Table 11.

3 Investigation of glomerular diseases

NEPHROTIC SYNDROME Investigations Positive findings

Urine microscopy Red cells, red-cell casts
Pathophysiology Urinary protein Nephrotic or sub-nephrotic
Hypoalbuminaemia. range proteinuria
Urinary protein loss of the order 3.5 g daily or more in an Serum urea May be elevated
adult is required to cause hypoalbuminaemia. In children, Serum creatinine May be elevated
Culture (throat swab, Nephritogenic organism (not
proportionately less proteinuria results in hypo-
discharge from ear, swab always)
albuminaemia. The normal dietary protein intake in the
from inflamed skin)
UK is of the order 70 g daily and the normal liver can Antistreptolysin-0 titre Elevated in post-
synthesize albumin at a rate of 10-12 g daily. How then streptococcal nephritis
does a urinary protein loss of the order of 3.5 g daily C3 and C4 levels May be reduced
result in hypoalbuminaemia? This can be partly explained Antinuclear antibody Present in significant titre in
systemic lupus
erythematosus
ANCA Positive in vasculitis
Anti-GBM Positive in Goodpasture's
syndrome
Cryoglobulins Increased in
cryoglobulinaemia
Creatinine clearance Normal or reduced
Chest X-ray Cardiomegaly, pulmonary
oedema (not always)
Renal imaging Usually normal
Renal biopsy Any glomerulopathy

by increased catabolism of reabsorbed albumin in the

proximal tubules during the nephrotic syndrome even
though actual albumin synthesis rate is increased. How-
ever, in addition, dietary intake of protein increases
albuminuria, so that the plasma albumin concentration
tends to decrease during consumption of a high-protein
diet. If the increase in urinary albumin excretion that
follows dietary augmentation is prevented by adminis-
tration of ACE inhibitors (ACEI), a high-protein diet
causes an increase in plasma albumin concentration in the
nephrotic syndrome. Therefore, to maximize serum
albumin concentration in nephrotic patients, a reduction
in urinary albumin excretion with an ACEI is always
necessary.

Proteinuria. The mechanism of the proteinuria is

complex. It occurs partly because structural damage to
the glomerular basement membrane leads to an increase
in the size and number of pores, allowing passage of more
and larger molecules. Electrical charge is also involved in
glomerular permeability. Fixed negatively charged
components are present in the glomerular capillary wall,
which repel negatively charged protein molecules.
Reduction of this fixed charge occurs in glomerular
disease and appears to be a key factor in the genesis of
heavy proteinuria.

Hyperlipidaemia. The characteristic disorder is an

increase in the low-density lipoprotein (LDL), very-low-
density lipoprotein (VLDL), and/or intermediate-density
lipoprotein (IDL) fractions, but no change or decrease in
HDL. This results in an increase in the LDL/HDL

620

cholesterol ratio. Hyperlipidaemia is the consequence of
increased synthesis of lipoproteins (such as apolipo-
protein B, C-III, Lp(a) lipoprotein), as a direct con-
sequence of a low plasma albumin. There is also a reduced
clearance of the principal triglycerides bearing lipo-
protein (chylomicrons and VLDL) in direct response to
albuminuria.
Oedema in hypoalbuminaemia. See Chapter 12 (p. 696).
Management
General measures
■ Initial treatment should be with dietary sodium
restriction and a thiazide diuretic (e.g. bendroflu-
methiazide). Unresponsive patients require furosemide
40-120 mg daily with the addition of amiloride (5 mg
daily), but the serum potassium concentration should
be monitored carefully. Nephrotic patients may
malabsorb diuretics (as well as other drugs) owing to
gut mucosal oedema. Resistance to oral diuretic
treatment may demand parenteral administration for a
time. Patients are sometimes hypovolaemic, and
moderate oedema may have to be accepted in order to
avoid postural hypotension.
■ A high-protein diet (approximately 80-90 g protein
daily) increases proteinuria and can be harmful in the
long term. Normal protein intake is advisable.
Infusion of albumin produces only a transient effect.
It is normally only employed in diuretic-resistant
patients and those with oliguria and uraemia in the
absence of severe glomerular damage, e.g. in minimal-
change nephropathy. Albumin infusion is combined
with diuretic therapy. Diuresis, when once initiated in
this way, often continues with diuretic treatment alone.
■ Hypercoagulable states predispose to venous
thrombosis. The hypercoagulable state is due to loss of
clotting factors (e.g. antithrombin) in the urine and an
increase in hepatic production of fibrinogen. Prolonged
bed rest should therefore be avoided as thrombo-
embolism is very common in the nephrotic syndrome.
In the absence of any contraindication, long-term
prophylactic anticoagulation is desirable. Once
renal vein thrombosis has occurred, permanent anti-
coagulation is required.
■ Sepsis is a major cause of death in nephrotic patients.
The increased susceptibility to infection is partly due
to loss of immunoglobulin in the urine. Pneumococcal
infections are particularly common and pneumococcal
vaccine should be given. Early detection and aggressive
treatment of infections, rather than long-term antibiotic
prophylaxis, is the best approach.
■ Lipid abnormalities are responsible for an increase in
the risk of myocardial infarction or peripheral vascular
disease in patients with proteinuria. Treatment of
hypercholesterolaemia is best with an HMG-CoA
reductase inhibitor, with fibrates if necessary (p. 1141).
■ ACE inhibitors and/or angiotensin II receptor
antagonists (AURA) are increasingly used for their
antiproteinuric properties in all types of GN. These
groups of drugs reduce proteinuria by lowering
Glomerulopathies
Table 11.4 Glomerulopathies associated with the
nephrotic syndrome
Nephrotic syndrome with 'bland' urine sediments
Primary glomerular disease Minimal-
change glomerular lesion Congenital
nephrotic syndrome Focal segmental
glomerular sclerosis Membranous
nephropathy
Secondary glomerular disease
Amyloidosis Diabetic
nephropathy
Nephrotic syndrome with 'active' urine sediments
(mixed nephrotic/nephritic)
Primary glomerular disease Mesangiocapillary
glomerulonephritis Mesangial proliferative
glomerulonephritis
Secondary glomerular disease Systemic
lupus erythematosus
Cryoglobulinaemic disease Henoch-
Schonlein syndrome Idiopathic
fibrillary glomerulopathy
Immunotactoid glomerulopathy
glomerular capillary filtration pressure; the blood
pressure and renal function should be monitored
regularly.
Specific measures
The aim is to reverse the abnormal urinary protein leak.
These are discussed in detail below.
Table 11.4 shows the glomerular lesions commonly
associated with the nephrotic syndrome. These are
divided into diseases with or without RBC casts (bland or
active urine sediments). Each of these entities may occur
as a primary renal lesion or as a secondary component of
a systemic disease.
Nephrotic syndrome with 'bland' urine
sediments
Minimal-change glomerular lesion (minimal-
change nephropathy)
In this condition the glomeruli appear normal on light
microscopy (Fig. 11.12). The only abnormality seen on
electron microscopy is fusion of the foot processes of
epithelial cells (podocytes) (Fig. 11.11). This is a non-
specific finding and is seen in many conditions associated
with proteinuria. Neither immune complexes nor anti-
GBM antibody can be demonstrated by immuno-
fluorescence. However, the immunological pathogenesis
of this condition is suggested by three factors:
■ its response to steroids and immunosuppressive drugs
■ its occurrence in Hodgkin's lymphoma, with remission
following successful treatment
■ patients with the condition and their family members
have a high incidence of asthma and eczema; remission
of the nephrotic syndrome following desensitization
or antigen avoidance has been described.
621
Fig. 11.12 Normal glomerulus on light microscopy in minimal change disease.

A suggested explanation for the proteinuria is the production by T lymphocytes of a factor that increases glomerular
permeability to protein.

Clinical features
Minimal-change nephropathy is most common in children, particularly males, accounting for the large majority of cases
of nephrotic syndrome (proteinuria is usually highly selective) in childhood. Oedema is present and in children this may be
facial. The condition accounts for 20-25% of cases of adult nephrotic syndrome. It is often regarded as a condition that does
not lead to chronic renal failure (but see focal sclerosis below).
Management
High-dose corticosteroid therapy with prednisolone 60 mg/m2 daily (up to a maximum of 80 mg/day) for a maximum
of 4-6 weeks followed by 40 mg/m2 every other day for a further 4-6 weeks corrects the urinary protein leak in more than
95% of children. Response rates in adults are significantly lower and response may occur only after many months (12 weeks
with daily steroid therapy and 12 weeks of maintenance with alternate-day therapy). Spontaneous remission also occurs and
steroid therapy should, in general, be withheld if urinary protein loss is insufficient to cause hypoalbuminaemia or oedema.
In children, one-third subsequently do not relapse, but further courses of corticosteroids are indicated in the remainder.
One-third of these patients relapse regularly on steroid withdrawal, and remission is once more induced with steroid
therapy; a course of cyclophos-phamide 1.5-2.0 mg/kg daily is given for 8-12 weeks with concomitant prednisolone 7.5-
15 mg/day. This increases the likelihood of long-term remission. Steroid unresponsive patients may also respond to cyclo-
phosphamide. No more than two courses of cyclo-phosphamide should be prescribed in children because of the risk of side-
effects, which include azoospermia.
In both children and adults, if remission lasts for 4 years after steroid therapy, further relapse is very rare.
 An alternative to cyclophosphamide is ciclosporin 3-5 mg/kg/day, which is effective but must be continued long term
to prevent relapse on stopping treatment. Excretory function and ciclosporin blood levels (recommended trough levels
80-150 ng/mL) must be monitored carefully, as ciclosporin is potentially neph-rotoxic. In corticosteroid-dependent
children, the anthelminthic agent levamisole 2.5 mg/kg to a maximum of 150 mg on alternate days is useful in maintenance
of remission but its mode of action is unexplained. Most of the controlled studies have been conducted in the paediatric
age group, making recommendations on treatment in adults difficult.

Congenital nephrotic syndrome

Congenital nephrotic syndrome (Finnish type) is an autosomal recessively inherited disorder due to mutations in the gene
coding for a transmembrane protein, nephrin, that occurs with a frequency of 1 per 8200 live births in Finland. Nephrin was
the first slit-diaphragm protein identified. Its loss of function results in massive proteinuria shortly after birth; these patients
usually have an enlarged placenta. This disorder can be diagnosed in utero; increased alpha-fetoprotein in amniotic fluid is
a common feature. The microscopic features of the kidney are varied. Some glomeruli are small and infantile, whereas others are
enlarged, more mature and have diffuse mesangial hypercellularity. Because of the massive proteinuria, some tubules
develop microcysts and are dilated. On electron microscopy, complete effacement of the foot processes of visceral epithelial
cells is observed. This condition is characterized by relentless progression to end-stage renal failure. Other inherited
nephrotic syndromes involve mutations in other genes that encode podocyte proteins such as podocin, alpha-actinin-4 and
Wilms' tumour suppressor gene.