GENERAL PATHOLOGY OF THE KIDNEY

A/Professor John Finnie

University Veterinarian, Office of the Deputy Vice-

Chancellor (Research)
University of Adelaide
 The kidneys:
“A pair of handy tea strainers”
The following extract from the ABC’s “Body Programme”, written by Dr Earle
Hackett, a former haematologist at the Institute of Medical and Veterinary
Science in Adelaide, neatly outlines the principal functions of the kidney and why
it is vulnerable to damage
 Renal characteristics

It is at the butchers that most people get a butchers at a pair of kidneys. There is one very
noticeable thing about them. The arteries and veins entering and leaving appear to be very large
….. almost a quarter of the circulating blood goes through the kidneys each time around

Everyone knows from experience that if you drink liquid, however turbid or flavoured or mixed,
before long some clear straw-coloured pee will flush out at your other end. Some kind of
filtering is going on. The connecting channel is the bloodstream. Water is absorbed into the
blood from the gut and removed from the bloodstream by the kidney. So what the kidney is
filtering is not tea, or beer, but blood. Urine is a concentrated filtrate of the blood
 Renal characteristics

The main artery that enters each kidney promptly branches and re-branches until
it has finally divided into about a million small blood vessels, tangled like a ball of
thread, termed a glomerulus (from glomus, a Roman lady’s ball of thread)

Each glomerulus hangs like a nipple into a small cellular receiving funnel that is
closed around it like a baby’s lips. Each of these funnels has a draining outlet that
connects up with its million fellows through collecting tubules to form the ureter
that carries pee to the bladder
 Renal characteristics

The fine walls of the very small blood vessels that form the glomerulus are leaky. They leak like sieves. They have
sieve holes that only hold back large molecules in the blood like plasma proteins, but let everything else through.
There are also a few smaller protein molecules that the sieve would not retain were it not for electrostatic
attractions

But everything else pours out from the blood through the little sieve holes into the collecting funnels – water
(gallons of it), salt, sugar, amino acids, bicarbonate, potassium, calcium, phosphates, and urea – everything small
and soluble. The only things that are held back are those that are differentially kept in the blood by being
specifically carried on large, special blood plasma molecules into which they are temporally slotted. If this was all,
the kidneys would be no more than blood strainers
 Renal characteristics

But you need most of the water and the sugars and salt and so on that is being filtered out at an enormous rate. The blood
vessel still continues in the kidney after it leaves the glomerulus
It continues beside the cell walls of the urinary tubule in which the watery filtrate is now flowing. The blood pressure in that
blood vessel is now slacker. The effect is that much of the water and sugar and salt in the filtrate moves back by osmosis across
the tube wall into the blood again

The rest of the urinary collecting tubes are quite lengthy, are lined by active cells that use energy to return to the blood the rest
of the sugar, salts and amino acids and so on that the body does not want to lose

So by this combined mechanism of heavy filtration followed by first passive and then specific chemical reabsorption, the kidney
eventually allows a concentrate of about 2 litres to run out as pee every 24 hours. Therefore, out of all that filtering of 200 litres
from the blood, 198 litres has been absorbed back into the blood again
 Renal characteristics

The kidney is cleansing the soluble components of the house of the body by constantly flinging
everything out, then reorganising and bringing back in again only the familiar and the useful,
and leaving the rest to leak away as unwanted sewerage

However, where the kidneys are vulnerable is where they are exceptional; which is where they
handle so much blood and where they concentrate things. For example, some mildly harmful
component that is in the circulation and damages small blood vessels could have heavy local
effects in the kidney. So also might a small amount of a cell poison that could have become extra
active when concentrated in the kidney tubules
 Renal functions
Central organ involved in maintenance of a constant extracellular environment in the body

Vital homeostatic functions are:

Excretion of waste products

Maintenance of normal concentrations of salt and water in the body
Regulation of acid-base balance
Production of hormones (erythropoietin, renin, prostaglandins)
Metabolism of vitamin D to its active form
 Essential requirements for normal renal function

Adequate perfusion with blood (pressure >60mmHg) – renal blood flow is

high (up to 25% of cardiac output) and decreased blood flow causes injury,
especially to the cortex. It is only reduced to preserve circulation to heart
and brain

Adequate functional renal tissue

Normal elimination of urine

 Renal functions

Water and salt are the most important constituents of body fluids and need to be conserved

Large quantities of metabolites also need to be excreted (nitrogenous wastes and a multitude
of other organic and inorganic substances)

Excretion of wastes and conservation of water requires a concentrating mechanism capable of

raising the osmotic pressure of urine above that of blood

Renal blood flow remains constant to ensure a stable glomerular filtration rate (GFR)
 Renal functions

The glomerulus produces an ultrafiltrate due to high capillary hydrostatic pressure and low hydrostatic pressure in
Bowman’s space and difference in osmotic pressure. The glomerular basement membrane (GBM) is semi-
permeable

Injury to the glomerulus can result from inadequate glomerular blood flow and/or structural changes that alter its
permeability

After crossing the GBM, the ultrafiltrate enters the tubular lumen and many filtered substances are then retrieved
by selective reabsoption

Main function of the kidney is regulation of salt and water balance, achieved by antidiuretic hormone (ADH) (also
termed vasopressin) and the renin-angiotensin-aldosterone system
 Renal pathology

In progressive renal disease, remaining nephrons hypertrophy as new nephrons cannot be

formed in a mature kidney and glomerular filtration and tubular function increase to maintain
homeostasis

All of the renal components are interdependent and, if one component is irreversibly damage,
the function of other components will be impaired

There is a tendency for chronic renal disease to affect multiple kidney components, resulting in
chronic renal failure and shrunken, scarred, end-stage kidneys (at which time, it can be
impossible to determine the initiating cause)
 Renal anatomy

Kidneys in domestic animals are classified as unipyramidal or unilobar (cats, dogs, small ruminants and horses) or
multipyramidal or multilobar (pigs, cattle)

On section, subdivisions of cortex and medulla are discernible

The functional unit of the kidney is the nephron, which consists of the renal corpuscle (glomerulus and Bowman’s
capsule), proximal and distal convolute tubules and the loop of Henle

4 main components of kidney: glomeruli, tubules, interstitium and blood vessels

MULTIPYRAMIDAL BOVINE KIDNEY
 Renal vascular supply

Renal artery divides to form interlobular arteries, which then branch as arcuate
arteries, then becoming interlobular arteries which in turn form prearterioles

Prearterioles give rise to glomerular afferent arterioles, then glomerular capillary

loops, which fuse to form efferent arterioles, then the peritubular capillary plexus

The glomerular capillary tufts are perfused at high pressure for filtration and the
capillary bed arising from efferent arterioles is low pressure for reabsorption
 Renal vascular supply

Renal arteries are end-arteries and occlusion leads to

infarction

Medulla is very sensitive to ischaemia because of its

relative avascularity
 Glomerular filtration

Glomerular filtration rate (GFR) is controlled by tubuloglomerular feedback – low GFR causes
decreased NaCl delivery to distal tubules, which is detected by the macular densa in these
tubules, leading to contraction of efferent arteriole and dilation of afferent arteriole, increasing
the GFR. A high GFR initiates the opposite response

Macula densa secretes prostaglandin E2, causing renin release from afferent arteriole
juxtaglomerular cells, which acts on angiotensinogen (produced by liver) to generate
angiotensin I which, in turn, is cleaved by angiotensin converting enzyme to angiotensin II, a
potent vasoconstrictor
 Angiotensin II also initiates (1) adrenocortical release of
aldosterone, which increases resorption of Na from distal
tubules and collecting ducts, resulting in water retention and
(2) secretion of ADH by the posterior pituitary, which increases
water resorption (via aquaporin channels) in collecting ducts
 Glomerulus

Vascular and epithelial structure designed for the ultrafiltration of

plasma
Visceral epithelium (podocytes) covers the abluminal surface of
glomerular capillaries, while parietal epithelium lines basement
membrane of Bowman’s capsule
Arterioles enter and leave the glomerulus at vascular pole and urine
enters proximal convoluted tubule at urinary pole
 Glomerular filtration membrane consists of 3 layers

Fenestrated capillary endothelium

Glomerular basement membrane (GBM), a complex, porous meshwork and size-

and charge-dependent barrier, produced by podocytes and endothelium

Podocytes, which have complex interdigitating trabeculae whose foot processes

(pedicels) are embedded in GBM. Pedicels are separated by filtration slits, which
are bridged by diaphragms with pores
 Glomerular basement membrane
GBM is highly permeable to water and small solutes, but
excludes high MW plasma proteins

Changes in GBM porosity and charge alter glomerular

permeability and can lead to proteinuria, a hallmark of
glomerular damage
The Irish surgeon and poet, Oliver St John Gogarty knew
the importance of proteinuria in renal disease, as can be
seen in the last 3 verses of his poem entitled: “John
Kidney who died of Acute Nephritis”
 For the walls of the And, though by the And there came
flesh which immure in doctors unbidden, he on the Dies
The spirit, as tubes do Passed out through Suprema
their lumen, these clouds to his That comes to all
Came urine, and, goal: who draw breath
mixed with the urine,
Albumen and coma Death, ushered in
Were clouds of and kidney by oedema,
albumen.
Secreted his soul. Oedema and
Death.
 Mesangium

Occupies the central region of glomerulus and composed of basement membrane-like glycoprotein and
phagocytic, contractile cells derived from vascular smooth muscle cells

Functions in phagocytic removal of macromolecules, removal of GBM, and may modulate

intraglomerular blood flow

Also produces a variety of cytokines

Mesanglial cell hyperplasia and increased mesangial matrix are common lesions in glomerular disease
 Renal tubules

These structures are correlated with function

Proximal convoluted tubule (PCT) has a well-developed brush border and numerous mitochondria and, since
energy for resorption is produced by mitochondrial oxidative phosphorylation, it is especially vulnerable to
hypoxia
Many toxins are resorbed/secreted by PCT, potentially causing chemical injury

60-80% of the glomerular ultrafiltrate is resorbed by PCT and the closely-associated peritubular capillaries permit
rapid absorption of Na and Cl, which water follows (also resorbs glucose, amino acids, Ca, K, uric acid, proteins and
phosphate – many of these are resorbed until a threshold is reached and, when this is exceeded, the substance
appears in urine)
 Renal tubules

Long loops of Henle penetrate deep into medulla and their urine concentrating ability is directly
related to their length. NaCl is actively pumped from ascending limb (which is impermeable to
water), draining water from descending limb and returning it to the cortex
If water preservation is required, ADH release increases the permeability of medullary
collecting ducts (CD) to urea and water. Urea diffuses into the interstitium and water follows

Kidneys ultimately correct acid-base balance by excreting excess alkali or acid responsible for
the disturbance
 Renal interstitium

Contains peritubular capillaries, pericytes, and

fibroblasts and any expansion (by oedema,
cellular infiltration, and fibrosis) is abnormal
 Histological examination of kidney

The kidney should be bisected longitudinally from

pole to pole into equal halves in order that a section
from capsule to papilla is for examination
 Reactions of glomeruli to injury
Combinations of:

Cellular proliferation
Mesangial expansion
Leucocyte recruitment
Remodelling of glomerular basement membrane (GBM)
Sclerosis
 Terminology

Uraemia (“urine in blood”) is a clinical syndrome of renal failure

Azotaemia is a biochemical abnormality characterised by increased

blood urea and creatinine, which can be prerenal (decreased renal
blood flow and lowered GFR) or postrenal (due to urinary tract
obstruction and hence oliguria or anuria)
 Renal tubular damage

Tubules, especially proximal convoluted tubule (PCT), are most

susceptible to ischaemia and toxins

Delay in fixation causes epithelial sloughing into the lumen

Proximal convoluted tubule epithelium may be present in Bowman’s
space due to squeezing of kidney, termed infraglomerular herniation or
reflux
 Renal failure

Renal disease is usually subclinical, but

When severe, can lead to renal failure which can be:
Acute and potentially reversible (rapid onset of oliguria (reduced urine
flow) or anuria (no urine flow) and azotaemia from glomerular, tubular
or interstitial damage or
Chronic and usually irreversible with prolonged uraemia
 Evolution from normal renal function to uraemia occurs in 4 stages

Diminished renal reserve – glomerular filtration rate (GFR) ~50% of normal and asymptomatic

Renal insufficiency – GFR 25-50% of normal and azotaemia occurs

Renal failure – GFR 20-25% of normal, kidney cannot maintain homeostasis, and uraemia
ensues

End-stage renal disease – GFR <5% of normal and terminal stages of uraemia are present
 Clinical pathology
Biochemical disturbances of uraemia reflect impairment of the kidney’s regulation of fluid volume
(resulting in dehydration), regulation of electrolytes (excess/deficit in plasma Na, K, and Ca) and acid-
base balance, excretion of wastes, and metabolism of hormones

Elevated blood levels of urea and creatinine indicate decreased glomerular filtration and are a useful
test of renal function, but

Azotaemia occurs only after loss of >75% of GFR and is thus an insensitive indicator of renal disease

Uraemia also causes a non-regenerative anaemia

 Renal disease

With “end-stage” kidney disease and severe uraemia, kidney is fibrosed and
mineralised (glomerulus and tubular basement membranes) with globally
sclerotic glomeruli and a mixture of atrophic and hypertrophic tubules

Interstitial fibrosis and glomerulosclerosis are slowly progressive lesions that are
common in end-stage renal disease, the former believed to be the final common
pathway to chronic renal failure
 Azotaemia

Azotaemia (increased blood urea nitrogen and creatinine) develops

when GFR is reduced to 25% of normal
Before this stage, adaptive changes in intact nephrons maintain renal
function at an adequate level as other nephrons are lost
The glomerulus is probably the limiting factor in this compensation as
it has relatively limited ability to increase its function
 Renal failure/infarction

Chronic renal failure tends to be progressive

GFR also decreases with normal ageing, leading to decreased renal reserve and lowered
compensatory ability

Renal infarction is common due to necrosis produced by embolic and thrombotic occlusion of
the renal artery or one of its branches and sequelae depend on whether the obstructing
material is septic or sterile and size and number of vessels occluded
 Glomerular disease

Important because interference with glomerular blood flow alters the formation of an ultrafiltrate and
impairs peritubular perfusion, which can lead to loss of an entire nephron

Glomerulitis = inflammation restricted to glomerulus (e.g. in acute septicaemia)

Glomerulonephritis implies primary glomerular disease is complicated by secondary tubulointerstitial

and vascular changes

Glomerulopathy = glomerular disease without inflammatory cells or of uncertain

aetiology/pathogenesis
 Glomerular disease

Proteinuria as a result of increased glomerular permeability is

suggestive of glomerular disease, in the absence of urinary tract
inflammation.

When there is proteinuria, hypoalbuminaemia, generalised oedema

and hyperlipidaemia, the term nephrotic syndrome is applied
Proteinuria leading to the formation of many protein casts in tubular lumina
 Glomerular disease
Can be:

Diffuse (involves >50% of glomeruli)

Focal (involves <50% of glomeruli)
Global (involves the entire glomerular tuft)
Segmental (involves only part of a glomerulus)
Mesangial (affects primarily the mesangial region)
 Classification of glomerular disease

Glomerular disease can be further classified as:

Membranous – GBM remodelling secondary to immune complex deposition with

normal to mild hypercellularity

Proliferative – increased cellularity without significant alterations to GBM

 Classification of glomerular disease (cont)

Mesangioproliferative – increased cellularity limited to mesangium with evidence of immune complex deposition
in this region

Mesangiocapillary proliferation – capillary and mesangial proliferation with remodelling of capillary loop from
immune complex deposition between endothelium and GBM

Segmental glomerulosclerosis – segmental effacement of capillary loops by ECM

Global glomerulosclerosis – tuft is shrunken, eosinophilic and hypocellular

 Histological changes in glomerular disease

Cellularity of glomerular tuft may be increased by proliferation of endothelial,

epithelial or mesangial cells + inflammatory cell infiltration
Mesangial cells may also migrate out into capillary loop (mesangial cell
interpositioning)
Fibrin exudation and rupture of GBM results in proliferation of visceral and
parietal epithelium + infiltration of macrophages, neutrophils and interstitial
fibroblasts, forming glomerular crescents
 Histological changes in glomerular disease

Swelling of foot processes with subsequent retraction –

reversible and associated with protein leakage

Thickening and remodelling of GBM due to immune complex

deposition
Chronic diffuse immune-mediated glomerulonephritis. Cortical surface is finely
granular.
Chronic glomerulonephritis – thickening of glomerular and capsular basement membranes (PAS stain)
Glomerulonephritis – left panels show glomerular basement membrane thickening (PAS stain) and right
panels show the pattern of immunofluorescence staining for IgG deposition
Fibrinous glomerulonephritis – fibrin deposition and leucocytic
infiltration
Chronic glomerulonephritis – thickening of glomerular and capsular basement membranes and hyperplasia
of parietal epithelium. Interstitial lymphocytic infiltration.
 Protein cast

Chronic glomerulonephritis – abundant periglomerular fibrosis and hypercellularity of glomerular tuft

Chronic glomerulonephritis – “end-stage” glomerulus with marked basement membrane thickening and hyalinisation
 Pathogenesis of glomerulonephritis

May result from:

Deposition of circulating, non-glomerular origin, antigen-antibody immune complexes
in various glomerular sites (subendothelial, intramembranous, subepithelial, mesangial)

Formation in situ of antibodies against intrinsic GBM antigens

Activation of the alternative pathway of complement

Idiopathic
 Pathogenesis of glomerulonephritis

Once immune complexes have formed, complement fixation occurs

with resultant chemotaxis of neutrophils, which ingest complexes, but
also release lysosomal enzymes, cytokines and free radicals that cause
GBM damage
Complement fragments cause histamine release from mast cells, which
increases capillary permeability and allows deposition of more immune
complexes
 Pathogenesis of glomerulonephritis

Many glomerular, tubular and interstitial elements also release

chemokines (chemotactic cytokines) that attract leucocytes

Monocytes can remove immune complexes, but also cause enzymatic

damage and mesangial cells can produce inflammatory mediators
 Morphology of glomerulonephritis

In the acute phase, there is hypercellularity, mostly due to

inflammatory cell infiltration, but also endothelial and mesangial
proliferation

In subacute phase, often mesangial hypercellularity and/or remodelling

of GBM
 Morphology of glomerulonephritis

In chronic phase, scarring of glomeruli occurs, the interstitial reaction initiated in acute
phase progresses with fibrosis and lymphocytic infiltration, tubules atrophy and are
replaced by scar tissue, and fibrosis becomes self-perpetuating

Remaining tubules connected to functioning glomeruli show epithelial

hypertrophy/hyperplasia

Once GFR has decreased to 30-50% of normal, progression to end-stage renal failure
tends to become unavoidable
 Diseases of renal tubules

Primarily reflected in morphological changes in epithelial cells, but

tubules and interstitium are intimately associated and damage to one
affects the other

Diseases involving both simultaneously = tubulointerstitial diseases

Regeneration of tubular epithelium can occur

 Histopathology of tubular damage

Acute cellular swelling results from damage to mitochondria with clear spaces/vacuoles in epithelial cytoplasm
(potentially reversible)

Necrotic tubular epithelial cells are hypereosinophilic, have pyknotic nuclei and slough into the lumen, where they
form cellular casts

Tubules filled with proteinaceous fluid usually indicates increased glomerular permeability and hyaline droplets
form in PCT cytoplasm (lysosomes swollen by resorbed protein). Tamm-Horsfall mucoprotein is produced in
ascending loop of Henle and distal tubules

Thickening of tubular basement membrane occurs in chronic disease and, in renal amyloidosis, amyloid deposition
occurs in tubular basement membrane as well as glomeruli
Degeneration and desquamation of tubule lining epithelium

Leucocytic cast (neutrophilic)

Acute tubular necrosis

 Amyloid

Renal amyloidosis – amyloid deposition in glomeruli (Congo red stain)

 Acute tubular injury

Acute tubular injury is an important cause of acute renal failure,

produces oliguria/anuria, and can cause death in days, chiefly caused
by ischaemia and nephrotoxins

Haemoglobin from massive haemolysis and myoglobin from severe

skeletal muscle breakdown are also primary nephrotoxins
Haemoglobinuric nephrosis
Haemoglobinuric nephrosis – numerous haemoglobin casts in tubular lumina
 Tubulointerstitial disease

Involve both interstitium and tubules and acknowledges that these

inflammatory and degenerative diseases almost always impair tubular
function

Caused by a vast array of agents, including infections, toxins,

immunological disorders, chemicals and therapeutic drugs
 Tubulointerstitial disease

Clinically, usually results in impaired urine concentrating ability or specific tubular defects of resorption or
secretion

Histologically, interstitial inflammation and fibrosis and tubular dilatation and atrophy (versus persistent
proteinuria with glomerular disease)

Non-suppurative interstitial nephritis – focal lymphohistiocytic inflammation with slight scarring is common in
domestic animals (e.g. leptospirosis)

Suppurative interstitial nephritis – with bacterial infection, either haematogenous (embolic suppurative nephritis)
or ascending from the lower urinary tract (pyelonephritis with inflammation of pelvis and renal parenchyma)
Suppurative nephritis – numerous pale nodules
Multifocal embolic bacterial nephritis – scattered pale cortical foci