Endovascular Versus Medical Management of Atherosclerotic Renovascular Disease: Update and Emerging Concepts.

Atherosclerotic renovascular disease is the most frequent cause of renovascular hypertension and its prevalence increases with age and in specific subset of patients, such as those with end-stage chronic kidney disease, heart failure, and coronary artery disease. Besides hypertension, atherosclerotic renovascular disease is responsible for several clinical manifestations, including life-threatening conditions, such as recurrent flash pulmonary edema, rapidly progressive chronic kidney disease, or acute kidney injury. Atherosclerotic renovascular disease is usually part of a more diffuse atherosclerotic process and requires a combination therapy including antihypertensive, antiplatelet and lipid-lowering agents, as well as optimization of antidiabetic treatment, if needed. Besides medical therapy, percutaneous renal angioplasty was supposed to be the most effective therapy for atherosclerotic renovascular disease, by leading to blood flow restoration. However, despite an apparently solid rationale, several randomized clinical trials failed to confirm the favorable effects of percutaneous renal angioplasty on blood pressure control, kidney function, cardiovascular and renal outcomes, previously reported in observational, retrospective and single-center cohorts, switching off the enthusiasm for this procedure. Several studies' limitations may partly account for this failure, including heterogeneity of diagnostic techniques, overestimation of the degree of renal artery stenosis, inappropriate timing of revascularization, multiple protocol revisions, frequent crossovers, and most importantly exclusion of patients at higher likelihood to respond to angioplasty. The purpose of this review is to summarize studies' potential weaknesses and provide guidance to the clinician for identification of patients who may benefit most from revascularization.

Pathophysiology of the Nondipping Blood Pressure Pattern.

The nondipping blood pressure (BP) pattern corresponds to a disruption in the circadian BP rhythm with an insufficient decrease in BP levels during nighttime sleep as observed using 24-hour ambulatory BP monitoring. Patients with nondipping BP pattern have poorer renal and cardiovascular outcomes, independent of their average 24-hour BP levels. The pathophysiology of nondipping BP is complex and involves numerous mechanisms: perturbations of (1) the circadian rhythm, (2) the autonomic nervous system, and (3) water and sodium regulation. This review provides an outline of the pathways potentially involved in the nondipping BP profile in different conditions. A recent hypothesis is also discussed involving the role of gut microbiota in the dipping/nondipping patterns, via the fecal diet-derived short chain fatty acids.

Long-Term Results up to 12 Months After Catheter-Based Alcohol-Mediated Renal Denervation for Treatment of Resistant Hypertension.

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Diabetes insipidus and acute myeloid leukemia harboring monosomy 7: report of two cases and literature review.

Acute myeloid leukemia (AML) is unusually associated with diabetes insipidus (DI) in patients bearing monosomy 7 or chromosome 3 aberrations. To date, 84 cases have been reported worldwide. Physiopathological mechanisms linking these chromosomal abnormalities to DI are not yet understood. We report two patients with AML/DI and review the medical literature on those conditions.

Feasibility and cost of FH cascade screening in Belgium (BEL-CASCADE) including a novel rapid rule-out strategy.

BACKGROUND: Familial hypercholesterolaemia (FH) is underdiagnosed in most countries. We report our first experience from a national pilot project of cascade screening in relatives of FH patients. METHODOLOGY: Participating specialists recruited consecutive index patients (IP) with Dutch Lipid Clinic Network (DLCN) score ≥6. After informed consent, the relatives were visited by the nurses to collect relevant clinical data and perform blood sampling for lipid profile measurement. FH diagnosis in the relatives was based on the DLCN and/or MEDPED FH (Make-Early-Diagnosis-to-Prevent-Early-Deaths-in-FH) criteria. RESULTS: In a period of 18 months, a total of 127 IP (90 with definite FH and 37 with probable FH) were enrolled in 15 centres. Out of the 270 relatives visited by the nurses, 105 were suspected of having FH: 31 with DCLN score >8, 33 with DLCN score 5-8 and 41 with MEDPED FH criteria. In a post-hoc analysis, another set of MEDPED FH criteria established in the Netherlands and adapted to Belgium allowed to detect FH in 51 additional relatives. CONCLUSION: In a country with no national FH screening program, our pilot project demonstrated that implementing a simple phenotypical FH cascade screening strategy using the collaboration of motivated specialists and two nurses, allowed to diagnose FH in 127 index patients and an additional 105 of their relatives over the two-year period. Newly developed MEDPED FH cut-offs, easily applicable by a nurse with a single blood sample, might further improve the sensitivity of detecting FH within families.

Lessons for the clinical nephrologist: an uncommon cause of pulmonary-renal syndrome.

Pulmonary-renal syndrome refers to the combination of elevated plasma creatinine concentration and/or abnormal urinalysis with diffuse alveolar hemorrhage, and involves both an urgent diagnostic approach and care. We report the case of a 24-year-old man presenting with diffuse alveolar hemorrhage as well as a nephritic syndrome associating kidney failure, moderate hypertension, hematuria and selective glomerular proteinuria. The initial high suspicion of anti-glomerular basement membrane (GBM) disease or ANCA-associated vasculitis justified intravenous pulse-corticotherapy in association with plasma exchange. Renal biopsy was remarkable for an IgA nephropathy, lesions of active thrombotic microangiopathy (TMA) and a positive staining for complement factor C4d. Because anti-GBM and ANCA antibodies returned negative, plasma exchange was discontinued, but oral corticosteroids were maintained to prevent alveolar hemorrhage recurrence. In the absence of renal function recovery, hemodialysis was initiated. TMA lesions are frequently seen in IgA nephropathy and are associated with a poorer prognosis. Complement activation seems to be involved in the development of those lesions and contributes to disease progression. Conversely, alveolar hemorrhage in the setting of IgA nephropathy is uncommon. It is thought to result from non-specific mucosal hemorrhage, an immune complex mediated basement membrane damage and an IgA-mediated capillaritis against basement membrane antigens.

Alcohol-Mediated Renal Denervation Using the Peregrine System Infusion Catheter for Treatment of Hypertension.

OBJECTIVES: The aim of this multicenter, open-label trial was to evaluate the safety and efficacy of alcohol-mediated renal denervation using a novel catheter system (the Peregrine System Infusion Catheter) for the infusion of dehydrated alcohol as a neurolytic agent into the renal periarterial space. BACKGROUND: The number of hypertensive patients with uncontrolled blood pressure (BP) remains unacceptably low. The renal sympathetic nervous system has been identified as an attractive therapeutic target. METHODS: Forty-five patients with uncontrolled hypertension on ≥3 antihypertensive medications underwent bilateral renal denervation using the Peregrine Catheter with 0.6 ml alcohol infused per renal artery. RESULTS: All patients were treated as intended. Mean 24-h ambulatory BP reduction at 6 months versus baseline was -11 mm Hg (95% confidence interval [CI]: -15 to -7 mm Hg) for systolic BP and -7 mm Hg (95% CI: -9 to -4 mm Hg) for diastolic BP (p < 0.001 for both). Office systolic BP was reduced by -18/-10 mm Hg (95% CI: -25 to -12/-13 to -6 mm Hg) at 6 months. Antihypertensive medications were reduced in 23% and increased in 5% of patients at 6 months. Adherence to the antihypertensive regimen remained stable over time. The primary safety endpoint, defined as the absence of periprocedural major vascular complications, major bleeding, acute kidney injury, or death within 1 month, was met in 96% of patients (95% CI: 85% to 99%). Two patients had major adverse events of periprocedural access-site pseudoaneurysms, with major bleeding in one. There were no deaths or instances of myocardial infarction, stroke, transient ischemic attack, or renal artery stenosis. Transient microleaks were noted in 42% and 49% of the left and right main renal arteries, respectively. There were 2 cases of minor vessel dissection that resolved without treatment. CONCLUSIONS: Primary results from this trial suggest that alcohol-mediated renal denervation using the Peregrine Catheter safely reduces blood pressure and as such may represent a novel approach for the treatment of hypertension.

Prevalence and characteristics of renal artery fibromuscular dysplasia in hypertensive women below 50 years old.

BACKGROUND: Renal fibromuscular dysplasia (FMD) is typically diagnosed in young hypertensive women. The 2014 European FMD Consensus recommended screening in all hypertensive women <30 yo. However, the prevalence of renal FMD in young/middle-aged hypertensive women remains unclear. The aim of this work was to assess the prevalence and characteristics of renal FMD in hypertensive women ≤50 yo. METHODS: We retrospectively included all consecutive women aged ≤50 years referred to our Hypertension Unit from 2014 to 2017 and collected standardized information on patient characteristics and screening modalities. RESULTS: Of 1083 incident hypertensive patients, 157 patients fitted with inclusion criteria. The prevalence of renal FMD varied between 3.2% in the whole sample and 7.5% in patients explored by CTA and/or MRA (n = 67). In the subgroup of patients ≤30 yo (n = 32), the corresponding figures were 3.1% and 5.6%. The yearly prevalence of FMD tended to increase over time, in parallel with increased use of CTA/MRA as a first-line imaging modality. Out of 5 patients with renal FMD, 2 were revascularized and 1 had extra-renal FMD. CONCLUSIONS: The prevalence of renal FMD in young/middle-aged hypertensive women is probably one order of magnitude higher than previously assumed, in the range of 3%-8%, depending on imaging modalities. While the diagnosis of FMD does not influence short-term management in all patients, it may allow close monitoring and prevention of complications of the disease over time. This analysis provides the rationale for a prospective, multicentre study aiming at determining the cost-effectiveness of systematic screening for renal FMD.

Predictors of blood pressure control in patients with resistant hypertension after intensive management in two expert centres: the Brussels-Torino experience.

Background: Management of resistant hypertension (RHTN) is challenging and often implies the use of complex polypharmacy and interventional therapies. The main objectives of this study were (i) to describe the characteristics of patients with RHTN referred to two expert centres; (ii) to identify predictors of blood pressure (BP) control after intensive management. Methods: We reviewed electronic medical files of all patients referred for RHTN to the Brussels and Torino centres, and extracted detailed clinical data, informations on drug adherence and psychological profile. All patients with confirmed diagnosis of RHTN, according to office and ambulatory BP monitoring (ABPM) measurements, were considered eligible. Results: 313 patients (51% men; age: 56 ± 12 years; office BP 177/98 mmHg; 24-hour ABPM 153/90 mmHg) were included. At the end of follow-up (median: 2 years [1-4]), only 26% of patients (n = 81) reached BP control. When compared to patients remaining resistant, patients eventually controlled had lower pulse pressure (71 vs. 82 mmHg, p < 0.001), less often myocardial infarction (6% vs. 20%, p < 0.005) and showed a higher recourse to cognitive reappraisal as far as emotion regulation is concerned (4.8 ± 1.1 vs. 3.9 ± 1.2, p = 0.009; ERQ Questionnaire). In a multivariate analysis looking for predictors of controlled BP, only the psychological characteristic of cognitive reappraisal (i.e., changing one's thoughts about a potentially emotion-eliciting event) remained significant (OR 2.06 [1.10; 3.84], p = 0.02). Conclusions: Even in expert centres, only a minority of patients with RHTN reached BP control, irrespective of the centre involved or the interventions applied. Patients who eventually responded to therapy had lower arterial stiffness and less cardiac organ damage. Furthermore, besides vascular damage, the single predictor of BP control was the ability to modify the emotional impact of stressful situations.

Adherence to antihypertensive drug treatment in patients with apparently treatment-resistant hypertension in the INSPiRED pilot study.

PURPOSE: Drug adherence may be a major problem in the therapy of hypertension and in the diagnosis of therapy resistance. Adherence can be assessed by indirect methods or by direct methods like drug detection in urine with liquid chromatography-mass spectrometric methods. MATERIALS AND METHODS: The current analysis included patients with apparently treatment- resistant hypertension (TRH) referred for renal denervation (RDN) and included in the the INSPiRED pilot trial (NCT01505010). Adherence was repeatedly assessed by toxicological urine analysis over a time range of up to 17 months in a total of 18 patients. RESULTS: In the first urine samples of 18 patients the adherence rate (percentage of number of detected vs. prescribed medical drugs) ranged from 0 to 100% with a median of 73.2%. In further urine samples collected during the following up to 17 months every individual patient exhibited considerable changes in the adherence rate, neither a constancy nor a tendency could be deduced. CONCLUSIONS: Urine analysis results exhibit variation over time and an assessment at a certain time point cannot be regarded as representative or predictor for future behavior. Therefore, it appears necessary to perform drug adherence testing repeatedly over time.

Genomics of Fibromuscular Dysplasia.

Fibromuscular Dysplasia (FMD) is “an idiopathic, segmental, non-atherosclerotic and non-inflammatory disease of the musculature of arterial walls, leading to stenosis of small and medium-sized arteries” (Persu, et al; 2014). FMD can lead to hypertension, arterial dissections, subarachnoid haemorrhage, stroke or mesenteric ischemia. The pathophysiology of the disease remains elusive. While familial cases are rare (<5%) in contemporary FMD registries, there is evidence in favour of the existence of multiple genetic factors involved in this vascular disease. Recent collaborative efforts allowed the identification of a first genetic locus associated with FMD. This intronic variant located in the phosphatase and actin regulator 1 gene (PHACTR1) may influence the transcription activity of the endothelin-1 gene (EDN1) located nearby on chromosome 6. Interestingly, the PHACTR1 locus has also been involved in vascular hypertrophy in normal subjects, carotid dissection, migraine and coronary artery disease. National and international registries of FMD patients, with deep and harmonised phenotypic and genetic characterisation, are expected to be instrumental to improve our understanding of the genetic basis and pathophysiology of this intriguing vascular disease.

Clinical Assessment of a Nocardia PCR-Based Assay for Diagnosis of Nocardiosis.

The diagnosis of nocardiosis, a severe opportunistic infection, is challenging. We assessed the specificity and sensitivity of a 16S rRNA Nocardia PCR-based assay performed on clinical samples. In this multicenter study (January 2014 to April 2015), patients who were admitted to three hospitals and had an underlying condition favoring nocardiosis, clinical and radiological signs consistent with nocardiosis, and a Nocardia PCR assay result for a clinical sample were included. Patients were classified as negative control (NC) (negative Nocardia culture results and proven alternative diagnosis or improvement at 6 months without anti-Nocardia treatment), positive control (PC) (positive Nocardia culture results), or probable nocardiosis (positive Nocardia PCR results, negative Nocardia culture results, and no alternative diagnosis). Sixty-eight patients were included; 47 were classified as NC, 8 as PC, and 13 as probable nocardiosis. PCR results were negative for 35/47 NC patients (74%). For the 12 NC patients with positive PCR results, the PCR assay had been performed with respiratory samples. These NC patients had chronic bronchopulmonary disease more frequently than did the NC patients with negative PCR results (8/12 patients [67%] versus 11/35 patients [31%]; P = 0.044). PCR results were positive for 7/8 PC patients (88%). There were 13 cases of probable nocardiosis, diagnosed solely using the PCR results; 9 of those patients (69%) had lung involvement (consolidation or nodule). Nocardia PCR testing had a specificity of 74% and a sensitivity of 88% for the diagnosis of nocardiosis. Nocardia PCR testing may be helpful for the diagnosis of nocardiosis in immunocompromised patients but interpretation of PCR results from respiratory samples is difficult, because the PCR assay may also detect colonization.

Results of a randomized controlled pilot trial of intravascular renal denervation for management of treatment-resistant hypertension.

OBJECTIVE: Previous trials of catheter-based renal-artery denervation (RDN) as treatment modality in resistant hypertension (rHT) generated unconvincing results. In the Investigator-Steered Project on Intravascular Denervation for Management of Treatment-Resistant Hypertension (INSPiRED; NCT01505010), we optimized selection and management of rHT patients. METHODS: With ethical clearance to randomize 18 patients, three Belgian hypertension centers screened 29 rHT patients on treatment with ≥3 drugs, of whom 17 after optimization of treatment (age <70 years; systolic/diastolic office blood pressure (BP) ≥ 140/90 mm Hg; 24-h BP ≥130/80 mm Hg; glomerular filtration rate [eGFR] ≥ 45 mL/min/1.73 m2; body mass index <40kg/m2) were randomized and 15 were analyzed 6 months later, while medical treatment was continued (n = 9) or combined with RDN by the EnligHTN™ multi-electrode system (n = 6). RESULTS: The baseline-adjusted between-group differences amounted to 19.5/10.4 mm Hg (change in control vs. intervention group, +7.6/+2.2 vs. -11.9/-8.2 mm Hg; P = .088) for office BP, 22.4/13.1 mm Hg (+0.7/+0.3 vs. -21.7/-12.8; mm Hg; P ≤ .049) for 24-h BP, the primary efficacy endpoint, and 2.5 mL/min/1.73 m2 (+1.5 vs. -1.1 mL/min/1.73 m2; P = .86) for eGFR, the primary safety endpoint. At 6 month, ECG voltages and the number of prescribed drugs (P ≤ .036) were lower in RDN patients, but quality of life and adherence, captured by questionnaire and urine analysis were similar in both groups. Changes in BP and adherence were unrelated. No major complications occurred. CONCLUSIONS: The INSPiRED pilot suggests that RDN with the EnligHTN™ system is effective and safe and generated insights useful for the design of future RDN trials.

Renal Artery Stenosis in Patients with Resistant Hypertension: Stent It or Not?

After three large neutral trials in which renal artery revascularization failed to reduce cardiovascular and renal morbidity and mortality, renal artery stenting became a therapeutic taboo. However, this is probably unjustified as these trials have important limitations and excluded patients most likely to benefit from revascularization. In particular, patients with severe hypertension were often excluded and resistant hypertension was either poorly described or not conform to the current definition. Effective pharmacological combination treatment can control blood pressure in most patients with renovascular hypertension. However, it may also induce further renal hypoperfusion and thus accelerate progressive loss of renal tissue. Furthermore, case reports of patients with resistant hypertension showing substantial blood pressure improvement after successful revascularization are published over again. To identify those patients who would definitely respond to renal artery stenting, properly designed randomized clinical trials are definitely needed.

Tubular proteinuria in patients with HNF1α mutations: HNF1α drives endocytosis in the proximal tubule.

Hepatocyte nuclear factor 1α (HNF1α) is a transcription factor expressed in the liver, pancreas, and proximal tubule of the kidney. Mutations of HNF1α cause an autosomal dominant form of diabetes mellitus (MODY-HNF1A) and tubular dysfunction. To gain insights into the role of HNF1α in the proximal tubule, we analyzed Hnf1a-deficient mice. Compared with wild-type littermates, Hnf1a knockout mice showed low-molecular-weight proteinuria and a 70% decrease in the uptake of ß2-microglobulin, indicating a major endocytic defect due to decreased expression of megalin/cubilin receptors. We identified several binding sites for HNF1α in promoters of Lrp2 and Cubn genes encoding megalin and cubilin, respectively. The functional interaction of HNF1α with these promoters was shown in C33 epithelial cells lacking endogenous HNF1α. Defective receptor-mediated endocytosis was confirmed in proximal tubule cells from these knockout mice and could be rescued by transfection of wild-type but not mutant HNF1α. Transfection of human proximal tubule HK2 cells with HNF1α was able to upregulate megalin and cubilin expression and to increase endocytosis of albumin. Low-molecular-weight proteinuria was consistently detected in individuals with HNF1A mutations compared with healthy controls and patients with non-MODY-HNF1A diabetes mellitus. Thus, HNF1α plays a key role in the constitutive expression of megalin and cubilin, hence regulating endocytosis in the proximal tubule of the kidney. These findings provide new insight into the renal phenotype of individuals with mutations of HNF1A.