Post renal transplant Castleman's disease resolved after graft nephrectomy: a case report.

Angiofollicular lymphoid hyperplasia (Castleman's disease) is a lymphoproliferative process thought to be mediated by overexpression of II interleukin-6. Castleman's disease has two variants: Castleman's disease has two variants: Hyaline vascular type and plasma cell variant (multicentric Castleman's disease). The hyaline vascular type tends to be localized, and the plasma cell variant shows more systematic signs and carriers a worse clinical prognosis. Castleman's disease is associated with B-cell lymphoma, Kaposi sarcoma, Human herpes virus 8 (HHV-8), and Epstein-Barr virus. Castleman's disease have been described thrice post kidney transplant. In this report, we document the course of a renal recipient who developed the plasma cell variant of Castleman's disease at 16 months after failure of his allograft and return to dialysis. He displayed clinical resolution of this complication after graft nephrectomy. To our knowledge, this is the first case where the disease manifestations disappeared after graft removal. Our patient experienced chronic renal allograft rejection which may have driven all the systematic manifestations of multicentric castleman's disease and possibly reactivated a latent HHV-8 infection. In this case immunohistochemical testing for HHV-8 was not available to prove a role for this agent.

Interaction between cyclosporin A and nonsteroidal antiinflammatory drugs.

OBJECTIVE: Although cyclosporin A (CyA) has been shown in a series of controlled trials to be of benefit to patients with rheumatoid arthritis (RA), the majority of patients continue to require nonsteroidal antiinflammatory drugs (NSAID) for relief of joint pain and stiffness. Our aim was to determine whether there is a clinically important difference in calculated creatinine clearance when CyA is given concurrently with NSAID with high cyclooxygenase activity (indomethacin and ketoprofen) compared with sulindac, which has been claimed to have fewer renal effects than other NSAID, and compared with a simple analgesic, paracetamol. METHODS: Patients with RA started 2.5 mg/kg CyA/day and dosage was increased cautiously to 5 mg/kg/day or less if the serum creatinine rose by > or = 30% above baseline. The mean stabilized dose was 171.43 +/- 48.94 mg/day. Once CyA dose was stabilized, patients were allocated in random order to possible sequences of 4 week periods of acetaminophen, indomethacin, ketoprofen, and sulindac. Monitoring of cyclosporine levels, nephrotoxicity, and hepatoxicity, and adjustment of doses were by an "unblinded" clinician not in direct contact with study patients. All other assessments were made by a "blinded" clinician. Patients were instructed to take the identical appearing gelatin capsules qid. The multiple crossover design was analyzed using analysis of variance procedures for repeated measures. RESULTS: 35 patients were enrolled, of whom 32 patients completed the acetaminophen and at least one course of NSAID. The calculated creatinine clearance was increased by 2.79 ml/min (3.5%) on average for acetaminophen versus all 3 NSAID (6% for indomethacin, 2.3% for ketoprofen, 2.6% for sulindac). The study had adequate power to detect a true difference of more than 10% in mean creatinine clearance for each major comparison. CONCLUSION: NSAID studied did not produce a clinically important difference in the calculated creatinine clearance in these patients-the difference with acetaminophen was modest and not of clinical significance. There is no evidence that any of the 3 NSAID studied have an advantage or disadvantage. It seems reasonable to allow patients to continue an NSAID of their or their clinician's choice.

Economic analysis of Neoral in de novo renal transplant patients in Canada.

This pilot economic evaluation was performed as part of the Canadian arm of an international randomized, controlled, double-blind safety and tolerability trial (OLM-105/NOF-2). The clinical study compared the safety and tolerability of a new microemulsion oral formulation of cyclosporine A (Neoral) with the oral cyclosporine. A preparation currently in use (Sandimmune SGC)/(SGC). To assess the economic impact of Neoral in newly grafted renal transplant patients, primary cost data were collected at the five participating Canadian centers and evaluated from the Ministry of Health (MOH) and hospital perspectives. The results of this cost analysis are presented in this paper. Since the new formulation has shown more consistent absorption and a more predictable pharmacokinetic profile, medical resource utilization and, consequently, cost of treatment could be expected to be lower for those renal transplant recipients treated with Neoral than for those receiving standard SGC. The findings of this study support this hypothesis. Robustness of the conclusion was confirmed with sensitivity analyses. Reduced health care costs for patients treated with Neoral were primarily a result of fewer hospitalization days and lower physician costs for inpatient and outpatient procedures.

Combination therapy of cyclosporine with methotrexate and gold in rheumatoid arthritis (2 pilot studies).

OBJECTIVE: To evaluate the efficacy and toxicity of cyclosporine A (CyA) in combination with gold and methotrexate (MTX) in patients with rheumatoid arthritis (RA). METHODS: Twenty patients with RA with partial response to oral MTX and 20 patients with partial response to im gold had CyA added to their regimen for 6 months, withdrawn over 2 months and the patients monitored for 4 months. RESULTS: There was a significant improvement in joint count, joint score, joint swelling, grip strength and joint pain in patients taking the combination with no significant increase in adverse reactions. CONCLUSION: CyA in combination with gold or MTX may, over a 6 month period, increase efficacy in patients with refractory RA without significant increase in toxicity.

Development of a central matching system for the allocation of cadaveric kidneys: a simulation of clinical effectiveness versus equity.

OBJECTIVES: 1) To develop a computer-based simulation to prospectively study the impacts of explicitly incorporating different equity criteria into the process of allocating kidneys to recipients, given the scarcity of this resource. 2) To assess the tradeoffs between systems that allocate kidneys based only on medical criteria, systems that allocate kidneys based only on equity criteria, and systems that consider both medical and equity criteria. METHODS: A computer-based simulation was developed that describes the flows of patients and kidneys. This model provides information at various time points about the number of patients in the system who are awaiting transplants, the number of kidneys available for transplantation, the number of transplantations performed for each matching algorithm, and the number of kidneys discarded (when applicable), as well as the means and standard deviations of the HLA-match scores, number of days from registration to transplantation, and number of days (from registration) of those who are still waiting for transplants. Five different matching algorithms were compared, ranging from determination of the allocation by a single medical criterion (i.e, HLA match) to determination by a single equity criterion (i.e., relative position in the waiting queue). The remaining algorithms represent different strategies of weighting these two considerations. Estimates regarding the main parameters of the model were derived utilizing data collected through the Multiple Organ Retrieval and Exchange Programme of Ontario, Canada. RESULTS: The simulation was set to run for a period of ten years. A tradeoff between graft survival (or improved HLA matching) and equal treatment of patients regardless of their likelihood to benefit was found. It is clear that an algorithm that allocates kidneys based only on temporal location of patient on the waiting list is likely to be unacceptable because of the very poor average HLA-match scores that it yields. Pool size was found to be a major determinant in the attainment of optimal matching from a medical perspective. CONCLUSIONS: 1) The final choice about any allocation algorithm to be used requires that a value judgment be made, i.e., how great a reduction in HLA-match score should be traded in order to improve equity score (or vice versa). 2) A computer-based simulation model is a feasible way to prospectively test the impact of any given allocation algorithm on any given system.

Renal biopsy specimens from patients with rheumatoid arthritis and apparently normal renal function after therapy with cyclosporine. Canadian Multicentre Rheumatology Group.

Renal biopsies were performed in 14 patients with severe rheumatoid arthritis who had no evidence of compromised renal function after completion of treatment with low-dose cyclosporine (< or = 5 mg/kg/d). Mean serum creatinine at the time of biopsy was 0.84 mg/dL (range, 0.59 to 1.23 mg/dL). In the 13 patients who had received 6 months of cyclosporine therapy, mild glomerular expansion was noted in two biopsy specimens, obsolescent glomeruli (range, 5% to 20%) in five, and glomerular amyloid deposits in one. Five biopsy specimens had mild and three had mild to moderate interstitial fibrosis. Moderate interstitial fibrosis with a striped pattern was attributed to cyclosporine in the 14th patient. The results of a second biopsy performed in one patient after a further 18 months of therapy were unchanged. Although the renal biopsy changes were minimal in 13 patients and pathologic features characteristic of cyclosporine nephropathy were absent from all but one biopsy, a greater frequency of adverse effects due to cyclosporine could not be excluded. In the absence of clinical data, long-term cyclosporine therapy must be administered with caution to patients with rheumatoid arthritis, who commonly have underlying renal damage, and the value of renal biopsies in predicting and preventing end-stage renal failure remains to be determined.

Cyclosporin A nephropathy in patients with rheumatoid arthritis.

Patients with RA are at risk of cyclosporin A (CyA) toxicity as they have an increased incidence of underlying renal pathology and because of the probable co-administration of NSAIDs. CyA dose, blood levels, and changes in serum creatinine are linked to the severity of renal biopsy changes in patients with RA and other autoimmune disorders, but only limited data regarding the safety of long-term CyA therapy have been reported. Low-dose CyA (preferably without NSAID co-administration) should be reserved for those patients with a poor prognosis who can be carefully monitored using a combination of renal function studies, CyA blood levels and renal biopsy assessment. Consideration should be given to the development of a management strategy that includes renal biopsy at defined intervals in order to detect the onset of progressive renal damage, and which could potentially allow eligible patients to benefit from long-term CyA therapy.

The quality of life in renal transplantation--a prospective study.

Methodologically sound measures of quality of life are required to judge accurately the impact of successful renal transplantation on patient well-being. The time trade-off (TTO) method is a reproducible and valid measure which we used to prospectively assess changes in the quality of life of 27 patients on maintenance dialysis who subsequently underwent renal transplantation. TTO scores approaching 0 signify a very poor quality of life, while scores approaching 1 represent perfect health. Of 98 dialysis patients who completed baseline TTO interviews, 31 consecutive patients subsequently received 28 cadaveric and 3 living related kidney transplants. Four of 31 patients did not complete a second TTO assessment, because of death in 2 patients and graft loss in 2 others. The remaining 27 patients completed a second TTO interview an average of 30.9 months following transplantation (range 1.5-52, 95% confidence interval [CI] 24.4-37.5) and formed the study cohort. At the time of study the mean serum creatinine for the cohort was 173 mumol/L (range 90-290, 95% CI 152-195 mumol/L). The employment rate rose 27% following transplantation (P = 0.10); but when males alone were analyzed, a significant increase of 38% (P = 0.048) was noted. During the dialysis period, the mean baseline TTO score was 0.41 (95% CI 0.33-0.49), confirming the observations of others. Following transplantation, the mean TTO score rose to 0.74 (95% CI 0.67-0.81), a difference that is statistically significant (P < 0.001). The mean increase in TTO score observed as a result of successful transplantation was 0.33 (95% CI 0.26-0.40). This magnitude of improvement was found in 20 of 27 patients (74%), whose TTO scores lay within or above the 95% CI (0.26-0.40) for the mean change in score of 0.33. One patient's score fell, while the remaining 6 patients had improvements in their TTO score which fell below the lower 95% CI value (0.26) for the mean change in score. We conclude that the 95% CI of 0.26-0.40 identifies a range in which clinically important improvements in quality of life will be found for the majority of patients receiving successful kidney transplants.

Terminal loop cutaneous ureterostomy in renal transplantation.

Patients presenting for renal transplantation with urinary diversion abnormalities pose serious problems. The use of a terminal loop cutaneous ureterostomy (TLCU) in patients whose outcome was satisfactory was first described in 1977. Primary urinary drainage was achieved in 3 recipients of cadaver renal allografts by creating a TLCU. This method of drainage has been satisfactory in these patients with follow-up between four and thirty months. We suggest that this simple technique should be considered more frequently for selected patients who require supravesical urinary diversion.

Cyclosporine nephrotoxicity in rheumatoid arthritis: no effect of short term misoprostol treatment.

We assessed the effect of the prostaglandin E1 analog misoprostol on cyclosporine nephrotoxicity in patients with rheumatoid arthritis (RA). Thirteen patients with RA were given cyclosporine with misoprostol tablets, 800 micrograms/day for one week in a randomized, double blind, placebo controlled crossover trial. All had cyclosporine nephrotoxicity, documented by an increase in serum creatinine of at least 15% over the values before the start of cyclosporine treatment. Mean glomerular filtration rate (GFR) (single shot 51Cr-EDTA plasma clearance) at baseline was 77.3 ml/min (SD, 22.0). After misoprostol, it was 80.0 ml/min (SD, 18.9); after placebo, 79.1 ml/min (SD, 20.0). None of these changes were statistically significant. Serum creatinine levels and whole blood cyclosporine levels were also unchanged. Power to detect at least a 5 ml/min rise in GFR was 0.92. Short term misoprostol treatment does not improve the GFR of patients with RA on cyclosporine.

A comparison of evaluative indices of quality of life and cognitive function in hemodialysis patients.

In the setting of end-stage renal disease, the reproducibility and responsiveness of three health-related quality-of-life instruments were evaluated. The Time Trade Off instrument (TTO) is a generic instrument used to evaluate the utility of a health state. The Hemodialysis Quality-of-Life questionnaire (HQL) is a disease-specific instrument. A series of function-specific tests evaluated neurocognitive function. The TTO and HQL instruments are patient centric in that patient values define the health status while the neurocognitive function tests reflect the values of healthcare professionals. Forty-seven chronic hemodialysis patients participated. Those with adequate dialysis, defined as a Kt/V (a measure of small solute removal during hemodialysis) above 1.0 were maintained at the level for two administrations of the three instruments separated by six to eight weeks. The test-retest intraclass correlation coefficient exceeded 0.90 for all five domains of the HQL questionnaire and exceeded 0.70 for nine neurocognitive function tests. Patients with inadequate dialysis (Kt/V less than 0.8) had Kt/V increased to above 1.0. The TTO was not responsive. For the HQL questionnaire, an item was considered responsive if a 1-point improvement, on a 7-point Likert type scale, occurred significantly more often among those with an improvement in hemodialysis treatment compared to those without improvement. Only one item had such a change and therefore the HQL cannot be considered responsive.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclosporine monitoring in autoimmune and other diseases.

Cyclosporine (CsA) is being increasingly used for the treatment of disorders other than transplantation. In contrast to transplant recipients, most of these patients can have CsA therapy discontinued without life-threatening consequences, and the dose of CsA can therefore be restricted in order to limit the incidence and severity of toxicity, including nephrotoxicity. The utility of either CsA blood levels or pharmacokinetic profiling to ensure adequacy of therapy or to prevent incipient as well as overt toxicity has not been confirmed in this group of patients, and prevention of nephrotoxicity usually depends on limiting the dose of CsA and careful assessment of renal function. Frequent measurement of CsA levels beyond the initiation period in patients with autoimmune and other nontransplant diseases cannot be currently justified, and should be reserved for those situations where drug interactions, unexpected toxicity or the possibility of inadequate therapy is likely.

Early function as the principal correlate of graft survival. A multivariate analysis of 200 cadaveric renal transplants treated with a protocol incorporating antilymphocyte globulin and cyclosporine.

We examined the factors determining graft survival in 200 consecutive cadaveric renal transplants managed on a quadruple-therapy protocol: Minnesota antilymphoblast globulin, cyclosporine, azathioprine, and low-dose prednisone. Perioperative central venous pressure monitoring and volume expansion were emphasized. To avoid CsA nephrotoxicity in the early posttransplant period, patients were treated with ALG until renal function was established (a mean of 7 days). Therapeutic CsA levels were achieved before ALG was discontinued. Azathioprine was used to supplement CsA in patients with nephrotoxicity or rejection. Twelve-month graft survival was 85% (first transplants 86%, retransplants 79%), with patient survival of 95%. ALG was not associated with excessive clinical cytomegalovirus infections, which occurred in 5% of patients, or with malignancy. When 3 technical failures were excluded, an analysis of numerous factors in the pretransplant and peritransplant period revealed that the strongest correlate of one-year graft survival was early renal function. Grafts with delayed function (DF) had 75% survival, compared with 91% for grafts with good early function (EF). A multivariate analysis confirmed this association: the relative risk of graft loss was increased 2.86 times for DF compared with EF. The mechanism of the deleterious effect of DF was apparently multifactorial: the DF group, by definition, contained all the kidneys that never functioned, but some risk also persisted in kidneys that achieved function. One reason for this may be that DF kidneys that achieved function had higher mean serum creatinine values at 1 month: elevated serum creatinine values at 1 month were strongly associated with increased risk of graft loss regardless of initial function. There was also a higher number of rejection episodes diagnosed in the DF group. These observations suggest that early renal function is a major determinant of graft outcome and should be a target for efforts to further improve renal graft survival.

Production in vitro of antibodies directed against alloantigen-specific recognition sites on T cells and on lymphocytotoxic HLA antibodies.

We have examined the mechanism of immunological unresponsiveness in a recipient (P.S.) with a long-term functioning renal allograft. P.S., whose HLA type is A1, A30; B14, B18; DR1, w8; DRw52; DQw1 and in whose serum we had earlier demonstrated the presence of antiidiotypic antibodies, received a kidney from a cadaver donor of HLA type A1, A10, B8 in March, 1970. Peripheral blood B lymphocytes from the patient were transformed with Epstein-Barr virus (EBV), and by the cluster-picking technique a B cell line was propagated with continuous production of antibodies. Antiidiotypic antibodies with two distinct biological functions were demonstrable; one specifically inhibiting the lymphocytotoxic activity of anti-HLA-B8, B5, and DR3 reference typing sera, and the other specifically inhibiting proliferative responses in MLC of the recipient's lymphocytes and of third party cells sharing B14, DR1, DQw1 with the patient against stimulator cells carrying B8, DR3 antigens. Immunodepletion experiments demonstrated that the inhibitory activity was associated with the IgM fraction. Absorption experiments suggested that different antibodies may be responsible for the inhibition of lymphocytotoxic activity of anti-HLA sera and of the proliferative responses in MLC. Antiidiotypic antibodies have been postulated to be important in maintaining allograft tolerance in vivo, thereby enhancing renal allograft survival. The availability of such antibodies in large quantities, produced in vitro, could provide antisera for the immunochemical characterization of specific idiotypic receptors on immunoglobulins and T lymphocytes.