THEMED WEEK 8: INVESTIGATION OF ABNORMAL RENAL FUNCTION

CSIM2.71 THE PATIENT WITH PROTEINURIA AND

HAEMATURIA

Focal
Diffuse

only a portion of glomeruli affected

all glomeruli affected

TERMS

Global

whole glomerulus affected

segmental

only a part of the glomerulus is affected (most focal lesions are also segmental)

proliferative

^cell numbers due to hyperplasia of one or more of the resident glomerular cells

membrane
alterations
crescent formation

capillary wall thickening

epithelial cell proliferation with mononuclear cell infiltration in Bowmans space

GLOMERULONEPHRITIS

Inflammatory condition of the glomeruli. Presented with Nephrotic or Nephritic

Syndrome
Common cause of ESRF in adults.
Presentation: Asymptomatic, haematuria (could be microscopic), proteinuria, renal failure or
HPT.
Abnormal Glomerulus
- Altered glomerular basement membrane (GBM) frequently result in significant renal
dysfunction.
- Crescent formation -> destruction of the affected glomerulus and is replaced by
fibrous scaring
Causes of PROTEINURIA
-

Glomerular dx
Tubulo-interstitial dx rarely
causes significant proteinuria
Physical exercise

Orthostatic proteinuria
Fever
Heart failure
Pregnancy

Inflammation of the glomeruli and nephrons which leads to;

- Damage to the glomerulus restricts blood flow, leading to compensatory ^BP
- Damage to the filtration mechanism allows protein and blood to enter urine.
- Loss of the usual filtration capacity leads to acute kidney injury
Looking for degree of damage and potential cause
- Imaging: CXR, renal ultrasound.

THEMED WEEK 8: INVESTIGATION OF ABNORMAL RENAL FUNCTION

-

Blood: FBC, U&E, LFT,

ESR, CRP;
immunoglobulins,
electrophoresis,
complement (C3, C4);
autoantibodies (p555):
ANA, ANCA, anti-dsDNA,
anti-GBM; blood culture,
ASOT, HB A , anti-HCV
Urine: RBC casts, MC&S,
s

Bence Jones protein, ACR (see p286).

Presentation

Diagnosis

Treatm
ent

Prognos
is

THEMED WEEK 8: INVESTIGATION OF ABNORMAL RENAL FUNCTION

IgA
Nephropathy
altered
regulation of IgA
^IgA possibly
due to infection,
which forms
immune
complexes and
deposits in
mesangial cells.
HenochSchonlein
Purpura (HSP)
Systemic IgA
nephropathy,
causing a small
vessel
vasculitis.
Systemic
lupus
erythematous
(SLE)

Common cause of
GN in adults
Young man (20-30
yo), Asians and
Caucasians with
episodic
macroscopic
haematuria,
recovery is often
rapid between
attacks
purpuric rash on
extensor surfaces
Arthralgias
Purpura
Abdominal pain,
GI bleeding
Hematuria

Mesangial
proliferation,
immunofluores
cence (IF)
shows deposits
of IgA and C3

+ IF for IgA
and C3 in skin
or renal biopsy.

Cough, chest pain, nasal congestion

Maculopapular rash over her chest
Haematuria, proteinuria,

Antiglomerular
basement
membrane
(GBM)
A.k.a.
Goodpastures
disease caused
by autoantibodies to
type IV collagen
an essential
component of
the GBM
Poststreptococcal
Strep. Ag is
deposited on
the glomerulus
causing a host
rxn and immune
complex form.

Pulmonary
haemorrhage
Haematuria/nephi
ritc syndrome
AKI may occur
within days of
onset of
symptoms
Malaise, fatigue,
anorexia, weight
loss, arthralgias,
myalgias

Occurs 1-12 wks

after a sore throat
or skin infection
Nephritic
syndrome

A/b develop
against 3
chain type IV
collagen in
GBM. Linear
deposition of
IgG along GBM
A/b detected
by ELISA
ANCA
capillary loop
staining with
IgG and C3
and extensive
crescent
formation
Urinalysis
Inflammation
rxn affecting
mesangial and
endothelial
cells
IF: IgG and C3
deposits
^ASOT ^C3

Control
BP with
ACEi,
immuno
suppres
sion
may
slow
decline
of renal
function
.

~15% ->
ESRF. If
same as
both
IgA
nephritic
nephrop
and
athy
nephroti
c 50% ->
ESRF
~1/3 SLE have renal
disease with vascular,
glomerular and
tubulointerstitial
damage.

Relapse
are rare.
Prognosi
s is poor
if
dialysisdepende
nt
presenta
tion.

Complica
tion
Severe
HPT,
renal
failure,
primary
disease
(SLE)

Plasma
exchan
ge,
steroids
,
Cycloph
ospham
ide

~20% ->
ESRF.
POOR
prognosi
s: Male,
^BP,
proteinur
ia or
renal
failure at
presenta
tion.

THEMED WEEK 8: INVESTIGATION OF ABNORMAL RENAL FUNCTION

Rapidly
progressive
Most aggressive
GN. Could cause
ESRF over days.

AKI +- systemic
features (fever,
myalgia, weight
loss,
haemoptysis)
Pulmonary
haemorrhage is
the commonest
cause of death

ANCA +ve
patients
-

Aggressive
immunosupresion with
high-dose IV steroids
and cyclophophamide
+- plasma exchange
5 year survival 80%

THEMED WEEK 8: INVESTIGATION OF ABNORMAL RENAL FUNCTION

NEPHROTIC SYNDROME
1. Definition: the renal excretion of more than 3.5g of protein during a 24 hour period
2. Assessed by the collection of a cumulative 24h urine specimen.
3. As a result of abnormalities of the basement membrane, large amounts of plasma
proteins are filtered into the glomerular ultrafiltrate
4. Not associated with significant glomerular inflammation and red blood cell casts or other
signs of glomerular inflammation are present
5. The loss of nephrotic quantities of proteins for prolonged periods can result in
hypoproteinamia
6. Peripheral oedema because of loss of plasma oncotic pressure

Criteria

OEDEMA

PROTEINURIA (> 3.5 G/DAY/1.73

M2 )

Structural damage to the glomerular

basement membrane leads to an
increase in the size and number of
pores -> allow more and larger
molecules.
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.

HYPOALBUMINAEMIA (< 3.5G/DL)

-

Urinary protein loss of the order 3.5g

daily or more in adult required to
cause hypoalbuminaemia
Increased of catabolism of reabsorbed
albumin in the proximal tubules
though actual albumin synthesis is
increased.

Expansion of the interstitial

compartment is secondary to the
accumulation of sodium in the
extracellular compartment.
This is due to an imbalance between
oral (or parenteral) sodium intake and
urinary sodium output, as well as
alterations of fluid transfer across
capillary walls.

HYPERLIPIDAEMIA (C > 250 MG/DL)

-

Hyperlipidaemia is the consequence of

increased synthesis of lipoproteins in
the liver, abnormal transport of
circulating lipid particles, and
decreased catabolism.
HypoA stimulates protein synthesis in
the liver. Protein synthesis, lipid
synthesis.

Nephrotic syndrome is NOT a diagnosis. Therefore, the underlying cause should always be
sought.

Presentation
i.
ii.
iii.

Facial oedema
Peripheral oedema
Pleural effusion

iv.
v.

Ascites
Genital and sacral oedema

vi.

Histological patterns of NS; Minimal change, membranous nephropathy

1. Attributed to minimal change, membranous nephropathy. Consequence rather than
cause of nephrotic syndrome.

THEMED WEEK 8: INVESTIGATION OF ABNORMAL RENAL FUNCTION

MEMBRANOUS NEPHROPATHY (COMMON CAUSE, 20-30% IN ADULT)

1. 75% are primary or idiopathic form but can be associated to 2 to;
- Malignancy (e.g. carcinoma of lung, colon, stomach, breast and lymphoma)
- drugs (penicillamine, gold, NSAIDs, probenecid, mercury, captopril),
- autoimmune disease (e.g. SLE, thyroiditis),
- Chronic infection (e.g. hepatitis B, hepatitis C, schistosomiasis, Plasmodium
malariae),
- SLE
2. At all stages, IF shows the presence of diffusely thickened
GBM of IgG and C3
3. COMMON: Adults, males
4. Asymptomatic proteinuria or frank nephrotic syndrome.
5. May present with macroscopic haematuria, hypertension
and/or renal impairment
6. POOR PROGNOSIS: HPT and higher degree of renal
impairment
7. 40% develop CKD
8. GOOD PROGNOSIS->
Younger, females, and
asymptomatic proteinuria of modest degree
9. 3 stages
Early: deposits are small can be missed on LM. EM
reveals small electron-dense deposits in the subepithelial aspects of the capillary walls
Intermediate: deposits are encircled by basement
membrane => appearance of spikes of basement membrane perpendicular to the
basement membrane on silver staining
Late: uniform thickening of the capillary basement membrane

MINIMAL CHANGE DISEASE

1. PAEDS: common cause, MALE good prognosis. X leads to CKD, facial oedema
2. ADULT: asso.
Idiopathic
With drugs (NSAIDs, lithium, antibiotics ( rifampicin, ampicillin, cephalosporins) ,
Hodgkins Lymphoma
3. Glomeruli appear normal on light microscopy but on EM, fusion of podocytes could be
seen
4. Tx: high dose corticosteroid therapy with prednisolone
60 mg/m2 daily (up to a maximum of 80 mg/day) for a
maximum of 46 weeks followed by 40 mg/m2 every
other day for a further 46 weeks corrects the urinary
protein leak in more than 95% of children
5. Two-thirds children have relapse and further courses of
corticosteroids are required.
6. One-third of these children regularly relapse on steroid
withdrawal, so that cyclophosphamide should be added
after repeat induction with steroids. A course of
cyclophosphamide 1.52.0 mg/kg daily is given for 8
12 weeks with concomitant prednisolone 7.515
mg/day.

MESANGIOCAPILLARY GN
1. Immune complex (IC)

THEMED WEEK 8: INVESTIGATION OF ABNORMAL RENAL FUNCTION

Driven by circulating immune complexes, which deposit in the kidney and activate
complement via the classical pathway. An underlying cause can be found in most
cases, eg Hep C, SLE and monoclonal gammopathies.
2. Complement mediated
Less common and involves persistent activation of the alternative complement
pathway
3. BIOPSY: mesangial and endocapillary proliferation, a thickened capillary basement
membrane, double contouring (tramline) of the capillary walls. IF can show Ig
staining, complement staining or light chains depending on cause. EM shows electron
dense deposits.

FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)

1. May be 1 or 2 (VUR, IgA nephropathy, Alports syndrome, vasculitis, sickle-cell disease)
2. Presentation: nephrotic syndrome or proteinuria. ~50% have impaired renal function.
3. BIOPSY: scarring of the glomeruli at certain segments (focal sclerosis). IF: IgM and C3
deposits at affected area.
4. Tx: corticosteroid. Resistant: cyclosphamide or ciclosporin
5. Untreated most progress ESRF

Complication
A. DVT
a. Hypercoagulable state due to urinary losses of anti-thrombin and thrombocytosis
b. Exacerbated by steroid therapy
c. Increased synthesis of clotting factors
d. Increased blood viscosity from the raised haematocrit
e. This is usually arterial and may affect the brain, limbs, and splanchnic circulation.
B. Pulmonary infection, Sepsis
a. Serum: IgG, complement, T cell function
b. Steroid: immunosuppressant toxicity
C. Accelerated atherosclerosis. Lipid abnormalities
D. Hypovolaemia
E. Acute renal failure (rare)

Investigation
DIAGNOSTIC
1.
2.
3.
4.
5.

Proteinuria +1> on 2/3 dipstick

P:C (> 200mg/mmol) (early morning)
Serum lipid
C3 level (sensitive n specific if other than MCD)
BP

FURTHER INVESTIGATION
1. Full blood count: HCT, WBC
2. Renal profile: normal in MCD
U+Es; Creatinine
3. Serum albumin: <25g/L
4. Urinalysis and quantification for
urinary protein excretion
abundant hyaline cast
Haematuria (other than MCD)
Na+ <10mmol/L in
hypovolaemia
Glucose

5. LFTs; ASOT
6. Urine culture
7. Varicella status should be known in
all children commencing steroids.
8. Other investigations
complement levels: suggest
other thn MCD
Antistreptolysin O titre and
throat swab
Hepatitis B antigen
9. Biopsy light microscopy/ EM/ IF

THEMED WEEK 8: INVESTIGATION OF ABNORMAL RENAL FUNCTION

6. Management

Initial treatment
- Na restriction and THIAZIDE diuretics
- Unresponsive patients require
FUROSEMIDE 40-120mg daily +
amiloride
Normal protein intake
Albumin infusion
- only produce a transient effect
- Indication: diuretic-resistant, oliguria
and uraemia in the absence of severe
glomerular damage e.g. in minimal
change nephropathy.
Hypercoagulable states
- Predispose to venous thrombosis

This is due to loss of clotting factors

in the urine and increase in hepatic
production of fibrinogen.
Sepsis
- Susceptibility to infection due to
loss of immunoglobulin in the urine
Lipid abnormalities
- Increased CVS disease. Give HMGCoA
ACEi
- Reduce proteinuria by lowering
glomerular capillary filtration
pressure

NEPHRITIC SYNDROME

Variable amounts of proteinuria with the presence of RED BLOOD CELL CASTS (linear
aggregates of RBC formed in tubules as a consequence of glomerular haemorrhage)
And other inflammatory features (WBC and tubular cell casts) on urinalysis

THEMED WEEK 8: INVESTIGATION OF ABNORMAL RENAL FUNCTION

Should get rapid evaluation of renal f(x)

Clinical features
i.
ii.
iii.
iv.
v.

Hypertension
Haematuria (usually micro, but can be macro)
Oliguria/acute renal failure
+/- odema
May be associated proteinurea

Crescenteric Glomerulonephritis

Proliferation of epithelial cells in

Bowmans space and signal the
dead of the glomeruli. Anti-GBM
Crescents on the renal biopsy
indicate acute severe glomerular
injury
Can occur in any type of
inflammatory glomerular injury
Start with a gap in the glomerular
capillary wall and GBM, plus gap in
Bowmans capsule
Circulating cells + inflammatory
mediators move into Bowmans
space
Fibrin, macrophages, T cells, fibroblasts start to proliferate
Crescents signify severe and aggressive immune damage and are a marker of severity of
renal damage
The percentage of glomeruli with crescents gives a guide to likely recovery
100% crescents is a poor outlook
10% crescents much better outlook

IgA Nephropathy
1.
2.
3.
4.

Young male patient, macroscopic haematuria after URTI

Deposition of IgA immunocomplexes in the glomeruli.
Less destructive
Routine tests
Haem FBC, Clotting factor
Biochemistry
i. U&E, LFT, calcium and albumin
ii. CRP/ESR
iii. Serum and urine Ig and electrophoresis
Immunology
i. Complement, dsDNA, ANA, ANCA, Rh factor, anti-GMB
Microbiology
i. Blood cultures
ii. MSU

Speed dealing with rapidly progressive GN

patients can rapidly become unwell with multisystem symptoms

all c ANCA positive patients are at risk of developing pulmonary involvement
rapid aggressive immunosuppression may salvage damaged nephrons and restore useful
renal function

THEMED WEEK 8: INVESTIGATION OF ABNORMAL RENAL FUNCTION

vasculitis will affect rest of body too

Untreated the kidneys will fail irreversibly

RECURRENT UTI
1. Same symptoms
2. No fixed definition of recurrent
a. 2 infections in 6 months
b. 3 infections in 12 months
3. After a single UTI there is a 30% risk of recurrence with 6 months
4. 60% will be the same organism (E coli)
5. After a first UTI 30-40% of patients will go onto have recurrent infections

Complicated or uncomplicated

a.
b.
c.
d.

Complicated: underlying anatomical or physiological abnormality

Uncomplicated: normal urinary tract
Complicated UTIs are more likely to recur but
Most recurrent infections occur in otherwise healthy women with a normal urinary tracts

Investigations

1.
2.
3.
4.
5.

Confirm infection dipstick and MSU

Other conditions can mimic infection
Confirm antibiotic sensitivities
History of previous antibiotic use
USS

Treatment

1. Be aware of the risk of resistance

2. Non-antibiotic treatments
Cranberry juice
Increase fluid intake
Probiotics
Regular and/or post coital complete voiding
Avoid spermicidal use/diaphragm
Topical oestrogens
3. Antibiotics
Long-term prophylaxis (1-2 yrs)
Low dose, at night
Single post-coital antibiotic dose
Self-treat
4.

5. Long term management

Low dose, once daily prophylactic antibiotics is an effective treatment for recurrent UTI.
Treatment significantly reduces the frequency of infection.
There is a risk on increasing antibiotic resistance and therefore treatment should be
reserved for patients with frequent, disabling infections.
Treatment should be for a limited period of time, usually 1-2 years, after which treatment
should be stopped and the patient re-assessed.
Single dose post-coital antibiotics can also be effective, particularly if infections follow
intercourse.

6.