to 1.48 +/- 0.26 because of a marked platelet deposition in the graft in episodes of acute vascular rejection. In 4 cases of microvascular CyA nephrotoxicity the same phenomenon of significantly increased PUR (1.33 +/- 0.18), could be encountered, too. Two of these 4 cases resembled the hemolytic uremic syndrome (HUS). The value of PUR measurement for diagnosis of acute vascular rejection and microvascular CyA nephrotoxicity together, was: sensitivity 0.62, specificity 0.95, predictive value of positive result 0.64, predictive value of negative result 0.94.(ABSTRACT TRUNCATED AT 250 WORDS)     

The utility of cyclosporine weaning in renal transplantation.

Abrupt conversion of cyclosporine immunosuppression to conventional treatment with azathioprine and prednisone avoids long-term cyclosporine nephrotoxicity, albeit at the cost of a 20% to 40% rejection rate. The authors investigated the benefits and risks of a cyclosporine weaning protocol in 24 cadaveric and 9 live donor kidney recipients treated with a sequential quadruple immunosuppressive protocol. In cadaver kidney recipients, slow tapering of cyclosporine resulted in a 19% (p less than 0.001) improvement in the glomerular filtration rate, as estimated by the inverse ratio of the plasma creatinine concentration. Cadaver kidney recipients were stratified according to graft function (GFR ratio greater than 0.76, less than 0.76) at the of cyclosporine discontinuation. In 12 patients with well-functioning grafts, a 24% improvement was observed, whereas in 12 patients with poor graft function, the gain was limited to 13%. Patients with limited graft function tended to have more acute rejection episodes before cyclosporine weaning (0.92 +/- 0.64 versus 0.42 +/- 0.64, not significant). When the 24 cadaver kidney recipients were stratified according to onset of graft function after transplantation (days to plasma creatinine of 250 mumol/L), need for dialysis, panel reactive antibodies (PRA), and duration of cyclosporine treatment, no significant differences in graft function were observed at the onset or end of cyclosporine weaning. Acute graft rejection before cyclosporine weaning was the only variable associated with a significantly lower estimated glomerular filtration rate ratio at the end of cyclosporine treatment (0.83 +/- 0.11 versus 0.67 +/- 0.16, p less than 0.01). Weaning of cyclosporine was associated with a minimal risk of acute graft rejection. A single patient with stable graft function at the onset of the weaning process experienced an acute but reversible rejection episode 2 months after cyclosporine was discontinued. In summary, gradual weaning of cyclosporine improves graft function, and eliminates the excessive risk of acute graft rejection without the need for additional corticosteroid treatment.     

Plasma atrial natriuretic factor and graft function in renal transplant recipients

In order to determine the relationships between allograft function and the recipient's plasma concentrations of atrial natriuretic factor (ANF), plasma ANF was measured by radioimmunoassay for 14 days after cadaveric renal transplantation in 9 patients aged 19-64 years. All received immunosuppression with prednisolone, azathioprine, and cyclosporine. No patient was in heart failure. During the study period, six grafts functioned, and three were nonfunctioning--two due to rejection and one to acute tubular necrosis. Plasma ANF concentration at the time of transplantation was 48 +/- 16 pmol/L (mean +/- SEM) range 15-145 pmol/L. In the six patients with functioning grafts, ANF declined in parallel with the fall in serum creatinine (658 +/- 35 to 210 +/- 34 mumol/L). In the three with nonfunctioning grafts, serum creatinine and plasma ANF concentration both increased. There was overall a significant linear relation between serum creatinine and plasma ANF (r = 0.527, P less than 0.001). The changes in plasma ANF after renal transplantation bore no relationship to changes in body weight or blood pressure. However, plasma ANF concentration was related to allograft fractional sodium excretion (r = 0.687, p less than 0.001). We conclude that elevated plasma ANF concentrations in end-stage renal disease are restored to normal by successful renal transplantation, implying that renal function is a determinant of plasma ANF concentration. Circulating plasma ANF may also have a direct effect on allograft sodium excretion.     

Intrarenal serotonin, dopamine, and phosphate handling in remnant kidneys

BACKGROUND: Serotonin (5-HT) and dopamine (DA) are intrarenal autocrine/paracrine substances that regulate phosphate reabsorption. The present studies explored intrarenal serotonin and DA metabolism and the implications for phosphate homeostasis in rats with remnant kidneys, a model for renal failure. METHODS: The intrarenal productions of serotonin and DA were determined from measurements of renal interstitial fluid (microdialysate) and urine in rats with remnant or intact kidneys. In clearance studies, the effects of infusion of methiothepin, a serotonin receptor antagonist, or gludopa, a renal selective DA precursor, on phosphate and sodium excretion were determined in rats with a remnant or intact kidneys. RESULTS: Renal interstitial serotonin (5-HT, 3.4 +/- 0.9 pg/min) was fourfold higher than DA (0.6 +/- 0.1 pg/min) in remnant kidneys. Conversely, urinary excretion of serotonin was fourfold less than DA in rats with a remnant kidney (5-HT 0.4 +/- 0.02 vs. DA 1.5 +/- 0.1 ng/min). Infusion of methiothepin or gludopa significantly increased the fractional excretion of phosphate (FE(Pi)) in rats with a remnant kidney from 54 +/- 3 to 67 +/- 7% (P < 0.05) and from 36 +/- 10% to 51 +/- 13% (P < 0.05), respectively. CONCLUSION: We conclude that serotonin preferentially accumulates in the renal interstitium, whereas DA exits primarily via the tubular lumen. Phosphate excretion is increased by both the acute infusion of the serotonin receptor antagonist and the infusion of gludopa, suggesting that both serotonin and DA modulate phosphate excretion in rats with remnant kidneys.     

Early computed colour echo Doppler imaging following renal transplantation

Thirty patients with renal allografts were monitored for 15 postoperative days by colour-coded Doppler imaging and categorized as stable, rejection, acute tubular necrosis and cyclosporine toxicity. All forms of graft dysfunction showed significantly raised resistance (P less than 0.01) and pulsatility (P less than 0.01) indices (RI and PI, respectively). It was not possible to use Doppler imaging to differentiate the cause of graft dysfunction, but stable grafts in patients with high cyclosporin levels had significantly higher RI (P less than 0.04) and PI (P less than 0.04) than similar grafts in patients with cyclosporine levels in the therapeutic range.     

Living donor kidney transplantation: impact of differentiated immunosuppressive regimen

INTRODUCTION: Recipients of related (R) and unrelated (NR) living donor kidney transplantations (LDKTX) receive immunosuppressive (IS) therapy 5 days in advance in order to achieve low rates of acute rejection episodes. We herein report the different IS regimens for R and NR transplants as well as acute rejection and primary function rates. METHODS: Ninety-five LDKTX (69% R, 31% NR) were performed with mean cold ischemia time (CIT) of 145 +/- 32 minutes. In R-LDKTX mean age of recipients was 31 +/- 12.5 years. This cohort included 41 men and 25 women whose mean age was 50 +/- 11.1 years. The therapeutic regimen for R-LDKTX included CyA/MMF/prednisone; for NR-LDKTX, FK/MMF/prednisone. Among the recipients of NR grafts the mean recipient age was 51 +/- 8.5 years. This cohort included 23 men and 6 women whose donor mean age was 50 +/- 8.8 years. The mean HLA mismatch among R-LDKTX (2.3) was significantly less than that in the NR-LDKTX cohort (3.51). RESULTS: At a mean follow-up of 35 months, 94.7% of grafts were functioning. DGF was seen in only one recipient (1%). Three grafts were lost due to acute (R) or chronic (NR) rejection or to multiorgan failures. Two recipients died with functioning grafts. Biopsy-proven rejection episodes were observed in 17.2% of NR-LDKTX and 9% of R-LDKTX. In R-LDKTX 50% of rejection episodes were corticoid-sensitive, while 33% needed ATG, and 16% were treated by a switch to FK. In NR-LDKTX 20% of rejections were corticoid-sensitive, 40% needed ATG, and 40% were treated with rapamycin rescue therapy. CONCLUSION: Although HLA mismatching is significantly different between R- and NR-LDKTX, no difference in outcome was observed, which may be due to the specific therapeutic regimen and short CIT.     

Mechanisms underlying continued survival of rat kidney allografts after a short period of chemical immunosuppression

Experiments have been carried out to investigate whether the continued survival of rat kidney allografts induced by two different methods-namely, immunological enhancement or a limited course of drug treatment with cyclosporine or cyclophosphamide, is maintained by similar mechanisms. (AS X AUG)F1 or AUG strain kidneys were transplanted to AS recipients that were treated for 14 days with cyclosporine or cyclophosphamide. The limited course of drug treatments induced indefinitely prolonged, or very extended, allograft survival. Long-surviving F1 kidney grafts were retransplanted into naive AS recipients, and by functioning for more than 100 days proved, like enhanced grafts, to be less immunogenic than normal (AS X AUG)F1 kidneys. Very prolonged survival of homozygous, incompatible AUG kidneys was only observed after the cyclosporine drug regimen-and when these grafts were retransplanted to naive second AS recipients, acute or chronic rejection ensued. However, the rejection was prevented if spleen cells from the first AS recipient were adoptively transferred to the second AS recipient at the time of retransplantation. It was concluded that suppressor cells must be present in the transferred spleen cell populations. The experiments show that, as in the case of immunological enhancement, very prolonged allograft survival brought about by a short course of immunosuppressive drug treatment is accompanied by reduction in graft immunogenicity, and by the induction of suppressor cells.     

Sequential use of Minnesota antilymphoblast globulin and cyclosporine in cadaveric renal transplantation

The use of Cyclosporine (CsA) immediately after renal transplantation may be associated with an increased incidence and duration of acute tubular necrosis (ATN) and permanent primary graft nonfunction. To avoid this potential interaction we treated recipients of primary cadaveric grafts initially with azathioprine (AZA), methylprednisolone (MP), and 5 daily doses of Minnesota antilymphoblast globulin (MAG) (postoperative days 3-7). AZA was discontinued and CsA started on day 6 if the graft was functioning by then. If ATN persisted beyond day 6, AZA and MAG (maximum 12 doses) were continued and CsA withheld until graft function was established (group 1-33 patients). This protocol is compared to our previous regimen of MAG (14 doses over the first 3 weeks), AZA and MP (group 2-68 primary cadaveric graft recipients). Improved one-year graft survival (81% vs. 60%, P less than 0.05) and patient survival (93% vs. 81%, P less than 0.05) were seen in group 1. The incidence and duration of ATN did not differ in the two groups. During the first year after transplantation more patients in group 1 were completely free of rejection episodes (40% vs. 20%, P less than 0.05) and the number of rejection episodes per patient was also lower in this group (1.0 +/- 15 vs. 1.6 +/- 49, P less than 0.05). The incidence of infections was not different in the two groups. No tumors have developed in either group. We conclude that in primary cadaveric renal transplantation the initial administration of a short course of MAG followed by CsA therapy results in excellent graft and patient survival while avoiding the potential adverse effect of CsA on an allograft already subjected to preservation injury.     

Diagnosis of rejection in renal allograft biopsies using the presence of activated and proliferating cells

Forty cyclosporine-treated renal allograft biopsies were stained with anti-Tac, a monoclonal antibody (MoAb) against interleukin 2 receptor (CD25), anti-transferrin receptor MoAb, and Ki67 MoAb (a proliferating cell marker), using a method of gold enhancement of the diaminobenzidine reaction product, in order to study the utility of these markers to differentiate rejection from other causes of graft dysfunction. Biopsies were selected on the basis of availability of sufficient frozen material and optical microscopy diagnosis, and only biopsies that showed acute cellular rejection and biopsies that did not show any sign of rejection (cyclosporine toxicity or a stable graft) were studied. In addition biopsies were stained with a panel of monoclonal antibodies reacting with CD45, CD3, CD4, CD8, EBM11 (a monocyte-macrophage marker), HLA-DR, DP, and DQ, using the usual indirect immunoperoxidase method. The clinical diagnosis (rejection versus no rejection) was made in ignorance of the biopsy findings. In 17 of 18 (94%) episodes of rejection, anti-Tac and anti-transferrin receptor-positive cells, and in 15 of 18 rejection episodes (83%), proliferating cells, were found in the interstitium. Anti-Tac-positive cells were never found in the 11 biopsies diagnosed as no rejection, and only in two a few anti-transferrin receptor-positive cells were present. The proportion of activated and proliferating cells in rejection episodes, expressed as the percentage of CD45-positive cells were: anti-Tac MoAb 4.1 +/- 2.9%, anti-transferrin receptor MoAb 6.9 +/- 3.9%, and Ki-67 MoAb 6.3 +/- 4.8%. There was a positive correlation between the total number of infiltrating cells and the number of cells stained with anti-Tac (r = 0.75, P less than 0.005), anti-transferrin receptor MoAb (r = 0.84, P less than 0.0001), and Ki-67 (r = 0.50, P less than 0.05). The episodes of rejection that took place when cyclosporine levels were high had fewer 1L-2R-bearing cells in the interstitium than those that took place when cyclosporine levels were low (r = 0.47, P less than 0.05). We conclude that during rejection the presence of activated and proliferating cells is a consistent finding, and that these markers could be useful in differentiating between rejection and other causes of graft dysfunction as well as in grading the severity of rejection.     

The adverse impact of cyclosporine on serum lipids in renal transplant recipients

The extent to which cyclosporine (CsA) directly, or indirectly, influences serum lipid levels in renal transplant patients treated with multiple-drug immunosuppression protocols is unclear. Indeed, patients treated with CsA have reduced corticosteroid requirements, fewer acute rejection episodes, and other differences from patients receiving conventional immunosuppression that may reduce serum lipid levels. We studied patients treated with low-dose CsA, corticosteroids, azathioprine, and Minnesota antilymphocyte globulin ([ALG] n = 205) versus conventional (three-drug) immunosuppression (n = 368) and evaluated the impact of CsA, acute rejection episodes, and other clinical parameters on serum lipids. Fasting serum lipid levels from stable patients transplanted between 1976 to 1989 were studied at 3 (n = 573), 12 (n = 565), 26 (n = 55), and 52 (n = 521) weeks posttransplant using multivariate, linear regression analysis. The incidence of acute rejection episodes was reduced by CsA, but patients with fewer acute rejection episodes in the early posttransplant period had higher serum total cholesterol (increased by .33 +/- .12 mmol/L [13 +/- 5 mg/dL] and .27 +/- .12 mmol/L [10 +/- 5 mg/dL], P less than 0.05, at 3 and 12 weeks, respectively) and low-density lipoprotein (LDL) (increased by .23 +/- .11 mmol/L [9 +/- 4 mg/dL] and .23 +/- .11 mmol/L [9 +/- 4 mg/dL], P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Experimental and clinical experience with urine amylase monitoring for early diagnosis of rejection in pancreas transplantation

Pancreas allograft rejection in dogs with pancreaticocystostomy can be predicted in advance of hyperglycemia by monitoring the urinary amylase (UA) concentration (U/L): In initial experiments, UA values declined to less than 1000 1.3 +/- 0.2 days before hyperglycemia in nonimmunosuppressed dogs, 3.3 +/- 1.0 days in dogs treated with cyclosporine (CsA), and 9.3 +/- 0.7 days in dogs treated with CsA, azathioprine (Aza), and prednisone (triple therapy). Autotransplanted control dogs maintained high urine amylase concentrations indefinitely (mean 125,544 +/- 36,931). In a subsequent experiment, in 19 dogs with bladder-drained pancreas allografts on CsA only for prophylactic immunosuppression, a five-day course of antirejection treatment with Aza (5.0 mg/kg) and antilymphocyte globulin ALG (1 mg/kg) was started in group A (n = 10) when a raise in serum glucose was detected, and in group B (n = 9) when a drop of UA below 1000 was observed. The functional allograft survival rate was 9.2 +/- 0.5 days in group A (treatment started after hyperglycemia) and 29.0 +/- 5.7 days in group B (treatment started after drop in UA) (P = .002). The UA dropped in all dogs before hyperglycemia, at a mean of 2.7 days in group A and 20.8 days in group B. Clinically, 8 patients received a whole cadaver pancreas transplant with urinary drainage of the exocrine secretions. All were followed with UA monitoring. Three recipients lost the grafts for technical reasons. Three recipients lost the grafts for technical reasons. One had a primary non-function and UA was below 1000 U/24 hr; two developed abscesses and the grafts were removed while functioning with high UA values. Five grafts are currently functioning; 3 recipients had no rejection episodes and their UA values ranged from 30,000 to 100,000 U/24 hr during their entire postoperative course. The other two had rejection episodes. In both cases UA decreased to baseline levels 1 and 4 days in advance of the hyperglycemia. After antirejection treatment UA rose again to high values and plasma glucose levels declined. Both patients are currently insulin-independent, with UA values ranging from 10,000 to 200,000 U/24 hr. Both experimentally and clinically UA is an early predictor of pancreas allograft rejection. The institution of early treatment of rejection episodes in dogs, based on UA, significantly improved allograft survival. Urine amylase monitoring in pancreas transplant recipients could lead to an early treatment of rejection and improve graft survival.     

The relevance of pressure changes in transplanted hearts and kidneys in immunosuppressed rats

The pressure within rat cardiac and renal allografts has been observed to rise during rejection. We wished to see if this pressure rise could be prevented or reversed with immunosuppression. Transplants were performed from Lewis or DA donors to Lewis recipients. The rats received either a heterotopic cardiac transplant or an orthotopic renal transplant and were then treated with different immunosuppressive protocols. Intramyocardial pressure was recorded using a fine-gauge needle connected to an air pressure manometer. In the case of the renal transplants, a pressure transducer was used as well and the two methods compared. Intramyocardial and intrarenal pressures rose dramatically in unimmunosuppressed recipients of DA allografts. No such rise was seen in isografted organs, although the pressures recorded remained significantly higher than those found in untransplanted hearts and kidneys. Cyclosporine 20 mg/kg/day was effective in suppressing rejection in both models, and inhibited any rise in intraorgan pressure. Cyclosporine 10 mg/kg/day was less effective, and with 2 mg/kg/day allograft function was considerably impaired, one-third of the cardiac grafts being rejected by 16 days. In both models intraorgan pressures became raised. The addition of methylprednisolone 16 mg/kg i.p. on days 7 and 8 to this low dose regimen of cyclosporine 2 mg/kg/day rapidly reversed the rise in pressure and restored graft function to normal. Intraorgan pressure levels therefore accurately reflected the state of function of transplanted hearts and kidneys. When a manometer and a transducer were compared as a means of measuring the pressure in the renal transplants, the manometer method was found to be superior.     

Successful use of 6 antigen HLA mismatched kidneys for cadaveric renal transplantation

PURPOSE: We retrospectively evaluated the outcome of transplantation with kidneys with 6 antigen HLA mismatches. MATERIALS AND METHODS: From October 1990 to September 2001, 1,270 cadaveric renal transplants were performed at our center, including 33 (2.59%) involving recipients of kidneys with 6 antigen HLA mismatches. Mean recipient age +/- SD was 40.2 +/- 14.4 years. Of the 33 recipients 19 were male, 14 were female, 31 received an initial transplant, 4 had diabetes and 6 had panel-reactive antibodies of greater than 10%. Mean donor age was 30.3 +/- 13.7 years and mean cold ischemia time was 22.9 +/- 7.8 hours. All recipients had negative current and previous B and T-cell lymphocytotoxicity cross-matching and all received a triple immunosuppression regimen consisting of the calcineurin inhibitor cyclosporine or tacrolimus combined with steroids and azathioprine. RESULTS: One-year patient and graft survival was 93.3% and 93.7%, respectively. Of the 33 grafts 31 (94%) functioned immediately. During the mean followup of 3.31 years 10 grafts (30%) were lost, including 6 (60%) due to death with a functioning graft and 4 due to chronic rejection. Acute rejection in 8 patients (24%) was reversed in 7 by steroid pulses. No graft was lost to acute rejection. Technical complications included wound infection in 2 patients (6%), transplant-ureteral obstruction in 1 (3%) and a urinary fistula in 1 (3%). CONCLUSIONS: Kidneys with 6 antigen HLA mismatches can be used effectively.     

A randomized prospective trial of anti-Tac monoclonal antibody in human renal transplantation.

Patient entry is now complete in a prospective trial of anti-Tac, a murine IgG2a monoclonal antibody directed against the p55 chain of the human IL-2 receptor, for the prevention of renal allograft rejection. Recipients of primary cadaver allografts were randomized to receive either anti-Tac (20 mg q.d. x 10 days beginning POD 1) plus low-dose CsA (4 mg/kg/day), azathioprine (2 mg/kg/day), and prednisone (30 mg q.d.), or conventional triple therapy with CsA (8 mg/kg/day), azathioprine, and prednisone. Forty patients were entered in each group, with current followup from 6 to 26 months. The results show a significant reduction in early rejection episodes in the anti-Tac-treated patients. During the 10-day treatment, 5 of 40 anti-Tac patients had rejection episodes, compared with 21 of 40 control patients (P less than 0.001). Anti-Tac significantly delayed the time to the first rejection (12.5 +/- 6.3 vs. 7.6 +/- 6.7 days) (P less than 0.05). Despite these effects, there were no differences in either actual or actuarial graft or patient survival between the two groups. Pneumonia, primarily CMV, developed in 5 treated and 4 control patients. In patients with functioning grafts mean serum creatinine at 3 months was 1.8 +/- 0.7 in the anti-Tac group and 2.0 +/- 0.8 in the control group (P = NS); at 12 months the values were 2.3 +/- 1.5 and 1.8 +/- 0.5, respectively (P = NS). The peak expression of IL-2 receptors on circulating T-cells was significantly lower in anti-Tac patients (15.1 +/- 3.6%) than in controls (21.9 +/- 4.5%) (P less than 0.05). Seven of 10 patients tested to date developed antimouse immunoglobulin antibodies, with antiidiotype shown in 6. These antibodies do not preclude subsequent treatment with OKT3. Five patients in this and previous anti-Tac protocols have received OKT3 for acute rejection despite known pretreatment antimouse antibodies, with resolution of rejection in all cases.     

Posttransplant tubulointerstitial nephritis: clinicopathological correlation

As a cause of graft dysfunction, tubulointerstitial nephritis (TIN) seems to be the third most common pathology after rejection and cyclosporine nephrotoxicity. Among 540 needle biopsies obtained from 280 renal transplant patients between 1996 and 1999, acute TIN was detected in 23 patients (8%). The cause of acute TIN was secondary to bacterial infection in 17 patients and secondary to cytomegalovirus (CMV) infection in three patients. The remaining three cases showed granulomatous pyelonephritis due to Mycobacterium tuberculosis (n = 2) and Candida albicans (n = 1). During follow-up, 13 of 23 patients (56.5%) showed at least one acute rejection episode. The average number of urinary tract infection (UTI) episodes in the 23 patients was 1.4 +/- 07. We observed that the number of UTI episodes showed a significant association with the development of chronic allograft nephropathy (P = .03) and graft loss (P < .01). Twelve patients (52.2%) lost their grafts during 5 years posttransplantation. Only 6 of 17 patients with bacterial TIN lost their graft at a mean time of 52.5 +/- 14 months. But all patients with CMV TIN or granulomatous TIN lost their grafts at a mean time of 31 +/- 3.1 months and 39 +/- 3 months, respectively (P < .05). In conclusion, these results support the pathological role of tubulointerstitial nephritis as a pathway of graft rejection or renal allograft deterioration among recipients after transplantation.