1. Management of progression of CKD 순천향 대학병원 신장내과 강혜란

2.  2012, KDIGO, CKD evaluation & management  3.1 PREVENTION OF CKD PROGRESSION  BP and RAAS interruption  3.1.1: Individualize BP targets and agents according to age, coexistent cardiovascular disease and other comorbidities, risk of progression of CKD, presence or absence of retinopathy (in CKD patients with diabetes)  3.1.2: Inquire about postural dizziness and check for postural hypotension regularly when treating CKD patients with BP-lowering drugs. (Not Graded)  3.1.3: Tailor BP treatment regimens in elderly patients with CKD by carefully considering age, comorbidities and other therapies, with gradual escalation of treatment and close attention to adverse events related to BP treatment, including electrolyte disorders, acute deterioration in kidney function, orthostatic hypotension and drug side effects.(Not Graded)

3.  2012, KDIGO, CKD evaluation & management  3.1 PREVENTION OF CKD PROGRESSION  BP and RAAS interruption  3.1.4: We recommend that in both diabetic and non-diabetic adults with CKD and urine albumin excretion 140 mmHg systolic or > 90 mmHg diastolic be treated with BP-lowering drugs to maintain a BP that is consistently < 140 mmHg systolic and < 90 mm Hg diastolic.(1B)  3.1.5: We suggest that in both diabetic and non-diabetic adults with CKD and with urine albumin excretion of > 30 mg/24 hours (or equivalent*) whose office BP is consistently > 130 mmHg systolic or > 80 mmHg diastolic be treated with BP-lowering drugs to maintain a BP that is consistently < 130 mmHg systolic and < 80 mm Hg diastolic.(2D)

4.  2012, KDIGO, CKD evaluation & management  3.1 PREVENTION OF CKD PROGRESSION  BP and RAAS interruption  3.1.6: We suggest that an ARB or ACE-I be used in diabetic adults with CKD and urine albumin excretion30-300 mg/24 hours (or equivalent*). (2D)  3.1.7: We recommend that an ARB or ACE-I be used in both diabetic and non-diabetic adults with CKD and urine albumin excretion > 300 mg/24 hours (or equivalent*). (1B)3.1.8: There is insufficient evidence to recommend combining an ACE-I with ARBs to prevent progression of CKD. (Not Graded)

5. Antihypertensive therapy and progression of nondiabetic CKD in adults  Background  In patients with chronic kidney disease (CKD)  urinary protein excretion ↑ : associated with a more rapid decline in GFR, regardless of the primary cause of the renal disease and the initial GFR  Observational studies show that  Patients with CKD and a diastolic pressure < 90 mmHg  better preservation of GFR than hypertensive patients  Lower blood pressure targets (<130/80 mmHg)  associated with better renal outcomes in patients with proteinuric CKD (urine protein excretion > 500 - 1000 mg/day)

6. Antihypertensive therapy and progression of nondiabetic CKD in adults  The effect of antihypertensive drugs on proteinuria varies with drug class and salt intake  Renin-angiotensin system (RAS) inhibitors (ACE inhibitors and ARBs)  more effective than other antihypertensive drugs in reducing proteinuria  due to a reduction in intraglomerular pressure and perhaps other factors  antiproteinuric effects of ACE inhibitors and ARBs appear to be similar  The non-dihydropyridine calcium channel blockers (diltiazem, verapamil)  significant antiproteinuric effects in patients with proteinuria  The dihydropyridines (amlodipine, nifedipine)  variable effect on proteinuria, ranging from an increase to no effect to a fall in protein excretion  Mineralocorticoid receptor antagonists (spironolactone, eplerenone)  further reduce protein excretion when added to an ACE inhibitor and/or ARB  In patients with proteinuric CKD, the antiproteinuric effect of RAS inhibitors and non-dihydropyridine calcium channel blockers is impaired with a high salt intake, even when blood pressure control seems appropriate, and is enhanced with salt restriction  If a low-salt diet is not achieved, administration of a diuretic can also enhance the antiproteinuric effect of RAS inhibitors

7. Antihypertensive therapy and progression of nondiabetic CKD in adults Multiple randomized clinical trials in patients with nondiabetic CKD demonstrated a benefit of antihypertensive therapy with RAS inhibitors, mostly ACE inhibitors, in patients with proteinuric nondiabetic CKD ARB have a similar renoprotective effect as ACE inhibitors in nondiabetic CKD but supportive data are limited When trying to slow the progression of nondiabetic CKD protein excretion > 500 - 1000 mg/day : benefit from antihypertensive therapy with RAS inhibitors protein excretion < 500 mg/day : no preferential benefit of RAS inhibitors The three major trials in adults that evaluated the effect of goal blood pressure on CKD progression renal benefit of more aggressive blood control is primarily restricted to patients with higher rates of protein excretion. Meta-analyses of randomized trials support this conclusion

8. Antihypertensive therapy and progression of nondiabetic CKD in adults  Management In patients with proteinuric (protein excretion > 500 -1000 mg/day) nondiabetic CKD recommend a renin-angiotensin system (RAS) inhibitor as first-line therapy for the treatment of hypertension (Grade 1A) In hypertensive patients with nonproteinuric nondiabetic CKD who have edema we suggest initiation of a diuretic as first-line therapy (Grade 2C) If there is no edema we suggest RAS inhibitors as first line therapy (Grade 2C) In patients with proteinuric nondiabetic CKD, we suggest a proteinuria goal : < 1000 mg/day (Grade 2C) In patients who are initially nephrotic and in whom this goal is unobtainable minimum reduction in proteinuria of at least 50 - 60 percent from baseline + protein excretion < 3.5 g/day

9. Treatment of hypertension in patients with diabetes mellitus The prevalence and time of development of hypertension in patients with diabetes mellitus varies with the type of diabetes type 1 diabetes the incidence of hypertension : 5 % at 10 years' duration, 33 % at 20 years, and 70 % at 40 years The blood pressure typically begins to rise within the normal range at or within a few years after the onset of moderately increased albuminuria ("microalbuminuria") and increases progressively as the renal disease progresses type 2 diabetes as many as 40 % are hypertensive at the time of diagnosis in approximately one-half of these patients, the elevation in blood pressure occurred before the onset of moderately increased albuminuria

10. Treatment of hypertension in patients with diabetes mellitus Choice of antihypertensive agents to prevent adverse cardiovascular events to slow progression of renal disease, if present In the ALLHAT trial diabetic patients had a significantly lower rate of new onset heart failure with low-dose chlorthalidone compared to amlodipine and lisinopril due at least in part to a lower attained blood pressure with chlorthalidone thiazide diuretics : adverse effect on glucose metabolism In the ACCOMPLISH trial combination of an ACE inhibitor + amlodipine better protection against cardiovascular outcomes in diabetic patients (vs combination of an ACE inhibitor + low-dose hydrochlorothiazide) ACE inhibitors and ARBs protect against the development of progressive nephropathy due to types 1 and 2 diabetes preferred as initial therapy in a hypertensive diabetic patient who has moderately increased albuminuria or severely increased albuminuria (formerly called "macroalbuminuria") in an attempt to slow renal disease progression

11. Renin-Angiotensin System Inhibitors and Kidney and Cardiovascular Outcomes in Patients With CKD: A Bayesian Network Meta-analysis of Randomized Clinical Trials Am J Kidney Dis. 2016;67(5):728-741

12.  Chronic kidney disease (CKD)  a major public health issue of international scope  8% -16% of the adult population  Blood pressure(BP)-lowering agents  foundation of management strategies for slowing the progression of CKD  a core aspect of strategies to reduce the risk for cardiovascular disease  Renin-angiotensin system (RAS) inhibitors  the best-studied agents for slowing the progression of kidney disease in this population  KDIGO (Kidney Disease: Improving Global Outcomes) guideline for hypertension  recommended that angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) should be first-line therapy for patients with CKD, especially those with proteinuria, as a result of their specific benefits for renal protection  The panel members appointed to the Eighth Joint National Committee (JNC8)  also recommended that initial antihypertensive treatment should include an ACE inhibitor or ARB to improve kidney outcomes in hypertensive populations with CKD Introduction

13.  However, several questions have not been clearly answered  How strong and consistent is the evidence regarding any additional protective effect of RAS inhibitors over other BP-lowering agents?  Is there a difference in the magnitude of the effect of ACE inhibitors compared with ARBs on kidney disease outcomes in patients with kidney disease? -> Systematic review and Bayesian network meta-analysis to evaluate the effect of ACE inhibitors or ARBs on kidney disease and cardiovascular outcomes in individuals with CKD Introduction

14.  Study design  Systematic review and Bayesian network meta-analysis  Setting & populations  Patients with CKD treated with renin-angiotensin system (RAS) inhibitors  Data Sources and Searches  Relevant studies were identified by searching the following data sources: MEDLINE (by Ovid; from 1950 to November 2014), EMBASE (from 1970 to November 2014), and the Cochrane Library database  used the Medical Subject Headings (MeSH) and text words of randomized controlled trial, chronic kidney disease, and all spellings of known ACE inhibitors and ARBs Methods

15.  Selection criteria for studies  Randomized trials in patients with CKD treated with RAS inhibitors  Randomized controlled trials (RCTs) : more than 20 participants  ACE inhibitors or ARBs were given for at least 6 months  CKD  glomerular filtration rate [GFR] < 60 mL/min/1.73 m2  elevated serum creatinine level or albuminuria with albumin excretion > 30 mg/d  abnormalities detected by histology  dialysis  Predictor  ACE inhibitors and ARBs compared to each other and to placebo and active controls  Outcome  Primary outcome  kidney failure  doubling of serum creatinine level, 50% decline in GFR, or end-stage kidney disease  Secondary outcomes  major cardiovascular events  fatal or nonfatal myocardial infarction, stroke, and heart failure  all-cause death Methods

16. Results

20. Compared with ARBs, ACE inhibitors were consistently associated with higher probabilities of reducing kidney failure, cardiovascular death, or all-cause death

21. Results

22.  Use of ACE inhibitors or ARBs in people with CKD  the risk for kidney failure and cardiovascular events ↓  ACE inhibitors  the risk for all-cause mortality ↓  possibly superior to ARBs for kidney failure, cardiovascular death, and all-cause mortality in patients with CKD  could be the first choice for treatment in CKD Conclusions

24. 16 th ISPD (2016.2.27 – 2016.3.1)

36. 감사합니다 ! ♥♥