Arnold G. Diethelm

Long-term results of a controlled prospective study with transfusion of donor-specific bone marrow in 57 cadaveric renal allograft recipients.

Experimental studies have shown that antilymphocyte globulin combined with transfusion of donor-specific bone marrow cells can induce partial tolerance to allograft tissue. We have adapted these protocols to clinical use and present the results of 57 cadaveric renal allograft recipients who received Minnesota ALG followed by the transfusion of cryopreserved donor-specific bone marrow. A group of 54 patients received the contralateral kidney and similar immunosuppression without the marrow transfusion and serve as controls. Both groups received quadruple immunosuppression with MALG, cyclosporin, azathioprine, and prednisone. In the bone marrow group, after a 10-14 day induction course of ALG, cryopreserved marrow was transfused on the seventh day after the last dose of ALG. The median follow-up in both groups is 16 months, (range 2.5-33 months). Six grafts have been lost in the bone marrow group, (three rejections, 2 deaths [Cr 2.0, 2.3], 1 recurrent disease). In the control group 16 grafts have been lost (13 rejections, 3 deaths [Cr 1.7, 2.5, 3.0]). Five patients in the control group have biopsy-proved chronic rejection compared to one in the bone marrow group. 17 patients in the bone marrow group have been tapered off the prednisone, and three of these patients have had mild late rejection episodes without graft loss. The two groups were compared for differences in the number of rejection episodes, estimated renal plasma flow, glomerular filtration rate, and urine protein. No differences were found. The allograft survival of the bone marrow group was significantly greater (P less than .01) than the control group. The graft survival rates for the bone marrow group at 12 and 18 months were 90% (confidence limits [CL] 85-94) and 85% (CL 78-90), respectively. In the the control group the 12 and 18 month allograft survival rates were 71% (CL 63-78) and 67% (CL 58-74), respectively. The survival in the control group was similar to our overall transplant experience with quadruple therapy. Mixed lymphocyte culture analysis shows a trend to diminished donor-specific responsiveness in the bone marrow group. The use of cryopreserved donor-specific bone marrow is associated with improved allograft survival in cadaveric kidney allograft recipients. However, a more effective induction protocol is needed to reduce the overall number of rejection episodes.

Hypertension in cyclosporine-treated renal transplant recipients is sodium dependent

PURPOSE Physicians increasingly prescribe cyclosporine as an immunosuppressive agent for both organ-transplant and non-organ-transplant recipients. Investigators have reported a high incidence of drug-induced hypertension even when clinical nephrotoxicity was not present. We wanted to determine the reason. PATIENTS AND METHODS A comparison was made of hypertension in 15 cyclosporine-treated transplant recipients with that in a similar group of 15 azathioprine-treated transplant recipients. RESULTS Hypertension in the cyclosporine group responded differently from that seen in the azathioprine group and from previously described forms of post-transplantation hypertension. Hypertensive cyclosporine-treated patients show a sodium acquisitive renal state that responds to sodium restriction. Unlike rat models, which suggest cyclosporine-induced stimulation of the renin-angiotensin system, or previous forms of post-transplant hypertension in humans, plasma renin levels were not elevated and blood pressure did not respond to a test dose of captopril. CONCLUSION Hypertension in cyclosporine-treated patients is an iatrogenic form of hypertension that may be associated with an early, subtle, renal defect in sodium excretion, a genesis of hypertension that is consistent with Guytons view of essential hypertension.

RS-61443-a phase I clinical trial and pilot rescue study

RS-61443, a morpholinoethyl ester of mycophenolic acid, inhibits the synthesis of guanosine monophosphate, which plays a pivotal role in lymphocyte metabolism. The drug blocks proliferative responses of T and B lymphocytes, and inhibits antibody formation and the generation of cytotoxic T cells. In vivo, RS-61443 prolongs the survival of islet allografts in mice, heart allografts in rats, and kidney allografts in dogs. Reversal of ongoing acute rejection was demonstrated in rat heart allografts and kidney allografts in dogs. Preliminary evidence suggests that the drug prevents chronic rejection. The purpose of this study was to test the safety and tolerance in patients receiving primary cadaver kidneys. RS-61443 in doses from 100 mg/day p.o. to 3500 mg/day p.o. was given to patients in combination with cyclosporine and prednisone. Further study goals were to evaluate the pharmacokinetics of RS-61443, watch for the occurrence of opportunistic infections and acute rejection, and establish dosages for further clinical trials. Forty-eight patients were entered, with six patients in each dose group. RS-61443 was well tolerated in all dose groups, with only one adverse event possibly related to the drug (hemorrhagic gastritis). There was a statistically significant correlation between rejection episodes and dose (P = 0.022), patients with rejection episodes versus dose (P = 0.038), and number of OKT3/prednisone courses versus dose (P = 0.008). There was no overt nephrotoxicity or hepatotoxicity. Preliminary results of a rescue trial in 20 patients with kidney transplants will also be presented.

Inhibition of Angiotensin-Converting Enzyme in Renal-Transplant Recipients with Hypertension

HYPERTENSION has a high prevalence among recipients of renal allografts.1 , 2 Such post-transplantation hypertension may contribute3 , 4 to the high mortality from atherosclerotic vascular disease ...

Improved survival of primary cadaveric renal allografts in blacks with quadruple immunosuppression.

Black recipients of cadaveric kidneys have been shown to have a lower rate of allograft survival than whites. Data were reviewed from 642 primary cadaveric transplants: results in 276 patients (163 white and 113 black) (group 1) who had received triple therapy (azathioprine-CsA-prednisone, 1985–87) were compared with those in 366 patients (180 white and 186 black) (group 2) receiving quadruple immunosuppres-sion (MALG-azathioprine-CsA-prednisone, 1987–90). Blacks in group 2 had better patient (97% vs. 91%, P=0.03) and graft (77% vs. 55%, P=0.0002) survival at 1 year than in group 1. There was no difference in these parameters among whites in either group. Racial differences in graft survival noted in group 1 disappeared in group 2. While HLA BDR matching improved in group 2 patients (P=0.0001), whites received better matched kidneys than blacks in both groups (P=0.001). HLA matching was associated with improved graft survival only in white recipients of 4 BDR-matched kidneys. In group 1, more blacks than whites had at least one episode of acute rejection (76% vs. 57%, P=0.001); blacks also lost more grafts to acute and chronic rejection. In group 2, there were no racial differences in the number of rejection episodes or immunologic graft losses. Of 14 potential variables examined by parametric analysis, only quadruple therapy significantly reduced risk of graft loss in blacks. Quadruple immuno-suppression improved primary cadaveric renal allograft survival in black recipients, abrogating previously noted racial differences.

Impact of donor/recipient size matching on outcomes in renal transplantation.

Interest in nonimmunologic factors affecting longterm graft survival has focused on adequacy of nephron dosing. Body surface are (BSA) is a reliable surrogate for nephron mass. In a retrospective study of 378 primary recipients of paired kidneys from 189 cadaveric donors, we assessed the impact of matching donor and recipient BSA on outcome over 7 years. BSA of donors was 1.82 +/- 0.26 m2. Initially, paired recipients of kidneys from a single donor were divided into two groups. Group 1 included the recipient with the larger BSA of the pair (1.97 +/- 0.17 m2), while group 2 consisted of smaller BSA recipients (1.69 +/- 0.19 m2). Although early function was better in group 2 patients, graft survival at 1 year (77% vs. 79%) and 5 years (54% vs. 55%) was identical between groups, as were most recent serum creatinine levels (2.0 +/- 0.1 vs. 2.1 +/- 0.1 mg/dl). A second analysis divided patients with a functioning allograft at discharge from initial transplant hospitalization (n = 345) into three groups based solely on donor to recipient BSA ratio: the ratio of group A (n = 30) was < or = 0.8, that of group B (n = 255) was between 0.81 and 1.19, and that of group C (n = 51) was > or = 1.2. Graft survival and kidney function over 5 years did not differ among groups. In multivariate analysis of 17 variables, donor:recipient BSA, independent of other risk factors, did not affect risk allograft loss. These data indicate that including nephron mass as a criterion for cadaveric organ allocation is unlikely to improve long-term results in renal transplantation.

Improved outcomes in cadaveric renal allografts with pulsatile preservation

Background: Early immunologic and non‐immunologic injury of renal allografts adversely affects long‐term graft survival. Some degree of preservation injury is inevitable in cadaveric renal transplantation, and, with the reduction in early acute rejection, this non‐immunologic injury has assumed a greater relative importance. Optimal graft preservation will maximize the chances of early graft function and long‐term graft survival, but the best method of preservation – pulsatile perfusion (PP) versus cold storage (CS) – is debated. 
Methods: Primary cadaveric kidney recipients from January 1990 through December 1995 were evaluated. The effects of implantation warm ischemic time (WIT) (≤20 min, 21–40 min, or >40 min) and total ischemic time (TIT) (< or ≥20 h) on death‐censored graft survival were compared between kidneys preserved by PP versus those preserved by CS. The effect of preservation method on delayed graft function (DGF) was also examined. 
Results: There were 568 PP kidneys and 268 CS kidneys. Overall death‐censored graft survival was not significantly different between groups, despite worse donor and recipient characteristics in the PP group. CS kidneys with an implantation WIT >40 min had worse graft survival than those with <40 min (p=0.0004). Survival of PP kidneys and those transplanted into 2 DR‐matched recipients was not affected by longer implantation WIT. Longer TIT did not impact survival. DGF was more likely after CS preservation (20.2% versus 8.8%, p=0.001). 
Conclusions: Preservation with PP improves early graft function and lessens the adverse effect of increased warm ischemia in cadaveric renal transplantation. This method is likely associated with less preservation injury and/or increases the threshold for injury from other sources and is superior to CS.

Fatal postoperative amiodarone pulmonary toxicity

Abstract Pulmonary toxicity is an important adverse effect of amiodarone that may complicate the course of approximately 5 to 7% of patients receiving long-term therapy. 1–3 Although the clinical presentation of amiodarone pulmonary complications is usually subacute or chronic, 1–3 in some patients there may be rapid progression to respiratory failure. 1,4 Recently, acute respiratory complications after cardiothoracic surgery 5,6 or pulmonary angiography 7 have been reported as manifestations of amiodarone pulmonary toxicity. Although the mechanism by which cardiac surgery may incite an acute lung reaction in patients receiving amiodarone is uncertain, cardiopulmonary bypass, oxygen toxicity, congestive heart failure and superimposed infection have been proposed as possible causes. 5 This report describes the clinical course of 4 patients receiving amiodarone who developed the adult respiratory distress syndrome after both cardiac and noncardiac surgery. The clinical features of these patients were compared with those of 288 patients receiving longterm amiodarone therapy, including 33 patients who underwent surgical procedures requiring general anesthesia.

Extent of surgery for intermediate-risk well-differentiated thyroid cancer

BACKGROUND Methods of assigning patients with papillary or follicular thyroid cancer (well-differentiated thyroid cancer) to risk groups for the purpose of determining appropriate therapy have been developed. Despite these efforts, the optimal extent of surgery for intermediate-risk patients remains controversial. METHODS A retrospective study was conducted of 208 patients with well-differentiated thyroid cancer (DTC) from two institutions. Univariate and multivariate analysis of patient- and tumor-related variables was performed. A regression model was obtained, three risk groups (low, intermediate, and high) were defined, and survival curves were generated. RESULTS Prognostic variables were age (P <0.001), distant metastases (P <0.001), tumor size (P <0.001) and an aggressive growth pattern (P = 0.03) by univariate analysis and age (P <0.001) and distant metastases (P <0.001) by multivariate analysis. Tumor size (P = 0.07) was included in the regression model. Total thyroidectomy appeared to provide a survival advantage for intermediate risk patients. High-risk patients treated by lobectomy had a poorer prognosis. CONCLUSIONS Total thyroidectomy may provide a survival advantage for intermediate-risk patients with DTC. A prospective randomized trial with 200 such patients is required to confirm this finding.

Effects of Enalapril on Erythrocytosis after Renal Transplantation

Excerpt Erythrocytosis afflicts 4% to 17% of renal allograft recipients. It appears most often within the first year after transplant, usually in patients with excellent graft function, and is asso...