Rémi Goupil

Lymphopenia and Treatment-Related Infectious Complications in ANCA-Associated Vasculitis

BACKGROUND AND OBJECTIVES ANCA-associated vasculitis (AAV) is treated with potent immunosuppressive regimens. This study sought to determine risk factors associated with infections during first-intention therapy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This retrospective study involved two separate cohorts of consecutive cases of AAV seen from 2004 to 2011 at two university hospitals. The following were assessed: vasculitis severity; therapy; and periods with no, moderate (lymphocyte count, 0.3-1.0× 10(9)/L), or severe (lymphocyte count ≤ 0.3×10(9)/L) lymphopenia and neutropenia (neutrophil count ≤ 1.5×10(9)/L). RESULTS One hundred patients had a mean age of 57±15 years and a Birmingham vasculitis activity score of 7.7±3.6. Therapy consisted of pulse methylprednisolone (59%), cyclophosphamide (85%), methotrexate (6%), and plasmapheresis (25%) in addition to oral corticosteroids. During follow-up, 53% of patients experienced infection and 28% were hospitalized for infection (severe infection). Only 18% experienced neutropenia, but 72% and 36% presented moderate and severe lymphopenia for a total duration of <0.1%, 73%, and 8% of the treatment follow-up, respectively. Lower initial estimated GFR, longer duration of corticosteroid use, and presence of lymphopenia were risk factors of infections. The rate was 2.23 events/person-year in the presence of severe lymphopenia compared with 0.41 and 0.19 during periods with moderate or no lymphopenia (P<0.001). Similarly, the rate of severe infections was 1.00 event/person-year with severe lymphopenia and 0.08 and 0.10 with moderate and no lymphopenia (P<0.001). This association remained independent of other risk factors. CONCLUSIONS Lymphopenia is frequent during the treatment of AAV, and its severity is associated with the risk of infectious complications.

Clinical value of inflammatory urinary biomarkers in overt diabetic nephropathy: A prospective study

AIMS The evolution of diabetic nephropathy is incompletely accounted by current clinical tools. New biomarkers may refine patient assessment and help monitor therapy. We compared the added predictive value of 7 candidate inflammatory urinary biomarkers to known risk factors of progression. METHODS We prospectively followed 83 patients with overt diabetic nephropathy for a median 2.1 years and obtained repeated measurements of proteinuria, IL-1β, IL-6, IL-8, MCP-1, TNF-α, TGF-β1, and PAI-1. RESULTS Patients had an initial estimated glomerular filtration rate of 25 ± 9 mL/min/1.73 m(2), blood pressure of 142/69 mmHg and used a median of 4 anti-hypertensive medications over the course of the study. The observed rate of renal function decline was 2.9 ± 3.0 mL/min/1.73 m(2)/year. All urinary biomarkers levels were collinear and for each one except IL-1β, elevated levels predicted a more rapid progression. MCP-1 was the only biomarker increasing during follow-up, which also correlated with a worst outcome. Using multivariate linear regression adjusting for clinical risk factors of progression, urinary MCP-1 and TGF-β1 predicted progression independently and additively to the degree of proteinuria. We dichotomized these 3 biomarkers and observed a renal function decline with 0, 1, 2 or 3 elevated biomarkers of -0.8 ± 1.4, -2.1 ± 2.1, -4.2 ± 2.8 and -6.0 ± 2.8 mL/min/1.73 m(2)/year, respectively (p<0.001). CONCLUSIONS Multiple urinary biomarkers predict outcome in overt diabetic nephropathy. However, urinary MCP-1 and TGF-β1 are also independent and additive to proteinuria in predicting the rate of renal function decline and could serve as useful clinical tools in patient risk stratification.

Arteriovenous fistula for the 80 years and older patients on hemodialysis: is it worth it?

Over the last years, the proportion of patients older than 80 years with end‐stage renal disease has been constantly growing. Arteriovenous fistula (AVF) is known as the best vascular access for hemodialysis, but evidence for its added value is lacking for elderly. We retrospectively identified new vascular access (AVF and central venous catheter) created or installed between June 2005 and June 2008 in patients 80 years and older and in patients between 50 and 60 years. For every new AVF, we calculated primary failure, primary and secondary patency durations. Fifty‐five and 57 patients had a new vascular access in the >80 years old and 50 to 60 years old groups. Among these, 25 and 41 were new AVF in the older and younger groups. Primary failure was more frequent in elderly than in the younger (40% vs. 17%, P = 0.04). Primary patency was not significantly different in both groups (P = 0.06). Secondary patency was shorter in elderly (P = 0.005). Among the older group, the presence of an AVF was not associated with a difference in mortality (46% vs. 60%, P = 0.28), whereas there was a lower mortality in the younger group with AVF (12% vs. 43% P = 0.008). These results indicate lower patency duration in very elderly patients compared to middle‐aged patients. Without leading to the exclusion of patients over 80 years old for AVF creation, it might reinforce the need of a careful selection and evaluation in this population prior to referral.

Clinical Management and Outcomes of Adrenal Hemorrhage Following Adrenal Vein Sampling in Primary Aldosteronism

Aldosterone-producing adenoma and bilateral adrenal hyperplasia account for >90% of all primary aldosteronism cases. Distinguishing between bilateral and unilateral disease is of fundamental importance because it allows targeted therapy. Adrenal vein sampling (AVS) is the only reliable means to preoperatively differentiate between unilateral and bilateral subtypes. A rare but serious complication of AVS is an adrenal hemorrhage (AH). We retrospectively examined in detail 24 cases of AH during AVS in 6 different referral hypertension centers. AH more often affected the right adrenal (n=18) than the left (n=5, P<0.001); 1 bilateral. Median duration of experience of the radiologist in AVS at the time of AH was 5.0 years (0.6–7.8) and AH occurred with both highly experienced (>10 years) and less experienced radiologists. Of 9 patients who suffered AH in the gland contralateral to an aldosterone-producing adenoma and who underwent complete (n=6) or partial (n=3) unilateral adrenalectomy, only one required long-term corticosteroid replacement for adrenal insufficiency. No reduction in blood pressure or biochemical resolution of primary aldosteronism occurred in any of those patients who experienced AH in the gland ipsilateral to an aldosterone-producing adenoma (n=6) or who had bilateral adrenal hyperplasia (n=9). No patient required invasive treatments to control bleeding or blood transfusion. In conclusion, AH usually has a positive outcome causing either no or minor effects on adrenal function, and AVS should remain the best approach to primary aldosteronism subtype differentiation.

Central blood pressures in early chronic kidney disease: an analysis of CARTaGENE

Background Vascular stiffness and advanced chronic kidney disease (CKD) are strong determinants of higher central blood pressure (BP) and are associated with high cardiovascular morbidity and mortality. Whether mild-to-moderate CKD is associated with higher central BP independently of other comorbid conditions remains uncertain. Methods We evaluated the central hemodynamic profile [central systolic BP, central pulse pressure (PP), augmentation index, PP amplification, augmented pressure] of Stage 3 CKD patients and compared it with participants with estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m 2 in the CARTaGENE populational cohort through propensity score matching and multivariate regression analyses. Results Of the 20 004 participants, 13 114 had valid pulse wave analysis and eGFRs >30 mL/min/1.73 m 2 , of which 515 had Stage 3 CKD. These 515 patients had significantly higher peripheral systolic BP (127 ± 16 versus 125 ± 15 mmHg, P = 0.01) and central PP (43.0 ± 11.4 versus 39.7 ± 10.0 mmHg, P <0.001) than the control group (eGFR >60 mL/min/1.73 m 2 ). Propensity score matching allowed the creation of 500 pairs with similar clinical characteristics. In this matched cohort, central BPs were similar in Stage 3 CKD patients compared with controls (central PP 42.9 ± 11.3 versus 43.7 ± 11.3 mmHg, P = 0.3). Multivariate analysis using data from all patients also found that the higher central hemodynamic readings found in Stage 3 CKD patients disappeared after adjusting for comorbid conditions. In a subset of 609 participants in whom albuminuria levels were measured, urine albumin excretion was not independently associated with higher central hemodynamic indices. Conclusion In this large cohort from the general population, early CKD and albuminuria was not independently associated with detrimental central hemodynamic parameters.

Continuous venovenous hemofiltration using customized replacement fluid for acute kidney injury with severe hypernatremia

The initiation of continuous renal replacement therapy (CRRT) in acute kidney injury (AKI) with severe hypernatremia is challenging since sodium concentrations in commercial replacement fluid (RF) and dialysate solutions are usually fixed at 140 mEq/L. We present a case of AKI with severe hypernatremia successfully treated with CRRT using commercial RF solutions customized to prevent rapid correction of hypernatremia. None of the few case reports published on hypernatremia and AKI requiring CRRT have included formulas to help modulate the sodium content in the solutions. We present an equation to facilitate adjustment of the sodium concentration in this setting.

Central and Brachial Blood Pressures, Statins, and Low-Density Lipoprotein CholesterolNovelty and Significance: A Mediation Analysis

Central blood pressure may be a better predictor of cardiovascular disease than brachial pressure. Although statins reduce brachial pressure, their impact on central pressure remains unknown. Furthermore, whether this effect is mediated through a decrease in low-density lipoprotein cholesterol (LDL-c) is unknown. This study aims to characterize the association of statins and LDL-c with central and brachial blood pressures and to quantify their respective effects. Of the 20 004 CARTaGENE participants, 16 507 had available central blood pressure, LDL-c, and Framingham risk score. Multivariate analyses were used to evaluate the association between central pressure and LDL-c in subjects with or without statins. The impact of LDL-c on the association between statin and pressure parameters was determined through mediation analyses. LDL-c was positively associated with systolic and diastolic central pressure in nonusers (&bgr;=0.077 and 0.106; P<0.001) and in participants with statins for primary (&bgr;=0.086 and 0.114; P<0.001) and secondary prevention (&bgr;=0.120 and 0.194; P<0.003). Statins as primary prevention were associated with lower central systolic, diastolic, and pulse pressures (−3.0, −1.6, and −1.3 mm Hg; P<0.001). Mediation analyses showed that LDL-c reduction contributed to 15% of central systolic and 44% of central diastolic pressure changes associated with statins and attenuated 22% of the effects on central pulse pressure. Similar results were found with brachial pressure components. In conclusion, reduction of LDL-c was associated with only a fraction of the lower blood pressures in statin user and seemed to be mostly associated with improvement of steady (diastolic) pressure, whereas non–LDL-c–mediated pathways were mostly associated with changes in pulsatile pressure components.

Heart rate dependent and independent effects of beta-blockers on central hemodynamic parameters: a propensity score analysis.

Objectives: Central hemodynamic parameters are better predictors of the cardiovascular burden than peripheral blood pressure (BP). Beta-blockers are known to reduce central BP to a lesser extent than peripheral BP, a hypothesized mechanistic consequence of heart rate (HR) reduction. Methods: The association between beta-blocker use, HR and central hemodynamics indices was studied in treated hypertensive participants of the CARTaGENE study using propensity score analyses and multivariate linear regressions. Results: Of the 20 004 participants, 2575 were treated hypertensive patients with valid pulse wave analysis. Using propensity score analyses, beta-blocker users (n = 605) were matched to nonusers having similar clinical characteristics with (Model 1) and without (Model 2) adjustment for HR. This resulted in 457 and 510 pairs with adequate balance, except for a HR difference in Model 2 (62.5 ± 10.5 vs. 70.4 ± 11.5 bpm, p < 0.001). In Model 1, the central pulse pressure (PP) was 46.5 ± 12.9 mmHg with beta-blocker compared with 45.4 ± 11.0 mmHg without (p = 0.045). PP amplification, augmentation index and augmented pressure were also less favorable with the use of beta-blocker. The HR difference in Model 2 further increased the difference in central PP observed with beta-blocker to 46.5 ± 13.0 vs. 43.3 ± 11.3 without (p < 0.001). These findings were similar when atenolol, metoprolol and bisoprolol were assessed separately using multivariate linear regression models. Conclusion: This study shows that the unfavorable central hemodynamic profile of beta-blocker has both HR-dependent and HR-independent components that are similar for all frequently used &bgr;1-selective beta-blocker.

The utility of renal venous renin studies in selection of patients with renal artery stenosis for angioplasty: a retrospective study

Objectives: Recent studies of renal artery stenosis (RAS) failed to demonstrate greater benefit from angioplasty in terms of blood pressure (BP) lowering than medical treatment. Not all RAS are haemodynamically significant and identification of patients likely to benefit from angioplasty remains essential. Methods: We examined whether performing renal venous renin studies under stringent conditions might predict BP improvement. Patients with at least 60% RAS who underwent renal venous renin measurements in 2008–2013 were identified. Renal venous renin lateralization ratios (RVRRs) were calculated by dividing venous renin from the stenotic kidney with contralateral levels before and after stimulation with enalaprilat or captopril. Benefit was defined as BP less than 140/90 mmHg without medication, 10% decreased mean BP without increased daily defined doses (DDDs) or decreased DDD without a significant increase of mean BP. Results: Twenty-eight patients were treated medically and 42 with angioplasty (median age 60.1 years, 41% male, 29% chronic kidney disease, 50% resistant hypertension). At 11.4 ± 3.3 months, 69% of patients treated with angioplasty had BP benefit compared with 25% with medical treatment (P < 0.001). Logistic regression identified resistant hypertension [odds ratio (OR) 0.18, 95% confidence interval (95% CI) 0.04–0.82, P = 0.03] and baseline DDD (OR 0.69, 95% CI 0.48–0.98, P = 0.04) as being negatively associated, and positive stimulated RVRR (OR 21.6, 95% CI 3.50–133.3, P = 0.001) positively associated with benefit from angioplasty. On multivariate logistic regression, only stimulated RVRR positivity predicted BP benefit (OR 20.5, 95% CI 2.9–145.0, P = 0.003). Conclusion : These findings suggest that a positive stimulated RVRR measured under optimal conditions may help to identify patients with RAS likely to improve from angioplasty.

Use of plasma metanephrine to aid adrenal venous sampling in combined aldosterone and cortisol over-secretion

Summary In patients with primary aldosteronism (PA) undergoing adrenal venous sampling (AVS), cortisol levels are measured to assess lateralization of aldosterone overproduction. Concomitant adrenal autonomous cortisol and aldosterone secretion therefore have the potential to confound AVS results. We describe a case where metanephrine was measured during AVS to successfully circumvent this problem. A 55-year-old hypertensive male had raised plasma aldosterone/renin ratios and PA confirmed by fludrocortisone suppression testing. Failure of plasma cortisol to suppress overnight following dexamethasone and persistently suppressed corticotrophin were consistent with adrenal hypercortisolism. On AVS, comparison of adrenal and peripheral A/F ratios (left 5.7 vs peripheral 1.0; right 1.7 vs peripheral 1.1) suggested bilateral aldosterone production, with the left gland dominant but without contralateral suppression. However, using aldosterone/metanephrine ratios (left 9.7 vs peripheral 2.4; right 1.3 vs peripheral 2.5), aldosterone production lateralized to the left with good contralateral suppression. The patient underwent left laparoscopic adrenalectomy with peri-operative glucocorticoid supplementation to prevent adrenal insufficiency. Pathological examination revealed adrenal cortical adenomas producing both cortisol and aldosterone within a background of aldosterone-producing cell clusters. Hypertension improved and cured of PA and hypercortisolism were confirmed by negative post-operative fludrocortisone suppression and overnight 1 mg dexamethasone suppression testing. Routine dexamethasone suppression testing in patients with PA permits detection of concurrent hypercortisolism which can confound AVS results and cause unilateral PA to be misdiagnosed as bilateral with patients thereby denied potentially curative surgical treatment. In such patients, measurement of plasma metanephrine during AVS may overcome this issue. Learning points Simultaneous autonomous overproduction of cortisol and aldosterone is increasingly recognised although still apparently uncommon. Because cortisol levels are used during AVS to correct for differences in dilution of adrenal with non-adrenal venous blood when assessing for lateralisation, unilateral cortisol overproduction with contralateral suppression could confound the interpretation of AVS results Measuring plasma metanephrine during AVS to calculate lateralisation ratios may circumvent this problem.