Management of Hypertension in Patients With Diabetic Kidney Disease: Summary of the Joint Association of British Clinical Diabetologists and UK Kidney Association (ABCD-UKKA) Guideline 2021

Abstract

Diabetic kidney disease (DKD) accounts for >40% cases of chronic kidney disease (CKD) globally. Hypertension is a major risk factor for progression of DKD and the high incidence of cardiovascular disease and mortality in these people. Meticulous management of hypertension is therefore crucial to slow down the progression of DKD and reduce cardiovascular risk. Randomized controlled trial evidence differs in type 1 and type 2 diabetes and in different stages of DKD in terms of target blood pressure (BP). Renin-angiotensin blocking agents reduce progression of DKD and cardiovascular events in both type 1 and type 2 diabetes, albeit differently according to the stage of CKD. There is emerging evidence for the benefit of sodium glucose cotransporter 2, nonsteroidal selective mineralocorticoid antagonists, and endothelin-A receptor antagonists in slowing progression and reducing cardiovascular events in DKD. This UK guideline, developed jointly by diabetologists and nephrologists, has reviewed all available current evidence regarding the management of hypertension in DKD to produce a set of comprehensive individualized recommendations for BP control and the use of antihypertensive agents according to age, type of diabetes, and stage of CKD (https://ukkidney.org/sites/renal.org/files/Management-of-hypertension-and-RAAS-blockade-in-adults-with-DKD.pdf). A succinct summary of the guideline, including an infographic, is presented here. Diabetic kidney disease (DKD) accounts for >40% cases of chronic kidney disease (CKD) globally. Hypertension is a major risk factor for progression of DKD and the high incidence of cardiovascular disease and mortality in these people. Meticulous management of hypertension is therefore crucial to slow down the progression of DKD and reduce cardiovascular risk. Randomized controlled trial evidence differs in type 1 and type 2 diabetes and in different stages of DKD in terms of target blood pressure (BP). Renin-angiotensin blocking agents reduce progression of DKD and cardiovascular events in both type 1 and type 2 diabetes, albeit differently according to the stage of CKD. There is emerging evidence for the benefit of sodium glucose cotransporter 2, nonsteroidal selective mineralocorticoid antagonists, and endothelin-A receptor antagonists in slowing progression and reducing cardiovascular events in DKD. This UK guideline, developed jointly by diabetologists and nephrologists, has reviewed all available current evidence regarding the management of hypertension in DKD to produce a set of comprehensive individualized recommendations for BP control and the use of antihypertensive agents according to age, type of diabetes, and stage of CKD (https://ukkidney.org/sites/renal.org/files/Management-of-hypertension-and-RAAS-blockade-in-adults-with-DKD.pdf). A succinct summary of the guideline, including an infographic, is presented here. People with diabetes and CKD are at risk of premature morbidity and mortality compared with those without these conditions; predominantly related to cardiovascular events, such as acute coronary syndrome, heart failure, and strokes, for which, hypertension is a common modifiable risk factor.1Roth G.A. Mensah G.A. Johnson C.O. et al.Global burden of cardiovascular diseases and risk factors, 1990–2019: update from the GBD 2019 study [published correction appears in J Am Coll Cardiol. 2021;77:1958-1959].J Am Coll Cardiol. 2020; 76: 2982-3021https://doi.org/10.1016/j.jacc.2020.11.010Crossref PubMed Scopus (807) Google Scholar End-stage kidney disease is another complication, mediated in part by hypertension, and is associated with poor quality of life, multiple hospital admissions, and increased burden to already stretched health care systems across the world.2GBD Chronic Kidney Disease CollaborationGlobal, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet. 2020; 395: 709-733https://doi.org/10.1016/S0140-6736(20)30045-3Abstract Full Text Full Text PDF PubMed Scopus (1116) Google Scholar,3Thurlow J.S. Joshi M. Yan G. et al.Global epidemiology of end-stage kidney disease and disparities in kidney replacement therapy.Am J Nephrol. 2021; 52: 98-107https://doi.org/10.1159/000514550Crossref PubMed Scopus (27) Google Scholar With the increasing worldwide prevalence of type 2 diabetes, DKD has emerged as a significant contributor to the burden of global disease.4Xie Y. Bowe B. Mokdad A.H. et al.Analysis of the Global Burden of Disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016.Kidney Int. 2018; 94: 567-581https://doi.org/10.1016/j.kint.2018.04.011Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar This has attracted research with novel agents such a sodium glucose co-transporter 2 inhibitors and nonsteroidal mineralocorticoid receptor antagonists in recent years. These new agents have been found to improve cardiorenal outcomes with a modest BP-lowering effect.5Heerspink H.J.L. Stefánsson B.V. Correa-Rotter R. et al.Dapagliflozin in patients with chronic kidney disease.N Engl J Med. 2020; 383: 1436-1446https://doi.org/10.1056/NEJMoa2024816Crossref PubMed Scopus (898) Google Scholar,6Bakris G.L. Agarwal R. Anker S.D. et al.Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.N Engl J Med. 2020; 383: 2219-2229https://doi.org/10.1056/NEJMoa2025845Crossref PubMed Scopus (364) Google Scholar The targets of therapy and agents used for BP control in people with DKD have evolved in the last 40 years. Agents that inhibit the renin-angiotensin-aldosterone system (RAAS) have been found to decrease adverse cardiorenal outcomes over and beyond BP-lowering effect.7Strippoli G.F.M. Bonifati C. Craig M. Navaneethan S.D. Craig J.C. Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists for preventing the progression of diabetic kidney disease.Cochrane Database Syst Rev. 2006; 2006: CD006257https://doi.org/10.1002/14651858.CD006257Crossref Scopus (201) Google Scholar Nevertheless, intensive BP control (systolic BP <120 mm Hg) has not been found to be associated with better outcomes than standard control (systolic BP <140 mm Hg) in people with diabetes.8Cushman W.C. Evans G.W. et al.ACCORD Study GroupEffects of intensive blood-pressure control in type 2 diabetes mellitus.N Engl J Med. 2010; 362: 1575-1585https://doi.org/10.1056/NEJMoa1001286Crossref PubMed Scopus (2642) Google Scholar People with DKD are often old, frail, and multimorbid. As such, lower BP targets are likely to be associated with increased adverse events, including symptomatic postural hypotension, falls, fractures, acute kidney injury, and hyperkalemia.9Dasgupta I. Zoccali C. Is the KDIGO systolic blood pressure target <120 mm Hg for chronic kidney disease appropriate in routine clinical practice?.Hypertension. 2022; 79: 4-11https://doi.org/10.1161/HYPERTENSIONAHA.121.18434Crossref PubMed Scopus (2) Google Scholar The 2021 update of the Joint Association of British Clinical Diabetologists and UK Kidney Association guideline provides guidance to practicing clinicians on personalized care of hypertension in people with DKD taking into account the type of diabetes (type 1 and type 2), age, stage of CKD, and degree of proteinuria (https://ukkidney.org/sites/renal.org/files/Management-of-hypertension-and-RAAS-blockade-in-adults-with-DKD.pdf).10Association of British Clinical Diabetologists and The Renal Association. Clinical practice guidelines for management of hypertension and renin-angiotensin-aldosterone system blockade in adults with diabetic kidney disease. London: ABCD, 2021. https://ukkidney.org/sites/renal.org/files/Management-of-hypertension-and-RAAS-blockade-in-adults-with-DKD.pdfGoogle Scholar The guideline emphasizes the importance of accurate BP measurement and monitoring, nonpharmacologic management, use of appropriate pharmacologic agents, and BP targets based on available evidence (Figure 111Unger T. Borghi C. Charchar F. et al.2020 International Society of Hypertension Global Hypertension Practice Guidelines.Hypertension. 2020; 75: 1334-1357Crossref PubMed Scopus (590) Google Scholar,12National Institute for Health and Care Excellence (NICE). Hypertension in adults: diagnosis and management. Published August 28, 2019. Last updated March 18, 2022. Accessed November 16, 2021. https://www.nice.org.uk/guidance/ng136Google Scholar and Table 1).Table 1Blood pressure targets in people with diabetes through stages of kidney function impairmentType of diabetesStage of kidney function impairmentNormal kidney function, normoalbuminuriaNormal kidney function, microalbuminuriaCKD stages 1–3CKD stages 4–5 (nondialysis)CKD stage 5 (dialysis)Type 1<140/80–90 (2D)<120/80 (2D)aLower targets for younger adults aged <30 yr. (for <30 yr)≤130/80 (1B)120/80 (2D)aLower targets for younger adults aged <30 yr.≤130/80 (1B)120/80 (2D)aLower targets for younger adults aged <30 yr.≤140/90 (1B)≤130/80 for those with albuminuria (2C)≤140/90 (2D)bMonitor and target interdialytic home BP for people on dialysis. (interdialytic BP)Type 2<140/90 (1D)<150/90 (2B)cFor frail adults >75 yr, a higher target >150/90 mm Hg may be appropriate to avoid side effects. (for ≥75 yr)<130/80 (2D)<130/80 (2D)<140/90 (1B)dFor adults >65 yr, a higher target >140/90 mm Hg may be appropriate.<130/80 for those with albuminuria (2C)<140/90 (2D)bMonitor and target interdialytic home BP for people on dialysis. (interdialytic BP)All BP are in mm Hg; the evidence grade is in brackets.BP, blood pressure; CKD, chronic kidney disease.a Lower targets for younger adults aged <30 yr.b Monitor and target interdialytic home BP for people on dialysis.c For frail adults >75 yr, a higher target >150/90 mm Hg may be appropriate to avoid side effects.d For adults >65 yr, a higher target >140/90 mm Hg may be appropriate. Open table in a new tab All BP are in mm Hg; the evidence grade is in brackets. BP, blood pressure; CKD, chronic kidney disease. The recommendations are based on review of literature initially between October 2013 and December 2016 and further detailed review until April 2021 for the current update. We searched the PubMed/MEDLINE, Cochrane Library, EMBASE, and Google Scholar and used the following key terms: type 1 diabetes, type 2 diabetes, hypertension, albuminuria, microalbuminuria, microvascular complications, nephropathy, CKD, angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARBs), and mineralocorticoid antagonists. The recommendation grades ranged from 1 (strong recommendation) to 2 (weak recommendation), and the corresponding evidence quality was as follows: A (high-quality evidence), B (moderate-quality evidence), C (low-quality evidence), and D (very low-quality evidence). In an area that lacks adequate evidence to support a recommendation, further research is suggested (Research Recommendation). Management of hypertension in people with DKD requires accurate measurements of BP, regular monitoring for side effects of medications, and personalized therapy. We suggest that the British and Irish Hypertension Society’s guidance on standardized, automated BP measurement is followed (https://bihsoc.org/wp-content/uploads/2017/11/BP-Measurement-Poster-Automated-2017.pdf).13British and Irish Hypertension Society. Blood Pressure Measurement. Using automated blood pressure monitors. Accessed November 16, 2021. https://bihsoc.org/wp-content/uploads/2017/11/BP-Measurement-Poster-Automated-2017.pdfGoogle Scholar The BP thresholds and targets in this guideline refer to standardized office BP readings unless specified otherwise. We encourage self (home) BP monitoring using a validated device which empowers patients and improves BP control. The guideline recommends a reduced salt intake, <90 mmol of sodium daily (<2 g of sodium or <5 g of sodium chloride daily), alcohol <2 units daily for men and 1 unit daily for women, regular exercise at least 30 minutes daily for 5 days a week, and to maintain a body mass index between 20 and 25 kg/m2. These recommendations are based on observational studies in people with type 2 diabetes and require regular reinforcement at each patient encounter. 1.In people with type 1 diabetes and urine albumin-to-creatinine ratio (ACR) of ≤3 mg/mmol), we recommend a threshold for BP therapy of a persistent upright (sitting or standing) BP that is ≥140/90 mm Hg (1B) ∗We suggest a target upright BP in younger adults of 120/80 mm Hg and 140/90 mm Hg for those aged >65 years (2D).∗We suggest a target upright BP in younger adults of 120/80 mm Hg and 140/90 mm Hg for those aged >65 years (2D). In children and adolescents with type 1 diabetes, the threshold for high BP is an average systolic BP and/or diastolic BP greater than the 95th percentile for the person’s sex, age, and height on >3 occasions (1B). ∗∗Between the ages of 30 and 65 years, for some people with higher lifetime risk through earlier age of onset of type 1 diabetes, it may be appropriate to target a diastolic BP of <80 mm Hg (2C).2.We recommend that ACEI therapy should be used as a first-line agent for BP lowering and, if ACEI therapy is contraindicated or not tolerated ARBs should be considered (1B).3.In most adults with type 1 diabetes mellitus and persistent ACR >3 mg/mmol, we recommend that ACEI therapy should be considered irrespective of BP and that the target upright BP should be ≤130/80 mm Hg in younger adults (1B), but ≤140/90 mm Hg for those aged >65 years (2D). We recommend that the dose of ACEI should be titrated to the maximum tolerated (1B).4.There is no current evidence to support a role for ACEI therapy for BP control or renal protection in people with type 1 diabetes mellitus who are normotensive and have urine ACR ≤3 mg/mmol (1C).5.There is some evidence to support the use of candesartan to prevent the development or progression of retinopathy in people with type 1 diabetes who are normotensive and have urine ACR ≤3 mg/mmol (1C).6.There is no firm evidence to support a role of dual blockade of the RAAS in people with type 1 diabetes mellitus (1C).7.We recommend that people with type 1 diabetes mellitus should be advised to hold RAAS-blocking drugs during periods of acute illness (1C).8.We recommend that women of childbearing age should be encouraged to hold RAAS-blocking drugs before actively considering pregnancy (1B). The guideline recommends tight control of BP in those with significant proteinuria. Proteinuria in type 1 diabetes is strongly associated with progression to stage G3 CKD (32% in 10 years) and end-stage kidney disease (16% in 10 years); treatment of hypertension slows progression and alongside glycemic control can induce regression of proteinuria with a decreased risk of declining glomerular filtration rate.14de Boer I.H. Afkarian M. Rue T.C. et al.Renal outcomes in patients with type 1 diabetes and macroalbuminuria.J Am Soc Nephrol. 2014; 25: 2342-2350https://doi.org/10.1681/ASN.2013091004Crossref PubMed Scopus (58) Google Scholar The recommended BP target in people with type 1 diabetes with ACR >3 mg/mmol is <130/80 mm Hg, whereas the target is <140/90 mm Hg ACR is ≤3 for treatment and targets in children are as in The of study study support a target BP of 120/80 mm Hg in type 1 et blood pressure thresholds for coronary disease risk in type 1 PubMed Scopus Google Scholar Nevertheless, for the targets are higher at to mm Hg T. an International of guidelines for type 1 diabetes mellitus with an on adults: an Med. 2020; PubMed Scopus Google Scholar the of the evidence from controlled the guideline recommends ACEI as the treatment of hypertension and for proteinuria without hypertension and ARBs if are not R. T. to Lower in Study in type 1 diabetic patients without of a controlled PubMed Scopus Google Scholar should not be used in normotensive without proteinuria during pregnancy and to be during an acute There is no evidence to support the use of and of BP is than the use of a RAAS-blocking 1.In people with type 2 diabetes mellitus and hypertension, we recommend salt of <90 mmol (<2 g of to 5 g of sodium people with type 2 diabetes CKD, and urine ACR ≤3 mg/mmol, we recommend that target upright BP should be <140/90 mm Hg, using antihypertensive therapy in the maximum tolerated people with type 2 diabetes CKD, and urine ACR >3 mg/mmol, we suggest for a target upright BP that is <130/80 mm Hg, using antihypertensive therapy in the maximum tolerated is no evidence to support ACEI or therapy as first-line BP-lowering agents in with antihypertensive agents in people with type 2 diabetes, renal function, and urine ACR suggest that ARBs if are not should be used in people with type 2 diabetes mellitus and CKD who have urine ACR >3 We recommend that the dose of ACEI should be titrated to the maximum tolerated is no evidence to support the role of home or BP monitoring in people with type 2 diabetes mellitus and CKD stages and G3 is no evidence to support the role of dual blockade of the RAAS in people with type 2 diabetes mellitus and CKD stages to G3 BP targets should be set at no mm Hg in those with type 2 diabetes mellitus who are aged ≥75 years recommend that people with type 2 diabetes mellitus should be advised to hold RAAS-blocking drugs during periods of acute illness and to from the illness recommend of antihypertensive agents in people with diabetes, CKD stages and and ACR ≤3 mg/mmol BP is >140/90 mm Hg and for a BP of <140/90 mm Hg during therapy suggest of antihypertensive agents in people with diabetes, CKD stages and and ACR >3 mg/mmol BP is mm Hg and for a target BP <130/80 mm Hg recommend the use of ACEI if ACEI is not as the BP-lowering agent in people with diabetes, CKD stages and and not recommend the use of of and ARBs in people with diabetes and CKD stages and suggest correction of and therapy to lower as in people with diabetes and CKD stages and for use of ACEI the use of novel in people with diabetes and CKD stages to if is or for and use of or people are not taking or are taking RAAS blockade of The recommendations for CKD stages to G3 and and are with as suggested For those with ACR ≤3 mg/mmol, we recommend a target BP of <140/90 mm Hg and <130/80 mm Hg if the ACR is >3 There is no evidence for BP such evidence in people without diabetes.8Cushman W.C. Evans G.W. et al.ACCORD Study GroupEffects of intensive blood-pressure control in type 2 diabetes mellitus.N Engl J Med. 2010; 362: 1575-1585https://doi.org/10.1056/NEJMoa1001286Crossref PubMed Scopus (2642) Google et trial of intensive standard blood-pressure control [published correction appears in Engl J Med. Engl J Med. PubMed Scopus Google Scholar The guideline the use of ACEI or as the antihypertensive agent in the of significant that ACR >3 mg/mmol to maximum dose et and blood targets for therapy in patients with diabetes and a analysis of the and PubMed Scopus Google Scholar but not in the of significant R. B. mellitus as a for use of angiotensin system systematic review and of [published correction appears in PubMed Scopus Google Scholar Nevertheless, the guideline recommends the use of dual ACEI and therapy to evidence of benefit and the risk of to et or both in patients at high risk for Engl J Med. PubMed Scopus Google Scholar For people years) with who are often frail and side effects of antihypertensive the target is mm Hg which is by evidence from hypertension R. B. mellitus as a for use of angiotensin system systematic review and of [published correction appears in PubMed Scopus Google B. B. T. and mortality in the in with Hypertension PubMed Scopus Google Scholar is common in patients with CKD with diabetes, in RAAS C. of in diabetic and patients with chronic kidney a J Nephrol. PubMed Scopus Google Scholar The novel may be used in patients with DKD with related to RAAS In people with diabetes and CKD stages to on RAAS blockade use of a novel in significant decrease in in G.L. B. et al.Effect of on in patients with and diabetic kidney the clinical trial [published correction appears in PubMed Scopus Google Scholar recommend that home or BP measurement should be used to BP in people with diabetes who are on or home BP measurement is not to BP in people with diabetes who are on we suggest using and standardized BP measurements for people who are on and using standardized BP measurements for people who are on recommend control as first-line management to BP control in people with diabetes who are on suggest salt to <5 g to BP control in people with diabetes who are on suggest a target upright interdialytic BP of <140/90 mm Hg for people with diabetes who are on dialysis. of the BP target may be in people who are with multiple to reduce adverse events of BP lowering recommend that should be in people with diabetes who are on suggest using or ARBs not in and blockers to reduce cardiovascular in people with diabetes and hypertension who are on suggest the use of for and BP control in people with diabetes who are on and have kidney function Randomized controlled trial evidence to BP management in patients on in those with diabetes, is of the recommendations in this are and based on to low-quality BP monitoring is in people with diabetes on to the and the of in The which with BP monitoring are interdialytic home BP R. Zoccali C. blood pressure monitoring in chronic kidney PubMed Scopus Google Scholar the guideline recommends the use of home BP for monitoring with a interdialytic BP target of <140/90 mm Meticulous management is suggested as the in the management of hypertension in patients on dialysis. A controlled trial of patients on to of or control of BP with R. in patients a controlled PubMed Scopus Google Scholar The guideline of as it is associated with increased mortality in patients on T. Y. M. as an risk factor for mortality in Int. Full Text Full Text PDF PubMed Scopus Google Scholar There is evidence from controlled to firm recommendations on of antihypertensive RAAS-blocking agents, and blockers are all may be used in the patients to in those with renal I. in BP management in 2020; PubMed Scopus Google Scholar The following evidence for the management of hypertension in people with DKD and further research is a role for home or BP monitoring in the diagnosis and management of hypertension in people with type 1 diabetes, in those who have diabetic tight glycemic control and BP lowering reduce the incidence of people microvascular in type 1 is the on renal function of lower BP targets in younger people with type 1 diabetes and is the role of receptor blockers in people with type 1 diabetes and is the lower for BP mm Hg) in people with type 2 diabetes who have CKD in terms of cardiovascular and renal are the and BP lowering agents in people with type 2 diabetes who have CKD and hypertension treatment improve cardiovascular and renal outcomes in patients with type 2 diabetes and BP measurement should be used to and mortality in people with diabetes who are on home or BP is the upright BP target for people with diabetes who are on treatment with or blockers to lower BP in people with diabetes who are on reduce cardiovascular morbidity and salt g in people with diabetes who are on BP control or cardiovascular The recommendations the Joint Association of British Clinical Diabetologists and UK Kidney Association guideline guidance that individualized therapy with BP targets that according to age, type of diabetes, and stage of CKD. The Joint Association of British Clinical Diabetologists and UK Kidney Association guideline is based on the available evidence evidence is available for stages of CKD to of controlled The guideline the of care in which provides the patients with outcomes quality of

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