SYSTEM WORKSHOP
Case I
A 66 year-old woman, having complained of chronic fatigue and malaise for a year, was
persuaded to seek medical attention. On questioning, she admitted to having had nocturia
for the past year. More recently she had developed anorexia and nausea and occasional
vomiting and diarrhoea. She also complained of pruritis and noticed that she bruised
easily. She had become breathless on exertion.
On examination, she appeared ill and listless. She had a yellowish-brown skin
pigmentation. The conjunctivae were pale. The skin was dry and there were scratch
marks on the arms and some bruising on the legs. It was noted that the distal half of the
fingernails had a brown discolouration. There was abdominal obesity. Examination of
the cardiovascular system revealed hypertension and a pericardial friction rub. There was
reduced sensation in the lower limbs but otherwise examination of the nervous system
was normal.
Investigations revealed the following:
 Normochronic normocytic anaemia.
 Normal white cell count and platelets but prolonged bleeding time.
 Blood urea and creatinine were markedly raised and there was a metabolic
acidosis
 Hypocalcaemia, hyperphosphataemia, hyperkalaemia,
hypercholesterolaemia and hypertriglyceridaemia were present
 The urine tests revealed a marked proteinuria but no haematuria
Results of imaging showed cardiomegaly and the kidneys were symmetrically reduced in
size.
Question 1
What is your diagnosis, i.e. what does this constellation of clinical findings indicate?
Answer:
Question 2
What is the pathogenesis of:a)
the gastrointestinal symptoms?
b)
the skin and nail changes?
c)
the breathlessness?
d)
the cardiovascular findings?
e)
the neurological findings?
Answer:
Question 3
What is the pathogenesis of:a)
the anaemia?
b)
the changes in potassium and calcium?
c)
the metabolic acidosis?
Answer:
Question 4
Having established the diagnosis, what are the possible common causes?
Answer:
Question 5
What other laboratory result would be relevant in this patient?
Answer:
Question 6
What are the microscopic findings in the kidney in a patient with this condition? (Renal
biopsy is not usually performed in these cases but may be indicated if, for example, dual
pathology is suspected)
Answer:
Question 7
What conditions would you consider in the histopathological differential diagnosis, i.e.
what might resemble these glomerular changes?
Answer:
Question 8
What other renal complications of diabetes mellitus are well known?
Answer:
Question 9
Returning to the general subject of chronic renal failure, what is the outcome of the
hypocalcaemia and hyperphosphataemia?
Answer:
ANSWERS
Answer 1
Chronic renal failure (CRF) with uraemia. The combination of clinical features in this
patient is typical of that seen in advanced CRF and uraemia. The most helpful laboratory
findings are the raised creatinine and urea and the proteinuria. Of these, creatinine is
most useful, providing approximation of the glomerular filtration rate. Albuminuria is a
sure sign of glomerular abnormality. The reduced size of the kidneys is a helpful sign but
patients with CRF can have normal sized or enlarged kidneys.
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Answer 2
a)
b)
c)
d)
e)
Back:
Gastrointestinal manifestations in uraemia are considered to be due to uraemic
autonomic neuropathy but an uraemic gastroenteritis is also implicated.
The skin pigmentation may be caused by retention of a melanocytestimulating hormone. The cause of the dry skin, pruritis and nail changes is
unknown. The bruising (and prolonged bleeding time) is due to factors in
uraemia which interfere with platelet function. Anaemia and vascular wall
abnormalities are also contributing factors.
The breathlessness may be due to anaemia and/or metabolic acidosis.
The pericarditis is a common occurrence in uraemia abut the exact
pathogenesis of this and other manifestations of uraemia is uncertain.
Accumulation of various toxic intermediate products of metabolism is a
possibility. Hypertension develops in about 80% of patients with CRF and
explains the cardiomegaly
The reduced sensation is attributed to peripheral neuropathy due to “toxic”
uraemic substances.
Answer 3;
a)
b)
c)
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Reduced erythropoietin synthesis by the failing kidneys, shortened red cell
survival, marrow depression due to toxic factors in uraemia and occult blood
loss are among the possible causes of anaemia in CRF. Typically it is a
normochronic normocytic anaemia attributed to the first three of the above
factors.
hyperkalaemia – retention of potassium due to low glomerular filtration rate.
Hypocalcaemia – failure of the kidney to convert cholecalciferol to the active
1,25-dihydroxycholecalciferol. This leads to diminished intestinal absorption
of calcium.
The metabolic acidosis in CRF is due to failure of hydrogen ion excretion.
Answer 4:
There are many possible causes of CRF. The four most common, in descending order,
are: diabetes mellitus
 glomerulonephritis
 interstitial nephritis
 hypertension
Less common causes include metabolic abnormalities (e.g. cystinosis, nephrocalcinosis),
dysproteinemias (e.g. amyloid, myeloma), vascular (renal artery stenosis, vasculitides),
congenital and inherited diseases (polycystic disease, Alport’s syndrome). A proportion
is cryptogenic.
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Answer 5:
Blood glucose. The random plasma glucose in this patient was in excess of 11.1μmol/l.
Urine testing revealed the presence of glycosmia and fasting plasma glucose was greater
than 7μmol/l. This is considered to be sufficient evidence for diabetes mellitus and
diabetic nephropathy to be a cause of the chronic renal failure. Confidence in the
diagnosis is further enhanced if the patient is found to have diabetic retinopathy.
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Answer 6:
Glomerular basement membrane thickening, diffuse increase in mesangial matrix,
nodular glomerulosclerosis (Kimmelstiel-Wilson lesion).
Other finding in diabetic nephropathy include hyaline arteriosclerosis affecting both
afferent and efferent arterioles (only afferent arterioles are involved in hypertensive
arteriosclerosis). In advanced cases, tubular loss and interstitial fibrosis are also present.
This is a normal glomerulus by light microscopy. The glomerular
capillary loops are thin and delicate. Endothelial and mesangial cells are
normal in number. The surrounding tubules are normal. Life is good.
This normal glomerulus is stained with PAS to highlight basement membranes of
glomerular capillary loops and tubular epithelium. The capillary loops of this normal
glomerulus are well-defined and thin.
This is nodular glomerulosclerosis (the Kimmelstiel-Wilson lesion) of
diabetes mellitus. Nodules of pink hyaline material form in regions of
glomerular capillary loops in the glomerulus. This is due to a marked
increase in mesangial matrix from damage as a result of non-enzymatic
glycosylation of proteins.
This is a PAS stain of nodular glomerulosclerosis (Kimmelstiel-Wilson
disease) in a patient with long-standing diabetes mellitus. Note also the
markedly thickened arteriole at the lower right which is typical for the hyaline
arteriolosclerosis that is seen in diabetic kidneys as well.
This PAS stain demonstrates diffuse glomerulosclerosis associated with
long-standing diabetes mellitus. There is an increase in mesangial matrix, a
slight increase in mesangial cellularity, and capillary basement membrane
thickening. These changes gradually advance until the entire glomerulus is
sclerotic.
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Answer 7:
Membranoproliferative glomerulonephritis. This involves all glomeruli to an equal
extent and shows increased glomerular cellularity. The lesions of diabetic glomerulosclerosis do not involve all glomeruli and show variation in severity between glomeruli.
There is no increase in cellularity. Amyloid can be distinguished by special stains such as
Congo Red and by typical fibrils on electron microscopy. Light chain deposit disease is
Congo Red negative and is granular on electron microscopy. Other conditions which
cause thickening of the basement membrane include membranous glomerulonephritis and
lupus nephritis.
This is membranoproliferative glomerulonephritis (MPGN). Those cases that
are idiopathic are divided into types I and II by pathologic findings. As seen
here, the glomerulus has increased overall cellularity, mainly increased
mesangial cellularity.
Here is the light microscopic appearance of membranous glomerulonephritis
in which the capillary loops are thickened and prominent, but the cellularity
is not increased. Membranous GN is the most common cause for nephrotic
syndrome in adults. Some cases of membranous GN can be linked to a
chronic infectious disease such as hepatitis B, a carcinoma, or SLE, but
many cases are idiopathic.
Seen here within the glomeruli are crescents composed of proliferating
epithelial cells. Crescentic glomerulonephritis is known as rapidly
progressive glomerulonephritis (RPGN) because this disease is very
progressive. There are several causes, and in this case is due to SLE. Note
in the lower left glomerulus that the capillary loops are markedly thickened
(the so-called "wire loop" lesion of lupus nephritis).
Glomerular disease with systemic lupus erythematosus (SLE) is common, and
lupus nephritis can have many morphologic manifestations as seen on renal
biopsy. In general, the more immune complex deposition and the more cellular
proliferation, the worse the disease. In this case, there is extensive immune
complex deposition in the thickened glomerular capillary loops, giving a socalled wire loop appearance.
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Answer 8
1. Diabetic patients are prone to develop papillary necrosis, especially in the
presence of acute pyelonephritis to which diabetics are also liable. It occurs in
25% of diabetic patients with acute pyelonephritis and is seen in 4% of diabetic
kidneys at autopsy. Its frequency is decreasing (because of earlier institution of
antibiotic therapy) but when present, it shortens survival. The blood supply to the
medulla is tenuous and further reduction due to diabetic vasculopathy and the
presence of inflammation may lead to necrosis. Necrotic tips of papillae can
slough off and be passed in the urine or may obstruct a ureter.
2. Diabetic patients have an increased incidence of occlusive vascular disease.
(Diabetes mellitus is a risk factor for atherosclerosis)
This is an ascending bacterial infection leading to acute pyelonephritis.
Numerous PMN's are seen filling renal tubules across the center and right of
this picture.
At high magnification, many neutrophils are seen in the tubules and
interstitium in a case of acute pyelonephritis. The neutrophils can collect in
the distal tubules and be passed in urine as WBC casts.
The pale white areas involving some or all of many renal papillae are areas
of papillary necrosis. This is an uncommon but severe complication of acute
pyelonephritis, particularly in persons with diabetes mellitus. Papillary
necrosis may also accompany analgesic nephropathy. [Image courtesy of
Dr. John Nicholls, Hong Kong University]
The large collection of chronic inflammatory cells here is in a patient with a
history of multiple recurrent urinary tract infections. This is chronic
pyelonephritis.
Both lymphocytes and plasma cells are seen in this case of chronic
pyelonephritis. It is not uncommon to see lymphocytes accompany just
about any chronic renal disease: glomerulonephritis, nephrosclerosis,
pyelonephritis. However, the plasma cells are most characteristic for chronic
pyelonephritis.
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Answer 9:
Secondary hyperparathyroidism in which all four parathyroid glands become hyperplastic
and parathormone production is markedly increased. This leads to renal osteodystrophy.
The spectrum of changes seen in the bone is complex. There is an interrelation between
renal failure, secondary hyperparathyroidism and altered vitamin D metabolism.
Parathyroid hyperplasia is shown here. Three and one-half glands have
been removed (only half the gland at the lower left is present). Parathyroid
hyperplasia is the second most common form of primary
hyperparathyroidism, with parathyroid carcinoma the least common form.
Chronic glomerulonephritis is an important cause of chronic renal failure. It is the end
stage of a number of specific types of glomerulonephritis but also of conditions whose
aetiology is unknown. The features are shown in the following illustrations which are
preceded by an example of a normal kidney.
Here is a normal adult kidney. The capsule has been removed and a pattern
of fetal lobulations still persists, as it sometimes does. The hilum at the mid
left contains some adipose tissue. At the lower right is a smooth-surfaced,
small, clear fluid-filled simple renal cyst. Such cysts occur either singly or
scattered around the renal parenchyma and are not uncommon in adults.
And finally, if all else fails, call it "chronic glomerulonephritis". Seen here are
atrophic kidneys with a thin cortex from a patient at autopsy with chronic
renal failure (CRF). About a third to half of patients with CRF slowly reach
end stage without significant signs or symptoms along the way, and at the
end stage renal disease (ESRD) there are no diagnostic features and,
therefore, no point in performing a renal biopsy. A steadily rising serum
creatinine and urea nitrogen are clues. Most patients will also be
hypertensive. (Some simple cysts are also seen here.)
The end result of many renal diseases -- whether they are renal vascular
diseases, glomerulonephritis, or chronic pyelonephritis--is end stage renal
disease (ESRD). In ESRD, the kidneys are small bilaterally, as shown here.
This condition is associated with chronic renal failure, and the patient's
blood urea nitrogen (BUN) and serum creatinine continue to increase.
Chronic renal failure can be treated by dialysis or by kidney transplantation,
as shown here.
The microscopic appearance of the "end stage kidney" is similar regardless
of cause, which is why a biopsy in a patient with chronic renal failure yields
little useful information. The cortex is fibrotic, the glomeruli are sclerotic,
there are scattered chronic inflammatory cell infiltrates, and the arteries are
thickened. Tubules are often dilated and filled with pink casts and give an
appearance of "thyroidization."
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