Expression patterns of RelA and c-mip are associated with different glomerular diseases following anti-VEGF therapy.

Renal toxicity constitutes a dose-limiting side effect of anticancer therapies targeting vascular endothelial growth factor (VEGF). In order to study this further, we followed up 29 patients receiving this treatment, who experienced proteinuria, hypertension, and/or renal insufficiency. Eight developed minimal change nephropathy/focal segmental glomerulopathy (MCN/FSG)-like lesions and 13 developed thrombotic microangiopathy (TMA). Patients receiving receptor tyrosine kinase inhibitors (RTKIs) mainly developed MCN/FSG-like lesions, whereas TMA complicated anti-VEGF therapy. There were no mutations in factor H, factor I, or membrane cofactor protein of the complement alternative pathway, while plasma ADAMTS13 activity persisted and anti-ADAMTS13 antibodies were undetectable in patients with TMA. Glomerular VEGF expression was undetectable in TMA and decreased in MCN/FSG. Glomeruli from patients with TMA displayed a high abundance of RelA in endothelial cells and in the podocyte nuclei, but c-mip was not detected. Conversely, MCN/FSG-like lesions exhibited a high abundance of c-mip, whereas RelA was scarcely detected. RelA binds in vivo to the c-mip promoter and prevents its transcriptional activation, whereas RelA knockdown releases c-mip activation. The RTKI sorafenib inhibited RelA activity, which then promoted c-mip expression. Thus, our results suggest that c-mip and RelA define two distinct types of renal damage associated with VEGF-targeted therapies.

Kidney injuries related to ipilimumab.

Monoclonal antibodies directed against the immune checkpoint protein cytotoxic T-lymphocyte antigen-4 (CTLA-4; CD152) have been investigated in metastatic melanoma and other cancers and have shown promising results. Inhibition of CTLA-4 characteristically induces well-known side effects called "immune-related adverse events" (irAEs). IrAEs mainly include colitis, dermatitis, hepatitis, endocrinopathies; uveitis, iridocyclitis, neuropathies, and inflammatory myopathy have occasionally been reported. Kidney involvement is rare. We report 2 cases of acute granulomatous interstitial nephritis and present, based on literature review, renal disorders related to Ipilimumab therapy. Autoimmune symptoms have to be carefully checked for patients treated with CTLA-4 inhibitors. In order to reduce the risk of sequelae, early recognition of irAEs and treatment initiation are crucial.

Role of HIV-1 DNA levels as clinical marker of HIV-1-associated nephropathies.

BACKGROUND: HIV-associated nephropathy (HIVAN) is usually diagnosed in virologically uncontrolled infected patients. However, HIVAN can occur in some cases with undetectable HIV-1 RNA levels. We suggested that intracellular HIV-1 proviral DNA load can be used as a marker in this particular patient population. METHODS: Renal tissue HIV-1 proviral DNA, peripheral blood mononuclear cells (PBMCs) HIV-1 proviral DNA, plasma HIV-1 RNA and peripheral blood CD4-positive lymphocyte counts were quantified and assessed in 100 HIV-1-infected individuals (49 with undetectable HIV-1 RNA level viraemia) who underwent a kidney biopsy for renal abnormalities in a prospective study. RESULTS: A proviral DNA load was detected in patients with HIV-1-associated nephropathy with a negative plasma viral RNA load. None of the patients with a proviral DNA load of <10 copies/1.5×10(5) PBMCs had HIVAN. In renal tissue, proviral DNA load was detected in all patients with HIVAN. CONCLUSIONS: PBMC HIV-1 proviral DNA load is potentially the optimal clinical marker to exclude the diagnosis of HIVAN. On the other hand, cellular incorporation of HIV-1 within the kidney is a requisite for the development of this disorder.

Renal biopsy practice in France: results of a nationwide study.

BACKGROUND: Although several risk factors associated with complications after renal biopsy (RB) have been identified, the gold standard for RB procedures remains to be defined. Practices vary widely among nephrologists, depending on personal experience and the availability of particular techniques. The purpose of our study was to depict the main aspects of the practice of RB in adults in France. METHODS: Members of the Société de Néphrologie in France were asked to participate in a questionnaire survey on RB procedures. RESULTS: Eighty-eight nephrologists from 74 units (27 in teaching hospitals, 35 in public general hospitals and 12 in private centres) participated in our study. Native kidney and graft biopsies were performed in 73 and 35 units, respectively. RB activity was highly variable among units, ranging from several hundred to <10 per year. Transjugular renal biopsy was judged to be smoothly accessible in 28 out of 73 units (38.4%). Significant variations in practices were observed regarding patient information before RB, assessment of haemorrhagic risk factors, management of patients with antiplatelet agents and haemorrhagic risk factors, and radiological guidance. Early discharge (<12 h) was the rule in 3 (4.1%) units for native kidney biopsies and in 10 (28.6%) units for graft biopsies. CONCLUSIONS: Our study is the first to provide a representative picture of 'everyday' RB practices in a country. Important variations in procedures were observed. Our study may represent a preliminary step for the elaboration of guidelines for all aspects of RB practices.

Rapidly progressive lupus nephritis and concomitant thrombotic microangiopathy.

Although uncommon, thrombotic microangiopathy (TMA) is one of the most serious complications in patients with systemic lupus erythematosus. A 30-year-old black woman admitted to our hospital because of fever, fatigue, 'dark' urine and rapidly progressive renal failure was found to have systemic lupus erythematous and atypical hemolytic uremic syndrome. Kidney biopsy showed WHO class IV lupus nephritis with crescents and TMA. Hemodialysis was initiated for worsening renal failure. The patient was treated with corticosteroids, monthly pulse intravenous Cyclophosphamide, plasmapheresis and Rituximab on a weekly basis for 4 weeks. The patient's blood pressure was aggressively controlled using antihypertensive agents. Despite this extensive therapy, she remained dialysis dependent although hematological parameters returned to normal values.

Self-medication in pain management: The state of the art of pharmacists' role for optimal Over-The-Counter analgesic use.

BACKGROUND AND OBJECTIVE: Self-medication is associated with an important utilization of Over-The-Counter (OTC) analgesics. The medical outcome resulting from therapeutic options bypassing the physician prescription is a major issue. In that context, pharmacists are expected to play a crucial role. The main objective of this review was to analyse the state-of-the art of pharmacists' role in pain management self-medication. DATABASES AND DATA TREATMENT: An expert multidisciplinary group dedicated to self-medication in pain was established. Selection of publications was performed from PubMedand EMBASE databases which was based on the use of "pain" and/or "self-medication" and/or "self-care" and/or "analgesics" and/or "painkillers" keywords, restricted to the past 10 years. RESULTS: A total of 480 papers were identified, 49 of which papers were considered relevant and finally kept for final discussion, on OTC pain management and pharmacist's role. Literature analysis demonstrates that OTC analgesics are generally safe when appropriately used. Risks associated with misuse or inappropriateness depend on patients' vulnerability (elderly, pregnancy) or behaviour. Social cognitive theory-based intervention and multimedia applications improve self-medication but do not replace health care professional advice Pharmacists' interventions may improve the benefits and safety of OTC analgesic medication, with a better management of pain. CONCLUSIONS: Considering the heterogeneity of patients' knowledge and behaviour reported worldwide, inappropriate use of OTC pain medication should not be underestimated. Community pharmacists are ideally placed to guide self-medication or recommend a medical advice when needed. Embedding pharmacists in primary care pain management is essential and pharmacist-led medication coupled with an appropriate training of pharmacy staffs should be encouraged. SIGNIFICANCE: Analgesics are widely used without prescription, all over the world. They represent the largest market of OTC drugs, with an overall benefit/risk ratio favourable when appropriately used. Because of potential individual risks associated to the ailment or to the patient's behaviour, pharmacists' interventions have proven to optimize analgesic self-medication, provided that pharmacy staffs are both available and more specifically trained. In the future, in pain management, especially self-medication, pharmacists should play an increasing role and should be included in educational programmes and pain management guidelines.

A case of acute renal failure associated with diffuse infiltrative lymphocytosis syndrome.

BACKGROUND: A 58-year-old African American man with an uncontrolled HIV infection presented to hospital with nephrotic syndrome and diffuse lymphadenopathy. The patient had been taking highly active antiretroviral therapy (HAART; lamivudine, abacavir, fosamprenavir and ritonavir) for 10 years. A renal biopsy showed acute granulomatous interstitial nephritis. Despite a negative tuberculin skin test, he was treated with antituberculosis drugs for 12 months without improvement of his renal profile. Two months after antituberculosis treatment was discontinued, the patient was readmitted to hospital because of acute renal failure. Corticosteroid therapy (prednisone) was started and resulted in a marked improvement in renal function. However, 18 months after steroids were discontinued, renal function declined dramatically. Furthermore, the patient had CD8+ lymphocytosis as well as interstitial tissue infiltration by CD8+ T lymphocytes. INVESTIGATIONS: Physical examination, plasma HIV viral load, lymphocyte counts, urinalysis, tuberculin skin test, liver function tests, renal ultrasonography, human leukocyte antigen (HLA) typing, renal and minor salivary gland biopsies, ophthalmological examination, chest radiography and culture of bronchoalveolar lavage fluid. DIAGNOSIS: Acute granulomatous interstitial nephritis secondary to diffuse infiltrative lymphocytosis syndrome. MANAGEMENT: HAART and prednisone.

Angiogenesis inhibitor therapies: focus on kidney toxicity and hypertension.

Angiogenesis inhibitors that target the epidermal growth factor (EGF) receptor (EGFR) and vascular endothelial growth factor (VEGF) constitute an important addition to the therapeutic armamentarium for the treatment of patients with metastatic disease. However, because the same growth factors are expressed in the kidneys, these treatment molecules have renal side effects. EGFR is expressed mainly in tubules (mainly distal and collecting segments) and mesangial and parietal epithelial cells. EGF is involved in maintaining tubular integrity and is a potent mitogen for cultured mesangial cells. Few cases of acute renal failure have been reported related to EGFR inhibitors. VEGF and VEGF receptors are still highly expressed in the kidney. VEGF is expressed in podocytes in the glomerulus, and VEGF receptors are present on endothelial, mesangial, and peritubular capillary cells. Signaling between endothelial cells and podocytes is essential for the proper development and maintenance of the filtration function of the kidney glomerulus. The most common renal class effects of VEGF antagonists are both manageable; hypertension and proteinuria commonly regressive on drug withdrawal. There was a dose-dependent increase in risk of proteinuria and hypertension in patients with cancer who received targeted therapies. Furthermore, few patients with glomerulonephritis or thrombotic microangiopathy secondary to treatment were reported. Hypertension is believed to be nitric oxide dependent, whereas proteinuria seems to be related to downregulation of podocyte tight junction protein. This article reviews data relating to hypertension and proteinuria associated with the use of these drugs.

[Public health benefits of non prescription medicines and self care]. / Automédication et santé publique.

Self-medication is one element of self-care. For Who, "responsible self-medication is the practice whereby individuals treat ailments and conditions with medicines which are approved and available without prescription, and which are safe and effective when used as directed". In France, Afssaps is the agency in charge of regulating the market in non prescription medicines. During the last ten years, major efforts have been made to rationalize this market. Measures include a revision of the indications of the oldest products, a definition of clinical indications than can be switched from prescription to non prescription, more readable patient information leaflets, adaptation of packaging to self-care, writing of guidelines and recommendations, and new modes of pharmacovigilance. Indeed, it is crucial to provide an appropriate framework for responsible self-care.

Renal tubular drug transporters.

The kidney plays an important role in the elimination of numerous hydrophilic xenobiotics, including drugs, toxins, and endogenous compounds. It has developed high-capacity transport systems to prevent urinary loss of filtered nutrients, as well as electrolytes, and simultaneously to facilitate tubular secretion of a wide range of organic ions. Transport systems for organic anions and cations are primarily involved in the secretion of drugs in renal tubules. The identification and characterization of organic anion and cation transporters have been progressing at the molecular level. To date, many members of the organic anion transporter, organic cation transporter, and organic anion-transporting polypeptide families have been found to mediate the transport of diverse organic ions. It has also been suggested that ATP-dependent primary active transporters such as MDR1/P-glycoprotein and the multidrug resistance-associated protein family function as efflux pumps of renal tubular cells for more hydrophobic molecules and anionic conjugates. Tubular reabsorption of peptide-like drugs such as beta-lactam antibiotics across the brush-border membranes appears to be mediated by two distinct H+/peptide cotransporters: PEPT1 and PEPT2. Renal disposition of drugs occurs through interaction with these diverse secretory and absorptive transporters in renal tubules. Studies of the functional characteristics, such as substrate specificity and transport mechanisms, and of the localization of drug transporters could provide information regarding the cellular network involved in renal handling of drugs. Detailed information concerning molecular and cellular aspects of drug transporters expressed in the kidney has facilitated studies of the mechanisms underlying renal disposition as well as transporter-mediated drug interactions.

[Hemoglobin target in hemodialysis patients]. / Quelle est la valeur optimale de li'hémoglobinémie du patient dialysé?

Targets for anaemia treatment have been largely evaluated. A target > 11 g/dL is currently recommended. High target (13-14 g/dl) is contraindicated in patients with cardio-vascular disease. In patients without cardiovascular disease, a target of 13-14 g/dl could bring an improvement in some symptoms of quality of life. In hemodialysis patients, a high target decreases the dialysis efficiency, increases the risk of clotting into the dialysis circuit and increase the risk of vascular access thrombosis, in particular in case of graft.

[Medication use in older patients with chronic renal failure]. / Médicaments et insuffisance rénale chronique du sujet âgé.

Adverse drug reactions in the elderly are of growing concern because of the increasing elderly population and the increasing numbers of medications prescribed to this group. Ageing and the frequent comorbid diseases in the elderly result in altered drug pharmacokinetics and pharmacodynamics increasing the risk of side effects. The decline in renal function affects the elimination of many drugs. Before prescribing an estimation of the glomerular filtration rate is of the highest importance. All the nomogramms and formulae are approximate in the oldest old. The Cockcroft and Gault formula is frequently used. Pharmacodynamic alterations are particularly important for the centrally active drugs that older people are more vulnerable to, for example increased and prolonged effects of anticholinergic, hypnotic and sedative drugs. Polypharmacy and self-medication is also common in these patients, with increased chance for drug-drug interactions. In France, the recent law on Public Health (August 09, 2004) requires for the next five years to decrease the frequency of inappropiate prescriptions in elderly people and of to decrease the frequency of the drug-induced hospitalisations. Undertreatment of the elderly is not the solution: it's necessary to optimize their medication: to well appreciate before prescription their motor and cognitive deficiencies interfering with compliance, to "start low and go slow" their medications, to review their drug consumption on a regular basis, to educate them and their family for a good observance.

Herbs and the kidney.

The use of herbal therapy has increased dramatically in past years and may lead to renal injury or various toxic insults, especially in renal patients. In most countries, herbal products are not regulated as medicines. Herbal poisoning may be secondary to the presence of undisclosed drugs or heavy metals, interaction with the pharmacokinetic profile of concomitantly administered drugs, or association with a misidentified herbal species. Various renal syndromes were reported after the use of medicinal plants, including tubular necrosis, acute interstitial nephritis, Fanconi's syndrome, hypokalemia or hyperkalemia, hypertension, papillary necrosis, chronic interstitial nephritis, nephrolithiasis, urinary retention, and cancer of the urinary tract. It seems critical that caregivers be aware of the potential risk of such often underreported therapy and carefully question their patients about their use of this popular branch of alternative medicine.

Unusual IgM fibrillar deposits in glomerulonephritis: ultrastructural and diffraction studies in a case report.

Morphological examination of 2 renal biopsy specimens obtained from a 69-year-old woman with a nephrotic syndrome, high blood pressure, and a reduced glomerular filtration rate revealed, in ultrastructural study, a type of a glomerulonephritis with fibrillar deposits in a subendothelial position which were unusual in their immunoglobulin components (mainly IgM). The fibrillar components were of irregular size, 13 to 18 nm in diameter and presented a very particular "barbed wire" morphological aspect, not hitherto described. Diffraction studies and image analysis, revealed spiraled fibrils with regular alternating elements that we suggest may correspond to IgM molecules. The clinical (isolated renal symptoms) and laboratory (traces of 3 monoclonal components in the serum and 2 normal bone marrow biopsy specimens) data provided no evidence of hematopoietic malignancy, viral hepatitis or cryoglobulinemia.

Kidney diseases associated with anti-vascular endothelial growth factor (VEGF): an 8-year observational study at a single center.

Expanded clinical experience with patients taking antiangiogenic compounds has come with increasing recognition of the renal adverse effects. Because renal histology is rarely sought in those patients, the renal consequences are underestimated. Antiangiogenic-treated-cancer patients, who had a renal biopsy for renal adverse effects from 2006 to 2013, were included in the current study. Clinical features and renal histologic findings were reviewed. Our cohort was 100 patients (58 women) with biopsy-proven kidney disease using anti-vascular endothelial growth factor (VEGF) therapy with a mean age of 59.8 years (range, 20-85 yr). Patients were referred for proteinuria, hypertension, and/or renal insufficiency. Kidney biopsy was performed 6.87 ±â€Š7.18 months after the beginning of treatment. Seventy-three patients experienced renal thrombotic microangiopathy (TMA) and 27 patients had variable glomerulopathies, mainly minimal change disease and/or collapsing-like focal segmental glomerulosclerosis (MCN/cFSGS). MCN/cFSGS-like lesions developed mainly with tyrosine-kinase inhibitors, whereas TMA complicated anti-VEGF ligand. Thirty-one percent of TMA patients had proteinuria up to 1 g/24 h. Half of TMA cases are exclusively renal localized. Pathologic TMA features are intraglomerular exclusively. MCN/cFSGS glomeruli displayed a high abundance of KI-67, but synaptopodin was not detected. Conversely, TMA glomeruli exhibited a normal abundance of synaptopodin-like control, whereas KI-67 was absent. Median follow-up was 12 months (range, 1-80 mo). Fifty-four patients died due to cancer progression. Hypertension and proteinuria resolved following drug discontinuation and antihypertensive agents. No patient developed severe renal failure requiring dialysis. Drug continuation or reintroduction resulted in a more severe recurrence of TMA in 3 out of 4 patients requiring maintenance of anti-VEGF agents despite renal TMA. In conclusion, TMA and MCN/cFSGS are the most frequent forms of renal involvement under anti-VEGF therapy. Careful risk-benefit assessment for individual patients should take into account risk factors related to the host and the tumor.

[Renal biopsy practice: results of a French study and recommendations]. / Pratique de la biopsie rénale: résultat d'une enquête en France, revue de la littérature et recommandations.

BACKGROUND: Although several risk factors associated with complications after renal biopsy (RB) have been identified, recommendations for RB procedures are still lacking. Our working group, appointed by the scientific commission of the Société de néphrologie in France, aimed to depict the main aspects of the practice of RB in adults in France, before establishing some guidelines. METHODS: Members of the Société de néphrologie in France were asked to participate to a questionnaire survey on RB procedures. RESULTS: Eighty-eight nephrologists from 74 units (27 in teaching hospitals, 35 in public general hospitals, and 12 in private centers) participated in our study. Native kidney and graft biopsies were performed in 73 and 35 units, respectively. RB activity was highly variable among units, ranging from several hundred to less than ten per year. Transjugular RB was judged to be smoothly accessible in 28 out of 73 units (38.4%). Significant variations in practices were observed regarding patient information before RB, assessment of hemorrhagic risk factors, care of patients with antiplatelet agents and hemorrhagic risk factors, and radiological guidance. Early discharge (<12 hours) was the rule in three (4.1%) units for native kidney biopsies and in ten (28.6%) units for graft biopsies. CONCLUSIONS: Our study is the first to provide a representative picture of "everyday" RB practices in a country. Consensual recommendations on all points mentioned are provided here.

Perspectives in clinical research of acupuncture on menopausal symptoms.

Seventy percentage of perimenopausal and early postmenopausal women will experience menopause symptoms. Primary menopause symptoms in Western countries included hot flashes, insomnia, somatic pain, depression, and fatigue. Hot flashes were most commonly treated. Menopausal hormone replacement therapy (HRT) continues to have a clinical role in the management of vasomotor symptoms, but since 2002 there has been a marked global decline in its use due to concerns about the risks and benefits of HRT; consequently many women with menopause symptoms are now seeking alternatives including acupuncture. Acupuncture has a long tradition of use for the treatment of different menopause symptoms. Its effectiveness has been studied for natural menopause or chemical and surgery induced menopause. Here we provide an update on recent advances in the field for clinicians. The recent systematic reviews on acupuncture in menopausal symptoms suggest that acupuncture is an effective and valuable option for women suffering from menopause. However, the science of acupuncture therapies is still inadequate to sufficiently support the benefits of acupuncture therapies. Finally, we discuss our points of view on clinical trials of acupuncture for menopause symptoms.