Reduction of Extended-Release Tacrolimus Dose in Low-Immunological-Risk Kidney Transplant Recipients Increases Risk of Rejection and Appearance of Donor-Specific Antibodies: A Randomized Study.

The aim of this study (ClinicalTrials.gov, NCT01744470) was to determine the efficacy and safety of two different doses of extended-release tacrolimus (TacER) in kidney transplant recipients (KTRs) between 4 and 12 mo after transplantation. Stable steroid-free KTRs were randomized (1:1) after 4 mo: Group A had a 50% reduction in TacER dose with a targeted TacER trough level (C0 ) >3 µg/L; group B had no change in TacER dose (TacER C0 7-12 µg/L). The primary outcome was estimated GFR at 1 year. Of 300 patients, the intent-to-treat analysis included 186 patients (group A, n = 87; group B, n = 99). TacER C0 was lower in group A than in group B at 6 mo (4.1 ± 2.7 vs. 6.7 ± 3.9 µg/L, p < 0.0001) and 12 mo (5.6 ± 2.0 vs. 7.4 ± 2.1 µg/L, p < 0.0001). Estimated GFR was similar in both groups at 12 mo (group A, 56.0 ± 17.5 mL/min per 1.73 m²; group B, 56.0 ± 22.1 mL/min per 1.73 m²). More rejection episodes occurred in group A than group B (11 vs. 3; p = 0.016). At 1 year, subclinical inflammation occurred more frequently in group A than group B (inflammation score [i] >0: 21.4% vs. 8.8%, p = 0.047; tubulitis score [t] >0: 19.6% vs. 8.7%, p = 0.076; i + t: 1.14 ± 1.21 vs. 0.72 ± 1.01, p = 0.038). Anti-HLA donor-specific antibodies appeared only in group A (6 vs. 0 patients, p = 0.008). TacER C0 should be maintained >7 µg/L during the first year after transplantation in low-immunological-risk, steroid-free KTRs receiving a moderate dose of mycophenolic acid.

[Acquired copper deficiency myelopathy]. / Myélopathie postérieure par carence en cuivre acquise.

INTRODUCTION: The hematological manifestations of acquired copper deficiency are well known. But the neurological manifestations have only been recognised in the past few years. The most common neurological manifestation in adults is a myeloneuropathy with prominent sensory ataxia and spastic gait. Electrophysiological tests reveal an axonal sensorimotor peripheral neuropathy. Spinal MRI shows an augmented T2 signal involving the dorsal column. The causes of acquired copper deficiency include gastric surgery, excessive zinc ingestion, and malabsorption but in most cases, the cause remains unclear. Early recognition and treatment may prevent neurological deterioration but improvement seems to be slight and inconstant. OBSERVATION: We report two new cases of acquired copper deficiency myeloneuropathy associated with a nephrotic syndrome and, in one case, with a major iron overload syndrome. Biological abnormalities disappeared under copper supplementation. A significant neurological improvement with disappearance of ataxia occurred in one patient who received copper supplementation eight months after symptom onset. CONCLUSIONS: Nephrotic syndrome might be another complication of acquired copper deficiency. Delayed treatment is not necessarily associated with a deleterious neurological prognosis. Significant neurological improvement under copper supplementation is possible.

[Immunosuppression, ongoing clinical trials]. / Immunosuppression, les essais cliniques en cours.

MONOCLONAL ANTIBODIES: Monoclonal antibodies have been humanized to improve their duration of action and their tolerance. Lymphocyte-depleting humanized anti-CD3 antibodies are globally well tolerated. Coupled with an immunotoxin, Campath 1H, a humanized anti-CD3 antibody with specific anti-CD52 depleting properties which also depletes immunocompetent cells, is being tested. There is increasing interest in the use of monoclonal antibodies in combination with rapamycin. SIROLIMUS AND EVEROLIMUS: The half-life of sirolimus is twice that of everolimus. Otherwise quite similar, these compounds have dose-dependent side effects: leukopenia, thrombocytopenia, hyperlipidemia. There use allows a lower dosage for the calcineurin inhibitor. Sirolimus is particularly active in reducing intimal proliferation within the vessel walls. Precise indications at the present time include induction of tolerance, withdrawal of the calcineurin inhibitor, use of low-dose calcineurin inhibitor, and corticosteroid withdrawal. ELIMINATING THE SIDE EFFECTS OF CORTICOSTEROIDS: Complications resulting from the use of corticosteroids, particularly bone complications, are still a problem with the low doses used in long-term regimens for transplant recipients. Several means have been proposed to reduce the risk. Total withdrawal is possible, but the risk of an increased rate of acute rejection limits indications. It appears that total withdrawal then complete abstention is not compatible immunologically. IMMUNOSUPPRESSORS IN PERSPECTIVE: Three groups of compounds have immunosuppressor potential: anti-adhesion molecule antibodies, co-stimulation blockers, and molecules inhibiting T-lymphocyte activators and their signalization factors.

Induction versus noninduction in renal transplant recipients with tacrolimus-based immunosuppression.

BACKGROUND: The aim of this study was to compare the efficacy and safety of induction treatment with antithymocyte globulins (ATG) followed by tacrolimus therapy with immediate tacrolimus therapy in renal transplant recipients. METHODS: This 12-month, open, prospective study was conducted in 15 centers in France and 1 center in Belgium; 309 patients were randomized to receive either induction therapy with ATG (n=151) followed by initiation of tacrolimus on day 9 or immediate tacrolimus-based triple therapy (n=158). In both study arms, the initial daily tacrolimus dose was 0.2 mg/kg. Steroid boluses were given in the first 2 days and tapered thereafter from 20 mg/day to 5 mg/day. Azathioprine was administered at 1-2 mg/kg per day. RESULTS: At month 12, biopsy-confirmed acute rejections were reported for 15.2% (induction) and 30.4% (noninduction) of patients (P=0.001). The incidence of steroid-sensitive acute rejections was 7.9% (induction) and 22.2% (noninduction)(P=0.001). Steroid-resistant acute rejections were reported for 8.6% (induction) and 8.9% (noninduction) of patients. A total of nine patients died. Patient survival and graft survival at month 12 was similar in both treatment groups (97.4% vs. 96.8% and 92.1% vs. 91.1%, respectively). Statistically significant differences in the incidence of adverse events were found for cytomegalovirus (CMV) infection (induction, 32.5% vs. noninduction, 19.0%, P=0.009), leukopenia (37.3% vs. 9.5%, P<0.001), fever (25.2% vs. 10.1%, P=0.001), herpes simplex (17.9% vs. 5.7%, P=0.001), and thrombocytopenia (11.3% vs. 3.2%, P=0.007). In the induction group, serum sickness was observed in 10.6% of patients. The incidence of new onset diabetes mellitus was 3.4% (induction) and 4.5% (noninduction). CONCLUSION: Low incidences of acute rejection were found in both treatment arms. Induction treatment with ATG has the advantage of a lower incidence of acute rejection, but it significantly increases adverse events, particularly CMV infection.

[Natural history of vascular ports for hemodialysis after renal transplantation]. / Histoire naturelle des abords vasculaires pour l'hémodialyse après transplantation rénale.

INTRODUCTION: The objective of this study was to assess the long-term outcome of AV shunts in renal transplant recipients, to discuss mechanisms affecting their functioning and the surgical strategy designed to optimally preserve the venous capital in the hypothesis of a return to dialysis. MATERIALS AND METHODS: 160 renal transplant recipients, with a mean age of 47 years, were reviewed. AV shunts were performed at the wrist in 95% of cases and in the cubital fossa in 13% of cases. The AV shunt had been performed an average of 29 months before renal transplantation. RESULTS: 62% of AV shunts were considered to be functional with a mean follow-up of 69 months after transplantation and 95 months after creation. The intraoperative and early and late postoperative thrombosis rates were 6%, 7.5% and 17%, respectively. The AV shunt was subsequently closed in 12 patients (7.5%). CONCLUSION: Native distal AV shunts, although not used after renal transplantation, have a prolonged survival. The main risk is thrombosis which can be prevented intraoperative and perioperatively. These results encourage a conservative attitude to all well tolerated AV shunts.

Contribution of 99Tcm-DMSA scintigraphy to aetiological diagnosis in renal transplant recipients with impaired renal function.

Routine 99Tcm-dimercaptosuccinic acid (DMSA) scintigraphy was performed in a series of 24 kidney transplant recipients with impaired renal function. Diagnostic findings on planar and tomoscintigraphic acquisitions obtained 3 and 4 h after the injection of 130-140 MBq 99Tcm-DMSA were compared with the diagnosis established by fine-needle biopsy in 13 patients and by clinical course and other examinations (ultrasonography, bacteriology) in 11 patients. Renal scintigraphy demonstrated segmental defects in patients with rejection (n = 2/6), immunosuppressor nephrotoxicity (n = 2/6), acute pyelonephritis (n = 3/3), renal artery stenosis (n = 1/1) and obstructive lymphocele (n = 1/1). Diffuse lack of uptake was observed in one patient with severe renal failure. The scintigram was normal in 14 patients, including three with lesions histologically compatible with graft rejection or immunosuppressor nephrotoxicity. 99Tcm-DMSA was thus found to contribute little to the differential diagnosis between graft rejection and immunosuppressor nephrotoxicity. However, it may be useful for identifying specific disease states, particularly acute pyelonephritis, seen as well-delimited systematized defects. 99Tcm-DMSA scintigraphy could also be used in late follow-up after pyelonephritis in renal transplant recipients.

[Polyradiculoneuropathy in an adult with primitive hyperoxaluria]. / Polyradiculoneuropathie au cours d'une hyperoxalurie primitive de l'adulte.

From the age of 31 a patient began to suffer from recurrent calcium oxalate urolithiasis. Liver biopsy showed a decrease in catalytic activity of the hepatic peroxisomal enzyme alanine: glyoxilate aminotransferase (AGT), which was mistargeted from peroxisomes to mitochondria. The genetic analysis revealed a mutation of the AGT gene. At age 47 he developed end-stage renal failure and underwent hemodialysis. After 12 months of hemodialysis he presented a rapidly declining clinical condition, a decrease of the residual renal function, a livedo reticularis with painful of extremities, and shortly thereafter a general weakness, which predominated on lower limbs. Apart from renal failure, routine biological examination and CSF were normal. Nerve conduction studies and electromyography supported the diagnosis of polyradiculoneuropathy. Pathological studies revealed mixed demyelinating-axonal lesions and deposits of calcium oxalate crystals within the media and the intima of epineural arterioles. A combined liver-kidney transplant was rapidly performed. The patient's condition improved in a few months and motor signs completely disappeared.

[Calcified intertrigo, a rare cause of cutaneous calcinosis]. / Intertrigo calcifie une forme rare de calcinose cutanee.

INTRODUCTION: Calcinosis cutis is classically described in patients presenting chronic renal failure with secondary hyperparathyroidism. There are three clinical types described in the literature: cutaneous necrosis (secondary to vascular calcification), panniculitis with calcification of the adipose tissue and necrosis of the skin and dermo-hypodermic calcinosis without necrosis usually called metastatic calcinosis. The latter can affect all tissues but skin involvement is rare. CASE REPORT: A case of calcinosis cutis is presented in a 50 years old woman with moderate secondary hyperparathyroidism and chronic renal failure caused by renal amyloidosis. She was referred by the renal unit to our service for erythematous, woody-hard, infiltrated plaques with petechial purpura satellite lesions, involving the flexural areas, that appeared within a few weeks. DISCUSSION: This observation is original by the topography of the cutaneous lesions the involvement of the fexural areas is unusual and by the histologic aspect of pseudoxanthome elastic-like. We must notice that the hyperparathyroidism had always been very moderate (normal parathormonemia) compared to the rapid development of an important dermic calcinosis.

[Neurotoxicity of acyclovir in peritoneal dialysis apropos of 1 case]. / Neurotoxicité de l'aciclovir chez le dialysé péritonéal à propos d'un cas.

We report a case of reversible myoclonic encephalopathy which appeared after intravenous acyclovir treatment in a patient in CAPD for which pharmacological dosages have been made in serum, peritoneal dialysate and cerebrospinal fluid (CSF). Encephalopathy appeared after two intravenous doses of 7.33 mg/kg (doses higher than recommended), administered on admission and 16 hours later. Pharmacological dosages indicated that acyclovir peritoneal clearance was negligible, and that acyclovir persisted a long time in plasma and CSF. Neurological symptoms persisted although serum concentrations returned to normal value. The diagnostic value of pharmacological dosages in serum and CSF is discussed. In addition, neurological symptoms disappeared following two consecutive hemodialysis procedures. Hence we suggest that hemodialysis could be used for drug removal in case of acyclovir overdose in CAPD patients.

[Anti-basement-membrane antibody mediated, rapidly progressive, glomerulonephritis. Diagnostic and therapeutic strategy based on a retrospective study of 14 cases]. / Glomérulonéphrites rapidement progressives à anticorps anti-membrane basale glomérulaire. Stratégie diagnostique et thérapeutique à partir d'une étude rétrospective de 14 cas.

Fourteen cases of anti-GBM antibody-induced RPGN were evaluated retrospectively in terms of renal function improvement and therapeutic risks. Nine men and 5 women (mean age: 55.3 years) were observed over a 9 year period; in three patients, hemoptysis was associated with renal disease (Goodpasture's syndrome). Most of these patients had received combinations of steroid therapy (ST), immunosuppressive drugs (IS) and plasma exchanges (PE). Age, duration of symptoms prior to diagnosis, initial renal function, therapeutic modalities and complications were assessed according to renal outcome: 9 patients (group A, "non-responders") remained on dialysis irrespective of the treatment administered; 5 patients (group B, "responders") recovered renal function. Complications, especially infections, were twice as frequent in group A. Two of the 4 recorded deaths were related to the disease or the treatment. Analysis of clinical and pathological values at the time of entry into the study for both groups indicated that oliguria/anuria, serum creatinine greater than 500 mumol/l and greater than 50% crescents, when associated, were factors predictive of poor renal outcome; in these patients, dialysis may be required except in cases of pulmonary hemorrhage. In all other patients, treatment with ST, IS and PE is recommended. Active hemoptysis necessitates pulse steroids or PE; if absent, further tests (carbon monoxide uptake, bronchoalveolar lavage, lung biopsy) are indicated before use of aggressive therapy.

Predictive factors of the blood pressure fall induced by intravenous nicardipine.

The effect on blood pressure of the dihydropyridine derivative nicardipine was studied in 87 essential hypertensive patients aged 25-77 years. A total cumulative dose of 8.75 mg nicardipine was administered over a 30-min period by continuous intravenous infusion. The dose was doubled every 10 min from 1.25 to 5.0 mg. The mean blood pressure fall and the heart rate rise were both dose-related. At 30 min, mean blood pressure fell by 18.9 +/- 7.5% vs. baseline values (p less than 0.001), heart rate increased by 28.0 +/- 11.8% (p less than 0.001), and the renin level by 20.7 +/- 32.5% (p less than 0.001). The blood pressure fall was correlated positively with age (r = 0.521; p less than 0.001) and negatively with the rise in heart rate (r = -0.308; p less than 0.01) and renin level (r = -0.205; p = 0.05). After eliminating the linear effects of age by the partial correlation method, blood pressure fall and the initial renin level were no longer correlated (r = -0.046, NS), whereas the positive correlation between age and blood pressure fall persisted after eliminating the effect of renin (r = 0.464; p less than 0.001). The slope of the regression line for the heart rate rise vs. the blood pressure fall was taken to reflect the baroreflex sensitivity. This sensitivity was negatively correlated to age (r = -0.515; n = 51; p less than 0.001) in the 51 of the 87 patients for whom it could be calculated.(ABSTRACT TRUNCATED AT 250 WORDS)