Chapter 1

Louise is a 56-year-old schoolteacher with type 2 diabetes diagnosed 6 years ago. She is attending her primary care diabetes review.

Recently performed blood tests showed: HbA1c 70 mmol/mol; eGFR 71 mL/min/1.73m2; cholesterol 4.1 mmol/L, non-HDL 2.3 mmol/L; normal liver function tests; urinary albumin–creatinine ratio (ACR) 7.4 mg/mmol.

Louise’s current medication comprises metformin 1 g twice daily and atorvastatin 20 mg once daily. She is known to have background retinopathy.

Clinic measurements: BMI 32.4 kg/m2; blood pressure (BP) 144/85 mmHg; and urine dipstick all clear.

What are your major concerns for Louise from these results?

Chapter 2

The key issues for Louise are: poor glycaemic control (recommended HbA1c target is 53 mmol/mol [1]); possible diabetic nephropathy; obesity; and suboptimal BP control (NICE-recommended target is systolic <130 mmHg [target 120–129 mmHg] and diastolic <80 mmHg in cases of diabetic retinopathy and diabetic nephropathy [2]).

How would you follow up the finding of a positive ACR result?

Chapter 3

A single positive ACR test needs to be repeated (ideally within 3 months) unless the initial ACR is 70 mg/mmol or more. Albuminuria is confirmed if there is one positive repeat out of the next two specimens (2). If further tests are negative, however, then a return to annual screening can be resumed.

In this case, the Practice Nurse checked Louise’s records and found that her last ACR test came back as 5.8 mg/mmol, confirming the recent finding of albuminuria.

A urinary ACR value of >3 mg/mmol is considered a positive test for albuminuria. It is of note that a urine dipstick would not test positive for proteinuria until an ACR of 30 mg/mmol.

Urinary ACR is a more sensitive test than protein:creatinine ratio, particularly in early nephropathy where albumin is primarily the protein found in the urine (2). ACR should ideally be performed on a first-pass morning urine sample.

If you would like more detail, Winocour and colleagues provide a comprehensive guide to screening for chronic kidney disease (CKD) in type 2 diabetes (3).

How should Louise’s finding of microalbuminuria be interpreted? What else might cause proteinuria and when might further investigation be necessary?

Section 4

The finding of two consecutive positive tests for albuminuria in a person with type 2 diabetes in the absence of other pathology or abnormal findings implies diabetic nephropathy (2). Bear in mind that albuminuria can be a transient finding, such as in cases of urinary tract infection (UTI), febrile illness and vigorous exercise. Chronic albuminuria may be caused by hypertension, glomerulonephritis or congestive cardiac failure. In contrast, the proteinuria of myeloma is characterised by monoclonal immunoglobulins (Bence Jones protein).

From a practical point of view, the urine sample sent for ACR should first be dipstick tested and then, if leucocytes, nitrites or blood are detected, consider treatment for infection and/or mid-stream urine analysis, and retest when the urinary tract infection (UTI) has been treated. Persistent microscopic haematuria will require further investigation.

Louise’s normal urinary dipstick test is important in excluding UTI as a confounding cause of albuminuria.

In the presence of diabetic retinopathy, the finding of albuminuria is very likely to be due to diabetic nephropathy (4,5). In the absence of other markers for diabetic microvascular complications, you should consider the possibility of alternative causes of albuminuria and the need for further investigation.

What other findings characterise diabetic nephropathy?

Chapter 5

Diabetic nephropathy consists of renal damage attributable to diabetes and is one cause of CKD. The key findings in diabetic nephropathy are albuminuria and declining estimated glomerular filtration rate (eGFR). Hypertension is likely to be a clinical feature as albuminuria progresses.

The KDIGO classification of CKD is outlined below in Chapter 16.

The onset of diabetic nephropathy is asymptomatic and hence the crucial importance of screening tests for kidney disease (ACR and eGFR). Importantly, early recognition provides the opportunity to halt progression of diabetic nephropathy and reduce the risk of complications.

Louise’s renal function is relatively well maintained and hypertension mild at this stage.

What complications are associated with diabetic nephropathy?

Chapter 6

Both eGFR <60 mL/min/1.73m2 and significant albuminuria are independently linked to increased risk of cardiovascular events, adverse renal outcomes and all-cause mortality in people with type 2 diabetes (6,7). If both factors are present, the risks are multiplied. Diabetic nephropathy is the commonest cause of end-stage renal disease (ESRD), both in the UK and worldwide (8).

As renal function declines (as defined by a falling GFR), anaemia secondary to erythropoietin deficiency may arise (typically when eGFR falls <30 mL/min/1.73m2). Further manifestations of advanced renal failure are hypocalcaemia secondary to reduced production of the active vitamin D metabolite responsible for absorption of this mineral (because the 1-alpha-hydroxylation process that takes place in the kidney is less effective) and hyperphosphataemia. The response to this is secondary hyperparathyroidism, which can lead to renal osteodystrophy (9).

As ESRD approaches (eGFR <15 mL/min/1.73m2), symptoms associated with severe uraemia (fatigue, nausea, anorexia, pruritus and weight loss) become prominent.

Patients with diabetic nephropathy are more prone to hypoglycaemia (induced by treatments) and are also more susceptible to acute kidney injury.

What are the key risk factors for diabetic nephropathy and what interventions make a difference to its progression?

Chapter 7

Key risk factors for the development and progression of diabetic nephropathy are duration of diabetes, poor glycaemic control and hypertension.

There is strong evidence that intensive glycaemic control can reduce the risk of development and progression of albuminuria and CKD in type 2 diabetes (10,11).

Control of hypertension is of great importance in reducing the decline in renal function and albuminuria. NICE advises a target of <130/80 mmHg for people with diabetes and CKD (2).

How would you set about improving Louise’s glycaemic control? What features would be useful in choosing an add-on treatment to metformin for Louise?

Chapter 8

Always preface any discussion of medical treatments by reinforcing the importance of diet, exercise and weight loss. If Louise wanted further help, she could be referred to the locally based diabetes lifestyle programme for type 2 diabetes.

In choosing an add-on treatment to metformin to improve glycaemic control, we might ideally choose an agent that offers renoprotection and the possibility of weight loss (1).

So what might be the best add-on treatment choice for Louise?

Chapter 9

You might consider an SGLT2 inhibitor as being particularly useful in improving glycaemic control in this situation. There is now robust evidence that SGLT2 inhibitors offer renoprotection in diabetic nephropathy.

In the cardiovascular outcome trials (CVOTs) in type 2 diabetes with empagliflozin (12), canagliflozin (13) and dapagliflozin (14) the secondary composite renal outcome showed significant improvement versus placebo. The renal outcome in the ertugliflozin CVOT fell just short of significant benefit (15). The CREDENCE randomised controlled trial comparing canagliflozin versus placebo in people with type 2 diabetes and albuminuric diabetic kidney disease showed significant reduction in the composite primary outcome of ESRD, doubling of serum creatinine and death from renal or cardiovascular causes (16). The DAPA-CKD trial showed a reduction in the primary composite renal and cardiovascular outcome for dapagliflozin versus placebo. Renoprotection was seen through the range of eGFR from 25 to 75 mL/min/1.73 m2, whether or not the individual had type 2 diabetes or not (17).

The ADA/EASD consensus statement recommends SGLT2 inhibitors as a first-line choice of add-on to metformin where CKD is a priority (1). Up-to-date comprehensive evidence-based reviews of CKD in diabetes can be found in the ADA Standards of Medical Care in Diabetes (18,19) and the KDIGO Diabetes Management in CKD Guideline (20).

Further benefits from using an SGLT2 inhibitor in Louise’s case include weight loss and a small reduction in BP.

If Louise had an eGFR <60 mL/min/1.73 m², how would this affect your choice of treatment for hyperglycaemia?

Chapter 10

Until recently, the SGLT2 inhibitors were licensed for initiation in the UK only if eGFR was ≥60 mL/min/1.73 m2. Following the results of the CREDENCE trial (16), canagliflozin gained a licence for initiation at 100 mg once daily with eGFR in the range 45 to 59 mL/min/1.73 m2, and for the eGFR range 30 to 44 mL/min/1.73 m2 if there is significant (>30 mg/mmol) albuminuria present (21). Thus, canagliflozin could still be used within licence if Louise’s eGFR was <60 mL/min/1.73 m2. However, it should be noted that whilst the renoprotective properties of SGLT2 inhibitors are maintained at lower eGFR, the HbA1c lowering potential falls in parallel with reducing eGFR (12–16). Also of note is that people usually see a fall in BP with an SGLT2 inhibitor.

If a larger HbA1c reduction was considered necessary, or if or an SGLT2 inhibitor was poorly tolerated or contraindicated, then consideration could be given to using a GLP-1 receptor agonist (RA) to provide glycaemic control, as they can be safely used in diabetic kidney disease (1). A beneficial effect on the attenuation of albuminuria is a consistent feature with the GLP-1 RAs and they may have a small effect on slowing CKD progression (22). A further benefit for Louise from utilising a GLP-1 RA would be weight loss. Access to an injectable GLP-1 RA may, however, require referral in some practices that do not initiate injectable drugs (although oral semaglutide could be considered).

What about using other agents in this situation to lower HbA_1c?

Chapter 11

A DPP-4 inhibitor is a reasonable choice in CKD, but is not a preferred second-line addition to metformin according to the ADA/EASD guideline (1). Some can be safely used down to an eGFR of 15 mL/min/1.73 m2, with some evidence for reducing albuminuria (23). Dose adjustment may be needed as eGFR falls, except in the case of linagliptin, which is minimally renally excreted.

Sulfonylureas and pioglitazone may be used for glycaemic control (including down to an eGFR of 30 mL/min/1.73 m2), but provide no benefit in diabetic nephropathy and carry the disadvantage of weight gain and fluid retention.

How would you address Louise’s hypertension?

Chapter 12

Firstly, repeat BP readings or use of home BP monitoring will be required to confirm the presence of hypertension. Target BP for the individual with diabetes who has diabetic nephropathy (or diabetic retinopathy) is systolic <130 mmHg (target range 120–129 mmHg) and diastolic <80 mmHg (2). Emphasise lifestyle measures that can benefit BP, including reduction in salt intake, avoidance of excess alcohol, weight loss and regular exercise. ACE inhibitors and angiotensin-receptor blockers (ARBs) are the first-line choices for hypertension in type 2 diabetes and provide a specific renoprotective effect, slowing the progress of albuminuria (24,25). If necessary, calcium-channel blockers and thiazide-like diuretics may be added. ACE inhibitors or ARBs may also be recommended in normotensive individuals who have diabetes and albuminuria, but the evidence for slowing progression of CKD is less strong than when hypertension is present (20). The combination of ACE inhibitors and ARBs should be avoided because of the increased risk of hyperkalaemia and acute kidney injury (26). ACE inhibitor or ARB should be titrated up to the optimal recommended level or the highest that is tolerated. Remember to check renal function within 2 weeks of initiation or up-titration of an ACE inhibitor or ARB, looking for any acute deterioration in renal function or the occurrence of hyperkalaemia. Provided the eGFR drop is <25%, or creatinine increase is <30% from baseline, the drug can be continued and the level rechecked in 1–2 weeks (2). Cardiovascular disease is the major cause of mortality in diabetic nephropathy – what should be on your checklist to address this risk?

Chapter 13

TDiabetic nephropathy represents a high-risk cardiovascular state and concerted efforts to reduce this risk should be made. Offer help with smoking cessation to all those motivated to change. As previously mentioned, BP should be controlled to systolic <130 mmHg (target range 120–129 mmHg) and diastolic <80 mmHg.

Statins are central to reducing cardiovascular risk and, in the absence of contraindications, atorvastatin 20 mg daily is recommended by NICE for all individuals with type 2 diabetes having CKD (without recourse to QRISK) (27).

Key take-away

Louise (whose eGFR was 71 mL/min/1.73 m²) was commenced on canagliflozin 100 mg once daily (subsequently up-titrated to 300 mg once daily) and losartan 25 mg once daily (subsequently up-titrated to 100 mg once daily, with monitoring of renal function).

Three months later, Louise was tolerating the new medications well. HbA_1c had fallen to 57 mmol/mol and BP had improved to 132/78 mmHg. She had lost 2.5 kg in weight.

Louise’s presentation highlights the importance of screening for diabetic nephropathy, with albuminuria frequently being the first indication of this condition. Early intervention to control hyperglycaemia (with drugs that offer specific renoprotection) and hypertension can slow down the progress of diabetic nephropathy.

SGLT2 inhibitors are the treatment of choice to add on to metformin to control hyperglycaemia and slow progression of renal disease in diabetic nephropathy. If these are not tolerated, GLP-1 RAs also possess renoprotective properties but, more importantly, have demonstrated cardiovascular disease protective effects in the CVOTs. DPP-4 inhibitors can be usefully employed with declining eGFR and are a safe alternative for intensification of glucose control after SGLT2 inhibitors and GLP-1 RAs.

A systolic BP target of <130 mmHg (range 120–129 mmHg) and <80 mmHg is advised in diabetic nephropathy to reduce progression of renal disease*, and also for cardiovascular protection. ACE inhibitors and ARBs are first-line antihypertensives. Attention to other cardiovascular risk factors is also crucial, with use of statins routinely recommended.

*At time of writing, a new NICE guideline on Chronic kidney disease: assessment and management is in development. It is due to be published in July 2021.

The KDIGO classification of CKD

CKD is classified according to eGFR (G1–G5) and urinary ACR (A1–A3) (28).

Thus, Louise, with an eGFR of 71 mL/min/1.73 m² and an ACR of 7.4 mg/mmol, would be classified as G2A2. If her eGFR was between 45 and 59 mL/min/1.73 m², it would be G3aA2.