Shen Sy

Acute effects of intravenous cyclosporine on blood pressure, renal hemodynamics, and urine prostaglandin production of healthy humans.

The acute renal failure associated with cyclosporine may result from vasoconstriction of intrarenal arterioles. To evaluate the mechanism of cyclosporine-induced nephrotoxicity, we acutely administered cyclosporine to eight healthy female volunteers with normal blood pressure and renal function. Cyclosporine (4 mg/kg) in 250 ml of 5% dextrose in water (D5W) was administered as a steady intravenous infusion over 6 hr. Glomerular filtration rate and renal plasma flow were measured by serum disappearance of 99m TcDTPA and 131I hippuran, respectively, during the last 3 hr of the infusion. D5W was given to the patients on separate days before the cyclosporine infusion to obtain control data. Systolic and diastolic blood pressure measured every hour during the infusions and renal vascular resistance were slightly higher during cyclosporine administration, but the increases were not statistically significant. Renal plasma flow was not affected by cyclosporine, being 479.6 +/- 24.9 ml/min during the control infusion and 463.3 +/- 12.7 ml/min during the cyclosporine infusion. However, glomerular filtration rate was reduced by cyclosporine in all patients (control, 108.8 +/- 2.5 ml/min, vs. cyclosporine, 91.1 +/- 2.2 ml/min, P less than .01), except one who demonstrated no significant change. Urinary excretion of thromboxane B2 during cyclosporine administration was markedly increased in all patients, being 39.9 +/- 8.2 ng/hr in the control period and 85.8 +/- 22.3 ng/hr during cyclosporine infusion (P less than .05), except for the one patient in whom no decrease in GFR was noted. There was no significant change in the urinary excretion rate for 6-keto-prostaglandin F1a or prostaglandin E during cyclosporine infusion. Serum averaged levels of peripheral renin activity, angiotensin II, and aldosterone did not change during with the cyclosporine administration compared with the control. All patients demonstrated a decrease in 24-h urinary excretion of sodium and potassium on the day of the cyclosporine infusion. Verapamil SR (240 mg daily for 7 days prior to cyclosporine infusion) did not reverse the reduction in glomerular filtration rate induced by cyclosporine; however, a significant reduction in renal vascular resistance and an increase in renal plasma flow (P less than .05) were noted when the volunteers were treated with both verapamil and cyclosporine compared with cyclosporine alone. Intravenous infusion of Cremophor EL, the vehicle to dissolve cyclosporine, demonstrated no significant effects on blood pressure, renal hemodynamics or urinary prostaglandin excretion.(ABSTRACT TRUNCATED AT 400 WORDS)

The prognostic value of the eosinophil in acute renal allograft rejection.

A case report of marked peripheral blood eosinophilia and eosinophilic infiltration of a rejected renal allograft in a transplant recipient stimulated our review of the clinical course of 132 consecutive renal transplant recipients. A total of 187 acute rejections occurred in 112 patients. Diagnosis was made by renal biopsy in 124 cases. The percentage of eosinophils in the leukocyte differential of patients with irreversible rejection was 5.2 +/- 5.7 (mean +/- SD) versus that seen in patients with reversible rejection, 2.9 +/- 3.5 (P less than .05). The difference in the total eosinophil counts in each group was not statistically significant. Patients with peripheral blood eosinophil percentages greater than or equal to 4% had a 37.9% irreversible rejection rate, whereas those who had less than 4%, had a 22.4% loss rate (P less than .01). Six of seven patients with greater than or equal to 2% eosinophils in the inflammatory infiltrate of their renal allograft lost their kidney, whereas grafts with less than 2% eosinophils had a 36.8% loss rate (P less than .02). We conclude that the increased presence of eosinophils in the peripheral blood and/or renal allograft biopsy specimen is an adverse prognostic factor for acute rejection outcome.

Incidence of cytomegalovirus disease in cyclosporine-treated renal transplant recipients based on donor/recipient pretransplant immunity

We retrospectively reviewed the clinical data of all renal transplant patients treated with cyclosporine as their main chronic immunosuppressive agent between 12/83 and 11/85 to identify cytomegalovirus-negative patients at our institutions who received cytomegalovirus (CMV)-positive kidneys. Using a latex agglutination test, twenty-two such patients were identified, of whom 2 were excluded due to early death and lack of posttransplant follow-up serology. Of the remaining 20 patients, 12 developed CMV antibody in the first 4 months post-transplant, and of these, 11 were hospitalized with complications related to primary CMV disease. Two of these seroconverting patients eventually died, and one lost her kidney. Of the 8 persistantly CMV-negative patients, 1 lost his kidney soon after transplantation, and one had a febrile illness 4 months posttransplant caused by a bacterial pneumonia. Concomitantly, 145 renal transplants (CMV-negative recipient receiving a CMV-negative kidney or CMV-positive recipient receiving either positive or negative kidneys) given to 142 patients functioned for at least 4 weeks. Only 3 cases of CMV reactivation disease occurred in previously antibody-positive patients. We conclude that the transplantation of a cytomegalovirus-positive kidney into a CMV-negative recipient carries a high risk of mortality/morbidity from primary cytomegalovirus disease. On the other hand, reactivation of CMV disease was uncommon early in the posttransplant course of cyclosporine-treated patients.

Effect of cyclosporine on total lymphocyte and T-cell counts in renal-transplant recipients.

Persons who are seropositive for HTLV-III are at risk for the development of T-cell immunosuppression of varying degrees of severity and those who are concurrently infected with Mycobacterium tuberculosis (i.e. those with positive tuberculin skin tests) may therefore also be at high risk for contracting and then transmitting tuberculosis. In the setting of a rapidly spreading AIDS epidemic preventive therapy with isoniazid in persons seropositive for HTLV-III and with a positive tuberculin skin test could be a major public health importance. Such chemoprophylaxis is likely to be effective since tuberculosis responds very well to standard treatment with antibiotics even among patients with AIDS. From January 1980 through October 1985 90 cases of tuberculosis associated with AIDS were documented in Florida. From January 1980 through June 1983 17 of 25 such reported cases (65%) occurred among Haitian immigrants. Since July 1983 28 of 65 such cases (43%) have occurred among Haitians and 29 of 65 (44.5%) have occurred among US natives. In Florida therefore cases of tuberculosis associated with AIDS seem to be increasing both in their total number and in the number and percentage of patients who are US natives. It is likely that the number of cases of tuberculosis related to HTLV-III immunosuppression exceeds that associated with AIDS since tuberculosis tends to precede the syndrome by months of years. Furthermore it is possible that some cases of tuberculosis related to HTLV-III immunosuppression are never followed by severe opportunistic infections or tumors diagnostic of AIDS. These factors at least in part may explain the recent abrupt increase in the incidence of tuberculosis (43%) among persons born in the United States and residing in southeast Florida. Furthermore the incidence of tuberculosis may increase in other areas of the US and in other parts of the world (e.g. developing countries) where tuberculosis infection is prevalent and the rates of HTLV-III infection and AIDS are rising. Tuberculosis is the only AIDS-related infection that is spread to normal persons by the aerosol route and is preventable by chemoprophylaxis. Persons with a confirmed positive HTLV-III serologic test (especially those in high-risk groups for AIDS) should be advised to have a tuberculin skin test. If the skin test is positive or if there has been a documented positive skin test in the past such persons should be offered isoniazid prophylaxis especially if T-cell testing already shows immunosuppression.

Incidence and morbidity of cytomegalovirus disease associated with a seronegative recipient receiving seropositive donor-specific transfusion and living-related donor transplantation: A multicenter evaluation

This retrospective study was conducted to identify the frequency of cytomegalovirus (CMV) disease in seronegative recipients of donor-specific transfusion (DST) and living-related donor (LRD) kidneys from seropositive donors. A total of 151 LRD transplants (TX) were performed at six transplant centers over a 3-year period. A total of 33 patients were identified as having been seronegative (pre-TX) for CMV, yet they had DST and a TX from a seropositive LRD. of these patients, 12 (36.45%) seroconverted within the first 6 months post-TX and developed clinical CMV disease. Additional patients seroconverted, but did not have evidencde of clinical disease and were not tested further. All TX centers, with the exception of one, had seronegative patients that became ill after receiving a seropositive DST/LRD TX. Six patients manifested their disease as a febrile illness with leukopenia and liver enzyme elevations, four had pneumonitis, and two developed CMV ulcerations of the colon (one of whom died from resultant sepsis). Of the 36 seronegative patients who received seronegative DST/LRD TX none became ill with CMV disease. Of the 72 seropositive patients who received DST/LRD TX, only 2 (2.8%) developed CMV illness (one, seropositive into seropositive, the other, seronegative into seropositive). Of the 33 seronegative patients receiving seropositive DST/LRD TX, 17 received antilymphocyte preparations (ALP), and 8 of these became ill (47.1%). Of 16 patients not receiving ALP, 5 (31.3%) developed clinical CMV illness. Of the 33 patients who were identified as having been seronegative for CMV seronegative for CMV yet received seropositive DST/LRD TX, the 12 who did develop CMV illness had two graft losses, one death, and a serum creatinine for the remaining 9 patients of 2.3pL1.6 at last follw-up. the remaining 21 patients who developed no illness had a serum creatining of 1.3pL0.6 with no graft losses at the last follow-up. This evidence suggests that a prospective TX recipient who is seronegative for CMV who received DST/LRD Tx from a seropositive family member has a significant risk for developing morbidity related to clinical CMV illness.

Effects of calcium channel blockers on in vivo cellular immunity in mice

In vitro studies have shown that calcium channel blockers (CCB) inhibit lectin-induced lymphocyte proliferation. However, no in vivo effects have been documented yet. In this study we evaluated the effects of CCB on in vivo cellular immunity by using contact sensitivity to oxazolone in mice. From 15 to 30 twelve-week-old female C3H mice were randomized into: 0.9 NS (sham), ethanol, CsA, dexamethasone (DXM), verapamil, diltiazem, and nifedipine groups. These study agents were given daily from day 1 to day 9 subcutaneously to the shaved abdominal wall. The mice were sensitized with oxazolone to the abdominal wall on day 2 and challenged with oxazolone on the right ear on day 8. Delayed-type hypersensitivity was measured on day 10 and defined as the difference in thickness between the right (challenged) and left (control) ear of each mouse. The mean DTH of each study group was compared with that of the sham, and the statistical significance was determined by a Students t test. The percentage of change in DTH from the sham was also calculated as: (mean DTH of study drug group-mean DTH of sham group)/mean DTH of sham group x 100%. A negative value meant a suppressive effect on DTH; a positive value, an enhancing one. The CsA, DXM, and nifedipine all had significant suppressive effects on DTH. Verapamil had a significant enhancing effect. Ethanol and diltiazem had no significant effect. More studies employing other antigens with several other cell-mediated response measurements along with DTH quantification should be done in order to determine the specificity of the immunosuppressive effect of CCB as well as the potential of any calcium antagonist as an adjuvant suppressive agent.

Reevaluation of T cell subset monitoring in cyclosporine-treated renal allograft recipients.

The predictive value of peripheral blood T cell subset monitoring in renal allograft recipients has been questionable, and there has been no information concerning the correlation of T cell subset changes with the clinical event related to cyclosporine nephrotoxicity. This study was conducted to investigate the clinical usefulness of serial T cell subset monitoring in 34 consecutive renal transplant patients treated with cyclosporine by determining the total peripheral lymphocyte count and T cell subset counts using Leu-4, Leu-3ab, and Leu-2a monoclonal antibodies and flow cytometry up to 6 months after transplantation. The absolute counts of all cells were lower in transplanted patients than those of normal controls, but were not different from those of hemodialysis patients. During infection, the helper/suppressor (H/S) ratio and the cell counts, except for suppressor cells, decreased significantly. Within one week prior to rejection, all cell counts also decreased significantly. Furthermore, cell counts before steroid-resistant rejection were significantly lower than those before steroid-responsive rejection. In contrast, lymphocyte and T cell counts were increased significantly within one week prior to cyclosporine nephrotoxicity being diagnosed; the H/S ratio was not correlated with rejection or toxicity. These results indicate that H/S ratio is not associated with clinical events of renal allograft recipients, but serial lymphocyte and T cell subset counts can provide valuable information for the differentiation of rejection from cyclosporine nephrotoxicity, and also for predicting the outcome of the allograft rejection.

Renal allograft biopsy and conversion of cyclosporine to azathioprine.

A prospective nonrandomized study was conducted to evaluate the results of two conversion protocols on two similar groups of renal graft recipients totaling 54 patients who were converted from CsA to AZA at 6-12 months posttransplant. With protocol I, 24 patients (3 haploidentical, 21 cadaveric recipients) were converted with a graft biopsy followed by a 14-day overlap of CsA and AZA before the CsA dose was tapered and discontinued in 6 days. Of the 24 patients, 8 were found to have occult rejection in biopsy and received methylprednisolone 500 mg boluses for three days before overlap started. Thirty patients (2 haploidentical, 28 cadaveric recipients) were converted with protocol II, which had CsA and AZA overlap and tapering schedules identical to those of protocol I without a preconversion biopsy. Follow-up extended as far as 3 years posttransplant. There was a substantial incidence of chronic rejection and graft loss after conversion in protocol II patients. We also found that there was a possible link between postconversion acute rejection and late graft loss from chronic rejection. The incidence of acute rejection after conversion was significantly lower among protocol I patients as compared with that of protocol II (4% vs. 37%, P less than 0.001). However, if 8 patients with occult rejection in the preconversion biopsy were added to the total number of postconversion rejection in protocol I, the incidence of postconversion rejection in this group (38%) would be similar to that of protocol II. Using the time of conversion as the onset of the risk, protocol I patients had better graft survival than protocol II (100% vs. 80%, P less than 0.005) at 3 years posttransplant. If conversion becomes necessary, we recommend a preconversion graft biopsy to identify and treat patients with occult rejection before the beginning of CsA and AZA overlap, especially for those patients whose creatinine is higher than 2 mg/dl without obvious cause before conversion.

Enzyme-linked Immunosorbent Assay For Serum Renal Tubular Antigen In Kidney Transplant Patients

A mouse monoclonal antibody, specific for binding with the epithelial surface antigen in human renal proximal tubules, was produced by hybridoma culture. Using this antibody, an enzyme-linked immunosorbent assay was developed to measure the human renal tubular epithelial antigen (HRTE) concentrations in serum samples from 25 normal subjects and 66 consecutive renal allograft recipients. In 46 patients treated with azathioprine and prednisone, serum HRTE was elevated more than two-fold in 56 of 62 rejection episodes 2–5 days before the clinical diagnosis was made. Of the 56 rejection episodes, the antigen level fell to baseline after treatment in 44 steroid-responsive episodes, but it remained elevated in 8 steroid-resistant rejections, and it became undetectable 3–4 days after the initial elevation in 4 episodes in which allografts were lost to rejection. In 20 patients treated with cyclosporine and prednisone, all 25 rejection episodes demonstrated a greater than two-fold increase of serum HRTE 1–6 days prior to the diagnosis of rejection. The antigen level fell to baseline in 23 reversible rejection episodes, however serum HRTE remained elevated in 2 steroid-resistant patients whose grafts were lost to rejection. Cyclosporine nephrotoxicity without rejection was confirmed in 6 episodes, each of which demonstrated a more than two-fold increase in HRTE 2–4 days before toxicity was diagnosed. When the cyclosporine dose was reduced, the antigen level decreased as the serum creatinine declined. Serial determinations of serum HRTE in renal transplant recipients can provide valuable information for the early diagnosis and management of allograft rejection and cyclosporine nephrotoxicity.