OCCASIONAL REVIEW

Diabetic nephropathy: whichteenagers are at risk andhow can risk be minimisedDavid V Milford

AbstractMicroalbuminuria is the first marker of renal damage in T1DM but does

not invariably progress to diabetic nephropathy and may be reversed in

some patients. An annual measurement of albumin to creatinine ratio

in an early morning urine sample is recommended, with serial daily

samples used to confirm increased excretion and early institution of

ACEi and/or AIIrb to treat persistent microalbuminuria. Good glycaemic

control from diagnosis is essential for good long term renal function.

Aggressive treatment of hypertension reduces the rate of renal decline

once diabetic nephropathy is established.

Keywords ACEi; AIIrb; diabetic nephropathy; hyperglycaemia; hyper-

tension; microalbuminuria

Introduction

The incidence of diabetic nephropathy (DN) in childhood is very

low. The Department of Nephrology at Birmingham Children’s

Hospital serves a population of approximately 6 million and is the

referral centre for 20 regional paediatric services. A review of 880

native (ie not renal transplant) kidney biopsies undertaken over

a 14-year period identified 9 biopsies undertaken in children with

type 1 diabetes mellitus (T1DM). Three biopsies were undertaken

for non-diabetic diagnoses (steroid responsive nephrotic

syndrome or persistent microscopic haematuria); one was

undertaken in a child with a diagnosis of Wolcott-Rallison

syndrome (a rare autosomal recessive condition characterized by

onset of diabetes mellitus in infancy and multiple epiphyseal

dysplasia) with proteinuria; the remaining five (0.6% of all biop-

sies) were in children with T1DM and proteinuria and who were

subsequently shown to have DN. Although overt DN is evidently

rare in childhood, low-grade proteinuria (microalbuminuria)

usually precedes its development and studies have found the

incidence to be greater than for DN. The Diabetic Unit at Bir-

mingham Children’s Hospital presently cares for 311 children with

T1DM and of these 23 (7.4%) have been noted to have elevated

urinary albumin excretion (personal communication). It is

consequently evident that for paediatric diabetic units micro-

albuminuria (MA) and DN are likely to be rare in childhood T1DM

affording an opportunity to develop and instigate strategies aimed

at preventing its development in adulthood. The purpose of this

article is to consider risk factors for the development of DN and to

identify therapeutic approaches to minimise this risk.

David V Milford BMDMFRCPFRCPCH is a Doctor in Department of Nephrology,

BirminghamChildren’s Hospital, Steelhouse Lane, BirminghamB46NH, UK.

PAEDIATRICS AND CHILD HEALTH 19:12 565

Microalbuminuria

Although albumin is normally almost totally excluded from the

glomerular ultrafiltrate a small amount does cross the glomerular

basement membrane. This filtered albumin is virtually totally

reabsorbed by endocytosis in proximal tubular cells but the

mechanism is easily saturated. Conventional dipsticks for urinal-

ysis detect protein when tetrabromophenol in the reagent pad

undergoes a colour change that is approximately proportional to

the protein concentration and although they are very sensitive are

unable to detect physiological levels of proteinura. Albumin is

more readily detected than other urinary proteins but in MA the

level of urinary albumin is too low to be detected by dipsticks and

requires sensitive radio-immunoassay methods. The definition of

MA differs between studies, but is generally accepted (including in

the National Standard Framework for Diabetes) as an albumin

excretion rate of 30e300 mg/day (20e200 mg/min) in adults and

these values are below the level of detection by dipsticks.

The gold standard for the measurement of urinary protein

excretion remains a 24 hour urine collection but this is notori-

ously unreliable in children because of inaccuracies as a conse-

quence of poor compliance with the methodology. Although

timed urine collections have been shown to correlate well with

24 hour urine collections these are also difficult to conduct

accurately and are increasingly difficult with reducing age.

Consequently, it is now common practice to measure the

albumin to creatinine ratio (Ua/Uc) in a first voided urine sample

because this has been shown to correlate well with albumin

excretion measured in a timed urine sample. There is some

difference of opinion regarding the Ua/Uc that defines the onset

of MA but studies in the normal population identified �2.5 mg/

mmol in a first voided sample for males and �3.5 mg/mmol in

females as the upper limit of normal. The Oxford Regional

Prospective Study defined MA in children with T1DM as Ua/Uc

3.5e35 mg/mmol in males, 4.0e47 mg/mmol in females and for

these values to be documented in two out of three consecutive

first voided urine samples. This same study also distinguished

between transient (seen in one year only) and persistent MA

(noted for at least two consecutive years).

Urinary protein excretion is altered by a number of factors

including age, sex, time of collection, exercise and state of health.

This variability has led to debate regarding the utility of Ua/Uc as

a screening test for MA. Ensuring only first voided urine samples

are collected and that urine sampling is undertaken when the child

is completely well increases the accuracy of the methodology.

Collection of urine samples on three consecutive mornings allows

the range of variability to be documented and, if necessary, raised

albumin excretion can be confirmed by a timed urine collection.

The incidence of MA has been reported to vary between 7%

and 20%; in the Microalbuminuria in Diabetic Adolescents and

Children cross sectional study of 1007 T1DM patients 9.7% had

Ua/Uc �2.0 mg/mmol in two out of three first voided urine

samples; in the Oxford Regional Prospective Study of 308 T1DM

patients 243 (78.8%) remained without MA throughout the study

using the definition above. This group has continued to study

patients enrolled and recently reported that in 527 participants

the cumulative incidence of MA was 25.7% (95% CI

21.3e30.1%) after 10 years of diabetes and 50.7% (95% CI

40.5e60.9%) after 19 years.

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OCCASIONAL REVIEW

Risk factors for development of microalbuminuria

0.6

>10 years

5–10 years

< 5 years

Log rank P = 0.1

Age at diagnosis of diabetes

0.4

0.2

0

0 5 10 15 20

Cu

mu

lati

ve p

reva

len

ce

Duration of type 1 diabetes

0.1

0.5

0.3

Figure 1 Survival curve showing cumulative prevalence of development of

MA in 527 children in relation to age at diagnosis of T1DM.

The Diabetes Control and Complications Trial was established in

the mid 1980’s and studied both adult and paediatric patients. A

cohort of 195 adolescent patients aged 13e17 years was enrolled.

The primary prevention cohort consisted of 125 patients who had

been diagnosed with T1DM for 1e5 years, who had no retino-

pathy and who had albumin excretion rates less than 28 mg/min.

This group was subdivided into 55 patients who received inten-

sive attention to maintain strict glycaemic control while the

remaining 70 continued with conventional treatment. The

secondary intervention cohort of seventy patients had been

diagnosed for 1e15 years, they had mild to moderate non-

proliferative retinopathy and had albumin excretion rates up

to 139 mg/min. This group was subdivided into 37 patients

who received intensive attention to glycaemic control and 33

who received conventional treatment.

Patients were followed for a mean of 7.4 years (range 4e9

years) and for a total of 1448 patient years. The number of episodes

of albuminuria exceeding 40 mg/24 hours/100 patient years was

least (5.8) in the intensively managed patients in the primary

prevention cohort. Patients in the intensive management group of

the secondary intervention cohort had statistically significantly

fewer episodes of albuminuria (6.6) than the conventionally

managed patients (12.7) in the cohort. This study clearly showed

that good glycaemic control reduced the risk of developing MA.

Studies of other patient groups have consistently shown that

patients with MA tend to have higher mean HbA1c values than

those who remain normoalbuminuric. Other risk factors include

female sex, duration of diabetes and increased blood pressure,

although other studies have not found blood pressure to be a risk

factor. Some studies have found no difference in the time to

development of MA for prepubertal or pubertal children, although,

in contrast, the Microalbuminuria In Diabetic Adolescents and

Children study found significantly more pubertal and postpubertal

patients had MA. The recent study reported by Amin et al exam-

ined the relationship between the onset of MA and age at diagnosis

of diabetes and found that although the cumulative prevalence at

the end of follow up was unaffected by age at diagnosis, in those

diagnosed before 5 years of age there was a longer interval to the

first appearance of MA (Figure 1).

Accurate information about the development of MA was

obtained by the Oxford Regional Prospective Study Group who

collected detailed annual information on 511 patients recruited

between 1986 and 1995. Seventy eight of this group developed

MA but of these 15 were noted to have MA at their first assess-

ment. The baseline albumin to creatinine ratio was measured at

1e2.5 years from diagnosis and the rate of increase in albumin

excretion prior to the development of MA was noted in the

remaining 63 children. These results were compared to

the findings in 396 persistently normoalbuminuric children. The

authors noted the baseline albumin to creatinine ratio was

significantly higher (but in the normoalbuminuric range) in the

children who went on to develop MA and that the rate of increase

in albumin excretion was also higher in this group. They felt their

findings indicated that in children with normoalbuminuria higher

levels of albumin to creatinine within the first 2 years from

diagnosis and a higher rate of increase in albumin excretion

within 5 years of diagnosis identified patients who later devel-

oped MA and that serial measurements of urinary albumin could

PAEDIATRICS AND CHILD HEALTH 19:12 566

consequently provide valuable prognostic information to inform

the use of interventions such as angiotensin converting enzyme

inhibitors (ACEi) in those with normal urinary albumin excretion.

The same group showed that a glomerular filtration rate

(GFR) >125 mls/min/1.73 m was predictive of later development

of MA and that patients who did not have hyperfiltration were

less likely to have MA.

Diabetic nephropathy

At a macroscopic level the kidneys show changes soon after the

development of diabetes. Renal enlargement has been noted in

newly diagnosed patients and is seen in experimental animals

within four days of the onset of diabetes. This enlargement is

secondary to tubular hypertrophy and expansion of the inter-

stitium and is thought to occur as a result of increased glomerular

filtration and increased tubular reabsorption.

Light microscopic findings

Glomerular enlargement occurs early in the course of diabetes as

a result of capillary lengthening and dilatation; although this

finding is noted in patients with established nephropathy the

presence of glomerular enlargement does not imply the patient

has developed DN. The hallmark of diabetic glomerulopathy is

diffuse mesangial expansion, associated with nodule formation

in a minority of patients. Most patients with long-standing dia-

betes show dense material in the central part of the glomerular

tuft but this may later expand and progressively obliterate the

glomerular capillaries leading to global glomerulosclerosis.

Glomerular nodules are pathognomonic for diabetes and were

first described by Kimmelstiel and Wilson. They are acellular,

eosinophilic, and lamellated structures, usually located at the

periphery of the tuft. Their pathogenesis is unclear, but it is

thought they may occur because of localized mesangial cell

damage with overlying endothelial cell detachment and subse-

quent sub-endothelial matrix deposition. Excess matrix deposi-

tion also disrupts the microfibrillar structure of the mesangium,

altering its porosity to proteins and further weakening

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OCCASIONAL REVIEW

attachments to the endothelium and glomerular basement

membrane (GBM), perhaps predisposing to nodule formation.

Afferent and efferent arteriolar hyalinosis are more commonly

seen in patients with microalbuminuria and these lesions become

more prominent as proteinuria increases.

Electron microscopy

The glomerulus is normal at the onset of T1DM but thickening of

the GBM up to three times the normal range is an almost

universal feature in patients with diabetes for more than 10

years. This thickening is more marked in patients with micro-

albuminuria and clinical nephropathy and occurs because of an

accumulation of type IV collagen. There is an associated reduc-

tion in other components of the GBM resulting in disruption of

both the ultrastructure and the electrostatic charge properties

leading to abnormal permselectivity and leakage of circulating

proteins. In advanced nephropathy segments of the GBM may

become thinned and irregular resulting in microscopic haema-

turia, presumably by a similar mechanism to that seen in thin

basement membrane nephropathy.

Pathophysiology of diabetic nephropathy

Microvascular disease is the hallmark of DN. The proposed

mechanisms for the leision includes the generation of advanced

glycation end products (AGE), the accumulation of sorbitol,

activation of intracellular pathways such as protein kinase C and

activation of the hexosamine pathway. More recently, the

generation of reactive oxygen species as a result of increased

mitochondrial oxidation in response to hyperglycaemia has been

proposed as a mechanism leading to various localized metabolic

abnormalities (including the generation of AGE) that culminate

in tissue damage. Important secondary mediators in the devel-

opment of renal damage include transforming growth factor b,

angiotensin II, endothelin and several inflammatory cytokines.

The rise in GFR early in the clinical course of T1DM has been

noted for many years and more recently has also been described

in T2DM. Animal studies have shown this occurs as a result of

afferent arteriolar vasodilatation and a degree of efferent arteri-

olar vasoconstriction. The resulting glomerular hypertension,

together with increased GBM permeability to proteins, leads to

albuminuria that exceeds the reabsorptive capacity of tubular

cells. In the early stages this proteinuria may be regarded as

a marker of glomerular capillary damage, but as it becomes

persistent and more marked it may contribute to renal damage

because proximal tubular epithelial cells acquire an inflamma-

tory phenotype and increase expression of angoitensinogen,

Stages of diabetic nephropathy

Stage GFR Albuminuria

Renal hyperfiltration Elevated Absent

Clinical latency High normal Absent

Microalbuminuria Within normal range 20e200 mg/min (30e300 m

Overt nephropathy Decreasing >200 mg/min (>300 mg/da

Renal failure Diminished Massive

Table 1

PAEDIATRICS AND CHILD HEALTH 19:12 567

endothelin and inflammatory cytokines when exposed to exces-

sively high protein levels in tubular fluid. These proximal tubular

cell products are secreted into the interstitium leading to acti-

vation of peritubular fibroblasts and interstitial fibrosis. The

localized generation of angiotensinogen leads to increased

angiotensin II, promoting efferent arteriolar vasoconstriction and

perpetuating hyperfiltration. Blockade of the renin-angiotensin

system is consequently particularly effective in reducing hyper-

filtration and improving renal plasma flow.

Stages of diabetic nephropathy

Once established, the clinical course of DN is invariably

progressive and predictable. Following the early stage of hyper-

filtration and increased GFR there is usually a time of clinical

latency which may last up to 20 years, with subsequent devel-

opment of persistent MA, and later DN, with decline in renal

function (Table 1). The important role of hyperglycaemia can be

deduced from transplantation of normal kidneys into diabetic

recipients who subsequently develop glomerulosclerosis. Further-

more, restoration of normal glucose control by isolated pancreas

transplants in patients with T1DM and nephropathy have been

shown to lead to regression of diabetic glomerulosclerosis.

Relationship between microalbuminuria and diabetic

nephropathy

Initial retrospective studies in adults reported patients with MA

had an approximately 80% risk of progressing to DN over the

subsequent 6e14 years and there has consequently been broad

agreement that MA is predictive of increased risk of DN. Recent

studies suggest the risk of progression from MA to overt

proteinuria over a 10 year period is less than previously noted

and is about 30e45%; additionally, some patients with MA

revert to normoalbuminuria. However, although it is becoming

increasingly evident that MA is a less reliable predictor of DN

than was originally suggested, it is nonetheless an important

prognostic marker and one that has the advantage of being

a simple, non-invasive investigation, that can be undertaken at

regular intervals to identify trends.

The first paediatric UK report questioning the inevitable

progression from MA to overt nephropathy was published in

1995. Nine children identified as having MA were re-examined

three years later. In five urinary albumin excretion was noted to

be normal and in three of the remaining four the level of MA had

diminished. In a later study of 233 children with T1DM with

a maximum duration of follow up of 10 years, a progressive

increase in the cumulative incidence of MA was noted with time

Blood pressure Time interval (yrs)

Normal At diagnosis

g/day) Rising within or above normal range 5e15

y) Increased 10e15

Increased 15e30

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OCCASIONAL REVIEW

and was persistent in a total of 34 children. The albumin excre-

tion increased over the duration of the study in 10 of the 34

children but remained stable in the remainder. Seven children

had episodes of overt nephropathy (Ua/Uc >45.5 mg/mmol) but

in only one child was this persistent.

A large study of newly diagnosed T1DM adult and adolescent

patients followed for a median of 18 years (range 1e21.5 years)

with a total of 4706 patient years reported 79 patients (33.6%,

95% CI 27.2e40%) developed MA for a minimum of two

consecutive years. Of these, 27 (14.6%, 95% CI 8.9e20.3%)

progressed to overt nephropathy. It is notable that, of the 79

with MA, continued follow up identified 15 who transiently

returned to normoalbuminuria and 13 who subsequently

remained normoalbuminuric. However, none of those noted to

have developed overt nephropathy regressed to MA or

normoalbuminuria.

A recent publication from the Oxford Regional Prospective

Study of T1DM in children specifically examined the develop-

ment of proteinuria and identified four patterns of proteinuria:

patients with MA for two successive years or more were defined

as having persistent proteinuria; patients noted to have MA in

alternate years were defined as having intermittent MA; patients

noted to have MA but who subsequently had regression to nor-

moalbuminuria were defined as having transient MA; and

patients with Ua/Uc >35 mg/mmol in males and >47 mg/mmol

in females were defined as having overt nephropathy. The

cumulative prevalence of MA was 25.7% (95% CI 21.3e30.1%)

after 10 years of diabetes and 50.7% (95% CI 40.5e60.9%) after

19 years. Of the 135 patients with MA at any time, 65 (48%)

developed persistent MA, 17 (13%) had intermittent MA and 53

(39%) had transient proteinuria, giving a cumulative prevalence

of regression to normoalbuminuria of 52% (95% CI 42.3e

61.5%) 4.9 years after the development of MA. Of those with

MA, 18 (13%) progressed to overt nephropathy a mean of 3.2

years after developing MA.

These studies demonstrate that the relationship between MA

and overt nephropathy is a complex one and that the clinical

course is not by any means one way, with a significant number of

patients showing normalisation of albumin excretion. The

mechanisms underlying this resolution are imperfectly under-

stood, in part because of the ethical difficulty in obtaining serial

renal histological samples to correlate urinary findings with

pathological changes. These studies do, however, confirm that

the development of overt nephropathy is more likely once MA

has developed and that it is unlikely to be reversible although the

rate of decline to end stage renal failure may not be as great as

reported in earlier studies.

Predictors of diabetic nephropathy

Diabetic nephropathy developing in patients with type 1 or type 2

diabetes mellitus is presently the single most common diagnosis

in adult patients coming to dialysis or transplantation. However,

not all patients with diabetes mellitus develop DN. These two

observations, taken together with the finding that progression

once DN has developed is relentless, has led to great interest in

the identification of risk factors that might be predictive for the

development of DN and that might also lead to strategies to

minimise or prevent this progression.

PAEDIATRICS AND CHILD HEALTH 19:12 568

Glycaemic control

All studies have shown the level of glycaemic control ispredictiveof

the development of MA and DN (a modifiable risk factor). Although

some studies have identified a threshold value for HbA1c above

which risk is significantly increased (>8%) others have shown

there is no threshold value below which MA does not develop.

Furthermore, both glycaemic control soon after diagnosis and more

recent control predict the risk of MA, and early intensive treatment

to achieve near normal glycaemia has long term beneficial effects

on delaying progression. It is becoming increasingly evident that

both early and more recent glycaemic control are equally impor-

tant, indicating that good glycaemic control should be achieved

from the onset of diabetes to minimise the risk of developing MA

and DN. There is good evidence this is not being achieved in the

United Kingdom, particularly in the adolescent age range.

Microalbuminuria

Both persistent and intermittent MA are important predictors of

the later development of DN. However, a significant number of

patients with MA become normoalbuminuric and do not progress

to DN. In general, patients with persistently high urinary albumin

excretion are more likely to progress to overt nephropathy while

those with intermittent and low level MA are more likely to

revert to normoalbuminuria with a low risk for the development

of nephropathy.

Modifiable risk factors

Glycaemic control is the most important of the modifiable risk

factors for the development of MA in a patient with normal

urinary albumin excretion. However, once overt DN is estab-

lished hypertension and proteinuria are the most important

drivers of progression and glycaemic control has a lesser influ-

ence on the rate of progression. Other potentially modifiable risk

factors include smoking, dyslipidaemia and obesity.

The role of hypertension in the development of microvascular

complications in both T1DM and T2DM has been long established

in adult studies. Ambulatory blood pressure studies in diabetic

adolescents have also consistently shown slight elevation in day

and night blood pressure and blunting of the nocturnal dip. These

changes may develop soon after the onset of diabetes and correlate

with urinary albumin excretion. However, the long interval

between the onset of diabetes and the development of DN has

prevented a close study of the relationship between childhood

blood pressure control and later DN as even large studies such as

the Oxford Regional Prospective Study are hampered by small

numbers of patients developing overt nephropathy.

Non-modifiable risk factors

Diabetic nephropathy is seen more commonly in some ethnic

groups (eg Indo-Asians, Africans, Hispanics, Aboriginal Austra-

lians, New Zealand Maoris) and has also been noted to demon-

strate familial clustering with a significantly increased risk of DN

conferred by a first degree relative with nephropathy. These

observations have led a number of groups to seek genes that may

code for DN (Table 2).

Minimisation of risk

The measurement of Ua/Uc in an early morning sample should

be undertaken annually from diagnosis because it is now widely

� 2009 Elsevier Ltd. All rights reserved.

Non-modifiable risk factors reported to be associatedwith development of microalbuminuria or diabeticnephropathy

Increased sodium-lithium counter transport

Angiotensin converting enzyme polymorphisms

Increased soluble CD40 ligand

Angiotensinogen M235T polymorphism

Increased connective tissue growth factor N fragment

Hepatic nuclear factor 4a and calcium channel TRPC1 dysregulation

Haptoglobin 2 DNA polymorphism

Single locus on 3q in Finnish population

Paraoxonase gene polymorphism (7q21e22)

Defective intracellular antioxidant enzyme production

Increased vascular endothelial growth factor

Table 2

Practice points

C Good glycaemic control from disease onset reduces the risk of

later nephropathy

C Annual measurement of urinary albumin excretion can

conveniently be undertaken in a first voided urine sample by

measuring the albumin to creatinine ratio

C Confirmation of persistent (more than 2 years) micro-

albuminuria warrants institution of treatment with ACEi and/or

AIIrb

C Excellent blood pressure control is important once diabetic

nephropathy is diagnosed

C Renal biopsy may provide useful prognostic information in

patients with overt nephropathy

OCCASIONAL REVIEW

accepted that a multifactorial strategy beginning from diagnosis

is required to minimise the risk of developing MA and progres-

sion to overt nephropathy. Although good glycaemic control is

undoubtedly essential, dietary advice, smoking cessation, dysli-

pidaemia control, avoidance of obesity and maintenance of

excellent blood pressure control are also valuable early treatment

goals. The strict maintenance of normal blood pressure is

thought to be especially valuable because the glomerular

hyperfiltration noted soon after diagnosis is thought to reflect

intra renal vasodilatation in response to hyperglycaemia with

consequent loss of glomerular arteriolar autoregulation.

However, the reduction of systemic blood pressure has been

shown to be only partially effective as concomitant reduction of

persistent proteinuria is also required to prevent development of

nephropathy. The use of ACEi or angiotensin II receptor blockers

(AIIrb) either individually or in combination, through their

vasodilatory action on the glomerular efferent arterioles, has

been shown to be beneficial not only by lowering systemic blood

pressure but also by reducing glomerular hypertension. This

action helps preserve the integrity of the filtration barrier and

reduces proteinuria. Although a number of studies in adults have

confirmed the benefit of these therapies similar studies have not

been undertaken in the paediatric diabetic population.

Studies showing that patients with high-normal urinary

albumin excretion may be at a greater risk of progressing to MA

and thereafter to overt nephropathy have led to the suggestion

that they may benefit from the institution of ACEi before the

onset of MA, but this proposal has not yet been tested by

controlled trial.

The assessment of renal damage is best undertaken by renal

biopsy but it is usually normal in T1DM without proteinuria,

hypertension or impaired renal function. Abnormal histological

findings are more likely in patients with overt nephropathy and the

severity of the changes increase with the magnitude of proteinuria

and when hypertension or impaired renal function complicates the

clinical course. Renal biopsy is unlikely to be a useful investigation

in adolescent patients when they are first found to have MA but

should be considered in any patient who has persisting and

increasing proteinuria, especially if this is associated with poor

PAEDIATRICS AND CHILD HEALTH 19:12 569

glycaemic control and hypertension. Histological confirmation of

DN is likely to add weight to the argument for better glycaemic

control through improved compliance with diet and blood sugar

testing and to justify the commencement of ACEi or AIIrb, espe-

cially if hypertension is also noted. A

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Amin R, Widmer B, Prevost AT, et al. Risk of microalbuminuria and

progression to macroalbuminuria in a cohort with childhood onset

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Diabetes Control and Complications Trial Research Group. Effect of

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� 2009 Elsevier Ltd. All rights reserved.