Effect of an Early Switch to Belatacept Among Calcineurin Inhibitor-Intolerant Graft Recipients of Kidneys From Extended-Criteria Donors.

Transplant recipients receiving a kidney from an extended-criteria donor (ECD) are exposed to calcineurin inhibitor (CNI) nephrotoxicity, as demonstrated by severe delayed graft function and/or a low GFR. Belatacept is a nonnephrotoxic drug that is indicated as an alternative to CNIs. We reported 25 cases of conversion from a CNI to belatacept due to CNI intolerance within the first 6 mo after transplantation. The mean age of the recipients was 59 years, and 24 of 25 patients received ECD kidneys. At the date of the medication switch, 12 of 25 patients displayed a calculated GFR (cGFR) <15 mL/min, six patients remained on dialysis, and the biopsies showed evidence of acute tubular damage associated with severe vascular or tubulointerstitial chronic lesions. Three patients did not recover renal function, and three patients died during the follow-up period. Among the remaining patients, renal function improved: The cGFR was 18.28 ± 12.3 mL/min before the medication switch compared with 34.9 ± 14.5 mL/min at 1 year after conversion to belatacept (p = 0.002). Tolerance of and compliance with belatacept were good, and only one patient experienced acute rejection. Belatacept is an effective therapy that preserves renal function in kidney transplant patients who are intolerant of CNIs.

Acute disseminated encephalomyelitis in two renal transplant patients: is there a role for Epstein-Barr virus reactivation?

Acute disseminated encephalomyelitis (ADEM) is a rare inflammatory demyelinating disease of the central nervous system, usually occurring after a vaccination or infectious disease. It has been exceptionally described in transplanted patients. The pathophysiology remains incompletely understood. We report the clinical, biological and magnetic resonance imaging (MRI) presentation and evolution of two kidney-transplanted patients with ADEM associated with local Epstein-Barr virus (EBV) reactivation. ADEM may occur in transplanted patients with favorable evolution. Its pathophysiology is uncertain, and the implication of EBV is discussed.

Antihypertensive effect of amlodipine and lack of interference with cyclosporine metabolism in renal transplant recipients.

The catabolism of various calcium channel blockers through cytochrome P-450 is heterogeneous and may be modified by concomitant use of cyclosporin A. In an open study we investigated the antihypertensive effect and clinical tolerance of the dihydropyridine amlodipine and its effects on cyclosporine kinetics in stable hypertensive renal transplant recipients not taking corticosteroids. Ten adult hypertensive patients grafted for 21.4 +/- 8.9 months and well stabilized with normal renal function were included in the study. Renal artery stenosis was ruled out by normal Doppler echography. After 2 weeks of placebo, amlodipine was started at a daily dose of 5 mg. The dose was then adjusted to 10 mg if necessary. Blood and urine chemistries and whole-blood cyclosporine trough levels were measured weekly. Cyclosporine kinetics were determined on a hourly basis before amlodipine administration and after 4 weeks of treatment. Normal blood pressure was obtained with the use of 5 mg/d amlodipine in 7 patients and 10 mg/d in 3, diastolic blood pressure decreasing from 98.7 +/- 3.8 to 81.3 +/- 9.1 mm Hg (P = .0007). Heart rate slightly increased by 10% (P < .02). The drug was well tolerated, and only minor ankle edema was found in 3 patients. Cyclosporine doses were not modified and cyclosporine levels remained unchanged throughout the study. Cyclosporine kinetic parameters were not significantly different at the beginning and end of the study. Bioequivalence was demonstrated indicating that cyclosporine biotransformation was not altered by the concomitant administration of amlodipine.(ABSTRACT TRUNCATED AT 250 WORDS)

Factors predicting the long-term success of maintenance cyclosporine monotherapy after kidney transplantation.

BACKGROUND: The theoretical aim of maintenance cyclosporine monotherapy (mCsA) after kidney transplantation is to reduce the incidence of the metabolic complications of corticosteroids and to minimize the adverse effects of excessive long-term immunosuppression. This study was performed in low-immunological-risk cadaveric kidney transplant recipients to evaluate the risks and benefits of mCsA and the long-term graft survival, and to determine the factors predicting success of this policy. METHODS: The multicenter retrospective study was conducted in 329 Caucasian patients receiving mCsA out of 728 first cadaveric kidney transplant recipients. The inclusion criteria were: HLA antibodies < or =25%, serum creatinine <200 micromol/L, and no rejection or only one rejection episode. At the end of the study, we compared the group of patients successfully treated with mCsA (successful group) with those requiring additional immunosuppressive agents (unsuccessful mCsA group). RESULTS: Overall patient and graft survival rates for the 728 first cadaveric graft were 92% and 64%, respectively, at 8 years. Out of 329 patients enrolled in mCsA, 240 were maintained on this treatment and 89 were withdrawn (3 deaths, 18 graft losses, 68 functional grafts). The 8-year graft survival in the 329 enrolled mCsA patients was 84%, 95% in the successful mCsA group, and 70% in the unsuccessful mCsA group. Multivariate analysis showed that the factors predicting success of mCsA were: donor age <40 years (P = 0.001), serum creatinine at mCsA initiation <125 micromol/L (P = 0.02), no rejection episode before mCsA initiation (P = 0.005), and glomerulopathy as the primary renal disease (P = 0.001). CONCLUSION: Numerous kidney transplant recipients with a low immunological risk and good and stable renal function may benefit from discontinuation of prednisone and azathioprine in order to reduce the complications related to these drugs. This therapeutic approach had no adverse impact on the overall long-term graft survival for "low risk" and successful patients.

Long-term follow-up of acute renal failure caused by angiotensin converting enzyme inhibitors.

Angiotensin converting enzyme (ACE) inhibitors are useful in the treatment of hypertension and heart failure. However, acute renal failure (ARF) may occur in patients who are taking these drugs in situations associated with decreased glomerular filtration pressure, such as dehydration caused by acute diarrhea or diuretic therapy. Sixty-four patients who were admitted to the intensive care unit for ARF associated with ACE inhibitor therapy were followed for more than 5 years. In this historical retrospective study, we documented that 45 patients were treated for hypertension (group I) and 19 were treated for heart failure (group II). Their mean age was 71.2+/-11.6 years. Patients with ARF presented with overt dehydration in 91% and 84% of the cases in groups I and II, respectively. Hypovolemia was caused by diuretics or gastrointestinal fluid loss. Bilateral artery-renal stenosis or stenosis in a solitary kidney was documented in 22% and 10% of patients in groups I and II, respectively. The probability of survival was 91% and 49% at 1 year and 64% and 18% at 5 years, for groups I and II, respectively. Acute renal failure required hemodialysis in seven patients, but none of them became dialysis dependent. In the subgroup of patients with preexisting chronic renal failure, all the patients except for one who belonged to group II died within 2 years. In both groups, after resolution of ARF, plasma creatinine concentration returned to baseline level and the course of renal function was not significantly worsened. In conclusion, ARF associated with ACE inhibitors is likely to occur in many patients without renal artery stenosis after unexpected dehydration, especially in older patients with congestive heart failure. In both groups of patients, in the absence of preexisting chronic uremia, recovery of renal function occurred without sequelae, even after an episode of acute tubular necrosis requiring dialysis.

Beta 2-microglobulin metabolism in uremic patients who are undergoing dialysis.

Plasma beta 2-microglobulin (beta 2m) is increased in chronically hemodialyzed patients and remains in a steady range once residual diuresis has stopped. Factors controlling such a steady state are unknown. We undertook metabolic studies to define whether plasma beta 2m is regulated by extrarenal proteolysis of the protein or by storage in a captation pool, a condition which may precede beta 2m-derived amyloidogenesis. Seventeen uremic patients on supportive therapy and five healthy controls were enrolled into the 6 to 10 day study. Using trace amounts of 131I-beta 2m and total body counting, half-life was between 2.4 and 8 days. 125I-beta 2m plasma kinetics was more suitable to calculate fractional catabolic rate and synthetic rate. A three compartment model was chosen to calculate turnover parameters in dialysis patients, whereas the regular two compartment model fitted best for healthy controls. beta 2m synthesis rate was increased in uremic patients when compared with controls (4.49 +/- 2.60 vs. 3.68 +/- 1.43 mg/kg/day, NS). The three compartment model did not integrate all the experimental data, since it was possible to calculate a captation compartment which accumulated beta 2m without fast proteolysis. The captation pool was positively correlated with plasma beta 2m concentration and comprised between 23% and 59% of the amount of the beta 2m disappearing from plasma per day. In conclusion, metabolic studies with radioiodinated beta 2m indicate a slight increase in beta 2m synthesis rate in uremic patients on supportive therapy, irrespective of the technique in use. Kinetic analysis requires a model taking into account a storage compartment which is more complex than the three compartment model.(ABSTRACT TRUNCATED AT 250 WORDS)

213 elderly uremic patients over 75 years of age treated with long-term peritoneal dialysis: a French multicenter study.

UNLABELLED: We report our experience in 213 elderly patients over 75 years treated by peritoneal dialysis (PD) as first and exclusive dialysis therapy. The mean age at start of PD was 79.4 +/- 3.6 years, and the cumulative time on PD was 4551 months (mean time: 21.4 +/- 19.8 months). Twenty-six patients lived in institutions and 187 lived at home. Thirty patients had an effective autonomy with the ability to carry on normal activities. One hundred and two patients were cared for by a private nurse at home, and 46 patients were cared for in a family environment. Most cases were treated by three exchanges per day (152 cases) and used a nondisconnect system (175 cases) on account of absence of autonomy. The rate of peritonitis per patient-month was one episode per 16.8 patient-months. Patient survival (Kaplan-Meier curves) was 74%, 59%, 45%, and 19% at one, two, three, and five years, respectively. The causes of death were various with a higher frequency of cardiovascular causes (48.3% of the 116 deaths). Thirty-three patients died in less than six months including 18 patients in less than three months. IN CONCLUSION: elderly uremic patients can be treated with long-term PD with relatively good results. Mortality is high but essentially due to age and poor general status-the dedication of private home nursing is very important in treating elderly PD patients. This fact often is a necessary condition in maintaining these elderly patients at home.

Detection of subclinical abdominal hernia by peritoneal scintigraphy.

This study investigated the incidence of subclinical abdominal hernia in patients starting peritoneal dialysis (PD). From April 1995 to August 1999, every new patient without clinical evidence of abdominal leakage underwent peritoneal scintigraphy. A total of 59 patients were enrolled in the study. Imaging of the peritoneal cavity was performed by mixing 74 MBq (2 mCi) of 99 m technetium sulfur colloid with 2 L of 1.36% dextrose peritoneal dialysis solution. Sequential gamma camera static images were obtained at 0 minutes, 60 minutes, and after drainage. Ten abdominal hernias (2 diaphragmatic leaks, 8 inguinal hernias) were observed in ten patients (6 males, 4 females; mean age: 65.1 years). One patient with diaphragmatic leak recovered partial renal function and stopped continuous ambulatory peritoneal dialysis (CAPD); the other was switched to automated peritoneal dialysis (APD). Among the eight patients with inguinal hernia, six had no clinical manifestations within eight months of follow-up. Two patients became symptomatic at 15 months and 25 months respectively. They underwent surgical repair. In CAPD patients without obvious abdominal hernias, peritoneal scintigraphy at onset of dialysis discovered 17% positive cases. The technique of scintigraphy is safe, with a low radiation exposure. Surgical repair for maintenance on CAPD is not always necessary, and a change in the PD strategy may be useful.

[A "sweet" hydrothorax]. / Un hydrothorax "sucré".

BACKGROUND: Hydrothorax is a rare complication of continuous ambulatory peritoneal dialysis (CAPD). CASE REPORT: A 68-year-old man on CAPD consulted for rapidly progressive dyspnea. An elevated glucose level in the pleural puncture fluid and Tc-99m peritoneoscitigraphy demonstrated pleuroperitoneal communication via Larrey's cleft led to the diagnosis of "sweet" hydrothorax. Resolution was achieved with pleurocentesis and interruption of CAPD. DISCUSSION: Although rare, hydrothorax should be retained as a possible diagnosis in patients who develop dyspnea within the first 2 months after institution of CAPD. Chemistry of the pleural fluid and Tc-99m scintigraphy provide the diagnosis. Conservative treatment by pleural puncture or pleurodesis is indicated. In most cases, CAPD can be resumed without recurrence.

[Treatment of legionellosis with ofloxacin in kidney transplanted patients. Lack of interaction with cyclosporin A]. / Traitement des légionelloses par ofloxacine chez le transplanté rénal. Absence d'interférence avec la ciclosporine A.

Seven cases of legionellosis were observed in a series of 81 renal transplant recipients. In the 6 patients with functional graft, pneumonia occurred 17 days on average after the beginning of transplant rejection treatment. The diagnosis was made by bronchoalveolar lavage: the direct immunofluorescence antigen technique was positive in 5 cases and culture in 6 cases. Legionella pneumophila sero-groups 5 and 1 were identified in one and 5 patients respectively. Six of the 7 patients were treated with ofloxacin. This fluoroquinolone was effective in all cases. It was administered as single therapy in 3 patients and did not interfere with ciclosporin A metabolism. Ofloxacin given in mean doses of 400 mg per day adjusted to renal function proved to be a simple, effective and well tolerated treatment of legionellosis in transplant recipients receiving ciclosporin A.

[Hemorrhagic fever with renal syndrome due to Hantaan virus or a serologically related virus]. / Fièvre hémorragique avec syndrome rénal due au virus Hantaan ou à un virus sérologiquement apparenté.

Seven cases of acute renal failure consecutive to haemorrhagic fever with renal syndrome (HFRS) due to the Hantaan virus or to a serologically related virus are reported. These cases were observed in north-eastern France between March, 1983 and January, 1984. All patients were of rural origin and had been in contact with field mice. The predominant initial clinical symptoms were signs of infection and diffuse muscle pain, without evidence of haemorrhage. However, massive proteinuria was noted, and acute anuric renal failure unaccompanied by oedema or arterial hypertension developed. Renal biopsy performed in 2 patients showed tubular and interstitial nephritis but no glomerular or vascular lesions. Two patients only required haemodialysis. All patients recovered within 2 to 8 weeks without sequelae. Antibodies directed against the Hantaan virus were detected by indirect immunofluorescence tests, and seroconversion could be demonstrated in 2 patients seen at a sufficiently early stage. The risk of epidemics suggested by this small outbreak of HFRS can only be evaluated after an exhaustive epidemiological study.

[Sympathectomy by phenol infiltration in the treatment of chronic obliterative arteriopathies of the lower limbs. Comparison between 60 statistical cases and 35 surgical sympathectomies (author's transl)]. / La sympathectomie au phénol dans le traitement des artériopathies chroniques oblitérantes des membres inférieurs. Comparaison d'une statistique de 60 cas avec 35 sympathectomies chirurgicales.

The authors compare the results obtained by the use of two different lumbar sympathectomy techniques in patients with chronic obliterative arterial disease of the lower limbs. Surgical resection was employed in 35 cases, and infiltration with phenol under radiological control in 60 cases. The proportion of successful results was about the same in both groups, best results being obtained in younger patients with less advanced disease. No mortality occurred in the group treated by phenol infiltration. Transient neuralgia was reported in some cases, but hospital stay was reduced by an average of 10 days, and many cases could be treated as out-patients. More than half of the patients did not require operation or amputation after phenol infiltration, which is, therefore, a very valuable associated therapeutic measure, especially in the elderly.

Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation.

Efficacy and safety of mycophenolate mofetil (MMF) may be optimized with individualized doses based on therapeutic monitoring of its active metabolite, mycophenolic acid (MPA). In this 12-month study, 137 renal allograft recipients from 11 French centers receiving basiliximab, cyclosporine A, MMF and corticosteroids were randomized to receive either concentration-controlled doses or fixed-dose MMF. A novel Bayesian estimator of MPA AUC based on three-point sampling was used to individualize doses on posttransplant days 7 and 14 and months 1, 3 and 6. The primary endpoint was treatment failure (death, graft loss, acute rejection and MMF discontinuation). Data from 65 patients/group were analyzed. At month 12, the concentration-controlled group had fewer treatment failures (p = 0.03) and acute rejection episodes (p = 0.01) with no differences in adverse event frequency. The MMF dose was higher in the concentration-controlled group at day 14 (p < 0.0001), month 1 (p < 0.0001) and month 3 (p < 0.01), as were median AUCs on day 14 (33.7 vs. 27.1 mg*h/L; p = 0.0001) and at month 1 (45.0 vs. 30.9 mg*h/L; p < 0.0001). Therapeutic MPA monitoring using a limited sampling strategy can reduce the risk of treatment failure and acute rejection in renal allograft recipients 12 months posttransplant with no increase in adverse events.

Kinin-dependent hypersensitivity reactions in hemodialysis: metabolic and genetic factors.

Although the association of angiotensin I-converting enzyme inhibitors (ACEis) with a negatively charged membrane is thought to be responsible for hypersensitivity reactions (HSRs) during hemodialysis, we hypothesize that these complications are due to changes in plasma aminopeptidase P (APP) activity and genotype. To test this hypothesis, we measured plasma APP activity in 14 patients who suffered HSR (HSR+) while dialyzed with an AN69 membrane and simultaneously treated with an ACEi. APP activity was also studied in a control group (n=39) dialyzed under the same conditions, but who did not suffer any side effect (HSR-). We found significantly decreased plasma APP activity (P=0.013) in HSR+ subjects as well as altered degradation of endogenous des-Arginine(9)-bradykinin, with a significantly lower beta value (P<0.001). The same analytical approach was taken in 171 relatives of HSR+ patients. Variance component analysis suggested that genetic differences may explain 61% of the phenotypic variability of plasma APP activity (P<0.001) and the kinetic parameters that characterized kinin degradation. We also showed that the C-2399A single-nucleotide polymorphism at the XPNPEP2 locus was a significant predictor of APP activity in the 39 HSR- controls (P=0.029). Furthermore, a recessive genetic model for the A allele disclosed a significant difference in mean APP activity by genotype (P<0.001). Finally, our study defined the nonspecific inhibition of recombinant APP by some ACEis. In conclusion, this paper highlights the complexity of HSR in hemodialysis, suggesting, as with angioedema, that these rare, but life-threatening adverse events are governed by several metabolic and genetic factors.