Specificity of histological markers of long-term CNI nephrotoxicity in kidney-transplant recipients under low-dose cyclosporine therapy.

The specificity of chronic histological lesions induced by calcineurin inhibitors (CNI) is often questioned, but few studies have directly compared long-term lesions in renal-transplant patients who received this treatment and those who did not. We therefore conducted a retrospective study of 141 kidney-transplant recipients treated with (n = 48) or without (n = 93) cyclosporine (CsA) to compare the histological lesions observed at 3-month, 24-month and 10-year protocol biopsies. All of the chronic elementary lesions (glomerulosclerosis, interstitial fibrosis, tubular atrophy, arteriolar hyalinosis, fibrointimal thickening) progressed in frequency and severity in both groups, although significantly more in the CsA group. Ten-year biopsy results showed that 92% of patients in the CsA-treated group and 65% in the control group had arteriolar hyalinosis lesions. When we focused on muscular arteriolar hyaline deposits more specific to CsA arteriolopathy, we observed these lesions in 68% of CsA patients and 28% of patients who had never received CsA. CsA was not the sole factor involved in the development of arteriolar hyalinosis and was independently associated with an increased risk of graft loss. In summary, we observed that histological lesions commonly attributed to CsA nephrotoxicity were not sufficiently specific to definitively diagnose CNI nephrotoxicity.

Interstitial fibrosis evolution on early sequential screening renal allograft biopsies using quantitative image analysis.

Screening renal biopsies (RB) may assess early changes of interstitial fibrosis (IF) after transplantation. The aim of this study was to quantify IF by automatic color image analysis on sequential RB. We analyzed RB performed at day (D) 0, month (M) 3 and M12 from 140 renal transplant recipients with a program of color segmentation imaging. The mean IF score was 19 ± 9% at D0, 27 ± 11% at M3 and 32 ± 11% at M12 with a 8% progression during the first 3 months and 5% between M3 and M12. IF at M3 was correlated with estimated glomerular rate (eGFR) at M3, 12 and 24 (p < 0.02) and IF at M12 with eGFR at M12 and 48 (p < 0.05). Furthermore, IF evolution between D0 and M3 (ΔIFM3-D0) was correlated with eGFR at M24, 36 and 48 (p < 0.03). IF at M12 was significantly associated with male donor gender and tacrolimus dose (p = 0.03). ΔIFM3-D0 was significantly associated with male donor gender, acute rejection episodes (p = 0.04) and diabetes mellitus (p = 0.02). Thus, significant IF is already present before transplantation. IF evolution is more important during the first 3 months and has some predictive ability for change in GFR. Intervention to decrease IF should be applied early, i.e. before 3 months, after transplantation.

A tribute to Jean Hamburger's contribution to organ transplantation.

Jean Hamburger, one of the pioneers of scientific medicine in the mid-20th century, who was involved in the inception of intensive care, nephrology, hemodialysis and scientific clinical research, has also been one of the very few fathers of human organ transplantation. He was involved in the primary French kidney transplantations in 1950, and in 1952, he realized the first allotransplantation in the world of a kidney removed from a voluntary living donor. At the same time, he was the first to describe the various clinical and pathological aspects of acute rejection. He suggested the use of cortisone for the treatment of rejection as early as 1950 and promoted nonlethal body irradiation, which was successfully used in 1959 both by John Merrill in Boston and by himself in Paris, to prevent allograft rejection. In October 1962, in collaboration with Maurice Goulon, he was the first to use a kidney removed from an individual in 'coma dépassé'. He and his group contributed to transplant immunosuppression, to transplant immunology, to organ preservation, to acute and chronic rejection pathology and so on. As early as 1956-1957, he understood the potential importance of Jean Dausset's discovery for transplantation.

Severe vascular lesions and poor functional outcome in kidney transplant recipients with lupus anticoagulant antibodies.

The impact of antiphospholipid antibodies (APA) on clinical outcome and graft histology following renal transplantation remains poorly known and controversial. We retrospectively explored the functional and histological significance of APA, primarily lupus anticoagulant (LA), in kidney transplant recipients using a systematic evaluation of 3- and 12-month posttransplant screening biopsies and glomerular filtration rate measurements (mGFR). During the study period, 37 patients had APA (2.7%), primarily LA, and 12 fulfilled antiphospholipid syndrome (APS) diagnostic criteria (0.8%) at the time of transplantation. Early after transplantation, 4 of the 12 APS patients died. Early thrombosis of graft vessels and deep venous thrombosis occurred more frequently in APA+ patients than in controls (27% vs. 7%, p < 0.05 and 35% vs. 14%, p < 0.05, respectively). The survival rate was significantly lower in patients with APS. Strikingly, the hallmark lesions of APS-associated nephropathy (APSN) were found in most of screening graft biopsies in APA+ patients but not in the controls. Accordingly, APA+ patients had a dramatic increase in chronic vascular scores and a faster decline in mGFR at 1 year. In conclusion, renal transplantation may be life-threatening in APS patients, and the presence of LA at the time of transplantation is associated with a high rate of allograft APSN and poor transplantation outcomes.

KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary

The 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on the monitoring, management, and treatment of kidney transplant recipients is intended to assist the practitioner caring for adults and children after kidney transplantation. The guideline development process followed an evidence-based approach, and management recommendations are based on systematic reviews of relevant treatment trials. Critical appraisal of the quality of the evidence and the strength of recommendations followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. The guideline makes recommendations for immunosuppression and graft monitoring, as well as prevention and treatment of infection, cardiovascular disease, malignancy, and other complications that are common in kidney transplant recipients, including hematological and bone disorders. Limitations of the evidence, especially the lack of definitive clinical outcome trials, are discussed and suggestions are provided for future research. This summary includes a brief description of methodology and the complete guideline recommendations but does not include the rationale and references for each recommendation, which are published elsewhere.

Kidney transplantation at Necker Hospital: the most recent 5-year period (2004-2009).

The results of our last 5 years activity in kidney transplantation clearly show that it is possible to perform high-risk transplantations with very acceptable results: ECD kidneys, dual transplantation, recipients with DSAs. In depth statistical analysis of these data should allow a clearer definition of the best strategies to use in these situations.

Donor-estimated GFR as an appropriate criterion for allocation of ECD kidneys into single or dual kidney transplantation.

It has been suggested that dual kidney transplantation (DKT) improves outcomes for expanded criteria donor (ECD) kidneys. However, no criteria for allocation to single or dual transplantation have been assessed prospectively. The strategy of DKT remains underused and potentially eligible kidneys are frequently discarded. We prospectively compared 81 DKT and 70 single kidney transplant (SKT) receiving grafts from ECD donors aged >65 years, allocated according to donor estimated glomerular filtration rate (eGFR): DKT if eGFR between 30 and 60 mL/min, SKT if eGFR greater than 60 mL/min. Patient and graft survival were similar in the two groups. In the DKT group, 13/81 patients lost one of their two kidneys due to hemorrhage, arterial or venous thrombosis. Mean eGFR at month 12 was similar in the DKT and SKT groups (47.8 mL/min and 46.4 mL/min, respectively). Simulated allocation of kidneys according to criteria based on day 0 donor parameters such as those described by Remuzzi et al., Andres et al. and UNOS, did not indicate an improvement in 12-month eGFR compared to our allocation based on donor eGFR.

Incidence, risk factors and clinical consequences of neutropenia following kidney transplantation: a retrospective study.

Neutropenic episodes in kidney transplant patients are poorly characterized. In this retrospective study, neutropenia was experienced by 112/395 patients (28%) during the first year posttransplant. The only factor found to be significantly associated with the occurrence of neutropenia was combined tacrolimus-mycophenolate therapy (p < 0.001). Neutropenic patients experienced more bacterial infections (43% vs. 32%, p = 0.04). Grade of neutropenia correlated with the global risk of infection. Discontinuation of mycophenolic acid (MPA) due to neutropenia was associated with an increased incidence of acute rejection (odds ratios per day 1.11, 95% confidence intervals 1.02-1.22) but not with reduced renal function at 1 year. The time from onset of neutropenia to MPA discontinuation correlated with the duration of neutropenia. Granulocyte colony-stimulating factor (G-CSF) administration was safe and effective in severely neutropenic kidney graft recipients, with absolute neutrophil count >1000/microL achieved in a mean of 1.5+/-0.5 days. Neutropenia is an important and frequent laboratory finding that may exert a significant influence on outcomes in kidney transplantation. As well as leading to an increased incidence of infection, it is associated with a higher rate of allograft rejection if MPA is discontinued for >6 days (p = 0.02). G-CSF accelerates recovery of neutropenia and may be a good therapeutic alternative for severely neutropenic patients.

Sirolimus may reduce fertility in male renal transplant recipients.

Assessment of sex hormones in organ transplant recipients suggests that sirolimus may impair testicular function. The aim of this study was to evaluate the frequency and severity of sirolimus-associated alterations in sperm parameters and their impact on fathered pregnancy rate. An observational study was carried out in male patients aged 20-40 years who received a kidney transplant during 1995-2005. Patients were sent a questionnaire by post, and sperm analysis was proposed. The fathered pregnancy rates according to the immunosuppressive regimen were estimated and compared using the Poisson model. Complete information was obtained from 95 out of 116 recipients. Patients treated with sirolimus throughout the post-transplant period had a significantly reduced total sperm count compared to patients who did not receive sirolimus (28.6 +/- 31.2 x 10(6) and 292.2 +/- 271.2 x 10(6), respectively; p = 0.006), and a decreased proportion of motile spermatozoa (22.2 +/- 12.3% and 41.0 +/- 14.5%, p = 0.01). Moreover, the fathered pregnancy rate (pregnancies/1000 patient years) was 5.9 (95% CI, 0.8-42.1) and 92.9 (95% CI, 66.4-130.0) in patients receiving sirolimus-based and sirolimus-free regimens, respectively (p = 0.007). Of six patients in whom sirolimus treatment was interrupted, only three showed a significant improvement in sperm parameters. Sirolimus is associated with impaired spermatogenesis and, as a corollary, may reduce male fertility.

Polymorphisms in the novel serotonin receptor subunit gene HTR3C show different risks for acute chemotherapy-induced vomiting after anthracycline chemotherapy.

The aim of this study was to correlate chemotherapy-induced nausea and vomiting (CINV) with commonly occurring single nucleotide polymorphisms (SNP) in the 5-hydroxytryptamine receptor 3 genes (HTR3). Women with breast cancer without previous chemotherapy were eligible for this prospective study. All patients received epirubicin, with or without cyclophosphamide, and preventive medication with ondansetron and dexamethasone. The patients documented every vomiting event on an hourly basis. Real-time polymerase chain reaction (PCR) analysis was performed for the following nonsynonymous SNPs: p.Y129S (HTR3B), p.K163N (HTR3C) and p.A405G (HTR3C). The overall proportion of patients (total n = 110) who reported vomiting in the first 24 h after chemotherapy was 31.8%. The variant genotype of K163N (HTR3C) was associated with vomiting, which occurred in 50.0% (P = 0.009). Polymorphisms in the HTR3C gene could serve as a predictive factor for CINV in patients undergoing moderately emetogenic chemotherapy.

Patients' attitudes to totally implantable venous access port systems for gynecological or breast malignancies.

AIMS: The aim of this study was to analyze patients' port-related quality of life. PATIENTS AND METHODS: 260 consecutive patients with gynecological or breast malignancies were asked to take part in a questionnaire-based survey including 26 questions, and 232 women agreed to participate in the study. The questionnaire inquired about port-related aspects of everyday life and the use of a central venous access port device for chemotherapy and supportive cancer care. Multivariate analysis was used to identify parameters associated with satisfaction and dissatisfaction in relation to the port. RESULTS: Most of the women were very satisfied with the use of a port to provide venous access for chemotherapy and supportive cancer care. Faster hospital procedures, good cosmetic results, and the ability to cope with the social environment had a significant influence on the degree of satisfaction. Fear of port punctures, inconvenient heparinization of the port, and fear of complications were found to be negative variables associated with the method. CONCLUSIONS: Port catheters are well accepted by patients for chemotherapy and supportive cancer care. Generally ports should be rapidly removed after the end of antineoplastic treatment in order to improve patients' satisfaction with the procedure.

[Sirolimus-induced onychopathy in renal transplant recipients]. / Onychopathie associée au sirolimus chez les transplantés rénaux.

INTRODUCTION: A large number of drugs may be responsible for the development of nail changes. Sirolimus is an immunosuppressive drug recently developed in organ transplantation. Herein, we evaluate sirolimus-induced nail abnormalities in renal transplant recipients. PATIENTS AND METHODS: The nails of 80 consecutive renal transplant recipients receiving sirolimus have been evaluated in a systematic dermatological study in 2003. The patients were mainly men (60%) with a mean age of 48 years. The mean duration of the graft was 6 years and of sirolimus treatment 18 months. Mycophenolate mofetil and steroids were combined with sirolimus in 86% of patients. RESULTS: Fifty-seven patients (74%) complained for nail alterations. The most frequent anomalies (88%) were matrix alterations including slow growth, onychomalacia, onychorrexis, and leukonychia. Nail bed alterations (onycholysis), vascular phenomenon (erythema, splinter hemorrhages), and periungual anomalies (mainly pyogenic granulomas) were observed in 42, 42 and 19% of cases respectively. One observation of type 1 photo-onycholysis was described. DISCUSSION: This study reports a new drug-induced onychopathy. Responsibility of sirolimus is highly suggested. The main pathogenesis hypothesis to explain these nail alterations is inhibition of EGF (epidermal growth factor) pathway by sirolimus.

Sirolimus-based therapy with or without cyclosporine: long-term follow-up in renal transplant patients.

This open-label, phase 3b, extension trial in renal transplant recipients (Sirolimus Study 311) assessed the long-term safety of sirolimus (SRL) administered with cyclosporine (CsA) (SRL + CsA group, n = 98) or without CsA (SRL group, n = 69). Renal transplant recipients who had either completed one of seven previous SRL studies sponsored by Wyeth Research or had participated for > or =3 months and reached a protocol-designated endpoint were eligible for enrollment. Data were available for 167 patients, all of whom initially received steroids. Mean total SRL exposure was 1526 days, including previous study participation. After enrollment in the extension study, there were significantly more acute rejections in the SRL + CsA group (6.1% vs 0%, P < .05). Differences in rates of graft loss (3.1% vs 1.4%) and death (6.1% vs 1.4%) were not significantly different between SRL + CsA and SRL groups, respectively. At 48 months after transplantation, calculated GFR (53.4 vs 70.9 mL/min) and hemoglobin (124.9 vs 136.6 g/L) were significantly better in the SRL group. Lipid values were not significantly different between groups at 48 months. The incidence of treatment-emergent increased creatinine, anemia, hypertension, headache, epistaxis, abnormal kidney function, and upper respiratory infection were significantly higher in the SRL + CsA group, whereas no adverse events were significantly higher in the SRL group. Malignancies were reported more frequently (11.2% vs 0%) with SRL + CsA. Results from this extension study indicate that SRL-based therapy without CsA is a safe alternative to combination therapy with CsA, offering long-term improvement in renal function with no increased risk of late acute rejection.

Awareness of breast cancer incidence and risk factors among healthy women.

The efficacy of early breast cancer detection programmes seems to be mainly influenced by the awareness of breast cancer in general among healthy women. This study aimed to provide information about women's understanding of breast cancer incidence and risk of disease. Based on a newly developed questionnaire 2108 healthy women were asked about their knowledge and perceptions in relation to breast cancer incidence, risk factors, risk perception and level of concern. Of these women 78.8% were well aware of breast cancer in general terms. However, there were major aspects such as incidence or risk factors that were poorly understood. Only one-third correctly estimated the incidence of breast cancer; 95% understood breast cancer in the familial history as a risk factor, but only 57% understood the age risk; 37.1% of women perceived hormonal contraceptives and 35.9% hormonal replacement therapy as risk factors of breast cancer. The latter estimation was significantly higher in women above 40 years. Recommendations for the improvement of cancer prevention programmes include targeting understanding of lifetime risk of breast cancer, age as a risk factor, survival from breast cancer or hormonal factors. There is a need to separately address the perceptions of women depending on age, social status and educational levels.

Mycobacterium xenopi pulmonary infection in two renal transplant recipients under sirolimus therapy.

Opportunistic infection is a major threat to immunocompromised patients. However, infection due to Mycobacterium xenopi is rare in renal transplant recipients. We report two new cases of M. xenopi pulmonary infection (one case of interstitial pneumopathy and one of a pulmonary nodule) in renal transplant recipients, detected in the same center at an interval of a few months. Both patients were on an immunosuppressive regimen including a recent switch to sirolimus. Sirolimus is a new immunosuppressive drug already known to be responsible for interstitial pneumonitis. It also inhibits interleukin-12-induced proliferation of activated T lymphocytes, which is critical for the development of the cell-mediated immunity that protects against mycobacteria. These two case reports suggest that sirolimus therapy may lead to an impairment of the immune response against intracellular pathogens such as M. xenopi.

[EBV-associated cutaneous plasmocytoma in a renal transplant patient]. / Plasmocytome cutané EBV+ isolé chez une malade transplantée rénale: efficacité d'un traitement par rituximab.

INTRODUCTION: Postransplant lymphoproliferative disorders are well known complications of solid organ transplant, usually associated with Epstein-Barr virus (EBV). OBSERVATION: A 25 year old renal transplant patient presented with two subcutaneous nodules on the lower limb that appeared 3 years after a second renal transplantation. Biopsy of one nodule showed an EBV associated plasmocytoma located in the subcutaneous tissue. A complete systemic evaluation showed no evidence of extracutaneous involvement. The patient was treated with anti CD20 therapy (rituximab), and complete remission was achieved. DISCUSSION: Extranodular localisations of postransplant lymphoproliferative disorders are usually reported, but cutaneous localizations are rarely described. Histological presentation are various, but plasmocytoma-type is infrequent. Initial therapy of cutaneous EBV-associated postransplant lymphoproliferative disorders without extracutaneous involvement consists in reduction of the immunosuppression therapy and/or an antiviral treatment and prolonged surveillance. Treatment with monoclonal anti-CD20 antibodies (rituximab) is proposed.

Bicêtre hospital experience with sirolimus-based therapy in human renal transplantation: the Sirolimus European Renal Transplant Study.

In 11 European centers, first cadaveric renal allograft recipients were randomized to CsA (n = 42) or sirolimus (n = 41). Dosing of these agents was concentration-controlled and open-labeled. All patients received corticosteroids and azathioprine. At 12 months, graft survival (98% sirolimus vs 93% CsA), patient survival (100% vs 98%), and incidence of biopsy-confirmed acute rejection (41% vs 38%) were similar. Serum creatinine was lower with sirolimus, significantly (P

[Progressive renal failure caused by lithium nephropathy]. / Insuffisance rénale évolutive par néphropathie au lithium.

OBJECTIVES: Study the renal consequences of lithium therapy and find out whether lithium-induced chronic renal toxicity can provoke a progressive nephropathy, leading to advanced renal failure, requiring periodical dialysis. METHODS: Fifty-three patients treated with long-term lithium salts were included in the study. They had developed chronic renal failure (creatinine clearance inferior to 80 ml/min) not due to any other cause. RESULTS: These patients had received lithium salts for a mean period of 17.7 years. The mean reduction in creatinine clearance was of 2.23 ml/min/year. Final clearance correlated negatively with the duration of lithium administration. In 7 patients treated a mean of 22 years, progression towards terminal kidney failure required periodical dialysis. Around 30% of patients exhibited mild hypercalcemia. CONCLUSION: Lithium nephropathy inducing progressive renal failure is a reality. Its prevalence in patients treated long-term with lithium should be assessed.