InnovAiT: The RCGP Journal for

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Diabetic Nephropathy
Rafay Iqbal and Shahzad Hussain Shah
InnovAiT 2011 4: 706
DOI: 10.1093/innovait/inr081

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 InnovAiT, Vol. 4, No. 12, pp. 706–711, 2011 doi:10.1093/innovait/inr081
 Advance access publication 7 June 2011

Diabetic nephropathy

D
iabetic nephropathy is the leading cause of renal failure in UK, accounting
for 24% of patients with end-stage renal disease (ESRD). In addition, it is a
risk factor for cardiovascular disease. Clinical trials have shown that it is
possible to alter the natural history of diabetic nephropathy by targeting multiple
risk factors. In clinical practice, this includes tight glycaemic control, aggressive
antihypertensive therapy and the use of angiotensin-converting enzyme inhibitors
(ACEIs) or angiotensin receptor blockers (ARBs). This article aims to describe
management of diabetic nephropathy in primary care and provide guidance on when
to refer to secondary care.

The GP curriculum and diabetic nephropathy

GP curriculum statement 15.6: Metabolic problems mentions type 1 and 2 diabetes mellitus as common and
important conditions within its knowledge base. It also requires GPs to:
OO Recognize that patients with metabolic problems are frequently asymptomatic or have non-specific symptoms and

that diagnosis is often made by screening or recognizing symptom complexes and arranging appropriate
investigations
OO Communicate the patient’s risk of complications from diabetes mellitus clearly and effectively in a non-biased

manner
OO Understand the systems of care for chronic disease management for patients with metabolic conditions, including

the roles of primary and secondary care, shared care arrangements, multidisciplinary teams and patient
involvement
OO Use albumin:creatinine ratio (ACR) or dipstick for detection of microalbuminuria

OO Describe the role of particular groups of medication in the management of diabetes (e.g. antiplatelet drugs, ACEIs,

ARBs and lipid-lowering therapies).

Definitions and diagnosis
Diabetic nephropathy is a clinical syndrome characterized by
OO persistent albuminuria
OO a relentless decline in glomerular filtration rate (GFR)
OO a raised arterial blood pressure (BP)
OO increased cardiovascular morbidity and mortality
Around 40% of patients with type 1 diabetes and 20% of
those with type 2 diabetes develop nephropathy. Kidney
damage in type 1 diabetes is the largest cause of renal
failure in the working age group. The fraction of patients
with type 2 diabetes developing nephropathy has grown
primarily because of a rising prevalence of diabetes, better
cardiovascular survival, better management of kidney
damage and a trend to younger onset type 2 diabetes.
Microalbuminuria is the earliest sign of diabetic nephropathy
and is defined by a urinary ACR of more than 2.5 mg/mmol
in men and more than 3.5 mg/mmol in women. Approximately
30–40% of patients with type 1 diabetes and 42% with type
2 diabetes develop persistent microalbuminuria over a 20
year period.
Urinary albumin excretion may progress from microalbu­
minuria to macroalbuminuria (proteinuria), which is defined
by an ACR of more than 30 mg/mmol. The cumulative
incidence of macroalbuminuria is 15–25% in people with
type 1 diabetes and 20% in type 2 diabetes 20 years from
diagnosis. Less than half of patients with microalbuminuria
will develop macroalbuminuria. As the urinary albumin
excretion approaches and exceeds macroalbuminuria
threshold, there tends to be a steady decline in GFR,
particularly in hypertensive people. Patients with type 2
diabetes and a normal urinary albumin excretion may still
demonstrate a declining GFR with time.
Diabetic nephropathy is a common cause of chronic kidney
disease (CKD) in general practice. Estimated GFR (eGFR) is
recommended to classify patients with diabetes into stages
of CKD as given in Table 1.

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 InnovAiT

Table 1. Stratification of CKD

Stage Description GFR (ml/minute/1.73 m2)

1 Kidney damage with normal or raised GFR 90 or more

2 Kidney damage with mild decrease in GFR 60–89

3A Moderately lowered GFR 45–59

3B 30–44

4 Severely lowered GFR 15–29

5 Kidney failure (ESRD) less than 15

To diagnose stages 1 and 2 CKD, an additional evidence of kidney damage must be present, e.g. proteinuria.
Reproduced from Scottish Intercollegiate Guidelines Network (SIGN). Management of diabetes (2010) with permission.

Diabetic nephropathy is a clinical diagnosis and is established

Box 1.  Features suggesting non-diabetic kidney
on the basis of persistent albuminuria in a diabetic patient
disease
with no evidence of non-diabetic kidney disease. Presence
of diabetic retinopathy may be helpful in making a diagnosis OO BP is particularly high or resistant to treatment
of diabetic nephropathy as the two coexist in 90% of OO Heavy proteinuria (ACR more than 70 mg/mmol)
patients with type 1 diabetes and in 70% of patients with with previously normal ACR
type 2 diabetes. Nephropathy, in the presence of retinopathy, OO Significant haematuria
is almost certain to be due to diabetes. In the absence of OO GFR has worsened rapidly
retinopathy, a definite diagnosis of diabetic nephropathy OO Person is systemically ill
can be established only on the basis of kidney biopsy.

In general practice, it is important to remember that

proteinuria and declining GFR in people with diabetes can
develop due to other causes. Up to 30% of people with renal
impairment and type 2 diabetes do not have diabetic
nephropathy but have another cause for their renal failure
such as hypertensive nephropathy or renovascular disease. In
many individuals, kidney disease will be due to a combination
of one or more of these factors. Non-diabetic kidney disease
should be suspected in individuals with features listed in Box 1.
Screening
Annual screening for diabetic nephropathy is recommended,
starting at age 12 years for those with type 1 diabetes and from
diagnosis for those with type 2 diabetes. The current Quality
and Outcomes Framework (QOF) rewards practices for
recording microalbuminuria and serum creatinine or eGFR in
patients with diabetes (Table 2). Screening involves checking
albumin excretion along with serum creatinine and eGFR.
Albumin excretion can be checked in a variety of ways but
the most usual approach is using ACR. Albumin excretion is
increased following exercise and with upright posture. A
spot sample can be used, but if the result is abnormal, the
test should be repeated on a first-pass morning sample
(timing will differ for people who work night shifts). Factors
such as concurrent illness may temporarily increase urinary
albumin loss. In addition, there is marked day-to-day
variability in albumin excretion. Therefore, microalbuminuria
is confirmed only if two of three tests are positive within a
3–4 month period.

Table 2. QOF targets relevant to diabetic nephropathy

Indicator Description Points Payment stages (%)

DM 13 The percentage of patients with diabetes who have a record of 3 40–90

microalbuminuria testing in the preceding 15 months (exception
reporting for patients with proteinuria)

DM 22 The percentage of patients with diabetes who have a record of 3 40–90

eGFR or serum creatinine testing in the preceding 15 months

DM 15 The percentage of patients with diabetes with a diagnosis of 3 40–80

proteinuria or microalbuminuria who are treated with ACE
inhibitors (or A2 antagonists)

DM, diabetes mellitus.

Source: BMA/NHS Employers. Quality and Outcomes Framework guidance for GMS contract 2011/12.

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 If the first test for ACR is positive (in the absence of
proteinuria or urinary tract infection), the test should be
repeated in about 4 weeks. If the second test is positive,
diabetic nephropathy is diagnosed and this diagnosis should
be entered onto the practice computer system. If the second
test is negative, the test should be repeated again in about
4 weeks. If this third test is positive, a diagnosis of diabetic
nephropathy can be made. After one positive and two
negative tests, diabetic nephropathy cannot be diagnosed
and ACR should be repeated in 12 months.
Conventional urine dipstick testing cannot reliably be used
to diagnose the presence or absence of microalbuminuria.
ACR is preferred over measuring the protein:creatinine ratio
(PCR) to screen for diabetic nephropathy as ACR has a
greater sensitivity than PCR for low levels of proteinuria.
However, in people with established disease, specialists may
subsequently use PCR instead of ACR to quantify and
monitor significant levels of proteinuria.
Prevention of diabetic
nephropathy
Diabetic nephropathy predicts end-stage renal failure,
cardiovascular morbidity and mortality and total mortality.
Preventing or delaying the development of microalbuminuria
is a key treatment goal for renal protection and possibly for
cardioprotection. Risk factors for the development and
progression of diabetic nephropathy have been identified,
many of which are modifiable (Box 2). Management should
focus on controlling these modifiable risk factors.
Box 2.  Risk factors for development and
progression of diabetic kidney disease
OO Hyperglycaemia
OO Raised BP
OO Baseline urinary albumin excretion
OO Increasing age
OO Duration of diabetes
OO Smoking
OO Genetic predisposition
OO Raised cholesterol and triglyceride levels
OO Male gender
Glycaemic control
Sustained poor glycaemic control is associated with a greater
risk for the development of nephropathy in both type 1 and
type 2 diabetes. Intensive glycaemic control should be
maintained to reduce this risk. Both the Diabetes Control
and Complications Trial (DCCT) in patients with type 1
diabetes (DCCT Research Group, 1993) and the United
Kingdom Prospective Diabetes Study (UKPDS) in patients
with type 2 diabetes (UKPDS Group, 1998) demonstrated
a significant reduction in the number of individuals
with diabetes developing microalbuminuria with intensive
blood glucose control as compared to more conventional
treatment.
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BP control
In diabetic patients, hypertension is an independent risk
factor for the development of diabetic nephropathy.
Reduction of BP has been clearly shown to be an
important and powerful intervention in protecting renal
function.
Non-pharmacological measures to reduce BP, such as salt
restriction and weight loss, are important. Prescribing an
ACEI is the first-line pharmacological treatment for
hypertension in people with diabetes. ACEIs have been
found to be effective for the primary prevention of diabetic
nephropathy independently of their effect on systemic BP.
An ACEI should be substituted with an ARB if poorly
tolerated due to cough or angioedema. BP should be
maintained below 130/80 mmHg.
Treatment of diabetic
nephropathy
Glycaemic control
Although strict glycaemic control should be maintained as
an overall goal in the management of diabetes, the evidence
for benefits of this on the progression of diabetic
nephropathy following the development of microalbuminuria
is limited. There is no conclusive data to suggest that
intensive glycaemic control slows down the rate of progression
of renal disease once microalbuminuria has occurred or
when GFR has worsened. This may indicate that the
maximum benefit from intensive glycaemic control occurs
when treatment is initiated at an earlier stage of the disease
process. However, in patients with type 1 diabetes and
diabetic nephropathy, pancreatic transplantation has
demonstrated histological improvements after 10 years of
complete glycaemic normalization. Such cases suggest that
glomerulopathy is potentially reversible and may take as
long to reverse as it does to develop.
Control of proteinuria and BP
Reducing proteinuria and control of BP are associated with a
reduced rate of CKD progression. Starting an ACEI, ARB or a
non-dihydropyridine calcium channel blocker (CCB) are the
main interventions available.
Kidneys of people with diabetes seem to be more sensitive
to the effects of high BP as hyperglycaemia may cause
loss of the physiological autoregulation that normally
protects the glomerular microcirculation from changes in
systemic BP. Hence, reducing systemic BP is crucial
to ameliorate glomerular hypertension and prevent
glomerular damage. Glomerular hypertension is also
reduced by ACEIs or ARBs. By suppressing the renin-
angiotensin system (RAS), these drugs preferentially
dilate the efferent renal arterioles, reducing intraglomerular
hypertension and reducing proteinuria independently of
their systemic BP effects. There is no lower target limit for
treatment of proteinuria. The greater the reduction from
baseline urinary protein excretion achieved, the greater
the benefit will be.

In addition to the renoprotective benefits of ACEIs and
ARBs, these drugs also confer cardioprotective benefits. The
advantages appear to be class effects so choice of agent
depends on cost and compliance issues.
Using ACEIs and ARBs
Once diabetic nephropathy is confirmed, an ACEI should be
started regardless of baseline BP levels and titrated to the full or
maximum tolerated dose. In cases of intolerance to ACEI (other
than renal deterioration or hyperkalaemia), an ARB should be
substituted. Although some specialists may combine an ACEI
and an ARB, there is insufficient evidence to support this
strategy in people with diabetic nephropathy and it is not
recommended in primary care. Up to three QOF points are
currently available for practices that ensure that people with
diabetic nephropathy are treated with an ACEI or ARB (Table 2).
In a woman of child bearing age, relative risks and benefits
of treatment with ACEI or ARB should be discussed to help
make an informed choice before initiating drug treatment.
Both of these drug groups may have adverse effects on the
developing foetus.
Testing for eGFR and serum potassium is imperative before
initiating treatment. An ACEI or ARB should not be started if
serum potassium is significantly above the normal reference
range. Renal function tests should be repeated 1–2 weeks
after starting treatment and subsequent to each dose increase.
The ACEI or ARB should be discontinued if serum potassium
rises above 6.0 mmol/l (after other drugs known to promote
hyperkalaemia have been withdrawn). If eGFR decreases by
25% or more, or plasma creatinine increases by 30% or more,
following the introduction or dose increase of an ACEI or ARB,
other causes of deterioration in renal function merit
investigation, e.g. volume depletion or non-steroidal anti-
inflammatory drugs (NSAIDs). If no other cause is found, the
ACEI or ARB should either be stopped or the dose reduced to
a previously tolerated lower dose. Alternative antihypertensive
medication can be added if required.
Other interventions
Both dyslipidaemia and smoking are risk factors not only for
diabetic nephropathy but also for cardiovascular disease.
Dyslipidaemia may contribute to the development and
progression of diabetic nephropathy by causing intrarenal
arteriosclerosis or direct toxicity to renal cells. However,
studies looking at the effect of lipid lowering on the
development and progression of diabetic nephropathy are
conflicting. Similarly, there is lack of evidence to suggest
benefit of weight reduction or exercise on the progression of
diabetic nephropathy. Nevertheless, these risk factors
should be addressed as part of more general cardiovascular
disease risk reduction.
Dietary protein restriction
Dietary protein restriction may retard progression of diabetic
nephropathy by reducing intraglomerular pressure. However,
this is not recommended in the early stages of kidney
disease, not least because of the potential detrimental effect
on nutritional status. However, in CKD stage 4, protein
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InnovAiT
intake should be restricted to no more than 1.0 g/kg
especially when hyperphosphataemia is present. This is
because foods that contain protein also tend to contain
phosphate. Dietary protein restriction should be done under
the guidance of an appropriately qualified dietician.
Multiple risk factor approach
Simultaneous targeting of multiple risk factors for diabetic
nephropathy has proved to be a successful management
strategy. The Steno 2 study in individuals with type 2
diabetes and microalbuminuria demonstrated that
combination of improved glycaemic control, BP control, lipid
lowering, aspirin, smoking cessation, exercise programmes
and dietary intervention had sustained benefits in reducing
development of proteinuria, vascular complications and all-
cause mortality (Gæde et al., 2008).
Monitoring
Once diabetic nephropathy is confirmed, ACR, serum
creatinine and eGFR should be monitored at least once a year
to assess response to treatment and progression of the
disease. More frequent assessment of eGFR may be necessary
in adults with established CKD, usually 6 monthly in stage 3
CKD, 3 monthly in stage 4 CKD and 6 weekly in stage 5 CKD.
Anaemia is a common finding in people with diabetic
nephropathy and develops at an earlier stage compared to
patients with CKD from other causes. Patients with diabetes
and CKD stages 3–5 should have their haemoglobin checked
at least annually.
Hypoglycaemic medication
and kidney disease
Hypoglycaemic medication must be reviewed as renal function
deteriorates. Table 3 lists hypoglycaemic agents that should
be used with care in patients with renal impairment.
Referral
Investigation, monitoring and management of diabetic
patients with mild to moderate kidney disease can be
undertaken in a variety of settings, provided that appropriate
expertise is available, there is a clear evidence-based
protocol and facilities for intensive monitoring are available.
NICE (2008a) guidance on the management of CKD
recommends the consideration of referral for a specialist
renal opinion when the ACR is more than 70 mg/mmol
unless already appropriately treated. Additionally, all
individuals with CKD stages 4 and 5 should usually be
referred to a specialist.
Patient education
Patient education and involvement are priorities. Besides
providing comprehensive and continuing education about
709
 Table 3. Cautions with hypoglycaemic medication in patients with renal impairment

Drug Caution in renal impairment (eGFR expressed in ml/minute/1.73 m2)

Metformin Review dose if eGFR is less than 45. Avoid if eGFR is less than 30

Sulfonylurea Use with care in mild to moderate renal impairment: risk of hypoglycaemia. Avoid where
possible in severe renal impairment

Acarbose Avoid if eGFR is less than 25

Meglitinides Repaglinide: use with caution in renal impairment

Thiazolidinedione No caution in renal impairment is mentioned in the current BNF, but due to the potential of
this drug to cause fluid retention, it should be used with caution in patients with oedema and in
severe renal insufficiency

Gliptins Avoid if eGFR less than 50

Exenatide Use with caution if eGFR is 30–50. Avoid if eGFR is less than 30

Liraglutide Avoid if eGFR is less than 60

Insulin Insulin requirements may fall in renal impairment; dose reduction may be necessary. In patients
with ESRD, there is some suggestion that long-acting insulin preparations should be avoided

diabetes, patients should be specifically educated about the

possibility of developing kidney disease as a complication of
diabetes. Special mention should be made of the need for
annual blood and urine testing. The role of lifestyle
modification and the role of medications for the treatment
of diabetic nephropathy should be emphasized. The
significance of medication concordance should be
highlighted along with education about potential side
effects. Every effort should be made to empower patients
with the appropriate knowledge and skills to tackle diabetic
nephropathy. Useful information for patients about diabetic
nephropathy is available from the Patient UK website
(www.patient.co.uk) and also Diabetes UK (www.diabetes
.org.uk).
Key points
OO Diabetic nephropathy is a complication of diabetes
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GP, Birchwood Medical Practice, North Walsham, Norfolk
E-mail: rafayiqbal@hotmail.com
Dr Shahzad Hussain Shah
Registrar in renal medicine, Norfolk and Norwich University Hospital
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