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Adenovirus infection of a renal allograft.

One month after renal transplantation, a 60-year-old man developed acute allograft dysfunction associated with gross hematuria and dysuria. Urinary cytological examination showed viral inclusion-bearing epithelial cells. A renal transplant biopsy specimen showed granulomatous interstitial nephritis, tubular necrosis, and ground glass-like intranuclear viral inclusion bodies in tubular cells caused by an adenovirus (ADV) infection. A reduction in baseline immunosuppressive therapy resulted in rapid normalization of allograft function and ultimately viral clearance. We report this case not only to illustrate an exceptional manifestation of an ADV infection in a renal allograft, but also to highlight the beneficial effect of reduction in immunosuppressive therapy on viral replication and clinical outcome.

Acute Kidney Injury↗

Enlarged photon-deficient area in expected site of renal allograft on Tc-99m DTPA study. A sign of renal vein thrombosis.

Tc-99m DTPA renal imaging has been routinely used in postrenal transplant evaluation. A patient's Tc-99m DTPA studies after transplantation are presented, showing a large photon-deficient area in the region of the allograft on the third postoperative day. The photon-deficient area is two to three times larger than that seen in the original, functioning allograft on the first postoperative day. Enlarged to a weight of 530 g, the allograft on gross and microscopic examination confirmed renal vein thrombosis. Enlargement of the photon-deficient area at the anatomic site of the allograft indicates a scintigraphic pattern of renal vein occlusion incompatible with a viable allograft.

Adult↗

Early graft loss secondary to massive hemorrhagic necrosis following orthotopic liver transplantation. Evidence for cytokine-mediated univisceral Shwartzman reaction.

Massive hemorrhagic necrosis (MHN) of the liver following orthotopic liver transplantation (OLT) occurs infrequently during an otherwise uneventful recovery 1 week after OLT. It is characterized by fever and sudden deterioration of allograft function leading to failure in the absence of vascular thrombosis. The etiology is unknown, although it is usually preceded by some degree of allograft rejection. Between 6 and 8 days after OLT, four patients (out of 150) became febrile, hypotensive, and experienced a rapid rise in transaminases within 48 hr. Two patients had evidence of mild rejection; the other two had moderate to severe acute cellular rejection. All patients were ABO identical, crossmatch negative. Bolus steroids were given followed by OKT3 in the two patients with severe rejection. Although sepsis was suspected, antibiotic therapy did not ameliorate the clinical course. Each patient progressed to MHN with severe centrilobular necrosis and variable portal infiltrate. High levels of interferon-gamma and tumor necrosis factor-alpha occurred prior to the rise in transaminases in each MHN patient (155 +/- 39 pg/ml and 414 +/- 201 pg/ml, respectively) compared with levels in OLT patients with severe rejection (14 +/- 4 pg/ml and 26 +/- 5 pg/ml, respectively, P < 0.05). These data support the concept of a cytokine-mediated inflammatory response leading to a univisceral Shwartzman reaction in the transplanted liver. Early recognition of this syndrome and retransplantation are critical for survival.

Adult↗

The quality of initial function following renal transplantation determined by creatinine elimination kinetics. Comparison of Minnesota antilymphocyte globulin and cyclosporine induction immunosuppression.

To compare the effect of type of induction immunosuppression on the quality of initial renal allograft function, we identified 35 cadaver donor kidney pairs in which one recipient of a kidney from a given pair received induction immunosuppression with Minnesota antilymphocyte globulin (MALG group) while the recipient of the contra-lateral kidney received cyclosporine from day zero (CsA group). In the absence of an existing quantitative measure to assess and compare the status of those grafts that function primarily, we defined the half-life of creatinine elimination (t1/2SCr) as such an outcome measure based on a review of creatinine elimination kinetics. All organs were procured with in-situ perfusion and en-bloc removal. Total cold storage times, rewarm times, and perioperative management were comparable for the two groups. In the MALG group, the mean t1/2SCr) was not different from that in the CsA group (1.38 +/- 0.96 days vs 1.35 +/- 1.2 days P = NS). Multiple regression analysis performed on the differences in recipient age, number of DR-B locus matches, total cold ischemia time, rewarm time, and central venous pressure at reperfusion of a given donor pair demonstrated no significant impact of any of these differences on the difference in t1/2SCr for the same pair set in this sample. The nadir of serum creatinine achieved in the first five days posttransplant was somewhat higher in the CsA group (234 +/- 131 mumol/L) as compared with the MALG group (200 +/- 132 mumol/L) but the difference was not significant. A similar nonsignificant trend was observed in the comparison of mean serum creatinine values at 30 days posttransplant (MALG group: 158 +/- 62 mumol/L vs. CsA group: 200 +/- 141 mumol/L). Only one of seventy recipients (CsA group) was dialyzed within the first 5 days posttransplant for an overall incidence of ATN of less than 2%. Fourteen of 35 (40%) recipients in both groups received treatment for acute rejection. The mean time to first treatment for acute rejection episode was shorter in the CsA group than the MALG group (10 +/- 8 days vs 23 +/- 24 days, P = 0.055). Graft survival at one year was not different for the two groups (92% vs. 87% for the MALG and CsA groups respectively, P = NS).(ABSTRACT TRUNCATED AT 400 WORDS)

Antilymphocyte Serum↗

The reversal of diabetes by pancreatic islet transplantation.

In this paper the theoretical basis of alloreactivity and its relevance to transplantation biology is discussed prior to a review of work showing that culture of adult mouse pancreatic islets for 7 days in 95% O2 and 5% CO2 facilitates successful grafting to nonimmunosuppressed allogeneic recipients. These allografts function by reversing both chemically induced and spontaneous diabetes. The fetal mouse pancreas is more immunogenic than adult islets, and even after a culture period of 10 days in 95% O2 and 5% CO2, BALB/c allografts are consistently rejected by nonimmunosuppressed recipient mice. The immunogenicity of fetal pancreas is thought to be due to the presence of contaminating lymphoreticular cells in the mesentery surrounding the fetal pancreas. Digestion of the fetal pancreas with collagenase allows the isolation of proislets that develop into functional islet tissue on transplantation. Fetal proislets are less immunogeneic than the whole fetal pancreas and may provide a source of tissue for clinical transplantation. Established islet allografts are relatively stable and are not rejected following nonspecific stimulation of the recipient's immune system or following passive transfer of either antibody or antibody and complement. After prolonged residence in the recipient a state of allograft tolerance develops and such grafts resist rejection by specific stimulation of the recipient. The administration of donor antigen in the form of uv-irradiated cells enforces this state of allograft tolerance.

Age Factors↗

Microhematuria after renal transplantation in children.

The renal transplant (Tx) recipient is at risk for developing various complications including urolithiasis, the only manifestation of which may be hematuria. However, there are no data on the prevalence of microscopic hematuria in renal Tx recipients. The objective of our study was to determine the prevalence of microhematuria in our pediatric Tx patients and to investigate the causes of microhematuria. Records of all pediatric renal Tx recipients followed at our center from September 1999 to September 2000 were retrospectively reviewed; of the 21 patients, seven (33%) had persistent microscopic hematuria that was first noted 2.9 years post-Tx. Patients with and without hematuria had similar baseline characteristics. Only one patient had pre-existing hematuria that continued post-Tx. The etiology of hematuria in the other six patients was: recurrent IgA nephropathy (one patient), CMV nephritis (one patient), and unexplained (four patients). None had renal calculi or hypercalciuria. Three of the four patients with unexplained hematuria have chronic allograft nephropathy, and the fourth (original disease dysplasia) has hypocomplementemia. At their last follow-up, 5.3 years after onset of hematuria, all patients are alive with stable allograft function. In conclusion, microscopic hematuria is not uncommon in pediatric renal Tx recipients. While causes of post-Tx hematuria are diverse, stones are not commonly seen. Whether chronic allograft nephropathy per se can be implicated as a cause of hematuria remains to be determined. Renal biopsies should be considered at the onset of hematuria if proteinuria and/or deterioration in renal function are seen concomitantly, to look for recurrent or de novo glomerulonephritis.

Adolescent↗

Effect of rearterialization on short-term graft function in orthotopic rat liver transplantation.

The orthotopic liver transplant model in rats has been very useful for immunological studies. However, differing opinions exist as to whether rearterialization of the graft is necessary for such experiments. Therefore, in this study we evaluated the short-term allograft function when rearterialized was compared to restored venous portal flow only and in situ hepatic artery ligation. The technique of orthotopic liver transplantation in the rat with and without rearterialization of the graft is described in detail. In addition, we evaluated the technical feasibility of sutured vascular anastomosis as compared to the traditional cuff technique. Urea synthesis rate was used as a sensitive marker of integrated liver function, including uptake, synthesis and excretion. Standard liver test of bilirubin, plasma aspergine aminotransferase and alanine aminotransferase were measured. We found no significant differences in the biochemical markers between allografts with portal venous flow only compared to the combination with arterial flow. Autopsy was performed after the biochemical studies at day 14. Histopathological analyses revealed no differences between the two groups of transplanted rats. The patency of sutured anastomoses was in our hands found to be superior to that of the cuff technique, with a success rate of more than 90% in rats with portal venous flow. This rat model in which vascular anastomosis is performed with a running suture technique and without rearterialization seems to be excellent for short-term studies of preservation and liver function after orthotopic liver transplantation.

Anastomosis, Surgical↗

Renal transplantation: a twenty-five year experience.

Boston has played a significant role in the development of renal transplantation. In Boston was performed the first successful isograft between identical twins (1954) the first successful allograft between fraternal twins (1959) and the first successful allograft from a cadaveric donor (1962). An immunosuppressive drug was also described in Boston by hematologists Schwartz and Dameschek (1959) and modified for renal transplantation in dogs (1961) and used for the first time in a human recipient in March 1962. By 1965 renal transplantation had become a clinical reality. Three hundred and ninety-eight of 589 recipients (68%) since 1950 are still alive, a remarkable figure considering that it includes all the earliest experimental transplants. One hundred and ninety-five of 295 (68%) with living-related donor transplants still have functioning allografts; 104/265 (39%) with cadaveric donor transplants have functioning grafts currently. Since 1968 transplants from living-related donors have an 80% one year survival whereas cadaveric donor transplants have approximately a 50% one year survival. Seventy-nine per cent of all one year survivors have had excellent psycho-social rehabilitation.

Animals↗

Logistics and technique for procurement of intestinal, pancreatic, and hepatic grafts from the same donor.

OBJECTIVE: To assess a technique for simultaneous recovery of the intestine, pancreas, and liver from the same donor. SUMMARY BACKGROUND DATA: With the more frequent use of pancreatic and intestinal transplantation, a procurement procedure is needed that permits retrieval of both organs as well as the liver from the same cadaveric donor for transplantation to different recipients. It is believed by many procurement officers and surgeons, however, that this objective is not technically feasible. METHODS: A technique for simultaneous recovery of the intestine, pancreas, and liver was used in 13 multiorgan cadaver donors during a 26-month period, with transplantation of the organs to 33 recipients. The intestine was removed from 11 donors separately and in continuity with the pancreas in the other 2. Six additional pancreases were excised and transplanted separately. Thirteen livers were retrieved, one of which was discarded because of steatorrhea. Ten of the remaining 12 livers were transplanted intact; the other 2 were split in situ and used as reduced-size hepatic allografts in four recipients. RESULTS: None of the 11 intestinal, 6 pancreatic, 2 intestinal-pancreatic, or 14 whole or partial liver allografts sustained serious ischemic injury or were lost as a result of technical complications. One liver recipient died 25 months after surgery of recurrent C virus hepatitis. The other 32 recipients had adequate allograft function with a mean follow-up of 8 months. CONCLUSION: It was possible using the described technique to retrieve intestine, pancreas, and liver allografts safely from the same donor and to transplant these organs to different recipients.

Adolescent↗

Late mortality and morbidity in recipients of long-term renal allografts.

The experience of the Peter Bent Brigham Hospital with 217 renal allografts functioning for more than 5 years is reviewed. Patient and graft survival were similar after 5 years, with patient survival being 88 and 66% at 10 and 15 years, respectively, and graft survival 85 and 75% at the same time intervals. Actuarial graft survival at 15 years was higher than patient survival because death with a functioning graft was not considered to be graft failure. No differences in patients or graft survival were found between living related and cadaver donor allografts. There were 33 deaths (15.2%), occurring from 5 1/2 to 20 1/2 years post-transplantation. Chronic liver failure and sepsis were the most common causes of death. Thirty-two patients (14.7%) lost their grafts after 5 years, most commonly from chronic rejection. Another 33 patients (15.2%) had evidence of graft dysfunction secondary to chronic rejection, recurrent glomerulonephritis, ureteral obstruction, or renal artery stenosis. Chronic rejection was generally not responsive to alterations in immunosuppressive medication. Complications of varying severity were common affecting 204 (94%) of the patients. The most frequent were hypertension, cataracts, avascular necrosis, malignancy, urinary tract infection, and pneumonia. These data demonstrate that transplant-related mortality and morbidity continue to occur in recipients of long-term renal allografts. These patients require careful and continuing care in medical centers experienced in transplantation.

Actuarial Analysis↗

Long-term follow-up of heart transplant recipients treated with murine antihuman mature T cell monoclonal antibody (OKT3): the Loyola experience.

We describe the long-term follow-up of 25 patients treated with murine antihuman mature T cell (OKT3) monoclonal antibody at Loyola University Medical Center. After OKT3 rescue therapy, 12 patients were monitored for 16.5 +/- 6.5 months. Twenty-two moderate and three severe rejection episodes occurred 11 to 469 days (166.8 +/- 126.0) after OKT3 therapy in nine of 12 patients. During the follow-up period three patients died, and one required retransplantation because of recurrent rejection. The coronary arteries of three failed allografts had severe intimal thickening and infiltration with lymphocytes. Thirteen patients received OKT3 for prophylactic immunosuppression, and their course was compared to that of 13 patients who underwent transplantation during the same period but were given prophylactic horse antihuman thymocyte globulins (HATG). There were no differences between the two drugs with respect to long-term incidence and severity of rejection and infection, cardiac allograft function, and survival. Our results indicate that, despite successful reversal with OKT3, heart transplant recipients with refractory rejection remain plagued by recurrent rejection. Cardiac allografts in recipients who die as a result of recurrent rejection show evidence of immune-mediated vasculitis, which results in severe and diffuse coronary luminal narrowing. OKT3 and HATG appear to be equally effective for rejection prophylaxis.

Adult↗

Renal transplantation in patients above 60 years of age in the modern era: a single center experience with a review of the literature.

A retrospective study was conducted of 797 patients receiving renal transplants from January 1985 to March 1997. Patient and graft survival was compared for patients above and below the age of 60. Sixty-nine patients < or =60 years old received 73 kidneys. Race: 73% Caucasian, 26% Black, 1% Other. Sex: 68% M. Hypertension (19) and PCKD (15) were the most common diagnoses. Mean peak panel reactive antibody (PRA) was 37.7%. Donor age was 2 to 66 years. Mean Cold ischemic time was 28.1 hours. Follow-up was until death or until 8/30/97. Patients <60 years included: 62% Caucasian, 34% Black, 4% Other; 60% male, Mean PRA 39.3. Of the 69 study patients, 27 died: 19 with a functioning graft, 8 within one year of transplantation. Cardiovascular causes (19 patients, 72%) and infection (7 patients, 24%) were most common. Common causes of graft loss were death with a functioning graft (19) and chronic rejection (15); other causes were acute rejection and primary non-function. Univariate analysis of 18 risk factors showed CHF and past history of vascular surgery significantly (p < 0.05) affected time of return to dialysis. Multi variate analysis did not show these independent variables to be significant. Abnormal ejection fraction and presence of q waves on EKG significantly affected time to death (p < 0.05) on uni- and multi-variate analysis. After censoring patients that died with functioning grafts, difference in graft survival between > or =60 and <59 years was not significant (p > 0.2). In this study, 68% of older patients had allografts functioning at 1 year. The fact that older patients succumb over time from natural causes should not keep patients from transplantation. Immunosuppressive agents need to be limited to reduce the incidence of infection. Criteria need to be refined to define those who are at prohibitive risk, who may not be candidates for transplantation.

Age Factors↗

[Aortic valve replacement in a renal transplant recipient].

A 65-year-old male was admitted to our hospital for surgical treatment of congestive heart failure with aortic regurgitation. He had received renal transplantation 15 years before in the United States, and had been under immunosuppressive regimen with ciclosporin and mycophenolate mofetil. Although the renal allograft function had been gradually deteriorating, and preoperative serum creatinine level was 1.8 mg/dl, and it decreased to 1.5 mg/dl after aortic valve replacement. Cryopreserved aortic allograft was needed for the aortic valve replacement. The reasons are; the patient may need hemodialysis (HD) or retransplantation of the kidney in the future, and the immunosuppressive therapy for kidney will provide good immunologic environment for second allograft, i.e.--aortic valve. He tolerated the operation well and the immunosuppressive agents were continued in the perioperative period. He is now in New York Heart Association (NYHA) class I.

Aged↗

Classic nephropathic cystinosis as an adult disease.

OBJECTIVE: To delineate the clinical characteristics of infantile nephropathic cystinosis in adult patients who have undergone renal transplantation. DESIGN: Case series. SETTING: Clinical research unit. PATIENTS: All 36 adult patients with nephropathic cystinosis referred to the National Institutes of Health. OUTCOME MEASURES: Longevity, growth, renal allograft survival, visual acuity, endocrine insufficiency, myopathy and swallowing dysfunction, cerebral calcifications, and occupational status. RESULTS: Of the 36 patients, seven were dead, five with functioning allografts. The 1-year and 5-year graft survival rates for 30 cadaveric allografts were 90% and 75%, respectively. The patients' mean height and weight were severely retarded. Five patients were legally blind, and three others had severely impaired vision in one eye. Thirty-one (86%) of 36 patients required thyroid hormone replacement therapy. One third had a distal myopathy, and 21 had moderate to severe swallowing abnormalities. Eight patients had cerebral calcifications on computed tomographic scan. Despite these complications, the sighted patients engaged in a normal variety of occupations. Only 11 patients were receiving adequate cystine-depleting therapy with cysteamine (mercaptamine) or phosphocysteamine. CONCLUSIONS: Adult patients with nephropathic cystinosis suffer serious complications of the disease.

Adult↗

Parameters associated with chronic renal transplant failure.

BACKGROUND: Although chronic progressive renal transplant failure (CPTF) is one of the leading causes of end-stage renal disease its exact pathogenesis is still incompletely understood. Histopathological as well as clinical similarities between chronic native kidney diseases and CPTF open the possibility that the latter condition is not exclusively due to a prolonged immunological insult to the grafted organ but also is caused by a mismatch between the metabolic demands of the recipient and the excretory capacity of the transplanted kidney. In this retrospective study we defined clinical parameters which are associated with CPTF. METHODS: Creatinine clearance was followed in 469 patients 45 +/- 0.9 months after transplantation for 2 years. Various immunological and non-immunological parameters were included in an univariate and multivariate regression analysis to define those which are independently associated with CPTF, defined as a decrease of creatinine clearance during the study period. RESULTS: Of all the parameters proteinuria, systolic blood pressure, high Cyclosporin trough concentrations and the cumulative steroid dose were found to be significantly associated with CPTF. A persistent proteinuria of > 2 g/d during the observation period was found to have a positive predictive value of 83% for a deterioration of excretory kidney function of > or = 25% within 2 years. CONCLUSION: In CPTF immunological as well as non immunological factors are independently associated with the decline of excretory allograft function in the late postoperative period.

Blood Pressure↗

Adverse impact of hypertension on diabetic recipients of transplanted kidneys.

The effect of hypertension on patient and allograft survival in 60 diabetic recipients of transplanted kidneys was assessed by retrospective chart analysis. Hypertension was present in 81% of recipients. Of eight of these patients who became normotensive after transplantation, all had functioning allografts and one died. By contrast, persistent hypertension after transplantation was associated with a higher mortality rate (25 of 54, 48%) and loss of kidney graft function (19 of 54, 35%). At a mean of 21 months after transplantation, living hypertensive diabetic recipients had worse renal function (mean serum creatinine of 3.1 mg/dl) than did nonhypertensive recipients (mean serum creatinine of 1.6 mg/dl). It is concluded that hypertension is a significant risk factor for diabetic patients and kidneys after transplantation.

Aged↗

Conversion to sirolimus in a population of kidney and kidney-pancreas transplant recipients.

INTRODUCTION: Calcineurin inhibitors (CI) are associated with nephrotoxicity that might reduce long-term graft survival. We report our experience with sirolimus (SRL) conversion among a population of kidney and kidney pancreas transplant recipients. METHODS: Thirty transplant recipients (6 women, 24 men; age 41 +/- 10.5 years old) were converted to SRL therapy at 25.97 +/- 32.5 months after transplantation. Indications for conversion were: intolerance to mycophenolate mofetil (n = 13), diabetes mellitus (n = 3), CI nephrotoxicity (n = 11), CI nephrotoxicity with chronic allograft rejection (n = 2), and side effects of azathioprine (n = 1). Follow-up after conversion is 3 to 45 months. RESULTS: No significant changes were observed in the 3 months postconversion in renal function, hematological profile, and mean arterial blood pressure. In contrast there was a significant increase in cholesterol values (pre: 198.7 +/- 49.4, versus post 221.2 +/- 60.8, P = .018). At a follow-up of 15.2 +/- 9.9 months after conversion two patients (6.7%) died with functioning allograft (one because of infection and one to myocardial infarct) three kidney allografts (10.7%) have been lost: two chronic rejection; one infection. In two patients SRL therapy was discontinued (one infection, one refractory edema). Neither significant change in renal function nor episodes of acute rejection were observed. CONCLUSIONS: Conversion to SRL was safe. There was no deterioration in renal function nor episodes of acute rejection. There was a significant increase in cholesterol values after conversion. The size of the sample and the time of follow-up may have determined our results.

Adult↗

Safety, efficacy, and cost analysis of thymoglobulin induction therapy with intermittent dosing based on CD3+ lymphocyte counts in kidney and kidney-pancreas transplant recipients.

BACKGROUND: In view of the superior T-cell depletion and prolonged half-life of thymoglobulin, we initiated a protocol to administer thymoglobulin intermittently based on peripheral blood CD3+ lymphocyte counts. METHODS: In this prospective study, 41 consecutive high-risk cadaver transplant recipients (panel reactive antibody level >30%, repeat transplant recipients, simultaneous pancreas and kidney or pancreas after kidney recipients, prolonged cold-ischemia time, prolonged donor hypotension, non-heart-beating donors) who received thymoglobulin induction therapy were included. The first dose (1.5 mg/kg) of thymoglobulin was administered intraoperatively. CD3+ lymphocyte count in the peripheral blood was determined daily and repeat doses were administered when the CD3+ count was >20 cells/mm3. Calcineurin inhibitors (CI) in low doses were introduced when the allograft function recovered and the serum creatinine level dropped by at least 25% from the pretransplant level. Thymoglobulin treatment was discontinued once therapeutic CI drug levels were achieved. Concomitant immunosuppression consisted of mycophenolate mofetil and prednisone. RESULTS: The mean individual thymoglobulin dose was 104 mg (1.4 mg/kg), and the total cumulative dose per patient was 318 mg (4.2 mg/kg). Patients received an average of three doses and a mean of six CD3 counts were obtained per patient. Introduction of CI was delayed for an average of 6 days posttransplantation. At a mean follow-up of 340 days, two (4.9%) patients died; three (7.3%) renal allografts and two (18.2%) pancreas allografts were lost. Five (12.2%) patients developed a total of six acute rejection episodes. The mean serum creatinine in the 38 patients with a functioning kidney was 1.47 mg/dl, and the mean blood glucose in the 9 pancreas allograft recipients was 89 mg/dl. Cytomegalovirus (CMV) infection occurred in one (2.4%) patient. No posttransplant lymphoproliferative disorders were seen in this patient cohort. The hospital pharmacy charge for a 100-mg dose of thymoglobulin at this center was $2,165, and the laboratory charge for a single CD3 determination was $70. In this study, the average charges per patient for the total dose of thymoglobulin and six CD3 determinations were $7305. In comparison, the charge for daily administration of 104 mg of thymoglobulin (which was the mean dose) for 6 days (mean time to CI therapy initiation) would be $13,510 and for 10 days (mean time to therapeutic CI levels) would be $22,516. This represents a savings of 46% and 68%, respectively. CONCLUSIONS: Intermittent thymoglobulin therapy, based on peripheral blood CD3+ lymphocyte counts, is safe and associated with low acute rejection rate in high-risk kidney and kidney-pancreas transplant recipients. A mean of three doses resulted in adequate suppression of CD3+ lymphocytes permitting delayed introduction of CI in low doses until recovery of renal function occurred. When compared to traditional daily administration, intermittent therapy results in significant cost savings and reduces the total cumulative dose of this potent immunosuppressive agent.

Antilymphocyte Serum↗