G U I D E L I N E
ASIAN PACIFIC SOCIETY OF NEPHROLOGY CLINICAL PRACTICE GUIDELINE ON DIABETIC KIDNEY DISEASE – AN EXECUTIVE SUMMARY
Adrian LIEW
1| Sunita BAVANANDAN
2| Narayan PRASAD
3| Muh Geot WONG
4,17| Jer Ming CHANG
5| Somchai EIAM-ONG
6|
Chuan-Ming HAO
7| Chiao Yuen LIM
8| Soo Kun LIM
9| Kook-Hwan OH
10| Hirokazu OKADA
11| Paweena SUSANTITAPHONG
6| Aida LYDIA
12|
Huong Thi Bich TRAN
13| Russell VILLANUEVA
14| See Cheng YEO
15| Sydney C.W. TANG
161The Kidney & Transplant Practice, Mount Elizabeth Novena Hospital, Singapore
2Department of Nephrology, Hospital Kuala Lumpur, Malaysia
3Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
4Department of Renal Medicine, Royal North Shore Hospital, Sydney, Australia
5Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Taiwan
6Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
7Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
8RIPAS Hospital, Bandar Seri Begawan, Brunei Darussalam
9Renal Division, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
10Department of Internal Medicine, Seoul National University, Seoul, Republic of Korea
11Department of Nephrology, Saitama Medical University, Saitama, Japan
12Division of Nephrology and Hypertension, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia-Dr Cipto Mangunkusumo Hospital, Jakarta, Indonesia
13Renal Division, Department of Medicine, University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam
14National Kidney and Transplant Institute, Manila, Philippines
15Department of Renal Medicine, Tan Tock Seng Hospital, Singapore
16Division of Nephrology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
17Division of Renal and Metabolic, The George Institute for Global Health, Sydney, Australia
Correspondence Adrian Liew
Email: [email protected]
E X E C U T I V E S U M M A R Y O F A S I A N P A C I F I C S O C I E T Y O F N E P H R O L O G Y C L I N I C A L
P R A C T I C E G U I D E L I N E O N D I A B E T I C K I D N E Y D I S E A S E
In the 2018 iteration of the United States Renal Data System (USRDS) report, 6 out of the top 10 countries in the world with
diabetic kidney disease (DKD) as the cause of end-stage kidney dis- ease (ESKD) were from the Asia-Pacific region, with Malaysia and Singapore topping the charts consistently over the previous years (1). It is, therefore, unsurprising that DKD is a significant healthcare burden for the Asia-Pacific countries, with a considerable amount of the countries’ medical expenditure being spent on kidney replace- ment therapy (KRT) (2). Specifically, the differences in healthcare infrastructure, resources and cultural beliefs among the Asia-Pacific countries have resulted in the heterogeneity of care and outcomes This article was originally published inNephrologyVol. 25 Issue S2. Republished with permission.
Nephrology.2020;25:809–817. wileyonlinelibrary.com/journal/nep © 2020 Asian Pacific Society of Nephrology 809
for people with DKD in the region. The Asian Pacific Society of Nephrology (APSN) consequently commissioned a Working Group (WG) to develop a set of clinical guidelines on the management of DKD, and in particular, to pay attention to nuances of health care across different countries in the region with the aim of making these guidelines applicable and implementable.
Scope of the Guideline
This guideline focuses on the recognition, screening, monitoring and management of diabetic kidney disease, with eventual consideration for KRT in those with advanced kidney failure. The guideline is struc- tured into 5 different chapters, focusing on the following aspects of clinical care:
1. Terminology, Screening and Monitoring of Diabetic Kidney Disease
2. Lifestyle Modification 3. Blood Pressure Control 4. Glycaemic Control
5. Kidney Replacement Therapy
Format of the Guideline
The format of the APSN Clinical Practice Guidelines has been harmo- nized with the way in which recent guidelines by Kidney Disease:
Improving Global Outcomes (KDIGO) had been presented, where Clini- cal Recommendation statements are interspersed with Practice Points.
Clinical Recommendations
A clinical recommendation statement is developed when a literature review suggested there is sufficient evidence of acceptable quality to support a stance on the research question. Clinical recommendation statements are graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (3) where the strength of the recommendation is indicated as Level 1 or Level 2, and the quality of the supporting evidence is shown as Grade A, B, C or D. The implications of the grading is articulated in Table A. Clinical recommendations will be accompanied by a summary of the rationale in developing the statements and supported by a dis- sertation of the available evidence, including the benefits and harms in making such a recommendation.
T A B L E A Implications of the Strength of the Recommendation and Quality of the Evidence using the GRADE Methodology Strength of the Recommendation
Grade Clinicians Patients Policy Makers
Level 1
“We recommend…”
Most clinicians, across different settings and working environment, would advocate that patients receive the recommended course of action.
Almost all patients in the particular situation would want and accept the
recommended course of action, and only a small proportion would not.
The recommendation can be considered for implementation on a large scale, evaluated for policy development or adopted as a performance measure.
Level 2
“We suggest…”
Clinicians would consider different choices for different patients, according to different healthcare settings, values and preferences.
The majority of patients in the particular situation would want and accept the recommended course of action, but many would not.
The recommendation is likely to be subjected to substantial debate and involvement of stakeholders. Obstacles will have to be overcome before policy can be determined.
Quality of the Evidence
Grade Quality of Evidence Interpretation
A High There is a high confidence that the true effect lies close to the estimate of the
effect.
Further research is very unlikely to change our confidence in the estimate of the effect.
B Moderate There is confidence that the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Further research may have an important impact on our confidence in the estimate of the effect and may change the estimate.
C Low The true effect may be substantially different from the estimate of the effect.
Further research is very likely to have a substantial impact on our confidence in the estimate of effect and is very likely to change the estimate.
D Very Low The estimate of the effect is very uncertain, and often will be far from the true effect.
Current research has very little value in informing the estimate of the effect.
Practice Points
Unlike clinical recommendation statements, practice points are not graded for strength of recommendation or quality of evidence. They are largely the expert opinions of the WG and are consensus state- ments regarding an aspect of care where evidence is lacking, or is of extremely poor quality. Occasionally, they make reference to observa- tions for which studies have not yet been performed but are of clinical significance, whereby the WG feels strongly that the lack of clinical guidance would have a detrimental effect on outcomes. Practice Points may also highlight an aspect of care peculiar to specific healthcare settings where applicable studies may be lacking. Practice points may take the form of a clinical statement, figure, table or algo- rithm. In areas where the WG had judged to be controversial, an explanation is provided on how the clinical decision has been derived, based on whatever available evidence, weak or otherwise.
Implications and Implementation Issues for the Asia- Pacific Countries
The WG is also cognizant of the diverse cultures, population composi- tion, healthcare infrastructure, policies and available resources among the Asia-Pacific countries and has taken the applicability and implemen- tation issues of the guideline in the region into consideration. While the APSN guideline has adopted the strong scientific evidence approach similar to most if not all international clinical practice guidelines, in crafting recommendation statements; the WG recognized that some recommendations are difficult to implement in many low-resource set- tings, rendering the majority of the guidelines obsolete in these coun- tries. In this regard, the WG, with broad representation from countries in the Asia-Pacific region, considered alternative options, while with very low quality of evidence, would be preferable practices than total disre- gard of the clinical aspect of care due to difficulties in implementation.
S U M M A R Y S T A T E M E N T S
Chapter 1: Terminology, Screening and Monitoring of Diabetic Kidney Disease
Practice Point 1.1:
Use the term “Diabetic Kidney Disease” instead of “Diabetic Nephropathy”to reflect the pathophysiology, histopathological het- erogeneity and clinical course of the condition.
Clinical Recommendation 1.1:
We recommend that urine albumin:creatinine ratio and esti- mated glomerular filtration rate be used for the screening of diabetic kidney disease in adults with diabetes mellitus. [1B]
Practice Point 1.2:
In areas where urine albumin:creatinine ratio is not feasible or available, screening with spot urine albumin concentration, urine protein:creatinine ratio or urine dipstick may be considered.
Clinical Recommendation 1.2:
We suggest that annual screening for diabetic kidney dis- ease be performed beginning 5 years after diagnosis of type 1 diabetes mellitus and at diagnosis of type 2 diabetes mellitus. [2C]
Practice Point 1.3:
Kidney biopsy is not routinely performed to diagnose dia- betic kidney disease. However, kidney biopsy should be consid- ered in individuals with diabetes mellitus if there is evidence suggesting the presence of non-diabetic kidney disease.
(Table PP1.3)
Clinical Recommendation 1.3:
We suggest that in adults with diabetes mellitus and albu- minuria, monitoring of albuminuria and estimated glomeru- lar filtration rate be performed to assess the progression of diabetic kidney disease. [2D]
Practice Point 1.4:
In people with established diabetic kidney disease, albuminuria and estimated glomerular filtration rate should be monitored at least 6 monthly. Monitoring should be performed more frequently if resources permit or in people who are at high risks of progression to ESKD. (Table PP1.4)
T A B L E P P 1 . 3 Situations in which a kidney biopsy should be considered in people with diabetes mellitus
Evidence suggestive of Non-Diabetic Kidney Disease
1. Absence of typical chronology, e.g. the onset of proteinuria is less than 5 years from the onset of type 1 DM.
2. Presence of rapidly declining eGFR.
3. Presence of rapidly increasing urine albumin or rapidly developing nephrotic syndrome.
4. Presence of active urinary sediment containing red cells and cellular casts.
5. Presence of systemic signs or symptoms suggestive of a non- diabetic cause for kidney disease.
6. Absence of retinopathy in people with type 1 DM.
Chapter 2: Lifestyle Modification
Clinical Recommendation 2.1:
We recommend that people with diabetic kidney disease who are smokers, undergo intervention for smoking cessa- tion. [1C]
Practice Point 2.1:
Educational materials detailing the adverse effects of smoking on diabetic kidney disease and general health, and the benefits of stopping smoking should be made available to all people with DM.
Clinical Recommendation 2.2:
We recommend that people with diabetic kidney disease maintain a normal body mass index. [1C]
Practice Point 2.2:
Weight reduction should start with lifestyle modification includ- ing dietary caloric restriction (with advice from a dietician) and avoidance of a sedentary lifestyle.
Practice Point 2.3:
In people with diabetes mellitus who are overweight or obese, consider the preferential use of anti-hyperglycemic agents with
weight reduction benefits such as metformin, SGLT-2 inhibitors or GLP-1 receptor agonists (See Chapter 4).
Practice Point 2.4:
A realistic weight reduction plan should be personalized to achieve gradual instead of an abrupt reduction to a target BMI.
Clinical Recommendation 2.3:
We suggest that people with diabetic kidney disease receive a protein intake of 0.8g/kg/day, and that ketoanalogues not be given for the purpose of preserva- tion of kidney function. [2C]
Practice Point 2.5:
The dietary plan should advocate a diet rich in plant-based pro- tein and avoidance of processed meats that are high in salt and phosphate content.
Chapter 3: Blood Pressure Control and Blood Pressure Lowering Agents
Clinical Recommendation 3.1:
We recommend that Angiotensin Converting Enzyme Inhibitors (ACEi) or Angiotensin II Receptor Blockers (ARB) be started in adults with diabetes mellitus and hyperten- sion, with or without albuminuria. [1B]
Practice Point 3.1:
The choice between an ACEi or ARB, or which ACEi or ARB to use for treatment in people with diabetes mellitus and hypertension, should be dependent on availability, side-effects and cost of the medication.
Practice Point 3.2:
ACEi or ARBs should be considered in adults with diabetes mellitus and albuminuria, who do not have hypertension.
Practice Point 3.3:
Figure PP3.3 suggests an approach to monitoring for side- effects after initiating or after an increase in dose of an ACEi or ARB.
T A B L E P P 1 . 4 Clinical Situations in which Albuminuria and estimated Glomerular Filtration Rate should be monitored more frequently (at least 2-3 monthly).
Clinical Situations Requiring More Frequent Monitoring 1. Uncontrolled hypertension >160/100 mmHg or poor blood
glucose control with HbA1c >10%.
2. High urinary albumin levels > 3.5 g/day or the presence of nephrotic syndrome.
3. Annual eGFR decline > 5 ml/min/1.73m2with Renin-Angiotensin System (RAS) blockade or > 10 ml/min/1.73m2without RAS blockade treatment.
4. Individuals who have contraindications to Angiotensin Converting Enzyme inhibitors (ACEi) or Angiotensin II Receptor Blockers (ARB) treatment.
5. Individuals with eGFR < 45 ml/min/1.73m2.
6. Individuals who have biochemical abnormalities or symptoms related to CKD.
Clinical Recommendation 3.2:
We recommend that dual Renin-Angiotensin System blockade with renin inhibitors, ACEi or ARB not be used in adults with diabetes mellitus and chronic kidney disease. [1B]
Clinical Recommendation 3.3:
We suggest that in adults with diabetes mellitus and chronic kidney disease, blood pressure be lowered towards 130/80mmHg for stroke and cardiovascular protection, and slowing of kidney disease progres- sion. [2C]
Practice Point 3.4:
Blood pressure targets should be individualized in people who are older and frail, with multiple comorbidities and lower life-expectancy.
Chapter 4: Glycaemic Control and Blood Glucose Lowering Agents
Clinical Recommendation 4.1:
We recommend that HbA1c and self-monitoring of blood glucose (SMBG) be used to assess glycaemic control in adults with diabetic kidney disease. [1C]
Clinical Recommendation 4.2:
We suggest that HbA1c be targeted towards and not lower than 7.0% in adults with diabetic kidney disease, balancing the risks of micro- and macrovascular complications and the development of hypoglycaemia. [2C]
F I G U R E P P 3 . 3 An Approach to Monitoring and Managing Side-Effects after Initiating or after Increasing the Dose of an ACEi or ARB
Clinical Recommendation 4.3:
We recommend that metformin be used as the first line therapeutic agent for hyperglycaemia in adults with type 2 diabetes mellitus and eGFR≥30ml/min/1.73m2. [1B]
Practice Point 4.1:
Avoid metformin in people who have conditions predisposing them to the development of lactic acidosis, including (Figure PP4.1):
• active or progressive liver disease;
• active alcohol abuse;
• unstable or acute congestive cardiac failure;
• previous history of lactic acidosis with metformin treatment;
• decreased tissue perfusion or hemodynamic instability due to sepsis or other causes.
Practice Point 4.2:
Start metformin at a low dose and titrate doses incrementally with glycaemic control to improve tolerability. Extended-release formulation of metformin can be considered in people who have developed gastrointestinal side-effects (Figure PP4.1).
Practice Point 4.3:
Monitor kidney function 3-6 monthly in people with chronic kid- ney disease on metformin treatment. Adjust the dose when eGFR falls to <60 ml/min/1.73m2and discontinue metformin when eGFR is <30 ml/min/1.73m2(Figure PP4.1).
Practice Point 4.4:
Temporarily discontinue metformin during a significant intercur- rent illness where there is a risk of volume depletion or in people with eGFR 30-60 ml/min/1.73m2 who are going for imaging with intravenous contrast (Figure PP4.1).
Clinical Recommendation 4.4:
We recommend that SGLT-2 inhibitors be used in adults with type 2 diabetes mellitus and eGFR≥30ml/min/1.73m2who have cardiovascular disease or diabetic kidney disease. [1A]
Practice Point 4.5:
Table PP4.5 outlines the dosing information for the common SGLT-2 inhibitors.
F I G U R E P P 4 . 1 Approach to Dosing Metformin in Diabetic Kidney Disease
Practice Point 4.6:
Counsel people starting on SGLT-2 inhibitors on the need for adequate hydration, genitourinary hygiene and risk factors for euglycaemic diabetic ketoacidosis.
Practice Point 4.7:
Perform screening for blood ketone levels in people taking SGLT-2 inhibitors during periods of intercurrent illness or poor oral intake (starvation), with inappropriate insulin dose reduction or excessive alcohol intake.
Practice Point 4.8:
Consider stopping SGLT-2 inhibitors when eGFR < 30 ml/min/1.73m2 or when dialysis is initiated. People with urinary albumin excretion > 300 mg/day and eGFR < 30 ml/min/1.73m2 should be referred to specialized centres for consideration of con- tinuing with SGLT-2 inhibitor treatment.
Clinical Recommendation 4.5:
We suggest that long-acting GLP-1 receptor agonists be used as an alternative to SGLT-2 inhibitors in people with type 2 diabetes mellitus and chronic kidney disease for both cardioprotection and renoprotection. [2C]
Practice Point 4.9:
Table PP4.9 outlines the dosing information for the common non-short-acting GLP-1 receptor agonists.
Practice Point 4.10:
Figure PP4.10 outlines the approach to choosing blood glucose lowering agents in people with type 2 diabetes mellitus and chronic kidney disease.
T A B L E P P 4 . 5 Common SGLT-2 Inhibitors and Dosing Information
Drug Name Starting Dose Maximum Dose Contraindications and Dose Adjustment
Empagliflozin 10 mg OM 25 mg OM • Contraindication when eGFR< 30 ml/min/1.73m2, ESKD, on dialysis.
• No dosage adjustment necessary for hepatic impairment.
Canagliflozin 100 mg OM 300 mg OM • Reduce dose to 100 mg OM when eGFR 30-60 ml/min/1.73m2.
• Not to start when eGFR < 30ml/min/1.73m2.
• May continue when eGFR < 30 ml/min/1.73m2with 100 mg OM if already on treatment and urinary albumin excretion > 300 mg/day.
• No dosage adjustment necessary for hepatic impairment.
• Contraindicated in ESKD, on dialysis.
Dapagliflozin 5 mg OM 10 mg OM • Contraindication when eGFR< 30 ml/min/1.73m2, ESKD, on dialysis.
• No dosage adjustment necessary for hepatic impairment.
T A B L E P P 4 . 9 Common Non-Short-Acting GLP-1 Receptor Agonists and Dosing Information Drug Name Starting Dose Maximum Dose Dose Increment
Intermediate-Acting
Liraglutide SC 0.6 mg once daily SC 1.8 mg once daily • Start at 0.6 mg once daily for 1 week and then increase to 1.2 mg once daily for at least 1 week.
• If further glycaemic control necessary, may increase to 1.8 mg once daily.
• 0.6 mg once daily is intended to reduce GI symptoms and does not provide adequate glycaemic control.
Long-Acting
Semaglutide SC 0.25 mg once weekly SC 1 mg once weekly • Start at 0.25 mg once weekly for 4 weeks and then increase to 0.5 mg once weekly for at least 4 weeks.
• If further glycaemic control necessary, increase to a maximum of 1 mg once weekly.
• 0.25 mg once weekly is ineffective for glycaemic control and is intended for improving tolerability during therapy initiation.
Dulaglutide SC 0.75 mg once weekly SC 1.5 mg once weekly • Start at 0.75 mg once weekly for glycaemic control.
• Increase to 1.5 mg once weekly if further glycaemic control necessary.
SC: Subcutaneous injection; GI: Gastrointestinal
No dose adjustments are necessary for hepatic or renal impairment.
Practice Point 4.11:
Additional blood glucose lowering agents can be added and personalized to the clinical needs of individuals based on their other non-glucose lowering properties (Figure PP4.11).
F I G U R E P P 4 . 1 1 Blood Glucose Lowering Agents and their other Non-Glucose Lowering Properties
F I G U R E P P 4 . 1 0 Approach to choosing blood glucose lowering agents in people with type 2 diabetes mellitus and chronic kidney disease
Chapter 5: Diabetic Kidney Disease and Kidney Replacement Therapy
Clinical Recommendation 5.1:
We suggest that adults with diabetes mellitus and chronic kidney disease be referred to a nephrology service when the eGFR < 30 mL/min/1.73 m2for preparation of kidney replacement therapy. [2C]
Practice Point 5.1:
In regions where there is a shortage of nephrologists, protocol- driven management of people with advanced diabetic kidney disease and shared care with primary care providers could be consid- ered to mitigate the high workload, with nephrology oversight.
(Figure PP5.1)
Clinical Recommendation 5.2:
We recommend that initiation of dialysis in adults with diabetes mellitus and chronic kidney disease be based on the develop- ment of clinical symptoms rather than on a specific eGFR. [1C]
R E F E R E N C E S
1. USRDS. Annual Data Report 2018. Chapter 11: International Compari- sons. 2018.
2. Tang SCW, Yu X, Chen HC, et al. Dialysis Care and Dialysis Funding in Asia.Am J Kidney Dis.2020;75(5):772-781.
3. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.BMJ.
2008;336(7650):924-926.
How to cite this article:LIEW A, BAVANANDAN S, PRASAD N, et al. ASIAN PACIFIC SOCIETY OF NEPHROLOGY CLINICAL PRACTICE GUIDELINE ON DIABETIC KIDNEY DISEASE–AN EXECUTIVE SUMMARY.
Nephrology. 2020;25:809–817.https://doi.org/10.1111/nep.
13804
F I G U R E P P 5 . 1 Components of a non-nephrologist dependent model of care for people with advanced DKD