These slides were sponsored by Janssen and developed in conjunction with the BRS CKD Strategy Group, following an advisory board that was organised by Janssen. Bedrock Healthcare Communications provided editorial support to members of the advisory board in developing the slides. Janssen reviewed the content for technical accuracy. The content is intended for a UK healthcare professional audience only. JOB CODE PHGB/VOK/0914/0018c Date of preparation: January 2015 SECTION D Appropriate monitoring for complications of diabetes in primary care – with a focus on CKD as one of these complications

Objectives and background for this learning resource Introduction: This learning resource has been developed as part of a medical education initiative supported by Janssen. The content of this slide kit has been developed by an advisory board of renal physicians, GPs and specialist nurses. The panel of experts includes members of the British Renal Society Chronic Kidney Disease (CKD) Strategy Group. Bedrock Healthcare, a medical communications agency, has provided editorial support in developing the content; Janssen has reviewed the content for technical accuracy. Educational objectives: To provide clear and applicable clinical guidance on chronic kidney disease (CKD) in people with type 2 diabetes to primary care healthcare professionals To advise primary healthcare professionals on what people with diabetes need to know about their own condition with relation to CKD Usability objectives: To provide essential, relevant and up to date information in concise presentations To enable primary healthcare professionals to locate, select and use the content of the learning resource, as appropriate to their needs To enable secondary care experts in CKD to refer their primary care colleagues to the resource 1

Contents overview This learning resource comprises the following 10 sections (A-E): 2 Section A Introduction and overview of chronic kidney disease (CKD) in people with diabetes Section B Long-term impact of diabetes and the importance of optimal management of the condition Section C Pathophysiology of diabetic nephropathy & risk factors for the development of CKD Section D Appropriate monitoring for complications of diabetes in primary care – CKD as one of these complications Section EPrevention of diabetic kidney disease

Contents overview (cont.) This learning resource comprises the following 10 sections (F-J): 3 Section F Optimal management of diabetic kidney disease: hypertension and glycaemia Section G How to involve people with diabetes and CKD in their own care – what information must they have to manage their own condition effectively? Section H What does the future hold for a person with well-managed diabetes and CKD? Section I What do the guidelines say and what do they mean in terms of the day-to-day management of CKD in people with diabetes? Section JSources of further information and reading list

Section D – 3 key learning objectives People with diabetes should be offered testing for CKD –Use eGFR to detect and monitor impaired renal excretory function –Use albumin:creatinine ratio (ACR) to detect and monitor albuminuria Monitoring should become more frequent as diabetic kidney disease progresses Test results should be interpreted according to guidelines; however, consideration of individual patient factors (e.g. age, weight) that may affect test results need to be taken into account 4

NICE guidance – who to test Offer testing for CKD using eGFR (estimated using serum creatinine) and ACR to people with any of the following risk factors: 1 –Diabetes –Hypertension –Recent history of acute kidney injury –Cardiovascular disease (ischaemic heart disease, chronic heart failure, peripheral vascular disease or cerebral vascular disease) –Structural renal tract disease, recurrent renal calculi or prostatic hypertrophy –Multi-system diseases with potential kidney involvement – for example, systemic lupus erythematosus –Family history of end-stage kidney disease (eGFR category 5) or hereditary kidney disease –Opportunistic detection of haematuria 5 Reference: 1. NICE clinical guideline 182. Chronic kidney disease early identification and management of chronic kidney disease in adults in primary and secondary care. July Available at Website last accessed on

Diagnosing CKD At least one of these factors is necessary for a diagnosis of CKD: –Impaired renal excretory function (measured by eGFR) 1 –Albuminuria (measured by ACR) 1 –Structural changes to the kidneys 1 When screening people at possible risk of CKD it is only necessary to test for the first two of the above 1 Ultrasounds are not indicated as a screening test for CKD except in highly specific circumstances e.g. diagnosis of autosomal dominant polycystic kidney disease 1 A mistaken diagnosis of CKD (or incorrect coding as CKD) is not benign: –There may be a psychological impact of being labelled with a chronic disease 1 –It can affect insurance premiums and future life choices, etc 1 Therefore, it is important to diagnose CKD correctly, to prevent unnecessary or inappropriate intervention 1 6 Reference: 1. Lewis R. Updated NICE guidelines for the diagnosis and management of chronic kidney disease: what they mean for your practice. Article submitted to Primary Care Cardiovascular Journal 2014.

Factors affecting creatinine-based eGFR results Persistently erroneous results In people with extremes of muscle mass (e.g. a bodybuilder) eGFR needs to be interpreted with caution, as increased muscle mass can lead to underestimation of eGFR 1,2 In people with reduced muscle mass (e.g. in elderly patients or those with a muscle wasting disorder) eGFR needs to be interpreted with caution, as reduced muscle mass can lead to overestimation of eGFR 1,2 Variably erroneous results People should be advised not to eat any meat in the 12 hours before a blood test for eGFR as exogenous creatinine from the diet enters the blood, affecting the assay 1,2 Dehydration can lower eGFR 2 Blood samples should be received and processed by the laboratory within 12 hours of venepuncture 1,2 Trimethoprim (antibiotic) interferes with creatinine secretion by the kidneys and can lower eGFR 2 7 References: 1. NICE clinical guideline 182. Chronic kidney disease early identification and management of chronic kidney disease in adults in primary and secondary care. July Available at Website last accessed on Lewis R. Updated NICE guidelines for the diagnosis and management of chronic kidney disease: what they mean for your practice. Article submitted to Primary Care Cardiovascular Journal 2014.

Considerations when using creatinine based eGFR An eGFR less than 60 mL/min/1.73m 2 is abnormal, but a single result is not sufficient to make a diagnosis of CKD 1 eGFR results have an intra-individual variation of +/-5% in CKD, therefore a difference of +/-5% between blood tests is not significant 1 –Other factors may also affect the interpretation of the result, such as diet and hydration state 1 A diagnosis of CKD should only be made if eGFR <60 mL/min/1.73m 2 on at least 2 separate occasions over a duration of 90 days 1 The accuracy of eGFR testing improves as renal function declines. It is less accurate with a normal eGFR 1 –Thus, it is important to take repeated readings and to consider the effect of confounding factors (such as diet or hydration state) 60 mL/min/1.73m 2 is the level below which CKD can be diagnosed on the basis of eGFR alone. However, it is important to realise that it is possible for CKD to exist in patients with results higher than this, if another marker of kidney damage is present 1 8 References: 1. Lewis R. Updated NICE guidelines for the diagnosis and management of chronic kidney disease: what they mean for your practice. Article submitted to Primary Care Cardiovascular Journal 2014.

Cystatin C eGFR vs. creatinine based eGFR Cystatin C is not a new test, but it has only recently found its place in clinical medicine and is not yet widely available from laboratories 1 –NHS England is developing a plan to expand the availability of Cystatin C testing 1 Cystatin C can be used to estimate GFR and is less susceptible to the errors which effect a creatinine-based estimation e.g. muscle mass and medication 1 Even though the cystatin C assay is ten times more expensive than the standard creatinine assay, this cost is justified if it reduces inappropriate diagnosis of CKD 1 Cystatin C estimation should be used as a “one off” to confirm a diagnosis of CKD, and is not intended as a substitute for creatinine measurements 1 9 Reference: 1. Lewis R. Updated NICE guidelines for the diagnosis and management of chronic kidney disease: what they mean for your practice. Article submitted to Primary Care Cardiovascular Journal 2014.

Cystatin C may be a useful alternative to creatinine for estimation of GFR when early CKD is suspected 10 Reference: 1. Lewis R. Updated NICE guidelines for the diagnosis and management of chronic kidney disease: what they mean for your practice. Article submitted to Primary Care Cardiovascular Journal Cystatin C to estimate GFRCreatinine to estimate GFR Produced by all nucleated cells 1 Produced by muscle cells 1 Almost 100% reabsorbed by the tubules and is undetectable in normal urine 1 100% filtered at the glomerulus with some tubular reabsorption 1 Blood level independent of muscle mass or diet 1 Blood level depends on muscle mass and is also affected by meat content of diet 1 Blood level is falsely raised in hypothyroidism and lowered in hyperthyroidism 1 Unaffected by thyroid activity 1 May be increased by inflammation 1 – Assay costs approximately £ Assay costs approximately £0.25 1

NICE 2014 diagnosis of CKD When to use cystatin C based eGFR: Consider using eGFR (estimated using cystatin C) at initial diagnosis to confirm or rule out CKD in people with: –An eGFR (estimated using serum creatinine) of 45–59 mL/min/1.73m 2, sustained for at least 90 days and: 1 –No albuminuria (ACR less than 3 mg/mmol) or other marker of kidney disease 1 How to interpret the result: Do not diagnose CKD in people with: –An eGFR (estimated using serum creatinine) of 45–59 mL/min/1.73m 2 and 1 –An eGFR (estimated using cystatin C) of more than 60 mL/min/1.73m 2 and 1 –No other marker of kidney disease e.g. albuminuria or structural changes to kidneys 1 11 Reference: 1. NICE clinical guideline 182. Chronic kidney disease early identification and management of chronic kidney disease in adults in primary and secondary care. July Available at Website last accessed on

Detecting albuminuria: ACR When: Recommended for initial detection of albuminuria and subsequent monitoring How: Preferably early morning spot urine (not dipstick or 24 hour urine collection) –ACR>3mg/mmol = abnormal 1 An early morning sample may not be practical. If so, send available spot urine. Once spot urine result has been returned then: 2 –If ACR<3mg/mmol there is no need to obtain early morning sample – the result is normal 2 –For ACR between 3 mg/mmol and 70 mg/mmol, proteinuria should be confirmed using a subsequent early morning sample 1,2 –If the ACR is >70 mg/mmol, a repeat morning sample need not be tested because this level of albuminuria is unequivocally abnormal and significant 2 12 References: 1. Adapted from: NICE clinical guideline 182. Chronic kidney disease early identification and management of chronic kidney disease in adults in primary and secondary care. July Available at Website last accessed on Lewis R. Updated NICE guidelines for the diagnosis and management of chronic kidney disease: what they mean for your practice. Article submitted to Primary Care Cardiovascular Journal 2014.

ACR categories ACR is categorised according to the following levels of severity: normal to mild, moderate, or severe 1 13 Reference: 1. NICE clinical guideline 182. Chronic kidney disease early identification and management of chronic kidney disease in adults in primary and secondary care. July Available at Website last accessed on ACR categoryA1A2A3 ACR level<3mg/mmol3-30mg/mmol>30mg/mmol TermNormal to mildly increasedModerately increasedSeverely increased Adapted from: NICE clinical guideline 182. Chronic kidney disease early identification and management of chronic kidney disease in adults in primary and secondary care. July 2014.

Factors that may cause a misleading ACR result It is often stated that the ACR should be measured in a fresh early-morning sample; this is because a misleading increase in ACR may result from exercise or even from being up-and-about during the day 1 –Strenuous exercise can cause an increase in proteinuria, so it is important that this be avoided in the 72 hours prior to giving the urine sample 2 Other factors that may affect ACR result include: –Urinary tract infection 3 –High dietary protein intake 3 –Congestive cardiac failure 3 –Acute febrile illness 3 –Menstruation or vaginal discharge 3 –Drugs (NSAIDs, ACE inhibitors, ARBs) 3 –Urine creatinine levels are also lower in people with lower muscle mass e.g. women compared to men and certain racial/ethnic groups 4 14 References: 1. Lewis R. Updated NICE guidelines for the diagnosis and management of chronic kidney disease: what they mean for your practice. Article submitted to Primary Care Cardiovascular Journal Lewis R,. Prim Care Cardiovasc J 2014;7: Johnson DW, Jones GRD, Mathew TH, et al. Med J Aust 2012; 197 (4): Mattix H, Hsu C, Shaykevich S et al. J Am Soc Nephrol 2002;13:

Monitoring CKD: what to do next NICE recommends that people with CKD in the following groups should normally be referred for specialist assessment 1,2 eGFR less than 30 mL/min/1.73m 2 (GFR category G4 or G5), with or without diabetes ACR 70 mg/mmol or more, unless known to be caused by diabetes (e.g. presence of retinopathy or absence of haematuria) and already appropriately treated ACR 30 mg/mmol (ACR category A3) or more, together with haematuria Accelerated progression (defined as a sustained decrease in GFR of 25% or more, and a change in GFR category or sustained decrease in GFR of 15 ml/min/1.73m 2 or more within 12 months) Hypertension that remains poorly controlled despite the use of at least four antihypertensive drugs at therapeutic doses Known or suspected rare or genetic causes of CKD Suspected renal artery stenosis 15 Reference: 1. NICE clinical guideline 182. Chronic kidney disease early identification and management of chronic kidney disease in adults in primary and secondary care. July Available at Website last accessed on Lewis R. Updated NICE guidelines for the diagnosis and management of chronic kidney disease: what they mean for your practice. Article submitted to Primary Care Cardiovascular Journal 2014.

Monitoring people with CKD Once diagnosed, people with CKD should be monitored regularly to: –Ensure that all remedial factors are being optimally addressed e.g. blood pressure control, glycaemic control, avoiding nephrotoxins –Identify those people who are progressing and may need additional input People diagnosed with CKD should be entered onto the CKD register Frequency of monitoring should be influenced by various clinical circumstances, including: –The underlying cause of CKD –Past patterns of eGFR and ACR (but be aware that CKD progression is often non-linear) –Comorbidities, especially heart failure –Changes to their treatment (such as ACE-inhibitors, NSAIDs and diuretics) –Intercurrent illness –If a patient has chosen conservative management of CKD 16 Reference: 1. Lewis R. Updated NICE guidelines for the diagnosis and management of chronic kidney disease: what they mean for your practice. Article submitted to Primary Care Cardiovascular Journal 2014.

Frequency of monitoring NICE recommends that frequency of monitoring increases from ≤once a year to ≥four times a year depending on kidney disease severity, as shown in the table opposite 1 –The frequency of monitoring should be agreed with the patient, bearing in mind that CKD is not progressive in many people 1 ACR is an important indicator of cardiovascular risk and progression 1 17 The numbers in this table indicate recommended frequency of monitoring per year ACR categories (mg/mmol), description and range A1 <3 Normal to mildly increased A Moderately increased A3 >30 Severely increased GFR categories (ml/min/1.73m 2 ), description and range G1 >90 Normal and high <1<11>1>1 G Mild reduction related to normal range for a young adult <1<11>1>1 G3a Mild-moderate reduction 112 G3b Moderate-severe reduction <2<22>2>2 G Severe reduction 223 G5 <15 Kidney failure 4>4>4>4>4 Increasing risk GFR = glomerular filtration rate, ACR = albumin creatinine ratio. Reference: 1. NICE clinical guideline 182. Chronic kidney disease early identification and management of chronic kidney disease in adults in primary and secondary care. July Available at Website last accessed on Adapted from: NICE clinical guideline 182. Chronic kidney disease early identification and management of chronic kidney disease in adults in primary and secondary care. July 2014.

What to monitor in people with CKD Conduct at least one review of blood pressure and eGFR per year in all CKD patients 1 All patients being screened for CKD should have urine ACR measured to establish the baseline level 1 At least annual measurements of ACR in all people with diabetes 1 Monitoring of ACR will be necessary, with the frequency depending upon a number of factors, including the underlying cause and initial results 1 It should be borne in mind that: –Albuminuria is a marker of worse cardiovascular outcomes and there is a relationship between the amount of albuminuria and risk 1 –ACR monitoring of patients with diabetes and CKD is a performance indicator in the diabetes QOF (in England) 1 –Frequency of monitoring should be acceptable to the primary care team and the patient 1 18 Reference: 1. Lewis R. Updated NICE guidelines for the diagnosis and management of chronic kidney disease: what they mean for your practice. Article submitted to Primary Care Cardiovascular Journal 2014.

Section D – summary Offer testing for CKD to people with diabetes After diagnosis of kidney disease, frequency of monitoring should increase as diabetic kidney disease progresses Use albumin:creatinine ratio (ACR) to detect and quantify albuminuria Use eGFR to diagnose and monitor progression of diabetic kidney disease Interpret test results according to guidelines, taking into consideration individual patient factors that may affect test results 19