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Diagnosis and Management of Resistant Hypertension: A Review

Author/s: 
Michel Azizi, Wanpen Vongpatanasin, Naomi D L Fisher, Felix Mahfoud, Laurence Amar, Ajay J Kirtane

Importance: Hypertension, defined as office systolic blood pressure (SBP) 130 mm Hg or greater and/or diastolic blood pressure 80 mm Hg or greater, affects 43.9% of women and 49.5% of men in the US. Approximately 19.7% of patients treated for hypertension have apparent resistant hypertension (blood pressure ≥130/80 mm Hg) despite using 3 or more antihypertensive medications, preferably a renin-angiotensin system blocker, a calcium channel blocker, and a thiazide-type diuretic, at maximally tolerated doses.

Observations: Approximately 10% of patients treated for hypertension have true resistant hypertension confirmed with home or 24-hour ambulatory blood pressure monitoring to exclude white-coat hypertension (approximately 37.5% of apparent resistant hypertension) and after excluding medication nonadherence (approximately 50%) and secondary hypertension such as primary aldosteronism (approximately 5%-25%). Conditions associated with resistant hypertension include obesity, diabetes, chronic kidney disease, and sleep apnea. Resistant hypertension is associated with increased risk of cardiovascular death vs controlled blood pressure at 5 years to 10 years (absolute risk increase, 10.3% [95% CI, 8.7%-12.1%]). Lifestyle modifications for resistant hypertension include a low-sodium diet (<1500 mg/d), reducing or avoiding alcohol, 150 min/wk or more of aerobic exercise, and weight loss. Illicit drugs (eg, cocaine) and medications that increase blood pressure (eg, nonsteroid anti-inflammatory drugs, serotonin-norepinephrine reuptake inhibitors) should be avoided. Sleep apnea should be treated when diagnosis is confirmed. Pharmacologic optimization includes use of combination tablets of antihypertensives; intensifying diuretic therapy by using chlorthalidone; and sequential addition of antihypertensive medications using evidence-based algorithms. In a meta-analysis of 20 studies (9 randomized clinical trials [RCTs] and 11 observational studies [331 participants]), use of antihypertensive therapies that combine 2 to 3 medications into a single formulation reduced SBP by -3.99 mm Hg (95% CI, -7.92 to -0.07) vs equivalent doses given separately. For patients with apparent or true resistant hypertension who have an estimated glomerular filtration rate of 45 mL/min/1.73 m2 or greater and a serum potassium level of 4.5 mmol/L or less, adding spironolactone (25-50 mg/d) compared with placebo lowers office SBP by -13.3 mm Hg (95% CI, -17.89 to -8.72 [4 RCTs]) and 24-hour ambulatory SBP by -8.46 mm Hg (95% CI, -12.54 to -4.38 [2 RCTs]) in a network meta-analysis of 24 RCTs (3485 patients with resistant hypertension). A meta-analysis of 10 RCTs (2478 participants) reported that compared with a sham procedure, catheter-based renal denervation, which disrupts the sympathetic nerves in the renal artery walls, decreased 24-hour ambulatory SBP by -4.4 mm Hg (95% CI, -6.1 to -2.7) and office SBP by -6.6 mm Hg (95% CI, -9.7 to -3.6).

Conclusions and relevance: True resistant hypertension affects 10% of patients treated for hypertension and is diagnosed after excluding white-coat hypertension, medication nonadherence, and secondary hypertension such as primary aldosteronism. First-line treatment includes lifestyle modifications, diuretic therapy with chlorthalidone, and combination tablets of antihypertensives. Spironolactone and renal denervation decrease blood pressure in patients with true resistant hypertension.

Keywords 
blood pressure Antihypertensive Agents Resistant Hypertension hypertension Hyperaldosteronism Anti-Inflammatory Agents

IgA Nephropathy in Adults: A Review

Author/s: 
Sinead Stoneman, Jia Wei Teh, Michelle Marie O’Shaughnessy

Importance IgA nephropathy (IgAN) is a chronic kidney disease involving deposition of IgA-containing immune complexes in the glomerulus, causing glomerular inflammation and scarring. It is the most common immune-mediated glomerular disease worldwide, and affects an estimated 198 887 to 208 184 persons in the US. Up to 50% of patients with IgAN develop kidney failure within 10 years of diagnosis.

Observations IgAN typically presents with nephritic syndrome and usually occurs in younger adults, with a mean age at diagnosis of 34 to 45 years. Incidence is highest in East Asia. Approximately 60% of cases are detected incidentally with hematuria or proteinuria on urinalysis. Up to 30% of patients present with episodic visible hematuria, often concomitantly with an upper respiratory or gastrointestinal tract infection (synpharyngitic hematuria). Less common presentations include nephrotic syndrome (<5%) and rapidly progressive glomerulonephritis (<5%). When IgAN is suspected (due to hematuria, proteinuria, or reduced kidney function), initial workup should include quantification of proteinuria and assessment for other causes of nephritic syndrome (eg, lupus nephritis). Adults with suspected IgAN and proteinuria greater than or equal to 0.5 g per day should undergo kidney biopsy. The diagnosis of primary IgAN is based on presence of IgA-dominant immune deposits in the glomerular mesangium after excluding other causes of this histologic appearance, ie, IgA vasculitis, IgA-dominant infection-related glomerulonephritis, and secondary IgAN from diseases such as cirrhosis, inflammatory bowel disease, celiac disease, infection (eg, viral hepatitis), and autoimmune diseases (eg, axial spondyloarthritis). Based on the Kidney Disease: Improving Global Outcomes 2025 clinical practice guideline for the management of IgAN, treatment for patients with proteinuria greater than 0.5 g per day includes behavioral modifications (eg, dietary sodium <2 g/d, smoking cessation, weight control, exercise), antihypertensive medications for goal blood pressure less than 120/70 mm Hg, and therapies to reduce the formation of IgA-containing immune complexes (eg, targeted-release budesonide), decrease glomerular injury (eg, systemic glucocorticoids, iptacopan), and manage existing IgAN-induced nephron loss (eg, renin-angiotensin system inhibitor or dual endothelin angiotensin receptor antagonist [eg, sparsentan] alone or in combination with a sodium-glucose cotransporter 2 inhibitor).

Conclusions and Relevance IgAN is the leading cause of immune-mediated glomerular disease worldwide. Patients with suspected IgAN and proteinuria greater than or equal to 0.5 g per day should undergo kidney biopsy to confirm the diagnosis. Treatment of IgAN includes behavioral modifications, blood pressure management, and therapies to decrease formation of IgA-containing immune complexes (eg, targeted-release budesonide), reduce immune complex–mediated glomerular injury (eg, systemic glucocorticoids, iptacopan), and manage IgAN-induced nephron loss (eg, renin-angiotensin system inhibitor, dual endothelin angiotensin receptor antagonist, and sodium-glucose cotransporter 2 inhibitor).

Keywords 
Antigen-Antibody Complex IgA Nephropathy Renal Insufficiency Angiotensin Receptor Antagonists renin-angiotensin system

Angiotensin-converting-enzyme inhibitor–induced angioedema

Author/s: 
Quickfall, D., Jakubovic, B., Zipursky, J. S.

Angiotensin-converting-enzyme (ACE) inhibitors are the leading cause of drug-induced angioedema Angiotensin-converting-enzyme (ACE) inhibitors are responsible for 20%–40% of emergency department visits for angioedema.1 The incidence of ACE inhibitor–induced angioedema is about 0.1%–0.7% in the first 5 years of treatment; symptoms occur within the first month in 10% of cases.1 Risk factors include concomitant use of dipeptidyl peptidase-4 inhibitors (e.g., sitagliptin), mammalian target of rapamycin (mTOR) inhibitors (e.g., sirolimus) and neprilysin inhibitors (e.g., sacubitril) (Appendix 1, available at www.cmaj.ca/lookup/doi/10.1503/ cmaj.202308/tab-related-content).1 Nonsteroidal anti-inflammatory drugs and statins can exacerbate angioedema, and the risk of ACE inhibitor–induced angioedema is fivefold higher in Black people.2

Keywords 
inhibitor-induced angioedema swelling airway compromise angiotensin

Meta-Analysis Evaluating the Effects of Renin-Angiotensin-Aldosterone System Blockade on Outcomes of Heart Failure With Preserved Ejection Fraction

Author/s: 
Kuno, T, Ueyama, H, Fujisaki, T, Briasouli, A, Takagi, H, Briasoulis, A

Clinical trials of renin-angiotensin-aldosterone system (RAAS) antagonists in heart failure with preserved ejection fraction (HFpEF) have suggested neutral results and treatment is focused on associated symptoms and comorbidities. MEDLINE and EMBASE were searched through October 2019 for randomized controlled studies investigating the effects of different RAAS antagonists in patients with HFpEF. The main outcomes were all-cause mortality, trial defined cardiovascular mortality, and heart failure (HF) hospitalizations. To compare different RAAS antagonists, a random-effects restricted-maximum-likelihood network meta-analysis based on a frequentist framework for indirect and mixed comparisons was used. We used p scores to rank best treatments per outcome. Our search identified 5 eligible clinical trials (PEP-CHF, perindopril; CHARM-preserved, candesartan; I-PRESERVE, irbesartan; TOPCAT, spironolactone; PARAGON-HF, sacubitril-valsartan and valsartan) enrolling a total 10,523 on RAAS antagonists and 6,259 controls. We did not identify any statistical difference in all-cause and cardiovascular mortality among RAAS antagonists and placebo. The combination of sacubitril-valsartan was associated with significantly decreased HF hospitalization risk compared with controls (odds ratio 0.73, 95% confidence interval 0.61 to 0.87) and angiotensin II receptor blockers (odds ratio 0.80, 95% confidence interval 0.71 to 0.91), without heterogeneity among studies (I2 = 0). Angiotensin receptor neprilysin inhibitor (ARNI) ranked better than other RAAS antagonists for HF hospitalizations (p value 0.9). In conclusion, RAAS antagonists do not affect mortality but the combination of sacubitril-valsartan is associated with lower HF hospitalizations in HFpEF patients.

Keywords 
RAAS Anatgonists heart failure

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

Author/s: 
Perkovic, Vlado, Jardine, Meg J., Neal, Bruce, Bompoint, Severine, Heerspink, Hiddo J. L., Charytan, David M., Edwards, Robert, Agarwal, Rajiv, Bakris, George, Bull, Scott, Cannon, Christopher P., Capuano, George, Chu, Pei-Ling, de Zeeuw, Dick, Greene, Tom, Levin, Adeera, Pollock, Carol, Wheeler, David C., Yavin, Yshai, Zhang, Hong, Zinman, Bernard, Meininger, Gary, Brenner, Barry M., Mahaffey, Kenneth W.

BACKGROUND

Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes.

METHODS

In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically.

RESULTS

The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture.

CONCLUSIONS

In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.)

Keywords 
type 2 diabetes nephropathy canagliflozin renal outcomes
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