[Skin pigmentation induced by meropenem and levofloxacin]. / Hyperpigmentation cutanée induite par le méropénème et la lévofloxacine.

BACKGROUND: Various cutaneous side-effects, including, exanthema, pruritus, urticaria and Lyell or Stevens-Johnson syndrome, have been reported with meropenem (carbapenem), a rarely-prescribed antibiotic. Levofloxacin (fluoroquinolone), a more frequently prescribed antibiotic, has similar cutaneous side-effects, as well as photosensitivity. We report a case of cutaneous hyperpigmentation induced by meropenem and levofloxacin. PATIENTS AND METHODS: A 67-year-old male was treated with meropenem (1g×4 daily), levofloxacin (500mg twice daily) and amikacin (500mg daily) for 2 weeks, followed by meropenem, levofloxacin and rifampicin (600mg twice daily) for 4 weeks for osteitis of the fifth metatarsal. Three weeks after initiation of antibiotic therapy, dark hyperpigmentation appeared on the lower limbs, predominantly on the anterior aspects of the legs. Histology revealed dark, perivascular and interstitial deposits throughout the dermis, which stained with both Fontana-Masson and Perls stains. Infrared microspectroscopy revealed meropenem in the dermis of involved skin. After withdrawal of the antibiotics, the pigmentation subsided slowly. DISCUSSION: Similar cases of cutaneous hyperpigmentation have been reported after use of minocycline. In these cases, histological examination also showed iron and/or melanin deposits within the dermis, but the nature of the causative pigment remains unclear. In our case, infrared spectroscopy enabled us to identify meropenem in the dermis. Two cases of cutaneous hyperpigmentation have been reported following use of levofloxacin, and the results of histological examination were similar. This is the first case of cutaneous hyperpigmentation induced by meropenem.

Renal Involvement in a French Paediatric Cohort of Patients with Lysinuric Protein Intolerance.

Lysinuric protein intolerance (LPI) is a rare autosomal recessive metabolic disorder, caused by defective transport of cationic amino acids at the basolateral membrane of epithelial cells, typically in intestines and kidneys. The SLC7A7 gene, mutated in LPI patients, encodes the light subunit (y+LAT1) of a member of the heterodimeric amino acid transporter family.The diagnosis of LPI is difficult due to unspecific clinical features: protein intolerance, failure to thrive and vomiting after weaning. Later on, patients may present delayed growth osteoporosis, hepatosplenomegaly, muscle hypotonia and life-threatening complications such as alveolar proteinosis, haemophagocytic lymphohistiocytosis and macrophage activation syndrome. Renal involvement is also a serious complication with tubular and more rarely, glomerular lesions that may lead to end-stage kidney disease (ESKD). We report six cases of LPI followed in three different French paediatric centres who presented LPI-related nephropathy during childhood. Four of them developed chronic kidney disease during follow-up, including one with ESKD. Five developed chronic tubulopathies and one a chronic glomerulonephritis. A histological pattern of membranoproliferative glomerulonephritis was first associated with a polyclonal immunoglobulin deposition, treated by immunosuppressive therapy. He then required a second kidney biopsy after a relapse of the nephrotic syndrome; the immunoglobulin deposition was then monoclonal (IgG1 kappa). This is the first observation of an evolution from a polyclonal to a monotypic immune glomerulonephritis. Immune dysfunction potentially attributable to nitric oxide overproduction secondary to arginine intracellular trapping is a debated complication in LPI. Our results suggest all LPI patients should be monitored for renal disease regularly.

Contribution of Raman spectroscopy in nephrology: a candidate technique to detect hydroxyethyl starch of third generation in osmotic renal lesions.

BACKGROUND AND OBJECTIVES: HydroxyEthyl Starch (HES) has been one of the most commonly used colloid volume expanders in intensive care units for over 50 years. The first and second generation HES, with a high molecular weight (≥200 kD) and a high degree of substitution (≥0.5), has been associated with both renal dysfunction and osmotic nephrosis-like lesions in histological studies. Recently, third generation HES (130 kD/<0.5) has also been shown to impair renal function in critically ill adult patients although tubular accumulation of HES has never been proven in the human kidney. Our objective was to demonstrate the potential of Raman micro-imaging to bring out the presence of third generation-HES in the kidney of patients having received the volume expander. DESIGN: Four biopsies presenting osmotic nephrosis-like lesions originated from HES-administrated patients with impaired renal function were compared with HES-negative biopsies (n = 10) by Raman microspectroscopy. RESULTS: The first step was dedicated to the identification of a specific vibration of HES permitting the detection of the cellular and tissue accumulation of the product. This specific vibration at 480 cm(-1) is assigned to a collective mode of the macromolecule; it is located in a spectral region with a limited contribution from biological materials. Based on this finding, HES distribution within tissue sections was investigated using Raman micro-imaging. Determination of HES positive pixels permitted us to clearly distinguish positive cases from HES-free biopsies (proportions of positive pixels from the total number of pixels: 23.48% ± 28 vs. 0.87% ± 1.2; p = 0.004). CONCLUSIONS: This study shows that Raman spectroscopy is a candidate technique to detect HES in kidney tissue samples currently manipulated in nephrology departments. In addition, on the clinical aspect, our approach suggests that renal impairment related to third generation HES administration is associated with osmotic nephrosis-like lesions and HES accumulation in the kidney.

Fibrosis progression according to epithelial-mesenchymal transition profile: a randomized trial of everolimus versus CsA.

Markers of epithelial-mesenchymal transition (EMT) may identify patients at high risk of graft fibrogenesis who could benefit from early calcineurin inhibitor (CNI) withdrawal. In a randomized, open-label, 12-month trial, de novo kidney transplant patients received cyclosporine, enteric-coated mycophenolate sodium (EC-MPS) and steroids to month 3. Patients were stratified as EMT+ or EMT- based on month 3 biopsy, then randomized to start everolimus with half-dose EC-MPS (720 mg/day) and cyclosporine withdrawal (CNI-free) or continue cyclosporine with standard EC-MPS (CNI). The primary endpoint was progression of graft fibrosis (interstitial fibrosis/tubular atrophy [IF/TA] grade increase ≥1 between months 3-12) in EMT+ patients. 194 patients were randomized (96 CNI-free, 98 CNI); 153 (69 CNI-free, 84 CNI) were included in histological analyses. Fibrosis progression occurred in 46.2% (12/26) CNI-free EMT+ patients versus 51.6% (16/31) CNI EMT+ patients (p = 0.68). Biopsy-proven acute rejection (BPAR, including subclinical events) occurred in 25.0% and 5.1% of CNI-free and CNI patients, respectively (p < 0.001). In conclusion, early CNI withdrawal with everolimus initiation does not prevent interstitial fibrosis. Using this CNI-free protocol, in which everolimus exposure was relatively low and administered with half-dose EC-MPS, CNI-free patients were overwhelmingly under-immunosuppressed and experienced an increased risk of BPAR.

Long-term impact of subclinical inflammation diagnosed by protocol biopsy one year after renal transplantation.

The long-term impact of subclinical acute rejection (SCAR) on renal graft function remains poorly understood. Furthermore, the interpretation of borderline lesions is difficult and their incidence is variable. The aim of this study was to analyze the characteristics of subclinical inflammation (SCI) in protocol biopsies performed 1-year after renal transplantation. SCI was defined as the presence of borderline lesions or SCAR according to the Banff 2005 classification. The patients included were a subpopulation of the CONCEPT study in which patients were randomized 3 months after transplantation to receive either sirolimus (SRL) or cyclosporine A (CsA) in combination with mycophenolate mofetil. At 1 year, we observed SCI in 37 of the 121 patients observed with an evaluable biopsy. The incidence was more frequent in the SRL group (SRL 45.2% vs. CsA 15.3%). At 30 months , SCI was associated with a significantly lower level of estimated glomerular filtration rate (mean MDRD 50.8 [±13.3] vs. 57.7 [±16.3] mL/min/1.73 m(2) , p = 0.035). In conclusion, SCI at 1-year posttransplantation is associated with worsening renal function and is more frequent in SRL-treated patients. Therefore, evaluation of SCI may be a valuable tool to allow the optimization of immunosuppressive regimens.

[Schoenlein-Henoch purpura as a presentation of squamous cell bronchial carcinoma]. / Purpura rhumatoïde révélateur d'un carcinome épidermoïde bronchique.

Schoenlein-Henoch purpura is a systemic vasculitis involving the small vessels. In adults it is rare and is sometimes associated with malignancies such as bronchial carcinoma. We report the case of a 74-year-old male ex smoker who was admitted with necrotic skin lesions associated with a nephrotic syndrome, and was found to have a right upper lobe squamous cell bronchial carcinoma. The renal biopsy led to a diagnosis of IgA nephropathy related to Schoenlein-Henoch purpura. Curative surgical resection of the bronchial carcinoma (ypT2N0M0) was associated with remission of the purpura. The synchronous diagnosis of bronchial carcinoma and Schoenlein-Henoch purpura suggests a potential relationship between these two pathologies. Our observation and other published data strongly suggest a direct link on account of: the synchronous diagnosis, the clinical and biological remission of the Schoenlein-Henoch purpura after curative treatment of the bronchial carcinoma. It is important to recognise both the therapeutic and prognostic significance of this connection.

[Membranous glomerulonephritis as a paraneoplastic manifestation of melanoma]. / Glomérulonéphrite extramembraneuse paranéoplasique au cours d'un mélanome.

BACKGROUND: Membranous glomerulonephritis (MG) is generally idiopathic. Causes of secondary MG (15 % of cases), namely solid or haematological cancers, are common, with parallel development between the two diseases suggesting paraneoplastic syndrome. However, paraneoplastic syndrome is rare in melanoma. We report a case of a patient with stage III melanoma presenting MG developing in parallel to the melanoma. PATIENTS AND METHODS: A 61-year-old man was referred for melanoma on the right side with a Breslow index of 3mm, and without ulceration. While the patient had no adenopathy, he was presenting severe hypertension diagnosed two months earlier as well as diffuse pitting oedema, with weight gain of 15kg in one month. Additional treatment of the patient's melanoma included extended excision, examination of the two right axillary sentinel nodes (positive), and axillary lymph node dissection revealing four more metastatic nodes. A thoracic-abdominal-pelvic CAT scan showed no further metastasis. Investigation of the oedema revealed nephrotic syndrome with hypoalbuminaemia of 14g/L and proteinuria of 5g/24h. Renal biopsy resulted in the diagnosis of MG. Histological and immunohistochemical examination (HMB-45, Melan A, S100 protein) showed no tumour cells in the kidney, and urinary cytology was negative. Non-tumoral causes of MG were thus ruled out. The oedema regressed rapidly following surgical treatment of the melanoma, with no specific renal or oncological treatment being given. Two years after axillary lymph node dissection, the patient was in complete remission of his melanoma and renal tests showed spontaneous regression of nephrotic syndrome, with disappearance of the oedema, normalisation of blood pressure and gradual correction of serum albumin (40g/L) and proteinuria (1g/24h). DISCUSSION: Paraneoplastic MG has been described particularly in patients with gastrointestinal and pulmonary cancer. To our knowledge, this is only the second case associated with melanoma. Our report suggests the need for routine cutaneous examination as part of the initial investigations for MG.