Diabetic Kidney Disease

Introduction

Identification and monitoring of diabetic kidney disease

Screening for albuminuria

Estimation of glomerular filtration rate

Other kidney diseases in people with diabetes

Screening recommendations

Prevention, treatment and follow up

 

Sick day rules

Modifications of antidiabetic drugs in patients with type 2 diabetes mellitus

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(See Strength of Recommendations Taxonomy (SORT) for explanation of Grade A-C)

 

SEMDSA 2017 Recommendations
In adults, screening for CKD in diabetes should be conducted using a random urine ACR and a serum creatinine converted into an eGFR	C
Screening should commence at diagnosis of diabetes in individuals with type 2 diabetes and repeated yearly thereafter	C
A diagnosis of CKD should be made in patients with a random urine ACR ≥ 2.0 mg/mmol and/or an eGFR < 60 mL/min on at least two of three samples over a three month period	C
All patients with diabetes and CKD should receive a comprehensive, multifaceted approach to reduce cardiovascular risk	A
Adults with diabetes and CKD with either hypertension or albuminuria should receive an ACE inhibitor or an ARB to delay progression of CKD	A
People with diabetes on an ACE inhibitor or an ARB should have their serum creatinine and potassium levels checked at baseline and within one to two weeks of initiation or titration of therapy, and during times of acute illness	C
Adults with diabetes and CKD should be given a “sick day” medication list that outlines which medications should be withheld during times of acute illness	C
Combination of agents that block the renin-angiotensin-aldosterone system (ACE inhibitor, ARB, DRI) should not be routinely used in the management of diabetes and CKD	A
Doses of anti-diabetic drugs may require adjustment as renal function declines	C
People with diabetes should be referred to a nephrologist or endocrinologist with an expertise in CKD in the following situations: Chronic, progressive loss of kidney function ACR persistently >60 mg/mmol eGFR<30 mL/min Unable to remain on renal-protective therapies due to adverse effects such as hyperkalaemia or >30% increase in serum creatinine within 3 months of starting an ACE inhibitor or ARB Unable to achieve target BP (could be referred to any specialist in hypertension)	C

Abbreviations:
ACE, angiotensin-converting enzyme; ACR, albumin-to-creatinine ratio;
ARB, angiotensin II receptor block; CKD, chronic kidney disease; DRI, direct renin inhibitor.

INTRODUCTION

Chronic kidney disease (CKD) is defined as the presence of kidney damage (usually detected as urinary albumin excretion of ≥30 mg/day, or equivalent) or decreased kidney function (defined as estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m²) for three or more months, irrespective of the cause.¹ The persistence of the damage or decreased function for at least three months is necessary to distinguish CKD from acute kidney injury (AKI). Kidney disease attributable to diabetes is referred to as diabetic kidney disease (DKD).²

In South Africa, hypertension and type 2 diabetes are the dominant diseases associated with kidney failure, particularly in black ethnic groups.³ Hypertension and other common chronic kidney diseases may also contribute to the aetiology of chronic kidney disease (CKD) in diabetic patients. In Africa, the overall prevalence of CKD in patients with diabetes varied from 11% in Tunisia to 83.7% in Tanzania.⁴ The prevalence of DKD in South Africa is 14-16%⁵ and 30.4% of patients on renal replacement therapy have diabetes.⁶

IDENTIFICATION AND MONITORING OF DIABETIC KIDNEY DISEASE

Albumin excretion (albuminuria) and glomerular filtration rate (GFR) are both required to diagnose and monitor DKD.

SCREENING FOR ALBUMINURIA

Albumin excretion is an indicator of kidney damage in DKD.² Classic DKD progresses from subclinical disease to the earliest clinically detectable stage, which is characterised by persistent proteinuria (Figure I).^7,8 The rate of progression from normal albuminuria to moderately increased albuminuria, then to severely increased albuminuria is usually slow and it may take 5 years or longer to progress through each albuminuria stage (Table I). During the advanced overt proteinuria phase, the rate of decline of renal function can accelerate.⁷ Risk factors for DKD include long duration of diabetes, poor glycaemic control, hypertension, male gender, obesity and cigarette smoking.⁷ Apart from predicting DKD, moderately increased albuminuria (formerly known as microalbuminuria) is also a marker of cardiovascular disease risk.⁹

There is considerable intra-individual variation in daily albumin excretion necessitating the collection and testing of more than one specimen.² Daily albumin excretion may be increased by episodic hyperglycaemia, high blood pressure, high protein diet, fever, exercise, urinary tract infection and heart failure.² Moderately increased albuminuria (albumin excretion between 30-300 mg/day) is potentially reversible by treating raised blood pressure, plasma glucose and serum lipid levels to target in patients with type 1 diabetes,¹⁰and by administering drugs that inhibit the renin angiotensin aldosterone system (RAAS) in patients with type 2 diabetes.^1,11

Figure I. Level of urinary albumin by various test methods and stage of diabetic kidney disease. ACR, urine albumin-to-creatinine ratio. Adapted from.⁷

 

Table I. Classification of chronic kidney disease based upon albuminuria^1,7

Albuminuria Stages	Qualitative description	AER (mg/day)	Urine ACR (mg/mmol)
1	Normal to mildly increased	< 30	< 2
2	Moderately increased	30 - 300	2-20
3	Severely increased (may be subdivided into nephrotic and non-nephrotic and for differential diagnosis, management, and risk prediction)	> 300	> 20

*Adapted from References.^1,7 Values are for urinary albumin, not total urinary protein, which will be greater than urinary albumin levels.

Table II. Classification of chronic kidney disease based upon glomerular filtration rate ^1,7

Stages of chronic kidney disease of all types
GFR stages	Qualitative description	Renal function (ml/min/1.73m2)
1	Kidney damage - normal or high GFR	< 90
2	Kidney damage - mildly ↓ GFR	60 - 89
3a	Kidney damage – mildly to moderately ↓ GFR	45 - 59
3b	Kidney damage – moderately to severely ↓ GFR	30 - 44
4	Kidney damage - severely ↓ GFR	15 - 29
5	Kidney failure (or dialysis)	< 15

*Adapted from References.^1,7

Table III. Factors favouring the diagnosis of classical DKD or alternative renal diagnoses.^2,7

DKD vs. Alternative renal disease
Favours DKD	Favours alternative renal diagnosis
Persistent albuminuria	Extreme proteinuria (>6 g/day)
Bland urinary sediment	Persistent haematuria (micro- or macroscopic) or active urinary sediment
Slow progression of disease	Rapidly falling eGFR
Low eGFR associated with overt proteinuria	Low eGFR with little or no proteinuria
Other complications of diabetes present	Other complications of diabetes (e.g. retinopathy) not present or relatively not as severe
Known duration of diabetes > 5 years	Known duration of diabetes < 5 years
	Refractory hypertension
	> 30% reduction in eGFR within 3 months after initiation of an ACE-inhibitor or an ARB
	Family history or non-diabetic renal disease (e.g. polycystic kidney disease)
	Signs or symptoms of systemic disease

 

ESTIMATION OF GLOMERULAR FILTRATION RATE 

Glomerular filtration rate is used to quantify kidney function.² Estimated glomerular filtration rate (eGFR) is recommended to determine and monitor kidney function in DKD and other causes of CKD.² In spite of limitations, the Modification of Diet in Renal Disease Study Group (MDRD) formula¹³ remains the preferred method of calculating eGFR.² This equation requires knowledge of the patient’s age, sex, serum creatinine and race. The eGFR is particularly useful for assessing changes in renal function over prolonged periods but should not be used in situations where kidney function may be acutely compromised e.g. during dehydration. CKD can be conveniently staged according to eGFR (Table II).

OTHER KIDNEY DISEASE IN PEOPLE WITH DIABETES 

Relying on albuminuria alone may be insufficient in identifying all patients with diabetes who have renal disease.⁷ In a biopsy series it was found that hypertensive or ischaemic nephropathy was as common as diabetic glomerulosclerosis in patients with type 2 diabetes with evidence of chronic kidney disease (CKD).¹⁴
Health care workers should be aware that other common diseases may be the cause of kidney disease in a patient with diabetes or that other diseases may co-exist in these patients. This is especially true in South Africa with its high burden of HIV and the potential for HIV-associated CKD.³ The most important distinguishing features between DKD and other causes of CKD are shown in Table III. Additional testing and/or referral may be necessary to determine the cause of kidney disease in patients with diabetes exhibiting any of these features.

SCREENING RECOMMENDATIONS 

Precautions

Exclude transient causes of albuminuria (e.g. recent strenuous exercise, menstruation, fever, urinary tract infection, pregnancy, uncontrolled heart failure, acute severe elevation in blood pressure or blood glucose), low eGFR (e.g. dehydration, hypovolaemia), and acute renal failure on clinical grounds before each screening and urine dipstick testing.⁷

Figure II. Screening for chronic kidney disease (CKD) in people with diabetes. ACR, albumin-to-creatinine ratio; eGFR, estimated glomerular filtration rate⁷

Indications for screening

Annual screening for DKD is indicated in all post-pubertal people with type 1 diabetes 5 years after diagnosis, and in all people with type 2 diabetes at the time of diagnosis and annually thereafter.⁷

Screening for CKD in people with diabetes should ideally be performed with the measurement of the albumin level in a first morning urine specimen and a serum creatinine measurement that is then converted into an eGFR and the result expressed as ACR8 (Figure II). When a first morning urine specimen is inconvenient, an untimed “spot” urine sample is acceptable.⁸

An abnormal screening test should be confirmed by repeat testing of the eGFR within three months, and two more urine ACR measurements performed during that interval.^7,8 If either the eGFR remains low or at least two of the three random urine ACRs are abnormal, then a diagnosis of CKD is confirmed.⁸

The exception to this approach is when the random urine ACR indicates albuminuria in the severely increased albuminuria range, as this level of proteinuria rarely resolves spontaneously, so confirmatory testing is usually unnecessary.⁷

Once a diagnosis of CKD has been made, a urine sample for dipstick and microscopy should be ordered^.7 In the absence of any significant abnormalities other than proteinuria, a presumptive diagnosis of kidney disease due to diabetes can be made. The presence of clinical or laboratory abnormalities suggesting nondiabetic kidney disease indicates the need for appropriate workup or referral.⁷

Table V. Modifications of antidiabetic drugs in patients with type 2 diabetes

Class	Drug	Dosing recommendation stages 3 and 4 CKD or kidney transplant	Dosing recommendation dialysis
Second-generation Sulfonylureas	Glipizide, gliclazide Glibenclamide Glimepiride	Preferred sulfonylurea No dose adjustment Avoid Initiate at a low dose, 1mg/day	Preferred sulfonylurea No dose adjustment Avoid Avoid
Glucosidase inhibitors	Acarbose	Not recommended if serum creatinine >180μmol/L	Avoid
Biguanides	Metformin	See text	Avoid
Meglitinides	Repaglinide Nateglinide	No dose adjustment Initiate at low dose (60mg before each meal)
Thiazolidinediones	Pioglitazone	No dose adjustment	No dose adjustment

Adapted from the Kidney Disease Outcomes Quality Initiative (KDOAI) guidelines.³

PREVENTION, TREATMENT & FOLLOW UP

Prevention

Tight blood sugar control in patients with type 1 diabetes reduces the risk of developing microvascular diabetes complications including DKD.¹⁵ Tight blood sugar control comes at the risk of hypoglycaemia and there is no firm evidence for specific blood glucose targets. There is a lack of evidence from RCTs on the effects of tight blood sugar control in older patient populations or patients with macrovascular disease. Although tight blood glucose control in patients with type 2 diabetes reduces the risk of developing albuminuria, evidence is lacking in terms of a benefit for clinically important renal endpoints.^16,17 

A recent Cochrane review concluded that angiotensin-converting enzyme inhibitors (ACEi) reduce the risk of new onset moderate and severe albuminuria with similar benefits in people with and without hypertension^.18 In this meta-analysis angiotensin receptor blocking agents (ARBs) were only of value in preventing kidney disease in high risk patients.

Treatment

Although intensive glycaemic control may slow down the progression of DKD in patients with type 2 diabetes,^19,20 lowering blood pressure is the most effective strategy in preventing end-stage renal disease in patients with established DKD.²¹Progression of DKD in patients with type 2 diabetes can be slowed down by the use of either an ACEi or an ARB.²² Since ACE inhibitors have been shown to reduce major CVD events in patients with diabetes, and since the risk of CVD is increased in patients with albuminuria, ACE inhibitors should remain firstline agents in the treatment of patients with diabetes who have established albuminuria.²³

Combination treatment with an ACEi and an ARB to prevent progression of DKD is not recommended on the grounds of increased risk of hyperkalaemia, and renal dysfunction^.24,25 A recent meta-analysis, however, showed that the most effective strategy to prevent end-stage kidney disease in patients with established DKD is by lowering blood pressure using dual treatment with an ARB and an ACEi,²⁷ while monotherapy with an ARB was also effective but less so than dual therapy.²¹Unfortunately, no blood pressure-lowering strategy prolonged survival in adults with diabetes and kidney disease.²⁶Any benefits of combined ACE inhibitor and ARB treatment need to be balanced against potential harms of hyperkalaemia and acute kidney injury.^21,26 At this stage combination therapy with an ACE inhibitor plus an ARB should not be used in patients with DKD.

Initiation of an ACEi in patients with diabetes and serum creatinine levels greater than 124 μmol/L is associated with acute increases in serum creatinine of up to 30% that stabilises within the first two months of ACEi therapy and long-term preservation of renal function²⁷ A significant increase in serum potassium and serum creatinine levels have been described in patients with bilateral renal artery stenosis within two weeks of initiation of a RAAS blocker.²⁸ 

For these reasons, the serum creatinine and potassium should be checked between one and two weeks after initiation or titration of a RAAS blocker.⁷ For patients in whom a significant change in creatinine or potassium is seen, further testing should be performed to ensure that these results have stabilised.⁷

Any degree of albuminuria increases the risk of cardiovascular events in diabetic as well as in non-diabetic individuals.²⁹Cardiovascular risk factors must be treated in all patients with CKD to address this risk. An intensified long-term intervention aimed at multiple risk factors in patients with type 2 diabetes and moderate albuminuria reduces the risk of cardiovascular and microvascular events by 50 percent.³⁰

There are no randomised controlled trials of blood pressure levels in diabetes that have examined CKD events as outcomes. Blood pressure levels below 140/90 mmHg in diabetes are recommended to reduce CVD mortality and slow CKD progression (KDIGO, 2012). In individuals with albuminuria,consider lower blood pressure targets of < 130/80 mmHg.^20,21

People with diabetes should be referred to a nephrologist or specialist physician with an expertise in CKD in the following situations:

• Chronic, progressive loss of kidney function
• ACR persistently >60 mg/mmol
• eGFR<30 mL/min
• Unable to remain on renal-protective therapies due to adverse effects such as hyperkalaemia or >30% increase in serum creatinine within 3 months of starting an ACE inhibitor or ARB
• Unable to achieve target BP (could be referred to any specialist in hypertension).

SICK DAY RULES 

If patients become ill and are unable to maintain adequate fluid intake, or have an acute decline in renal function (e.g. due to gastrointestinal upset or dehydration), they should be instructed to withhold medications which will increase the risk for decline in kidney function or have reduced clearance and increased risk of adverse effects (Table IV).⁷ Patients should be instructed that increased frequency of self-monitoring of blood glucose will be required and adjustments to their doses of insulin or oral antihyperglycaemic agents may be necessary.

Table IV. Medications that should be withheld or dose reduced during acute illness⁷

Analgesics

Angiotensin-converting enzyme inhibitors

Angiotensin receptor blockers

Direct renin inhibitors

Diuretics

Metformin

Non-steroidal anti-inflammatory agents

SGLT2-inhibitors

Sulfonylureas

MODIFICATIONS OF ANTIDIABETICS DRUGS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS³

Patients with stages 3-5 kidney disease are at increased risk of hypoglycaemia due to decreased renal clearance of insulin and sulfonylureas and also due to reduced gluconeogenesis. This has the following implications:

• In patients with type 1 diabetes, insulin needs may change with decreasing renal function, as CKD is associated with insulin resistance and there is decreased renal clearance of insulin with advancing CKD.
• Metformin should be used with caution in patients with stages 4 and 5 CKD. Its use in CKD carries a small risk of severe lactic acidosis; the risk increases with decreasing glomerular filtration rate (GFR) and the dose should be adjusted. The use of metformin should be reviewed when the patient reaches stage 3 CKD and its use is contraindicated in stages 4 and 5 CKD.
• Sulfonylureas: First-generation sulfonylureas should be avoided. Second-generation sulfonylureas may be used in patients who have learnt to avoid hypoglycaemic episodes, as long as their diabetes is controlled and nutritional status is satisfactory.
• Thiazolidinediones: These may be used in patients without heart failure. Caution is advised in patients with ischaemic heart disease.
• Insulin: When insulin therapy is used, care should be taken to avoid hypoglycaemic episodes, as the renal clearance of insulin declines with advancing renal impairment.
• DPP-4 antagonists (vildagliptin, saxagliptin) can be used with dose adjustments (sitagliptin – caution). Avoid combination drugs that also contain metformin.
• GLP-1 receptor agonists (exenatide, liraglutide): These should not be used in moderate renal function impairment (creatinine clearance <30 mL/min).

Author: Willie Mollentze

Editor: Nazeer A Mohamed

References

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