Peter N. Madras

Influence of rejection therapy on fungal and nocardial infections in renal-transplant recipients

Abstract Of 51 renal-transplant recipients, 15 had twenty infections caused by fungus or nocardia. Of these 15 patients, aspergillus was found in 11, nocardia in 4, cryptococcus in 2, candida in 2, and phycomycetes in 1. All 11 patients with aspergillus died, and in 8 of these patients aspergillus was judged to have been the principal cause of death. There was a significant correlation between the frequency of episodes of rejection (and their treatment) and the subsequent development of fungal or nocardial infection. These infections developed in 3 of the 23 patients with no rejections, as compared with 12 of the 31 patients treated for one or more rejection episodes (P

Hemodynamic evaluation of intra-aortic balloon pumping in man.

Intra-aortic balloon pumping is effective in reducing left ventricular peak systolic pressure and increasing cardiac output in patients with severe cardiogenic shock secondary to acute myocardial infarction. Associated with these effects is a reduction in intravenous catecholamine requirements and increased sensitivity to diuretics. Reduction in left ventricular end-diastolic pressure is implied by improvement in arterial blood gas saturation (reduced arterioalveolar gradient) and was shown directly in one patient. Total myocardial oxygen consumption is probably reduced by counterpulsation. Platelet levels have not fallen significantly with adequate heparinization and the slow infusion of low molecular weight dextran. No complications have occurred related to femoral artery cannulation, nor has there been significant damage to the aorta. The findings suggest that this system is a safe means of assisting the failing left ventricle. The high mortality in this series (seven of eight patients) is related to the extent of irreversible myocardial damage which may be reduced by more aggressive, earlier application of counterpulsation.

SEQUENTIAL DETERMINATIONS OF URINARY CYTOLOGY AND PLASMA AND URINARY LYMPHOKINES IN THE MANAGEMENT OF RENAL ALLOGRAFT RECIPIENTS

Urine cytology, plasma (P), and urinary (U) interleukin-2 (IL-2)* and IL-2 receptor (IL-2R) levels were evaluated as immunological monitoring techniques in 65 renal allograft recipients. Normal individuals showed normal urine cytology, IL-2(U) = 0, IL-2(P) = 0.4 +/- 0.1 ng/ml (mean +/- SEM) and IL-2R(P) = 318 +/- 26 U/ml. Stable transplants also showed normal urine cytology, no IL-2(U), IL-2(P) = 0.8 +/- 0.2 ng/ml, and IL-2R(P) = 326 +/- 29 U/ml. Rejection episodes (n = 21) were accompanied by cytologic changes, including lymphocyturia, exfoliation of immature tubular cells, platelet aggregates, and fibrin deposits. The corresponding lymphokine changes were IL-2(U) = 39.6 +/- 1.4 ng/ml, IL-2(P) = 79 +/- 21 ng/ml, and IL-2R = 1884 +/- 202 U/ml, all markedly increased. Successful treatment was associated with return of all parameters to normal; treatment failure was associated with continued abnormalities. Fourteen rejections unresponsive to Solumedrol (500 mg x 5 days) required OKT3 rescue (5 mg x 14 days). In the 11 that were reversed, onset of OKT3 therapy was characterized by markedly increased exfoliation of necrotic cellular debris, lymphocytes, and collecting duct cells. Interestingly, serum creatinine increases of 57.2 +/- 18.9% (range 25-90%) over pre-OKT3 levels were noted. Maximal changes occurred 48-72 hr after the first dose, followed by gradual return to normal. Rejections unresponsive to OKT3 (n = 3) showed no cytologic changes from the pretreatment mean creatinine increase of 13.2 +/- 2.7% (range 9-15%), and maximum change occurred 24 hr after the first dose. Rejections responsive to Solumedrol only (n = 4) showed gradual improvement of all parameters. Rejections treated with Solumedrol following failed OKT3 prophylaxis (n = 3) did not reverse and continued to show rejection associated cytologic changes and abnormal creatinines. Patients experiencing CsA toxicity (n = 12) showed mild creatinine elevations, normal or negative IL-2(P) and IL-2R(P) levels, and no IL-2(U). They showed distinctive cytologic changes consisting of swollen convoluted tubular cells with nuclear pyknosis and cytoplasmic vacuoles. Pretransplant IL-2(P) levels of patients who subsequently rejected were elevated, with 19/21 patients with preoperative IL-2 levels greater than 15 ng/ml having subsequent rejections. In contrast, pretransplant creatinine, urine cytology, and IL-2(U) levels showed no correlation to subsequent clinical course.(ABSTRACT TRUNCATED AT 400 WORDS)

Management of Thrombophilia in Renal Transplant Patients

Renal allograft recipients with thrombophilia (a hypercoagulable state) are at higher risk for early allograft loss. Following an episode of allograft renal vein thrombosis in a patient subsequently diagnosed with protein C deficiency, we adopted universal screening for hypercoagulable risk factors. Patients with a history of a thromboembolic event underwent laboratory screening for thrombophilia. Eight patients with a defined hypercoagulable disorder or a strong clinical history of thrombosis even in the absence of hematologic abnormalities were treated with anticoagulation following renal transplantation. We reviewed the outcomes of these eight patients and all renal transplant recipients at our center who developed thrombotic complications after renal transplantation.

Use of Dacron cuffed silicone catheters as long-term hemodialysis access.

Sixty-five Dacron™ cuffed, dual lumen, silicone central venous dialysis catheters (Quinton PermCath, Seattle, WA) were inserted in 51 patients as the sole form of permanent access for chronic hemodialysis. Six and 12 month actuarial survival rates of patients for all catheters were 53% and 35%, respectively. When calculations included revisions, 6 and 12 month actuarial catheter survival rates were 61% and 43%, respectively. The major limiting factors in survival using long-term catheters remain infection and thrombosis. Dacron cuffed, dual lumen, central venous, dialysis catheters can provide long-term vascular access for hemodialysis in high risk patients.

Correlation of clinical outcomes after tacrolimus conversion for resistant kidney rejection or cyclosporine toxicity with pathologic staging by the Banff criteria.

BACKGROUND Refractory rejection and cyclosporine (CsA)-induced nephropathy remain important causes of renal allograft loss. Previous studies demonstrated that 70-85% of the episodes of refractory acute rejection (AR) occurring in renal allograft recipients on a CsA-based immunosuppressive regimen could be salvaged by conversion to tacrolimus. No data are available regarding the correlation between allograft histology at the time of conversion and the response to tacrolimus. We examined the response to tacrolimus conversion in relation to preconversion biopsies stratified by the Banff criteria. METHODS Since May 1992, we have converted 22 patients from CsA to tacrolimus as part of a rescue protocol. We report on 18 patients in whom 6-month follow-up was available after conversion for biopsy-proven AR (n=13) or CsA toxicity (n=5). Sixteen patients were recipients of renal allografts, including three second transplants, and two were recipients of kidney-pancreas transplants. All patients with AR were treated with one or more courses of methylprednisolone and OKT3 before conversion. Renal allograft biopsies were interpreted by a transplant pathologist blinded to the clinical history, and graded according to the Banff criteria. Responses to tacrolimus were scored as improved (creatinine returned to within 150% of baseline), stabilized (creatinine rise arrested), or failed (returned to dialysis). RESULTS; Mean follow-up was 17.3+/-8 months. Fourteen of 18 patients (78%) showed improvement or stabilization in renal function as assessed by creatinine at 6 months or 1 year (when available). Of the 13 patients with histological AR, nine (69%) improved, including five of six with borderline AR, two of three with grade I AR, and two of four with grade II AR. Of the four other patients with AR, two stabilized and two failed. Three of five patients with severe clinical rejection requiring dialysis (range 2-16 weeks) recovered renal function after conversion. Of five patients with CsA toxicity, two (40%) improved. Seven of eight patients who were converted to tacrolimus less than 90 days after transplantation improved, compared with only 4 of 10 who were converted more than 90 days after transplantation. No grafts were lost in patients with a creatinine <3.0 mg/dl at the time of conversion versus two of seven grafts lost when the creatinine was 3.1-5.0 mg/dl and two of eight grafts lost when the creatinine was >5.0 mg/dl. CONCLUSION The majority of steroid and antilymphocyte antibody (OKT3 or ATGAM) unresponsive rejections in patients on CsA-based immunosuppression will improve or stabilize after conversion to tacrolimus. There was no correlation with allograft histology stratified by the Banff criteria and the response to tacrolimus. Although there was a trend toward a poorer response with more severe histological rejection, higher serum creatinine at the time of conversion, and longer time from transplantation to conversion, favorable responses were noted in all groups. This indicates that a trial of conversion is warranted, irrespective of the histological severity of injury.

Bioavailability and Patient Acceptance of Cyclosporine Soft Gelatin Capsules in Renal Allograft Recipients

OBJECTIVE: To evaluate the relative bioavailability and patient acceptance of cyclosporine (CSA) soft gelatin capsule versus oral solution in renal allograft recipients. DESIGN, SETTING, AND PATIENTS: The bioavailability of CSA capsules was compared with that of CSA solution with crossover study design in the outpatient clinic setting. Nine renal allograft recipients with stable renal function participated in this study. METHODS: CSA dose was switched from solution to capsule in each patient for seven days. At steady-state, nine blood samples were obtained over a 12-hour period from each patient on day 7 for CSA solution and on day 14 for CSA capsules. CSA blood samples were analyzed by HPLC and fluorescence polarization immunoassay (FPIA) methods. Time to peak concentration (Tmax), peak concentration (Tmax), and area under the curve (AUC) were calculated on days 7 and 14, and compared using the matched Students t-test. Patient acceptance was evaluated by patient preference on the questionnaire. RESULTS: For CSA blood concentrations measured by HPLC assay, the Tmax, Cmax, and AUC were 3.4 ± 1.3 h, 569 ± 240 nmol/L, and 4659 ± 2144 h • nmol/L (mean ± SD), respectively, with solution and 4.2 ± 2.1 h, 560 ± 257 nmol/L, and 4765 ± 1799 h • nmol/L (mean ± SD), respectively, with capsules. These differences were not significant (p>0.1). The bioavailability was not significantly different between capsules and solutions when it was measured by PFIA assay (p>0.1). The mean (± SD) relative bioavailability of capsules compared with solution was 109 ± 29 percent AUC (0–12 h) measured by HPLC and 111 ± 27 percent AUC (0–12 h) measured by FPIA. All patients expressed preference for capsules over the solution. CONCLUSIONS: CSA oral soft gelatin capsule is bioequivalent to CSA oral solution and most patients preferred the capsule to the oral solution.

Renal Transplantation in the Diabetic

The practices and recent results from a transplant center servicing a large proportion of uremic diabetics were reviewed to highlight modern management issues. The focus is taken off the diabetic as a “high-risk” renal transplant recipient and brought to bear on the laborintensive aspects of his or her management. With special attention to perioperative cardiovascular status, operative mortality (30 day) can be less than 3.5% and morbidity minimized. Living related donors continue to offer advantages in terms of organ availability, early postoperative function, and most likely long-term function, but in the cyclosporin era cadaver renal transplants have evolved competitive 1-year patient survival rates of 96% and 1-year graft survival rates of 88%. Still, the proportion of graft losses due to death of the patient from nonimmunologic causes, chiefly cardiac and cerebrovascular events, remains relatively high in the diabetic at 35.8%. Rehabilitation of the diabetic post-transplant is less complete than that of the nondiabetic transplant recipient, but is clearly superior to that of alternative modes of therapy for the uremic diabetic.

Binding of antihuman globulin by exfoliated renal tubular cells following kidney transplantation.

Exfoliated renal tubular epithelial cells (RTCs) from kidney allograft recipients may bind antibody against human globular proteins. Urine from sixty consecutive transplant recipients was studied in the first month following transplantation to relate this binding to the clinical course and rejection. The spun, washed sediment was incubated with fluoresceinated goat antihuman globulin and examined under light and fluorescent microscopy for fluoresceinated RTCs. Of 28 patients who were never positive, 27 manifested no clinical rejection episodes. Of 22 total rejection episodes, 21 were preceded by the appearance of fluorescent RTCs. Five patients in this group did not revert to negative in this test, and all went on to loss of graft from acute rejection. Of 46 patients who were discharged from the hospital with negative RTCs, only four were readmitted within one month for treatment of rejection. In contrast, of the 11 patients who were positive at the time of discharge, 10 were readmitted in the first month. Graft survival was only 55% (6/11) in this latter group as compared with 91% (42/46) in the former. There were 11 patients with transiently positive tests who did not warrant a clinical diagnosis of rejection. In no case of acute tubular necrosis (ATN) alone or in obstructive uropathy was the assay positive. However, in some cases, in which the ATN merged imperceptibly into rejection, the RTCs started to fluoresce well in advance of the clinical suspicion of rejection. Information obtained from this examination may be used to assess the cause of renal failure in the early posttransplant period and to differentiate rejection from ATN and obstruction. This phenomenon of fluorescent RTCs may be an early manifestation of an immunological change occurring in a cell that is targeted by the host for rejection.