Asian Pacific Society of Nephrology Clinical Practice Guideline on Diabetic Kidney Disease – An Executive Summary

Abstract

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 disease (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 replacement 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 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. The format of the APSN Clinical Practice Guidelines has been harmonized with the way in which recent guidelines by Kidney Disease: Improving Global Outcomes (KDIGO) had been presented, where Clinical Recommendation statements are interspersed with Practice Points. 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 dissertation of the available evidence, including the benefits and harms in making such a recommendation. Level 1 “We recommend…” Level 2 “We suggest…” 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. 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. 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. 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. 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 statements regarding an aspect of care where evidence is lacking, or is of extremely poor quality. Occasionally, they make reference to observations 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 algorithm. 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. The WG is also cognizant of the diverse cultures, population composition, healthcare infrastructure, policies and available resources among the Asia-Pacific countries and has taken the applicability and implementation 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 settings, rendering the majority of the guidelines obsolete in these countries. 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 disregard of the clinical aspect of care due to difficulties in implementation. Practice Point 1.1: Use the term “Diabetic Kidney Disease” instead of “Diabetic Nephropathy” to reflect the pathophysiology, histopathological heterogeneity and clinical course of the condition. We recommend that urine albumin:creatinine ratio and estimated 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. We suggest that annual screening for diabetic kidney disease 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 diabetic kidney disease. However, kidney biopsy should be considered in individuals with diabetes mellitus if there is evidence suggesting the presence of non-diabetic kidney disease. (Table PP1.3) We suggest that in adults with diabetes mellitus and albuminuria, monitoring of albuminuria and estimated glomerular 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) We recommend that people with diabetic kidney disease who are smokers, undergo intervention for smoking cessation. [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. 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 including 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. 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 preservation of kidney function. [2C] Practice Point 2.5: The dietary plan should advocate a diet rich in plant-based protein and avoidance of processed meats that are high in salt and phosphate content. We recommend that Angiotensin Converting Enzyme Inhibitors (ACEi) or Angiotensin II Receptor Blockers (ARB) be started in adults with diabetes mellitus and hypertension, 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. 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] 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 progression. [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. We recommend that HbA1c and self-monitoring of blood glucose (SMBG) be used to assess glycaemic control in adults with diabetic kidney disease. [1C] 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] 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: 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 kidney disease on metformin treatment. Adjust the dose when eGFR falls to <60 ml/min/1.73m2 and discontinue metformin when eGFR is <30 ml/min/1.73m2 (Figure PP4.1). Practice Point 4.4: Temporarily discontinue metformin during a significant intercurrent 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). We recommend that SGLT-2 inhibitors be used in adults with type 2 diabetes mellitus and eGFR ≥ 30ml/min/1.73m2 who 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. 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 continuing with SGLT-2 inhibitor treatment. 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. 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). 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 m2 for 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 considered to mitigate the high workload, with nephrology oversight. (Figure PP5.1) We recommend that initiation of dialysis in adults with diabetes mellitus and chronic kidney disease be based on the development of clinical symptoms rather than on a specific eGFR. [1C]

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