Diabetic Nephropathy
CPG for DM in CKD (KDIGO 2020)
26 1 月, 2021 / By 王介立醫師
Reference Keys
CKD is defined as abnormalities of kidney structure or function, present for >3 months, with implications for health. CKD is classified based on Cause, GFR category (G1–G5), and Albuminuria category (A1–A3), abbreviated as CGA.
Introduction
Summary of recommendation statements and practice points
Chapter 1: Comprehensive care in patients with diabetes and CKD
1.1 Comprehensive diabetes and CKD management
Practice Point 1.1.1: Patients with diabetes and chronic kidney disease (CKD) should be treated with a comprehensive strategy to reduce risks of kidney disease progression and cardiovascular disease (Figure 2).
1.2 Renin–angiotensin system (RAS) blockade
Recommendation 1.2.1: We recommend that treatment with an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB) be initiated in patients with diabetes, hypertension, and albuminuria, and that these medications be titrated to the highest approved dose that is tolerated (1B).
►IRMA-2: Irbesartan 300mg qd (vs placebo) for proteinuria > 300mg/g, 可減少GFR下降
►INNOVATION: Telmisartan可預防overt nephropathy
►IDNT: For proteinuria > 1g/d, Irbesartan可改善腎預後
►RENAAL: For proteinuria > 1g/d, Losartan可改善腎預後及死亡
►Cochrane (2006): ACEi及ARB皆有效改善腎預後
►此建議適用T1D, T2D及腎移植後, 但不適用於透析
►ACEi及ARB之療效相等
Practice Point 1.2.1: For patients with diabetes, albuminuria, and normal blood pressure, treatment with an ACEi or ARB may be considered.
►對normoalbuminuric及normotensive者, ACEi/ARB並無證據可改善預後
Practice Point 1.2.2: Monitor for changes in blood pressure, serum creatinine, and serum potassium within 2–4 weeks of initiation or increase in the dose of an ACEi or ARB (Figure 4).
Practice Point 1.2.3: Continue ACEi or ARB therapy unless serum creatinine rises by more than 30% within 4 weeks following initiation of treatment or an increase in dose (Figure 4).
►CRE在2個月後會穩定
►對升高>30%者, 臨床要排除renal artery stenosis
Practice Point 1.2.4: Advise contraception in women who are receiving ACEi or ARB therapy and discontinue these agents in women who are considering pregnancy or who become pregnant.
►2nd及3rd trimester的證據最明確
Practice Point 1.2.5: Hyperkalemia associated with the use of an ACEi or ARB can often be managed by measures to reduce serum potassium levels rather than decreasing the dose or stopping the ACEi or ARB immediately (Figure 4).
Practice Point 1.2.6: Reduce the dose or discontinue ACEi or ARB therapy in the setting of either symptomatic hypotension or uncontrolled hyperkalemia despite the medical treatment outlined in Practice Point 1.2.5, or to reduce uremic symptoms while treating kidney failure (estimated glomerular filtration rate [eGFR] <15 ml/min per 1.73 m2).
Practice Point 1.2.7: Use only one agent at a time to block the RAS. The combination of an ACEi with an ARB, or the combination of an ACEi or ARB with a direct renin inhibitor, is potentially harmful.
Practice Point 1.2.8: Mineralocorticoid receptor antagonists are effective for the management of refractory hypertension but may cause hyperkalemia or a reversible decline in glomerular filtration, particularly among patients with a low eGFR.
►時機: resistant HTN, normokalemia, GFR > 45 ml/min/1.73m2
►eGFR 25-45ml/min/1.73m2: 加上patiromer可使病人tolerate MRA達12週
1.3 Smoking cessation
Recommendation 1.3.1: We recommend advising patients with diabetes and CKD who use tobacco to quit using tobacco products (1D).
►Only observational data
►藥物: nicotine replacement therapy, bupropion, varenicline
►Practice Point 1.3.1: Physicians should counsel patients with diabetes and CKD to reduce secondhand smoke exposure.
Chapter 2: Glycemic monitoring and targets in patients with diabetes and CKD
2.1 Glycemic monitoring
Recommendation 2.1.1: We recommend using hemoglobin A1c (HbA1c) to monitor glycemic control in patients with diabetes and CKD (1C).
►GA及fructosamine反應2-4週的血糖控制
►Advanced CKD者, 沒有哪一個是準的, 基本上還是推薦驗HbA1c
►可能不適用HbA1c的情況: advanced CKD, anemia, RBC transfusions, iron supplements
Practice Point 2.1.1: Monitoring long-term glycemic control by HbA1c twice per year is reasonable for patients with diabetes. HbA1c may be measured as often as 4 times per year if the glycemic target is not met or after a change in antihyperglycemic therapy.
►HbA1c若不準, 通常是低估, 較少是高估
Practice Point 2.1.2: Accuracy and precision of HbA1c measurement declines with advanced CKD (G4–G5), particularly among patients treated by dialysis, in whom HbA1c measurements have low reliability.
►但還是推薦HbA1c
Practice Point 2.1.3: A glucose management indicator (GMI) derived from continuous glucose monitoring (CGM) data can be used to index glycemia for individuals in whom HbA1c is not concordant with directly measured blood glucose levels or clinical symptoms.
►GMI推薦在advanced CKD病患使用, 其結果會以HbA1c表示, 可用來校正抽血的HbA1c
Practice Point 2.1.4: Daily glycemic monitoring with CGM or self-monitoring of blood glucose (SMBG) may help prevent hypoglycemia and improve glycemic control when antihyperglycemic therapies associated with risk of hypoglycemia are used.
Practice Point 2.1.5: For patients with type 2 diabetes (T2D) and CKD who choose not to do daily glycemic monitoring by CGM or SMBG, antihyperglycemic agents that pose a lower risk of hypoglycemia are preferred and should be administered in doses that are appropriate for the level of eGFR.
►Advanced CKD者使用有低血糖風險的藥物, 應每日測SMBG
Practice Point 2.1.6: CGM devices are rapidly evolving with multiple functionalities (e.g., real-time and intermittently scanned CGM). Newer CGM devices may offer advantages for certain patients, depending on their values, goals, and preferences.
2.2 Glycemic targets
Recommendation 2.2.1: We recommend an individualized HbA1c target ranging from <6.5% to <8.0% in patients with diabetes and CKD not treated with dialysis (Figure 9) (1C).
►嚴格控糖需要好幾年預後才會改變
►整體的證據品質不佳
►對於預防moderate albuminuria及nonfatal MI的證據品質較佳
►T2D的HbA1c≤6%, 低血糖風險最大, 且死亡率上升
Practice Point 2.2.1: Safe achievement of lower HbA1c targets (e.g., <6.5% or <7.0%) may be facilitated by CGM or SMBG and by selection of antihyperglycemic agents that are not associated with hypoglycemia.
►在CKD含dialysis, CGM及SMBG較準確
Practice Point 2.2.2: CGM metrics, such as time in range and time in hypoglycemia, may be considered as alternatives to HbA1c for defining glycemic targets in some patients.
►HbA1c在eGFR <30 ml/min/1.73m2不準確
►CGM metrics在trial中常用的outcome有glucose time in range (70-180 mg/dL)及time in hypoglycemia (<70 and 54 mg/dL)
Chapter 3: Lifestyle interventions in patients with diabetes and CKD
3.1 Nutrition intake
►營養研究大都是觀察及回溯性的; 對dm及CKD建議主要來自一般族群之外推
►Practice Point 3.1.1: Patients with diabetes and CKD should consume an individualized diet high in vegetables, fruits, whole grains, fiber, legumes, plant-based proteins, unsaturated fats, and nuts; and lower in processed meats, refined carbohydrates, and sweetened beverages.
Recommendation 3.1.1: We suggest maintaining a protein intake of 0.8 g protein/kg (weight)/d for those with diabetes and CKD not treated with dialysis (2C).
►0.8 g/kg/d是來自WHO針對一般人的建議
►整體證據品質是低的
►針對過重者, 計算蛋白攝取的體重, 應使用病患身高的中位數體重
►0.4-0.6 g/kg/d在CKD可能造成營養不良
►同KDOQI 2020建議
Practice Point 3.1.2: Patients treated with hemodialysis, and particularly peritoneal dialysis, should consume between 1.0 and 1.2 g protein/kg (weight)/d.
►同KDOQI 2020建議
Recommendation 3.1.2: We suggest that sodium intake be <2 g of sodium per day (or <90 mmol of sodium per day, or <5 g of sodium chloride per day) in patients with diabetes and CKD (2C).
►整體證據品質為低
►愛吃鹹是後天養成的, 可花4-6週矯正
►DASH diet因為高鉀, 未必適合CKD病患
►每日鈉攝取至少1.5 g
►Practice Point 3.1.3: Shared decision-making should be a cornerstone of patient-centered nutrition management in patients with diabetes and CKD.
Practice Point 3.1.4: Accredited nutrition providers, registered dietitians and diabetes educators, community health workers, peer counselors, or other health workers should be engaged in the multidisciplinary nutrition care of patients with diabetes and CKD.
►Practice Point 3.1.5: Health care providers should consider cultural differences, food intolerances, variations in food resources, cooking skills, comorbidities, and cost when recommending dietary options to patients and their families.
3.2 Physical activity
Recommendation 3.2.1: We recommend that patients with diabetes and CKD be advised to undertake moderate-intensity physical activity for a cumulative duration of at least 150 minutes per week, or to a level compatible with their cardiovascular and physical tolerance (1D).
►整體證據品質低下
►三分之二的CKD未達最低建議之運動量 (450-750 METs/min/wk)
Practice Point 3.2.1: Recommendations for physical activity should consider age, ethnic background, presence of other comorbidities, and access to resources.
►透析中運動也是有效的
Practice Point 3.2.2: Patients should be advised to avoid sedentary behavior.
Practice Point 3.2.3: For patients at higher risk of falls, health care providers should provide advice on the intensity of physical activity (low, moderate, or vigorous) and the type of exercises (aerobic vs. resistance, or both).
►運動內容應包含有氧、肌力及平衡訓練
Practice Point 3.2.4: Physicians should consider advising/encouraging patients with obesity, diabetes, and CKD to lose weight, particularly patients with eGFR ≥30 ml/min per 1.73 m2.
►BMI>30 kg/m2為肥胖, 亞裔族群在27.5以上預後即變差
Chapter 4: Antihyperglycemic therapies in patients with type 2 diabetes (T2D) and CKD
Practice Point 4.1: Glycemic management for patients with T2D and CKD should include lifestyle therapy, first-line treatment with metformin and a sodium–glucose cotransporter-2 inhibitor (SGLT2i), and additional drug therapy as needed for glycemic control (Figure 18).
Practice Point 4.2: Most patients with T2D, CKD, and eGFR ≥30 ml/min per 1.73 m2 would benefit from treatment with both metformin and an SGLT2i.
►SGLT2i對HbA1c的下降較弱, 尤其是eGFR 30-59區間, 但對CKD及CVD的預後改變卻很大, 且與eGFR無關
►SGLT2i的臨床試驗, 大都同時有服用metformin
►單用metformin有達到控糖目標, 仍應加上SGLT2i (證據較弱)
►無證據指示應先用metformin或SGLT2i, 習慣上先用metformin
►若病患狀況許可, 也可一開始就metformin + SGLT2i
eGFR掉到30以下, metformin要停掉, 但SLGT2i應繼續至透析才停 (來自CREDENCE – canagloflozin的研究)
Practice Point 4.3: Patient preferences, comorbidities, eGFR, and cost should guide selection of additional drugs to manage glycemia, when needed, with glucagon-like peptide-1 receptor agonist (GLP-1 RA) generally preferred (Figure 20).
►GLP1RA特別indicated在有ASCVD者, 或許可改善腎預後
►DPP4i無法證實可改善心腎預後, 且不建議與GLP1RA併用
4.1 Metformin
Recommendation 4.1.1: We recommend treating patients with T2D, CKD, and an eGFR ≥30 ml/min per 1.73 m2 with metformin (1B).
►在降糖效果, metformin與SU或TZD相當, 優於DPP4i
►比起SU或insulin, metformin不會增胖
►Metformin明確能降低CV events及CV mortality, 但對all cause mortality或microvascular complications則證據較少
►Phenformin在1977年因為lactic acidosis而下市; metformin和lactic acidosis之間的因果其實仍未明
►Metformin in CKD, 無RCT, 僅有觀察研究
►Metformin單方可降HbA1c 1.5%
►Metformin immediate release發生GI副作用比例為25%, 會造成5-10%停藥
►Extend release的GI副作用可能會少一點, 若immediate release吃不下去, 建議再試extend release
Practice Point 4.1.1: Treat kidney transplant recipients with T2D and an eGFR ≥30 ml/min per 1.73 m2 with metformin according to recommendations for patients with T2D and CKD.
►無良好實證
Practice Point 4.1.2: Monitor eGFR in patients treated with metformin. Increase the frequency of monitoring when the eGFR is <60 ml/min per 1.73 m2 (Figure 22).
Practice Point 4.1.3: Adjust the dose of metformin when the eGFR is <45 ml/min per 1.73 m2, and for some patients when the eGFR is 45–59 ml/min per 1.73 m2 (Figure 22).
►eGFR 30-45, metformin之最大劑量應減半
Practice Point 4.1.4: Monitor patients for vitamin B12 deficiency when they are treated with metformin for more than 4 years.
►不需常規補充vitamin B12
4.2 Sodium–glucose cotransporter-2 inhibitors (SGLT2i)
SGLT2i的CV及renal好處, 不全是來自降糖
Recommendation 4.2.1: We recommend treating patients with T2D, CKD, and an eGFR ≥30 ml/min per 1.73 m2 with an SGLT2i (1A).
►[EMPA-REG OUTCOME] Empagliflozin在high-risk CVD病患可改善CV預後
►[CANVAS] Canagloflozin在high-risk CVD病患可改善CV預後, 但截肢風險增加
►[DECLARE-TIMI 58] Dapagliflozin, 僅41%有established CVD, primary outcome之MACE不變, secondary outcome之CV death及CHF住院有下降
►[CREDENCE] Canagliflozin在T2D+CKD, 降低secondary outcome (CHF住院及MACE)
有效減少CHF住院: EMPA-REG, CANVAS, DECLARE-TIMI 58
►[DAPA-HF] HFrEF (≤40%), eGFR≥30, 55%無DM, CV outcome改善
►[EMPEROR-Reduced] HFrEF (≤40%), eGFR≥20, 50%無DM, CV outcome改善
►在EMPA-REG OUTCOME預先設計好的腎臟分析, 發現renal outcome改善
►Meta-analysis in 2019 (EMPA-REG, CANVAS, DECLARE-TIMI), eGFR 30-60之間, SGLT2i可改善腎預後
►CREDENCE是第一個針對腎預後的SGLT2i RCT, 病患全為albuminuric CKD
►可能害處: DKA (CREDENCE), fracture (CANVAS), amputation (CANVAS)
►Genital mycotic infection一般用局部治療即可
►此建議不適用腎移植患者
►根據CREDENCE trial, 病患可一路吃到洗腎才停SGLT2i
►DAPA-CKD收案eGFR低至25, EMPA-KIDNEY收案eGFR低至20
►美國沒通過T1D使用SGLT2i, 但歐洲及日本則部份有
Practice Point 4.2.1: An SGLT2i can be added to other antihyperglycemic medications for patients whose glycemic targets are not currently met or who are meeting glycemic targets but can safely attain a lower target.
►單用SGLT2i會發生低血糖的風險並不高; 但若併用SU或insulin則低血糖風險會升高
Practice Point 4.2.2: For patients in whom additional glucose-lowering may increase risk for hypoglycemia (e.g., those treated with insulin or sulfonylureas and currently meeting glycemic targets), it may be necessary to stop or reduce the dose of an antihyperglycemic drug other than metformin to facilitate addition of an SGLT2i.
►GFR<45時, 用SGLT2i反而較不擔心會發生低血糖
Practice Point 4.2.3: The choice of an SGLT2i should prioritize agents with documented kidney or cardiovascular benefits and take eGFR into account.
Practice Point 4.2.4: It is reasonable to withhold SGLT2i during times of prolonged fasting, surgery, or critical medical illness (when patients may be at greater risk for ketosis).
Practice Point 4.2.5: If a patient is at risk for hypovolemia, consider decreasing thiazide or loop diuretic dosages before commencement of SGLT2i treatment, advise patients about symptoms of volume depletion and low blood pressure, and follow up on volume status after drug initiation.
►用SGLT2i後AKI的風險會降低
Practice Point 4.2.6: A reversible decrease in the eGFR with commencement of SGLT2i treatment may occur and is generally not an indication to discontinue therapy.
Practice Point 4.2.7: Once an SGLT2i is initiated, it is reasonable to continue an SGLT2i even if the eGFR falls below 30 ml/min per 1.73 m2, unless it is not tolerated or kidney replacement therapy is initiated.
Practice Point 4.2.8: SGLT2i have not been adequately studied in kidney transplant recipients, who may benefit from SGLT2i treatment, but are immunosuppressed and potentially at increased risk for infections; therefore, the recommendation to use SGLT2i does not apply to kidney transplant recipients (see Recommendation 4.2.1).
4.3 Glucagon-like peptide-1 receptor agonists (GLP-1 RA)
►GLP-1屬於incretin, T2D者之incretin降低或缺乏
►除了刺激insulin分泌外, GLP-1會減緩胃排空及減少腦部飢餓感
►T2D之HbA1c>7%者, GLP-1 RA可降低MACE及改善albuminuria
Recommendation 4.3.1: In patients with T2D and CKD who have not achieved individualized glycemic targets despite use of metformin and SGLT2i, or who are unable to use those medications, we recommend a long-acting GLP-1 RA (1B).
►七個RCT, 6個注射1個口服, ４種注射藥有CV益處 (LEADER, SUSTAIN-6, HARMONY, REWIND), 其它3種(ELIXA, EXSCEL, PIONEER 6)則為safe but neutral
►[LEADER] HbA1c ≥7% with high CVD risk, 含G4 CKD; liraglutide qd; 13% reduction in MACE in 3.8年; subgroup分析發現eGFR<60之MACE下降更大
降22%之secondary composite renal outcome (主要來自降new-inset severe albuminuria)
►[SUSTAIN-6] HbA1c ≥7% with known or high CVD risk; semaglutide qw; 降MACE 26%
New or worsening nephropathy之HR 0.64 (95% CI: 0.46-0.88)
►[HARMONY] HbA1c ≥7% with high CVD risk, eGFR<30 excluded; albiglutide qw; 1.6年降MACE 22%
►[REWIND] HbA1c of ≤9.5% (無下限, mean 7.2%), eGFR>15 excluded, 僅31.5%有established CVD; dulaglutide qw; 5.4年MACE降低12%
15% reduction in secondary composite renal outcome; 最強烈來自new severe albuminuriaI之HR 0.77 (5% CI: 0.68–0.87)
►[ELIXA], [EXSCEL]及[PIONEER 6]則為neutral
以上七個trials的[meta-analysis]: 可降CV death, stroke, MI及all-cause mortality; 首度發現可降CHF住院 (但效果不及SGLT2i)
►Renal outcome的改善主要是來自albuminuria下降
►[AWARD-7] G3a-4 CKD, HbA1c 7.5-10.5%, on ACEi/ARB; dulaglutide v insulin glargine; 兩組HbA1c下降相同為1%, 但►dulaglutide可減緩eGFR下降
►目前仍缺乏primary renal outcome之RCT
►GLP1-RA比起SGLT2i, 在CKD族群, 降糖及減重效果更明顯
Practice Point 4.3.1: The choice of GLP-1 RA should prioritize agents with documented cardiovascular benefits.
►Albiglutide已被GSK宣佈下市
►目前建議使用: liraglutide, injectable semaglutide, dulaglutide
Practice Point 4.3.2: To minimize gastrointestinal side effects, start with a low dose of GLP-1 RA, and titrate up slowly (Figure 27).
Practice Point 4.3.3: GLP-1 RA should not be used in combination with dipeptidyl peptidase-4 (DPP-4) inhibitors.
►應把DPP4i換成GLP1-RA
Practice Point 4.3.4: The risk of hypoglycemia is generally low with GLP-1 RA when used alone, but risk is increased when GLP-1 RA is used concomitantly with other medications such as sulfonylureas or insulin. The doses of sulfonylurea and/or insulin may need to be reduced.
►單用GLP1-RA的低血糖風險是低的, 但併用SU或insulins則低血糖風險升高
Chapter 5: Approaches to management of patients with diabetes and CKD
5.1 Self-management education programs
Recommendation 5.1.1: We recommend that a structured self-management educational program be implemented for care of people with diabetes and CKD. (1C).
►Practice Point 5.1.1: Health care systems should consider implementing a structured self-management program for patients with diabetes and CKD, taking into consideration local context, cultures, and availability of resources.
5.2 Team-based integrated care
Recommendation 5.2.1: We suggest that policymakers and institutional decision-makers implement team-based, integrated care focused on risk evaluation and patient empowerment to provide comprehensive care in patients with diabetes and CKD (2B).
►Practice Point 5.2.1: Team-based integrated care, supported by decision-makers, should be delivered by physicians and nonphysician personnel (e.g., trained nurses and dieticians, pharmacists, health care assistants, community workers, and peer supporters) preferably with knowledge of CKD (Figure 33).
►每12-18個月檢查眼底及足部
►每3-12個月檢查腎功能
►Review有無使用organ-protective medications: statins, RASi, SGLT2i, GLP1-RA
抽血
CRE
2-4 weeks after initiation of ACEi/ARB
CKD G3 on metformin: q3-6m
CKD G1-2 on metformin: q12m
K
1 week after initiation or dose-escalation of ACEi/ARB for borderline K or baseline low eGFR
2-4 weeks after initiation or dose-escalation of ACEi/ARB
HbA1C
Unstable: q3m
Stable: q6m
