Paul Kinnaert

Release of tumor necrosis factor, interleukin-2, and gamma-interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients

High levels of tumor necrosis factor-alpha, interleukin-2, and gamma-interferon appeared in the circulation of kidney transplant recipients after the first injection of the monoclonal antibody OKT3. This initial injection was systematically followed by fever. The three cytokines were released in all patients (n = 9), with peak serum levels of tumor necrosis factor occurring 1 hr after OKT3 injection and those of interleukin-2 and gamma-interferon after 2 hr. Cytokines were not released after the second and third OKT3 injections, when CD3+ cells had disappeared from blood. These findings suggest that circulating cytokines are released by T cells after activation by OKT3. These cytokines are probably involved in the systematic reactions observed after injection of OKT3.

Induction of thromboses within renal grafts by high-dose prophylactic OKT3

Among 93 consecutive kidney-transplant patients who received prophylactic OKT3 10 mg/day for 2 weeks, 9 had intragraft thromboses within 2 weeks of transplantation. The thromboses were in graft artery in 1 patient and veins in 3. The other 5 had thromboses in glomerular capillaries and thrombotic microangiopathy similar to that of haemolytic-uraemic syndrome. All attempted treatments failed, and the 9 grafts had to be removed. The finding that plasma concentrations of prothrombin fragment 1 and 2 were higher 4 h after the first OKT3 dose in OKT3 recipients than in transplant patients who received other prophylaxis (mean 5.88 [SEM 0.76] vs 2.25 [0.59] nmol/l, p less than 0.01) confirms that OKT3 has procoagulant effects in vivo.

Absence of deleterious effect on long-term kidney graft survival of rejection episodes with complete functional recovery.

BACKGROUND Rejection episodes (RE) exert a detrimental influence on long-term kidney graft outcome. However, the impact of the severity of those RE on graft survival and the factors that could predict this impact are ill defined. The present retrospective study was undertaken on adult patients who received 582 cadaver kidney transplants at our center during the last 12 years, to assess the impact on graft survival of RE occurring during the first year after transplantation and to uncover the factors associated with the severity of those RE. METHODS Three grades of rejection were defined: (1) rejection without loss of graft function (benign rejection); (2) rejection followed by partial loss of graft function (severe rejection); and (3) rejection with return to dialysis (irreversible rejection). The grafts were distributed among four groups: (1) grafts free of rejection; (2) grafts with benign RE (only grade 1 RE); (3) grafts with severe RE (one or more grade 2 RE); and (4) grafts with irreversible (grade 3) RE. RESULTS Multivariate analyses revealed that (1) the occurrence of RE during the first posttransplant year (group 1 versus groups 2, 3, and 4) was significantly associated with primary immunosuppression with CsA rather than with OKT3 monoclonal antibody, the number of HLA-B + DR mismatches, and the younger recipients age; (2) in patients with rejection, OKT3 monoclonal antibody prophylaxis was less often used in patients with irreversible RE (group 4) than in those with reversible RE (group 2, benign, and group 3, severe); and (3) no single factor was able to differentiate patients with benign RE (group 2) from those with severe RE (group 3). For grafts still functioning 1 year after transplantation, long-term graft survival was similar in grafts with either no RE or benign RE, but it was significantly lower (P<0.0001) in grafts with severe RE: 8-year survival rates were 89% and 60%, respectively. The decline in graft survival after 1 year was significantly correlated with the serum creatinine value but not with the dose of cyclosporine at 1 year. CONCLUSIONS Benign RE occurring during the first year after transplantation and resulting in no loss of graft function do not exert a detrimental influence on long-term kidney graft outcome. In contrast, the prognosis of grafts with severe RE during the same period of time is much poorer.

The long-term effects of prophylactic OKT3 monoclonal antibody in cadaver kidney transplantation : a single-center, prospective, randomized study

We conducted a randomized, prospective study to determine the long-term effects of prophylactic OKT3 in cadaveric renal transplantation. In the first group of patients (n=56) OKT3 (5 mg/day) was administered for the first 14 postoperative days in association with azathioprine (AZA) and low-dose steroids, cyclosporine (CsA) being introduced on day 11. The other group of patients (n=52) received CsA from the first POD, together with AZA and steroids. Both protocols were identical from POD 14 on. The total number of infections was higher in OKT3 patients (124/1455 patient-months [P-M] vs. 68/1320 in CsA patients, P<0.001) without impact on patient survival (94.5% in OKT3 vs. 93% in CsA patients). OKT3 patients experienced a lower number of rejection episodes (61 per 1455 P-M of risk exposure vs. 81/1320 in CsA patients, P<0.05). In addition, the frequency of corticoresistant rejection episodes was lower in OKT3 patients (9 out of 61 vs. 24 out of 81 in CsA patients, P<0.05). This resulted in a trend toward improved overall graft survival (83% vs. 75%, P=0.12) and in a significant increase in immunological graft survival (92% vs. 79%, P=0.02) in OKT3 patients at 3 years. Taken together, these data suggest that prophylactic OKT3 therapy might have long-term beneficial effects in cadaveric renal transplantation.

Ureteral Stenosis After Kidney Transplantation: True Incidence and Long-Term Followup After Surgical Correction

Between March 1965 and December 31, 1982, 421 kidney transplantations were performed in our department. The over-all incidence of ureteral stenosis was 5.5 per cent. However, when the number of patients at risk at various times after transplantation was considered the probability for ureteral stenosis to develop was 4.6 per cent at 1 year, 7.7 per cent at 2 years and 9.7 per cent at 5 years. Preoperative and postoperative complications were frequent. The wound infection rate was 21.9 per cent and 2 of the 24 patients died of septic shock. Graft survival rate after definitive surgical correction of ureteral stenosis was 71 per cent at 1 and 2 years, and 65 per cent at 3 years. Late results justify the efforts to re-establish correct urinary drainage of the graft.

Evidence that pentoxifylline reduces anti-CD3 monoclonal antibody-induced cytokine release syndrome.

Pretreatment with pentoxifylline (PTX), a methylxanthine known for its beneficial effects on tissue lesions induced by the injection of endotoxin or recombinant cytokines, was shown to decrease the systemic release of tumor necrosis factor and interleukin 2 occurring after the administration of the anti-CD3 monoclonal antibody 145–2C11 in mice. In parallel, PTX attenuated the hypothermia and the rise in blood urea nitrogen observed in this model. The protective effect of PTX on the toxicity of 145–2C11 was confirmed by the reduction of the mortality among D-galactosamine-sensitized animals. The mitigation by PTX of the release of cytokines did not affect the immunosuppression entailed by 145–2C11 as assessed by the unmodified cytotoxic T lymphocytes (CTL) unresponsiveness against alloantigens measured 48 hr after the injection of the mAb. In vitro experiments on human peripheral blood leu

Male recipients of kidneys from female donors are at increased risk of graft loss from both rejection and technical failure

The aim of the present retrospective study was to uncover the factor(s) responsible for the poor outcome of cadaver kidney grafts from female donors in male recipients.The 741 transplantations performed at our center from August 1983 to September 1997 were distributed into four groups according to recipient and donor gender: female donor to female recipient (F to F: n=117), male donor to female recipient (M to F: n=172), female donor to male recipient (F to M: n=170), and male donor to male recipient (M to M: n=282). All the patients received immunosuppressive therapy based on corticosteroids and cyclosporine, associated or not with either azathioprine or prophylactic anti‐lymphocyte globulin.Overall graft survival was lower in the F to M group than in the three other groups (p=0.009). Failures due to rejection were more frequent during the 1st post‐transplant trimester in female than in male donor grafts, irrespective of recipient gender (p=0.025). All failures due to technical problems occurred during the first 3 months post‐transplantation: they were more frequent in the F to M group than in the three other groups (p=0.040); this could be related to the older age of the donors in the former group. After the first post‐transplant year, failures due to causes other than rejection remained low in the F to F group but increased steadily in the three other groups (p=0.007). Specific survival rates were not correlated with the time‐evolution of mean serum creatinine values, daily doses and trough levels of cyclosporine in the four groups of grafts. In conclusion, the poor outcome of F to M grafts results from combined immunologic and technical factors exerting their effects early in the course of transplantation.

Renal transplantation exposes patients with previous Kaposi's sarcoma to a high risk of recurrence

It is currently estimated that about 0.5% of patients will develop Kaposis sarcoma (KS) after kidney transplantation. Tapering of immunosuppression often leads to KS remission, but also results in graft loss in more than 50% of cases. Whether retransplantation is safe in these patients is unknown. We here report on eight patients who developed KS recurrence after kidney transplantation-(A) Patients with previously treated KS: There were 4 patients who had clinical remission of KS (including three posttransplantation) for periods ranging from 5 months up to 19 years before transplantation. All 4 developed KS recurrence within months after transplantation. In 3 patients, KS regressed only when all immunosuppression was discontinued, at the price of allograft removal. Partial remission occurred in the fourth patient following reduction of immunosuppression and gancyclovir administration; (B) Patients with recurrent KS during a single transplant: 4 patients developed KS after transplantation that regressed following reduction of immunosuppressive therapy. Increased immunosuppression, in the form of steroid pulses in 3 patients was associated with recurrence of KS. Subsequent reduction of immunosuppression caused regression of KS in all 4 patients, but 2 recipients lost their allografts. These data emphasize the high risk of recurrence of KS after renal transplantation. If physicians decide to transplant patients with a history of KS, they should inform the future recipient of the possibility of KS recurrence.

Persistent Hyperparathyroidism Requiring Surgical Treatment after Kidney Transplantation

There are not many publications describing long-term follow-up of persistent hyperparathyroidism requiring surgical treatment after kidney transplantation (PHSKT). In some patients adenomas, rather than multiglandular disease, have been incriminated as the cause of PHSKT. We reviewed the charts of 45 patients followed for 12 to 146 months (median 45 months) after parathyroidectomy for PHSKT. We compared them with (1) those of 951 patients receiving a kidney graft during the same period but not submitted to parathyroidectomy or (2) 90 matched controls selected from this cohort to determine the characteristics of PHSKT patients. The duration of pretransplant dialysis was significantly longer in PHSKT patients than in controls (5.78 ± 0.41 vs. 3.41 ± 0.24 years; p < 0.0001). A total of 166 glands were removed or biopsied. Except for one questionable case, no true adenoma was observed even when only one gland was enlarged. The outcome of surgery was not influenced by the technique (subtotal parathyroidectomy versus total parathyroidectomy and autografting) but depended on the amount of resected parathyroid tissue: no failures and 4 cases of hypoparathyroidism in 34 cases with no missing gland at cervical exploration; 3 failures and no permanent hypoparathyroidism in 11 cases with one or two missing glands. Excision of the enlarged glands only was sufficient to cure the patient. No recurrence was observed. Our results suggest that single gland enlargement in PHSKT results in most cases from different rates of involution of the parathyroids after successful kidney transplantation. When fewer than four glands are discovered, resection of all visible glands with or without grafting corrects hypercalcemia in more than 70% of the cases.

Intermittent claudication of the hand after creation of an arteriovenous fistula in the forearm

Eighty-five patients were followed up at least 1 year after creation of an arteriovenous fistula in the forearm. The anastomosis was side-to-side in 33 patients, end-to-side in 33 and end-to-end in 19. Trophic lesions were not observed. Intermittent claudication of the hand was more frequent in patients with a side-to-side arteriovenous fistula (42 percent) than in those with end-to-side (21 percent) or end-to-end fistulas (16 percent). Clinical and x-ray studies indicate that two different mechanisms are responsible for cramping pains: arterial steal phenomenon and venous hypertension. Their relative importance depends on multiple hemodynamic factors that may vary with time.