Immune checkpoint inhibitors-induced systemic capillary leak syndrome: A report of two cases.

INTRODUCTION: The occurrence of systemic capillary leak syndrome under immune checkpoint inhibitors has seldom been reported in the literature. OBSERVATION: We report two cases of systemic capillary leak syndrome that occurred with nivolumab (anti-PD-1 antibody) for one, and with an anti-PD-1/CTLA-4 bi-specific antibody for the other. Patients presented with anasarca, hypoalbuminemia, acute kidney injury and, in one case, circulatory collapse. Immune checkpoint inhibitor causality was retained in the lack of evidence for other causes of secondary capillary leak syndrome or for an idiopathic form. The symptoms resolved after a few days of supportive measures (associated with glucocorticoids in one case). DISCUSSION: A high index of suspicion is required for the diagnosis of immune checkpoint inhibitors-induced systemic capillary leak syndrome because its presentation may differ from that of the idiopathic form. Activated CD8+ T-cells play a prominent role in the occurrence of immune checkpoint inhibitors-induced capillary leakage via their cytolytic action on the vascular endothelium. Treatment relies on supportive measures and discontinuation of the immune checkpoint inhibitor while the place of immunomodulatory drugs remains to be defined.

[Switch of methoxy-polyethylene-glycol-epoetin beta to darbepoetin alfa in 263 dialysis patients]. / Étude de la conversion du méthoxypolyéthylèneglycol-époétine bêta vers la darbépoétine alfa chez 263 patients hémodialysés.

In early 2012, due to national supply disruption, the methoxy-polyethylene glycol-epoetin beta (CERA) was no longer available and has been replaced by darbepoetin alfa (DA) in all dialysis patients. Official recommendations for the replacement of one by the other is missing or unclear. On this occasion, we wanted to examine how the shift from CERA to DA was done in terms of dose conversion factor and the other factors that could have influenced the dose of DA prescribed (hemoglobin, patient weight, dose of CERA). This retrospective multicenter open conducted in six dialysis centers in Alsace is the first large study (n=263) that evaluated the switch from CERA to DA in all chronic hemodialysis patients. We found that the instantaneous ratio of dose adjustment is close to 1 and that nephrologists are mainly based on the dose of CERA for determining the DA dose, before hemoglobin and weight. However, establishing a true dose-response ratio between the two molecules requires a long term prospective study.

[Association between blood pressure level and the follow up of the guidelines concerning the use of self blood pressure measurement]. / Association entre le niveau tensionnel en consultation et le suivi d'un protocole d'automesure.

OBJECTIVES: To evaluate the characteristics of hypertensive subjects who practise self measurement of blood pressure (SMBP) and their conditions of use, and to identify the properties of subjects using SMBP according the usual guidelines. METHODS: In 531 consecutive hypertensive subjects, referred to hypertension specialists, possessing a SMBP a questionnaire evaluating the condition of use of SMBP was given. Subjects following the guidelines about the use of SMBP have been compared to those using SMBP without specific design of supervision. RESULTS: In this population, aged 62 +/- 14 years, with 57% of men and a mean blood pressure of 147 +/- 23/82 +/- 12 mmHg, the SMBP devices have been bought without medical advice in 50% of cases (265/531). In 45% of cases (239/531), SMBP were made at the wrist. SMBP device was used every days in 26% of cases, every weeks in 27% of cases, every month or more in 22% of cases and only in case of uneasiness in 25% of cases. Blood pressure was measured only in the morning in 25% of cases, in the morning and evening in 31%, only the evening in 8% and at any time of the day in 36% of cases. More frequently 2 BP measurements were realized (47%) and in 19% of cases 3 measurements have been performed. In 15% of cases, the measurements were performed on 3 or 4 days consecutively, more frequently (85%) the measurements were realized without specific design ("once in awhile"). The data of SMBP were noted and showed to the doctor in 34% of cases. Only 12% (64/531) of subjects followed the usual guidelines concerning the use of SMBP (2 or 3 measurements, in the morning and the evening, during 3 or 4 consecutive days). Subjects following the guidelines for SMBP use have a higher SBP at the office than those using SMBP without specific design of supervision (155 +/- 25 mmHg vs 146 +/- 22 mmHg; p<0.01). CONCLUSION: Among hypertensives referred to hypertension specialists most of subjects use SMBP device without a specific design of supervision. Subjects with the most severe hypertension are those who have the best formation for SMBP.

[Rational choice for second antihypertensive agent after failure of the first monotherapy: therapeutic strategy]. / Choix raisonné du deuxième antihypertenseur après l'échec d'une première monothérapie: la stratégie des paniers thérapeutiques.

This study evaluated a strategy to treat naive hypertensive patients, based on a single monotherapy followed, in uncontrolled patients, by a rationale choice for the second antihypertensive treatment. Subjects with essential hypertension, entered into the study if their BP measured with an OMRON 705CP was > 140/90 mmHg on two separate visits. Patients were allocated to single treatment in a balanced randomized design to receive either a "group 1" treatment (ACE inhibitor, beta-blocking drug or ARB) or a "group 2" treatment (calcium channel-blocking drug or thiazide diuretic). After one month of treatment at a standard dose, if BP was > 140/90 mmHg, first adaptation was a fixed combination therapy with one drug from "group 1" and one drug from "group 2". At 3 months, patients with BP < 140/90 mmHg were considered to have reached BP goal. Forty-eight patients entered the study with a mean age of 53 +/- 11 years. Initial SBP/DBP (mmHg) was 164 +/- 16/97 +/- 8. After 1 month, 40% achieved the target BP, 52% were uncontrolled with no side effects and 8% were uncontrolled and had side effects. After 3 months, 84% achieved BP goal and a fixed combination therapy was prescribed in 52% of the controlled patients. The initial monotherapy was maintained alone or in combination in 70% of the controlled patients. A strategy based on a single monotherapy followed, if necessary, by a rational choice for the second treatment in a fixed combination therapy is effective to achieve BP control in 84% of naive hypertensive patients.

[Blood pressure self-monitoring contributes to improved patient education among hypertensive subjects]. / La possession d'un appareil d'automesure tensionnelle contribue à améliorer l'éducation des patients hypertendus.

UNLABELLED: Education of hypertensive subject must sensitize the patient to its pathway and to the prescribed treatment. Self-measurement of blood pressure, which directly implicates the patient, should ameliorate the education of hypertensive subject. OBJECTIVES: To evaluate if the possession of a self-measurement blood pressure device improves patients' knowledge of hypertension. METHODS: In 484 treated hypertensive subjects referred to hypertension specialists, a questionnaire evaluating patients knowledge of hypertension and its treatment was given before the consultation. During this consultation, the practitioner evaluated the concordance between antihypertensive treatments declared by the patient and those effectively prescribed. RESULTS: In this population, aged 61 +/- 12 years, with 55% of men, a self-measurement blood pressure device was possessed by 165 subjects (34%). These devices have been bought without medical advice by 83 patients. For a minority of subjects (n = 41), self-measurements of blood pressure were made at the wrist. Blood pressure level was similar in subjects with (141 +/- 19/80 +/- 10 mmHg) or without (140 +/- 19/80 +/- 10 mmHg) self-measurement devices. Subjects possessing a self measurement device had a better knowledge of their usual blood pressure level and of the normal blood pressure values (< 140/90 mmHg), than subjects without self measurement device (93% vs 77%, p < 0.01, and 56% vs 33%, p < 0.01, respectively). Moreover, subjects in possession of self-measurement devices had a better knowledge of their antihypertensive treatment than those without device (83% vs 70%, p < 0.05). Logistic regression analysis including age, sex, smoking, education level, blood pressure level and the number of antihypertensive tablets confirm the statistical differences observed. CONCLUSION: Hypertensive subjects who possess a self-measurement blood pressure device have a better knowledge of their hypertension. These results indicate that the possession of a self-measurement device contributes to the education of hypertensive patients.

Clinical features and contribution of virological findings to the management of Kaposi sarcoma in organ-allograft recipients.

OBJECTIVES: To describe the clinical features of Kaposi sarcoma (KS) in organ-allograft recipients and to determine the contribution of human herpesvirus 8 (HHV-8) investigations to the management of KS. DESIGN, SETTING, AND PATIENTS: We examined 20 organ-allograft recipients with KS at Pitié-Salpêtrière Hospital, Paris, France, between November 1, 1991, and May 31, 1999. METHODS: We detected HHV-8 antibodies using an indirect immunofluorescence assay and the HHV-8 DNA genome using nonnested polymerase chain reaction with KS-associated herpesvirus 330(233) primers in peripheral blood mononuclear cells collected at transplantation and KS diagnosis. We detected the HHV-8 genome in involved and uninvolved tissue specimens and in 10 patients' serum samples collected 1 month before the first manifestation of KS. We determined the HHV-8 double-strand DNA sequence and subtypes of open reading frame 26. INTERVENTION: Management of KS consisted of progressively tapering immunosuppressive therapy regardless of KS dissemination. Associated infections were treated when possible. Chemotherapy was prescribed only when a functional disability persisted, and polychemotherapy was prescribed for life-threatening disease. MAIN OUTCOME MEASURES: Percentage of recipients with KS remission and stabilization, organ-graft survival, and death rates. RESULTS: Remission of KS was obtained in 9 (45%) of the 20 patients independently of disease dissemination, with a mean follow-up of 35 months. The kidney graft survived in 12 (67%) of the 18 patients. Only 1 patient (5%) died of KS progression. All allograft recipients had anti-HHV-8 antibodies before transplantation. We detected HHV-8 DNA in all involved tissue samples but not in serum samples 1 month before KS onset. The most prevalent subtype was HHV-8 C (9 [53%] of 17 patients) and was not associated with extradermatological extension of KS compared with subtypes A and B'. CONCLUSIONS: Virological investigations of HHV-8 contribute poorly to KS management. Prospective studies are needed to determine the role of HHV-8 virological investigations and to identify associated cofactors so as to prevent KS in organ-allograft recipients.

[Tubular hypokalemia of genetic origin]. / Hypokaliémies tubulaires d'origine génétique.

Recent progress in molecular genetics have improved our understanding of the pathophysiology of several inherited diseases characterized by a renal hypokalemia. Some of these diseases result from inactivating mutations on the main cotransports involved in the reabsorption of sodium, namely the Gitelman and Bartter syndromes, that clinically mimics diuretic abuse with mild hypovolemia and low or normal blood pressure. Conversely some affections eventually lead to an increase in sodium reabsorption with hypervolemia and arterial hypertension: Liddle syndrome, apparent mineralocorticoid excess and dexamethasone suppressible hyperaldosteronism.

[Kidney and nitric oxide]. / Rein et monoxyde d'azote.

Nitric oxide (NO) pathway is involved in various physiological and pathophysiological processes. NO is synthesised by NO synthase. Three isoforms, ecNOS, nNOS, iNOS have been identified to date, that are encoded by 3 distinct genes on chromosome 7, 12 and 17 respectively. L-arginine is likely involved in the control of NO synthesis. In the kidney, NO regulates glomerular hemodynamics by modulating the ultrafiltration coefficient and afferent and efferent renal arteriolar resistance. NO is further involved in the pressure-natriuresis mechanism and in the tubuloglomerular feedback. Several physiopathological models have underlined the importance of the NO in arterial hypertension and in glomerular inflammation.

[Renal effects of AT1 angiotensin receptor antagonists (AT1ra)]. / Effets rénaux des antagonistes du récepteur AT1 de l'angiotensine (AT1ra).

RENIN-ANGIOTENSIN ANTAGONISTS: The renal effects of angiotensin II receptor antagonists (AT1 blockers) can be compared with another class of drugs inhibiting the renin-angiotensin-aldosterone system, i.e. the angiotensin I converting enzyme inhibitors (ACE1). SIMILAR BUT SPECIFIC EFFECTS: The renal effects of these two classes of drugs are similar but each class has specific effects explained by several mechanisms. i) The system includes a large number of active peptides (angiotensin II, angiotensin III, angiotensin 1-7) which exert various effects according to their specific receptor(s): ii) several types of angiotensin II receptors have been identified (AT1, AT2, AT4 ...). Only AT1 blockers are available in clinical practice. iii) Receptor or enzyme blockade can produce varying effects; ACE inhibition is not specific since increased bradykinin activity is associated with the suppression of angiotensin peptide generation. EXPERIMENTAL AND CLINICAL TRIALS: Experimental and recent clinical studies have shown that AT1 blockers can induce, like ACE1, hypotension, renal vasodilation and natriuresis. The definite effects on discrete renal structures (vessels, glomeruli, tubules) differ however in magnitude which may suggest specific indications according to the pathophysiological background (renal disease, congestive heart failure, etc.).

[In situ fibrinolysis of acute arteriovenous shunt obstructions during hemodialysis]. / Fibrinolyse in situ des oblitérations aiguës des fistules artério-veineuses chez les hémodialysés.

Several techniques (surgical revision, thrombectomy, ...) have been described for the treatment of thrombosed vascular access (VA) in hemodialysis patients. We propose a technique with local thrombolytic infusion in conjunction with angiography and percutaneous dilatation and/or recanalization. A total of fourteen patients with twenty-two episodes of thrombosed VA was studied. Eleven patients had a Brescia-Cimino fistula and three patients had a graft fistula. We used in 21 cases urokinase (243000 UI +/- 100000 UI) and in 1 case rt-PA (50 mg). Of the 22 VA, 19 issued in an immediate patency and were restored to full function; and whereof 17 remained patent more than 2 weeks. Failures occurred in 3 cases: localized bleeding from previous dialysis puncture sites (1), venous outflow obstruction (1), and resistant venous stenosis (1). There were no infectious complications, and no systemic bleeding complications. We observed one pseudoaneurysm and one humeral asymptomatic thrombo-embolism. Stenoses were the most frequent factor in precipitating thrombosis. We believe that our technique should be the first line of treatment of occluded hemodialysis vascular access.