Beruflich Dokumente
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9
Differential Diagnosis of
Proteinuria in Diabetic
Patients
DANIEL CORDONNIER, CLAIRE MAYNARD, NICOLE
PINEL AND SERGE HALIMI
Centre Hospitalier Universitaire, Grenoble, France
130
The aim of this chapter is to evaluate how important the problem is both
for the individual patient and for public health. For the patient, detecting
and treating a non-diabetic disease might greatly modify his/her future
because the evolution could be drastically changed, either spontaneously
or after therapy, but also because the diagnosis of the primary renal disease
could be of importance for the management of a (potential) future pregnancy or renal transplantation.
For the health care providers and Public Health Managers, it could be
questionable to expand investigations and their potential iatrogenic effects if
there is no global benefit to be expected, in other words, no modification of
incidence of endstage renal failure (ESRD) leading to renal replacement
therapy (RRT). The growing (``epidemic'') incidence, prevalence and cost
of so-called ``diabetic nephropathy'' (in fact, a composite of diverse renal
diseases in diabetic patients) in ESRD programmes worldwide makes this
problem a real one and its evaluation mandatory.
Nephrosclerosis
Crescentic glomerulonephritis
Glomerulonephritis (other)
Chronic pyelonephritis
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Urologic Apparatus
Two traditional complications of diabetes have considerably diminished in
incidence and are only historical observations in medically well-developed
countries: papillary necrosis (with the improvement of diabetes management)
and pyelonephritis (with early referral of any urinary infections) (1). We do not
know exactly what the impact is on the kidneys of the very frequent ``neurological bladder'', clinically perceptible as a post-micturitional residue (2).
More evident are the consequences of prostatic pathologies in male diabetics
aged over 50, the frequency of which has not been systematically evaluated.
Vascular Apparatus
Vascular renal diseases are, with diabetes, the main cause of RRT worldwide.
It is now very clear that some patients have both diabetes (mainly but not
exclusively type 2) and vascular disease(s) located to the kidney macro- or
microvasculature (3).
Diffuse Atheroma
Diffuse atheroma involving the aorta (with or without aortic aneurysm) and
inferior limbs is often but not always associated with atheroma of the renal
arteries.
Renal Artery Stenosis (RAS)
RAS is more frequent in diabetic than in non-diabetic persons in an autopsy
series (8% vs. 4%) (4). There are some limited series showing clearly that
1030% of type 2 diabetic patients with proteinuria and hypertension have
a ``significant'' RAS ( 5070% of diameter depending on the series) (5).
By contrast, in type 1 diabetic patients RAS is very rare. The practical
implications of a RAS is not completely clear. There is no consensus on
treatment.
Cholesterol Embolism
This is probably under-recognized and therefore under-reported in diabetic
patients. Like cruoric embolisms, cholesterol embolism could be responsible
for peripherical infarcts inducing cortical defects, either unique or multiple,
responsible for an irregular pattern of the renal cortex. It is quite infrequent
that both retinal (by fundoscopy) cutaneous (by biopsy) or nail embolism
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Figure 9.1 Fifty-six year-old male, type 2 diabetic patient for 14 years,
hypertensive-treated for 12 years, microalbuminuric 3 years ago and presently
proteinuric (1.54 g/24 h); GFR 105 ml/min/1.73 m2 . The patient had no diabetic
retinopathy but hypertensive grade 2 retinopathy. PAS staining: glomerulus exhibits
a focal multilayering of Bowman's capsule and a moderate shrinkage of the tuft.
Mesangial sclerosis predominates at the vascular pole area. Interstitial connective
tissue is enlarged, with some mononuclear inflammatory cells and atrophic tubules.
Fibrous endarteritis of interlobular artery can be seen on the right. The diagnosis of
ischaemic nephropathy was accepted
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glucose and blood pressure control and in general have been treated more
intensively, e.g. with ACE inhibitors or angiotensin II receptors antagonists.
In addition, however, the concept has emerged recently and arguments have
been brought in favour of the genetic predisposition of patients both to
evolve and to be resistant to the renoprotective effects of ACE inhibitors (11).
However, it is very clear that some patients will evolve at a slow and
some at a rapid pace towards ESRD. The rate of decline of GFR, the rate of
worsening of proteinuria, the importance of resistance of elevated blood
pressure to antihypertensive drugs are not by themselves sufficient to
give clear information concerning the nature of the underlying renal
disease.
PRACTICAL MANAGEMENT
Even if the possibility is slim that proteinuria might be due entirely or
partially to a non-diabetic renal disease, it should be evoked systematically
in every patient, whatever the type of diabetes mellitus. The diagnostic
process should be followed systematically (Figure 9.2) and should not be
modified, except in the case of contraindication to some investigation.
Clinical History
Typical history has been established for type 1 diabetic-associated nephropathy in five sequential stages of known duration, proteinuria being the
fourth after the hyperfiltration phase, the silent phase and microalbuminuria and occurring before uremia. In type 2 diabetes, this sequence is less
clear, since the beginning of diabetes might go unrecognized for a long time,
but it is generally admitted that the sequence of phases is very close to that
in type 1. An isolated proteinuria occurring at the expected time, following a
established phase of microalbuminuria and increasing regularly, is suggestive of DGS.
A proteinuria discovered in a patient who has no regular history of
microalbuminuria, particularly if heavy, should be suspected of being due
to another nephropathy. One should check the time of discovery of diabetes
and proteinuria. When proteinuria precedes or occurs simultaneously with
diabetes a non-diabetic nephropathy should be suspected. To have a family
history of type 2 diabetes and nephropathy might help considerably. This
favours the diagnosis of DGS.
Extra-renal and renal pathologies should be searched for carefully. Likewise, one should look for previous use of potentially nephrotoxic drugs,
such as non-steroidal anti-inflammatory agents, analgesics, antibiotics and
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Uncertain history
Systematic finding
Acute onset of the nephrotic syndrome
PROTEINURIA
Fundoscopy
RETINOPATHY
Renal
imaging
Normal or increased
and
symmetrical volumes
Decision
making
No more investigation
DGS* highly probable
NO RETINOPATHY
Constricted
and
symmetrical
volumes
Asymmetrical
Normal
volumes
and
with non
symmetrical
dilated urinary
volumes
tract
Consider
renal
biopsy **
Investigate
lower
urinary
tract
- Systemic
disease
- Immune
abnormalities
- Microscope
haematuria
- Urinary
tract
infection
- Prostatism
Investigate
main renal
arteries
- Tobacco
addiction
-Other
main vessels
pathologies
Dilated
urinary
tract
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Clinical Examination
Some points of particular interest should be focused upon:
.
.
.
Ensure that the patient has no (partial) obstacle to urinary flow (pelvic
examination; assess for neurologic bladder).
Search for diffuse atheroma (peripheral and abdominal pulses).
Search for a systemic disease, possibly involving the kidney.
Retinoscopy
This examination should be systematic in every diabetic, every year, whatever his/her renal status. For a proteinuric patient, not to have a diabetic
retinopathy is very suggestive of a non-diabetic nephropathy (12,13), even if
this is not completely true (14). The retinal status, provided that it is
evaluated in an established fashion, will greatly help in management of
the patient (see Table 9.1); the presence or absence of a peripheral neuropathy may also help.
Biology
Urinary Cells and Casts
Macro- or microscopic haematuria, particularly associated with normalshaped red cells, with or without crystals or abnormal urinary cells, will
lead to for a pyelography. Distorted red cells associated with casts are
suggestive of glomerulonephritis. White cells alone (without infection and
casts) should suggest the possibility of urinary tuberculosis. White cell cylinders are found in urinary centrifugates of proliferative glomerulonephritis.
Monoclonal Dysglobulinaemia
Discovering urinary monoclonal kappa chain dysglobulinuria does not
necessarily mean that a diabetic patient has a dysglobulinaemia. In doubtful
cases, however, a bone marrow examination should be performed.
Polyclonal Hyperglobulinaemia
This is very frequent in diabetes and does not help in practice. In particular
hyper IgA globulinaemia usually linked to mesangial IgA glomerulonephritis
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in non diabetics is of little aid in diabetic patients (15,16) except when the
level is particularly high (17) (Figure 9.3).
50 m
Figure 9.3 76 year-old male patient, referred for acute renal failure and type 2
diabetes known since 1963, treated with insulin since 1968; severe proliferative
retinopathy and peripheral neuropathy (1978), proteinuria (detected in 1991),
coronary bypass (1992), cardiac heart failure (1993, 1994, 1997) and benign IgG
dysglobulinaemia (1997). In August 1997 he was admitted to an endocrinology unit
for an infected wound of a toe. Despite antibiotic treatment, oedema with the
nephrotic syndrome and oliguria developed when creatininaemia rose in 3 days
from 101 to 365 mmol/l and in 7 days to 633 mmol/l. He then needed a transfer to a
nephrology unit and five sessions of haemodialysis. Necrotic purpura of the limbs
appeared. The C3 fraction of complement was very low and serum IgA level high
(4.6 g/l N 12 g/l). A biopsy was performed. Masson's trichrome stain, renal biopsy:
global mesangial sclerosis with superimposed endocapillary cellular proliferation
and inflammatory cell infiltration. Caryorhexis can be seen in different places (#) and
thickening of Bowman's capsule (*). Additional tubular lesions, probably related to
aminoside treatment, are also present. There are diffuse membranous IgA deposits
(not shown). Evolution: this very severe atypical glomerulonephritis related to a
cutaneous infection and to a necrotic purpura was treated with antibiotics and
corticosteroids. The patient was in good shape 4 months later with a controlled blood
pressure, a proteinuria of 2.6 g/24 h and a creatininaemia of 159 mmol/l
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Hypocomplementemia
Idea to feature of hypocomplementemia is a useful first step, leading to a
search for an acute diffuse glomerulonephritis, a lupus or a cryoglobulinaemia-associated glomerulonephritis or even to an idiopathic hypocomplementemic membranoproliferative glomerulonephritis (Figure 9.4).
Hyperuricaemia
This might testify to a gouty kidney, but also to hypertension-associated
renal lesions (nephrosclerosis), or to diuretic-induced haemocontraction or,
more simply, to an associated renal failure.
Hypokalaemia
With alkalosis, there can lead to the diagnosis of secondary hyperaldosteronism and specifically to renal artery stenosis.
Imaging
Both ultrasonography and Doppler ultrasonography are observer-dependent. They are good tools for detecting any abnormality, but further investigation will be needed, the nature of which will depend upon the level of renal
function. If this is normal for age, contrast media could be used in a prudent
manner (hyperhydratation, non-ionic agents, economy doses) in order to
clearly evidence the renal arteries and the urinary tract; if renal function is
altered (creatinine clearance < 30 ml/min) magnetic resonance imaging with
gadolinium as a contrast medium should be considered (Figure 9.5).
Figure 9.4 71 year-old male type 2 diabetic patient with heavy proteinuria, renal
insufficiency, no diabetic retinopathy, monoclonal IgM kappa peak, IgM k-IgG
cryoglobulinaemia, hypocomplementaemia (C4 , C 3 ) and diffuse atheroma.
(A) Masson's trichrome. (B) Immunofluorescence, anti-C3. (C) PAS. Glomeruli are
enlarged and hypercellular with a lobular pattern. Expansion of the mesangium
(cells and matrix) leads into compression of the vascular lumen. The peripheral
glomerular basement membranes are irregularly thickened with a double contour
or honeycomb. Amorphous masses are suggestive of a microthombus made of
cryoglobulins precipitates (#). Coarse peripheral deposits of C3 (and IgM) outline
the glomerular basement membranes: cryoglobulinemic mesangio-capillary glomerulonephritis. Evolution: Serology was stongly positive for hepatitis C. A liver biopsy
was performed and treatment with interferon was conducted. Six months later the
patient was in very good health, with a proteinuria of 0.16 g/24 h and a creatininaemia of 105 mmol/l
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Renal biopsy
Renal biopsy should be considered if: (a) no urologic or vascular disease has
been found; (b) no contraindication is present (very small or solitary kidney,
coagulation trouble, uncontrollable elevated blood pressure); (c) the patient
does not have a diabetic retinopathy; (d) nephrological (e.g. microscopic
haematuria), systemic (e.g. cutaneous) or immunological (e.g. hypocomplementemia, dysglobulinemia) signs or symptoms are present.
The risks of a renal biopsy performed in a well-equipped centre by a
highly skilled nephrologist, under ultrasonography with a gun-equipped
needle, has become very low (18). When the patient has a typical diabetic
retinopathy, it is acceptable not to perform a renal biopsy, assuming that it
will show a DGS. However, renal biopsy should be considered if there is
CONCLUSION
Particularly in type 2 diabetes, urological, vascular and cortical
(including glomerular) diseases can occur that are not due to diabetes.
These represent up to 30% in some series.
Retinal status does not completely coincide with renal status. The
differential diagnosis of proteinuria in a diabetic patient should not be
resolved with this ``tool'' alone.
There are relatively few tools available for making the differential
diagnostis of proteinuria, except for renal biopsy.
Prognosis, either spontaneously or via therapeutics, can be completely different depending upon the diagnosis. This is true both before
continues
Figure 9.5 Seventy-three year-old man with type 2 diabetes for 38 years and insulin
treatment for 11 years; referred for renal insufficiency (creatininaemia 163 mmol/l,
creatinine clearance 30 ml/min), high blood pressure (normalized under furosemide
40 mg/day and a b-blocker) and proteinuria (0.9 g/24 h). The patient, a non-smoker,
has been treated by laser therapy for a proliferative retinopathy. Two years ago he
underwent a coronary bypass. The left pedal pulse was not found. Ultrasonography
showed two kidneys of 9.5 cm and 10 cm length, with a cortex of 17 mm mean
thickness. Magnetic resonance imaging showed (A) bilateral stenosis with poststenosis dilatation. Both were confirmed by conventional arteriography (B) and
were treated by endoluminal balloon angioplasty to the right artery (C). Nine months
later, due to recurrence of left renal artery stenosis, an endovascular stent was
introduced (D). No progression of renal insufficiency or proteinuria was observed
within the following 36 months. Reproduced by courtesy of Dr Frederic Thony
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continued
any historical, anamnestic, clinical, biological or imaging abnormality suggestive of something unusual. It is also clear that renal biopsies are acceptable in well-designed trials for research purposes (18).
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
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