GFR Fall in Type 1 Diabetes Related to Abnormal Albuminuria and/or BP Elevation

Patients with completely normal albumin excretion rate usually preserve normal renal function (GFR) over many years, at least one or two decades. It should be noted here that there may, however, be a small probably age- related reduction in GFR. Also patients with persistent microalbuminuria usually maintain intact GFR, though a subsequent fall in GFR can be predicted, with progression to macroalbuminuria and possibly partly related to previous hyperfiltration. Only with the development of proteinuria (macroalbuminuria) is there a significant decline in GFR. Antihypertensive treatment may reduce or even normalize albumin excretion, and thus lead to misclassification of patients. Albumin excretion may again increase if treatment is stopped for some reason. Feldt-Rasmussen et al. observed a significant drop in GFR with the development of clinical nephropathy but most of their patients received antihypertensive treatment which modifies the level of UAE

Table 1. Stages in the development of renal changes and lesions in diabetes mellitus (mainly type 1 or younger type 2)

Stage Chronology

Main structural

Glomenular

Dextran clearance Albumin exception

Blood pressure Reversible by strict Arrestable or

changes or lesions filtration rate

(% of GFR)

insulin treatment reversible by AHT b

baseline UAE a exercise- induced UAE

No hypertension hypertrophy-

1 Acute renal Present at

Increased

Increased by

Normal

May be

Increased, but

Normal

Yes

present hyperfunction

diagnosis of

kideney size

increased, but

reversible

diabetes

Microcirculatory (reversible with

Increased

reversible

changes good control)

glomerular size

modifiable 2 Normo-

Normal (BP as Hyperfiltration Filtration fraction albuminuria

Almost all

On renal

Increased by

Normal

Normal by definition May be

reduced and UAE may be (UAE=20 lg/

patients normo- biopsy,

(15–20 lg/min may

abnormal after in background

reduced min)

albuminuric in

increased BM

be abnormal)

a few years

population)

first 5 years

thickness

Increase by 1 mm Hg/year

3 Incipient diabetic Typically after

Microalbuminuria Microalbuminuria nephropathy,

Further BM

Still supra-

Normal

Increase B20%/year

Abnormal

Incipient

stabilized, GFR reduced UAE 20–200 lg/ (in B35% of

6–15 years

thickening and

normal values,

(of glomerular

aggravation of

increase, B3

also stable (if HbA 1c Prevention of fall min

mesangial

predicted to

origin)

baseline UAE,

mm Hg/year

patients)

expansion,

decline with

related to BP

(if untreated)

is reduced). in GFR

arrestable with

development of

increase

Structural damage

slower 4 Proteinuria,

AHT

proteinuria

Higher fall in GFR Progression clinical overt

After 15–25

Clear and

Decline B10

Abnormal to

Progressive

c Pronounced

High BP,

increase by B5 with poor control reduced (aiming diabetic

years (in B35%

pronounced

ml/min/year

high molecular

clinical proteinuria

increase in BP

at 135/85 mm Hg) nephropathy

of patients)

abnormalities

with clear

dextrans (non-

of glomerular origin

mm Hg/year

proteinuria c specific and only

(if untreated)

with low GFR)

No failure

5 End-stage renal Final outcome,

Glomerular

10 ml/min

Not studied

Often some decline

Not studied

closure and

due to nephron

(if untreated)

years or more

BM>Basement membrane; UAE>urinary albumin excretion rate; AHT>antihypertensive treatment. a

The best clinical marker of early renal involvement. b Mostly ACE inhibition + diuretics. c Without antihypertensive treatment.

Nephropathy and Hypertension in Diabetic Patients 159 Nephropathy and Hypertension in Diabetic Patients 159

In conclusion, it is likely that abnormal albuminuria is the main predictor – or perhaps even a determinant – of future decline in renal function, although the nature of the initial permeability defect in glomeruli is not yet explained. Pressure dependency may play an important role. The underlying mechanism may either be an increased transglomerular traffic of proteins leading to further glomerular damage or an increased tubular reabsorption rate of albumin. The latter may cause interstitial damage, which in turn, may lead to structural damage in glomeruli. Another hypothesis for this self-perpetuating process involves glomerular hyperfiltration. Patients with a decline in GFR due to nephron closure are likely to show single nephron hyperfiltration in the re- maining glomeruli. On the other hand, patients with microalbuminuria usually do not exhibit any decline in GFR but some compensatory hyperfunction may still prevail on top of the usual diabetic hyperfiltration. Abnormal albuminuria is clearly associated with vascular damage in other organs.

GFR Fall in Type 1 Diabetes Related to Abnormal Albuminuria and/or BP Elevation