Hypertension and angiotensin system inhibitors: impact on outcome in sunitinib-treated patients for metastatic renal cell carcinoma.

BACKGROUND: To examine the association between hypertension (HTN), angiotensin system inhibitors (ASI) use and survival outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib (SU). METHODS: We retrospectively reviewed all patients with mRCC who received SU as first-line treatment in Gustave Roussy from April 2004 to November 2013. The HTN (either pre-existing or secondary to SU), use of ASI (either before or during SU) were analysed. Overall survival (OS) and progression-free survival (PFS) of different exposures were compared with log-rank test. The associations between exposures and survival outcomes were estimated with hazard ratios (HRs) and 95% confidence interval (CI) through a multivariable Cox model adjusted for age, gender, International mRCC Database Consortium risk group and histology. RESULTS: Among 213 patients with a 3.6-year median follow-up, 134 were hypertensive and 105 were ASI users with a significant association between the two exposures (P < 0.0001). Hypertensive patients have longer OS (median: 41.6 versus 16.4 months, P < 0.0001) and longer PFS (median: 12.9 versus 5.6 months, P < 0.0001) than non-hypertensive patients (n = 79). ASI users (n = 105) had more HTN_PRE compared with those (n = 108) who did not (65% versus 19%, P < 0.001). Multivariable analysis showed that hypertensive patients were significantly associated with OS (P = 0.05) and marginally with PFS (P = 0.06) while ASI intake was significantly associated with better OS [HR = 0.40; 95% CI (0.24-0.66), P < 0.001] and PFS [HR = 0.55 (0.35-0.86), P = 0.009]. The latter remain statistically significantly associated after controlling for the number of metastases. There is no difference on outcome between patients who receive ASI before starting SU and those who received ASI during SU treatment. CONCLUSION: Concomitant use of ASI may significantly improve OS and PFS in mRCC patients receiving SU. HTN is marginally associated with the outcome in these patients.

[Kimura's disease: an unrecognized cause of adult-onset nephrotic syndrome with minimal change disease]. / La maladie de Kimura: une cause méconnue de syndrome néphrotique à lésions glomérulaires minimes de l'adulte.

Kimura's disease (KD) is an angiolymphoid proliferative disorder of soft tissue with eosinophilia, with a predilection for head and neck regions in young Oriental men. Kidney disease is thought to be rare in KD. About a case of adult-onset nephrotic syndrome with minimal change disease, we comment Kimura's disease and its associated kidney damage. Kimura disease should be suspected and included in the diagnosis of adult-onset nephrotic syndrome with minimal change disease.

Acute tubular necrosis associated with mTOR inhibitor therapy: a real entity biopsy-proven.

BACKGROUND: The protein kinase mTOR (mammalian target of rapamycin) is a critical regulator of cellular metabolism, growth, and proliferation. Inhibitors of mTOR have immunosuppressive and anti-cancer effects, but their effects on the progression of kidney disease are not fully understood. Their most common side-effects include stomatitis, rash, dyslipidemia, hyperglycemia, fatigue, and pneumonitis. However, to the best of our knowledge these agents have not been previously reported to cause severe acute kidney injury (AKI). CASE PRESENTATION: We describe four cases of patients with cancer who developed AKI after starting mTOR inhibitor therapy. A kidney biopsy showed acute tubular necrosis (ATN) with prominent tubular dysfunction. Withdrawal of the drug leads to a rapid recovery in two cases. However, a fixed renal dysfunction was noted in the other two cases, one of which will remain dialysis-dependent. Such patients lead to a broad differential diagnosis of AKI including prerenal AKI, ATN, cancer-related GN, and drug-induced acute interstitial nephritis. Accurate history, physical examination, laboratory data, and kidney biopsy are highlighted in establishing the correct diagnosis in such patients. CONCLUSIONS: ATN have not been reported with mTOR inhibitor use. These cases demonstrated a potentially new and serious adverse consequence occurring with the use of an mTOR inhibitor, of which physicians need to be aware.

[Myeloproliferative neoplasms related glomerulopathy]. / Glomérulopathies associées aux syndromes myéloprolifératifs.

Myeloproliferative neoplasms (MPNs, formerly called chronic myeloproliferative disorders) are clonal hematopoietic stem cell disorders characterized by the expansion of one or more of the myeloid lineages, including polymorphonuclear, erythroid, megakaryocytic, and mastocytic. The major complications of MPN are transformation into acute myeloid leukemia (occurring particularly in chronic myelogenous leukemia) and thrombotic and hemorrhagic events (most commonly observed in polycythemia vera and essential thrombocythemia). Renal involvement by MPN is infrequent. MPN-related glomerulopathy enlarges the spectrum of glomerular diseases associated with haematological neoplasms. MPN-related glomerulopathy is an under recognized late renal complication of MPN with poor prognosis. It is characterized clinically by heavy proteinuria and renal insufficiency. The histologic features of MPN-related glomerulopathy include variable degree of mesangial sclerosis and hypercellularity, segmental sclerosis, features of chronic thrombotic microangiopathy, and intracapillary hematopoietic cell infiltration. PDGF and TGFß likely have a crucial role in the pathogenesis of MPN-related glomerulopathy. Furthermore, aggregation of circulating hematopoietic cells within glomerular capillaries could potentially result in endothelial injury and morphologic changes resembling chronic thrombotic microangiopathy. Greater awareness of this entity is needed to define diagnosis and possible therapies.

Management of hypertension in angiogenesis inhibitor-treated patients.

BACKGROUND: Hypertension (HTN) is one of the most frequent side-effects of systemic inhibition of vascular endothelial growth factor (VEGF) signaling. Its incidence and severity are dependent on the type of drugs, dose, and schedule used. The recognition of this side-effect is an important issue because poorly controlled HTN could lead to serious cardiovascular events. On another hand, HTN induced by anti-VEGF agents maybe a predictive factor of oncologic response. Knowledge of this clinical toxicity and/or therapeutic target or novel biomarker of drug activity can aid clinicians choosing the optimal and least toxic regimen suitable for an individual patient. METHODS: A Medline search was carried out using the following criteria: (i) all Medline listings as of 1 January 2000 with abstracts, (ii) English language, and (iii) Humans. The following phrases were used to query the database: ('hypertension', OR 'blood pressure') AND ('anti-VEGF' OR 'VEGF inhibition' OR 'bevacizumab' OR 'sunitinib' OR 'sorafenib' OR 'VEGF Trap'). The references of each article identified were carefully reviewed for additional reference. RESULTS: Lifestyle modification should be encouraged. However, these nonpharmacologic strategies are not always suitable to patients with altered performance status related to metastatic cancer necessitating early drug intervention. Only one randomized study showed a beneficial effect of a calcium channel blocker use to prevent or minimize HTN secondary to antiangiogenic therapy. Nitrates looks as effective in controlling such side-effect. CONCLUSIONS: No clear recommendation for an antihypertensive agent can be made in this context because there is a lack of controlled studies addressing the subject. Blood pressure-lowering drugs should be individualized to the patient's clinical circumstances and angiogenic inhibitors should be withheld only from patients who experienced hypertensive crisis.

[Regression of vena cava tumour thrombus in response to sorafenib]. / Régression d'un thrombus cave néoplasique sous traitement par sorafénib.

Ten percent of patients with kidney cancer have associated vena cava thrombus, which is associated with a high operative morbidity. Up to now, no medical treatment has allowed regression of vena cava tumour thrombus. The authors report the case of a 62-year-old patient with left kidney cancer associated with vena cava tumour thrombus. After surgical resection, the patient relapsed in the form of vena cava thrombus associated with right renal vein thrombus, responsible for renal insufficiency requiring dialysis. Sorafenib therapy allowed regression of the vena cava thrombus, suspension of haemodialysis and local disease control with a follow-up of one year. This case report justifies a review of the place of anti-angiogenic therapy in the treatment of kidney cancer.

Gadolinium-induced nephrotoxicity.

Because of the well-documented risk of acute renal failure with the iodinated contrast media in patients with underlying chronic renal insufficiency, the use of intravenous gadolinium-based contrast media in magnetic resonance imaging for diagnostic and interventional radiology procedures has become a well-established clinical practice in the recent years. Although originally thought to be safe and lack the nephrotoxic effects of iodinated contrast media, gadolinium-based contrast media have recently been reported to induce a usually reversible decrease of glomerular filtration rate in a high-risk population group, especially in patients with altered baseline renal function. Here we present the current experimental and clinical evidence on this new challenge for the nephrologist, gadolinium-induced nephrotoxicity in patients with chronic kidney disease.

[Pharmacokinetics of amprenavir in HIV-1 patients with renal insufficiency]. / Pharmacocinétique de l'amprénavir chez deux patients infectés par le VIH-1 et présentant une insuffisance rénale sévère et terminale.

Amprenavir is an HIV-1 protease inhibitor which is hepatically metabolized (>80%) with a low renal elimination. It has thus been suggested that no dosage adjustment is necessary in patients with renal dysfunction. However, no data are available on the pharmacokinetics of amprenavir in patients with renal insufficiency. We report on the pharmacokinetics of amprenavir in two HIV patients with severe and end-stage renal insufficiency. Amprenavir pharmacokinetics did not differ in our patients as compared with normal renal function subjects. Furthermore, amprenavir was not dialysable (FHD<25%). As a result, the drug may be administered at its normal dose in patients with renal failure, even when severe. In dialysis patients, amprenavir may be administered before or after the session.

Is low-dose methotrexate nephrotoxic? Case report and review of the literature.

Methotrexate (MTX) has become the most commonly prescribed disease-modifying anti-rheumatic drug. However, toxicity is an important drawback of MTX therapy and permanent discontinuation of MTX for adverse effects occurs in 1 patient out of 10. Although high-dose MTX is known to be nephrotoxic, data on low-dose MTX renal effects are scanty. We report an insidious and progressive deterioration of renal function during long-term low-dose MTX in a 59-year-old woman. Kidney biopsy revealed advanced kidney fibrosis with extensive interstitial and glomerular fibrosis, and vascular sclerosis. We suggest that patients on low-dose MTX therapy even alone, should be periodically monitored for creatinine levels.

PPAR-gamma-agonists' renal effects.

PPAR-gamma ligands, including thiazolidinediones, have recently become clinically available for treating insulin-resistant diabetes mellitus. Accumulating evidence suggests that these drugs not only significantly improve insulin sensitivity but also may have antiproteinuric effects in genetically obese diabetic rodents and patients with type II diabetes and diabetic nephropathy. Moreover, troglitazone reduced expression of ECM proteins and transforming growth factor-beta in glomeruli from streptozotocin-induced diabetic rats. Many other properties including antiproteinuric, hemodynamic, and antihypertensive effects in insulin-dependent diabetes mellitus suggest that PPAR-gamma ligands might have a direct, beneficial renal effect, independent of their capacity to improve glucose tolerance. Besides their antidiabetic effects, thiazolidinediones have been shown to lower blood pressure in diabetic patients with hypertension and patients with diabetic nephropathy through multiple mechanisms. Several studies showed the efficacy of PPAR-gamma agonists to ameliorate the progression of glomerulosclerosis. The effect is independent of insulin effects and could only be partially due to lipid effects. These renal protective effects of PPAR-gamma agonists suggest that they may provide a novel intervention strategy to prevent vascular and glomerular sclerosis.

Cardiac troponins in renal failure - time for an optimistic consensus?

Elevated cardiac troponin concentrations are now accepted as the gold standard biochemical markers for the diagnosis of myocardial damage in patients with unstable coronary syndromes, having also a demonstrated value in early risk stratification and in adopting different therapeutic strategies. The specificity and sensitivity of cardiac troponins for diagnosis of acute coronary diseases in renal failure have been a point of confusion over the past decade, mainly because of moderate elevations of these cardiac biomarkers, commonly observed in patients with chronic renal dysfunction and without any significant myocardial damage. This review discusses the cardiac troponins, their biochemistry, their currently accepted cut-off values and their real significance in chronic renal failure (CRF), concluding that troponins maintain their diagnostic and prognostic values in patients with CRF, being predictive not only of cardiovascular mortality but also of general mortality in this patient group.