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Glomerular Filtration &

Acute Renal Failure

Renal Blood Flow


Majority of RBF is directed to the cortex, with
only a small proportion delivered to the medulla
Thus the medulla is very sensitive to reduction in
RBF & oxygen delivery that may induce hypoxia,
and result in tubular damage, causing acute
renal failure Acute Kidney Injury / AKI
Main determinant of overall RBF :
State of vasoconstriction of the renal arterial tree

Glomerular Filtration
Process of filtration occurs across a complex
barrier consisting of
Thin fenestrated endothelial lining of the glomerular
capillary
The glomerular basement membrane
The foot processes of the epithelial cells

This filtration barrier allows free passage of


solutes
Up to a molecular weight of around 60,000D
But retain cells and protein within the circulation

Afferent art.

Efferent art
Pgc = 45 mmHg
Pt = 10 mmHg
gc = 25 mmHg
Puf = 10 mmHg

An overall expression of GFR:


GFR = Kf X P uf
Kf= ultrafiltration coefficient, made up of the product of the hydraulic
permeability of the filtration membrane times the surface area available
for filtration
Factors which interfere with any of these determinants of glomerular
filtration may lead to an abrupt fall in GFR and thus acute renal failure
unless adequate compensatory responses occur
The most important physiological determinant is the capillary
hydrostatic pressure, which may be reduced by
Reduction in perfusion pressure reaching the afferent arteriole
Increase in afferent arteriolar tone
A decrease in efferent arteriolar tone

Pressure in the tubular system may rise significantly during ureteric


obstruction, thus reducing the GFR
Changes in plasma oncotic pressure are less important in altering GFR
in physiological or pahological conditions
Pathologies involving the glomeruli may lead to alteration in the
ultrafiltration coefficient and impair GFR by
Decreasing the hydraulic permeability
Obliterating the total capillary surface area available for filtration
E.g. glomerulonephritis, DM

In the normal kidney minor perturbations in


levels of individual substances do not have
significant net effects on GFR because of
compensatory changes in other factors which
tend to maintain a haemodynamic steady state
If renal function is impaired, particularly because
of a low renal perfusion pressure, maintenance
of GFR is highly dependent on intrinsic
compensatory mechanisms such as afferent
arteriolar vasodilatation (PG) and efferent
arteriolar vasoconstriction (AII)
Factors that interfere with these mechanisms
NSAIDS, ACE-I, ARB blunt these
compensatory responses and may precipitate
ARF

Autoregulation of RBF & GFR

The myogenic mechanism


Intrinsic capacity of the afferent arteriolar smooth muscle cells to
increase their state of contraction in response to an increase in renal
perfusion pressure
This response, probably mediated by vasoactive agents produced by
endothelial cells acting on smc in the afferent arteriole, serves to blunt
the transmission of changed arteriolar pressure into the glomerular
capillary bed

The Tubuloglomerular feedback (TGF)


GFR in individual nephrons is regulated according to the rate of solute
flow through that (distal tubule) nephron
The ionic composition (and indirectly the flow rate) of the tubular fluid
can be sensed by the macula densa
Which signals directly to the vascular structures of the glomerulus to
influence GFR
During periods of avid tubular NaCl reabsorption, the [Na] of the luminal
fluid is reduced at the macula densa
Filtration in the corresponding glomerulus is increased, primarily by dilatation
of the afferent arteriole

When NaCl concentration and fluid delivery are high at the macula
densa,
afferent arteriole tone is increased and single nephron GFR falls

The mediator of the vasoconstrictor response involved in TGF appears


to be locally produced Adenosine, acting via the A1 receptor on the
afferent arteriole

Renal secretion and clearance


The rate at which a solute (s) is excreted by the kidney
(Es) is given by the product of the concentration of the
solute in the urine (Us) and the urine flow rate (V), which
is the urine volume over a defined period
Es = Us X V mmol/min, mg/min
The renal clearance (Cs) of solute (s) is defined as the
apparent volume of plasma from which the substance is
completely removed per unit time during passage
through the kidneys.
It is equivalent to the ratio of the excretion rate to the
simultaneous plasma concentration for that substance
(Ps)
Cs = (Us X V) / Ps ml/min,

Measuring the glomerular filtration rate

Inulin is freely filtered at the glomerulus and undergoes no reabsorption or secretion


During its passage through the tubular system. GFR = inulin clearance

In practice, an endogenous molecule whose


behavior approximates that of inulin is used for
clinical determination of GFR
CREATININE
For a given individual, the amount of creatinine
entering the circulation per day is dependent
almost exclusively on the skeletal muscle mass.
As long as renal function is stable, this same
daily amount will be excreted in the urine
Cr, like inulin is freely filtered at the glomerulus
and undergoes no tubular reabsorption, although
there is a small degree of secretion by the
tubules when renal function is impaired; may
increase to 30% at low GFR

Plasma Cr only starts to increase when


approximately 50% of renal function (GFR) is
already lost
Each such relationship is specific to a given
individual with a particular muscle mass, making
comparison of plasma Cr between patients of
different body size / muscle mass difficult
Crockcroft & Gault formula:
(140 age) X weight (kg)
Estimated GFR (ml/min) = 72 X plaama [Cr] (mg/dl)
X0.85 for women

Estimation of GFR with Modified Abbreviated MDRD Equation for Chinese, and a Composite Equation
Constituted From Modified MDRD Equation and the Solely cysC-based Equation. Hitachi Pcr was put into
modified abbreviated MDRD equation to estimate GFR (eGFR 3) (R2=0.86, standard deviation of residual=0.136,
P<0.001 for model fitting):[9]

Urea
Synthesized in the liver from amino acid metabolism
Freely filtered at the glomerulus, but
Undergoes approximately 50% reabsorption during
passage through the nephron.
The clearance of urea is approximately half the GFR,
and plasma urea varies inversely with GFR
The fraction of filtered urea that is reabsorbed is not
constant, being greater during conditions of dehydration
and low urine flow rate
It is also related to the amount of protein absorbed from
the gut, and to the protein catabolic rate

Acute Renal Failure


Acute Kidney Injury

ARF is a clinical term that encompasses many causes of


abrupt renal impairment;
that is, a fall in GFR over a period of hours to days which
results in impaired fluid & electrolyte homeostasis and
the accumulation of nitrogenous wastes.
The most common causes are haemodynamic,
immunological, toxic & obstructions.
Major predisposing factors include volume depletion,
drugs, and radiocontrast agents.
Elderly, diabetic, and chronically hypertensive patients
are at particular risk because of their predisposition to
underlying vascular disease & poor renal autoregulatory
responses
In the hospital population, hypotension, heart failure,
sepsis, and aminoglycoside use are common additional
factors
Sustained circulatory failure leading to ischemia-induced
ATN accounts for the majority of cases of ARF

In volume depletion,
depletion there is a decrease in renal plasma
flow, decrease in the intraglomerular capillary pressure.
Filtration fraction will remain the same under these
circumstances and GFR will fall. This is before the
neurohumoral responses kick in.
In response to this change in renal plasma flow, renal blood
flow, we have activation of the renin angiotensin system,
angiotensin II causing vasoconstriction and then a response
as well of vasodilatory prostaglandins causing a reduction in
the vasoconstriction in the afferent arteriole.
This results in actually a further decline in the glomerular
plasma flow but because of the vasoconstriction in the
efferent arteriole, intraglomerular pressure is restored to
normal, filtration fraction actually rises, and GFR is
maintained at a normal level; at the expense though of an
increase in sodium reabsorption and urea reabsorption
triggered both by the increase in angiotensin levels and the
increase in filtration fraction.

FE (urea)

<35%

>35%

Acute Tubular Necrosis

ATN: Urine sediment


The urine sediment classically has many tubular epithelial cells and granular casts, as
shown here with the classic muddy brown casts of ATN.

As a result of the endothelial injury, there is activation of


vasoconstrictors, impaired vasodilatation, endothelin
release, and nitric oxide inhibition.
There is increased expression of adhesion molecules
and increased leukocyte adhesion.
This goes on to cause capillary obstruction, continued
ischemia, which extends the tubular injury, goes back
and actually feeds back for further endothelial injury, but
importantly, both the tubular cell injury and the
endothelial injury trigger an inflammatory response that
also amplifies the injury to the kidney.
It has been shown that blocking of this inflammatory
response can actually ameliorate the injury and shorten
the course of acute renal failure in animal models.

Inflammation and leukocyte activation in ischemic


ATN
There is local production of inflammatory mediators, so
we have cytokines, complement, platelet activating
factor, metabolites of arachidonic acid, the production of
reactive oxygen species, and expression of the adhesion
molecules.
The activated leukocytes then infiltrate into the
interstitium, have further release of these mediators,
bringing in more lymphocytes and monocytes, further
injury, maintaining and extending the injury. When you
look at a patient who has ATN histologically, the
pathologist will frequently say there is ATN, but there is
also interstitial nephritis. The interstitial nephritis does
not mean there are two processes going on. The
interstitial nephritis that is seen, the interstitial
inflammation, is part and parcel of the ATN.

ATN is not just a disease of the kidneys,


The inflammatory process that is triggered in the kidney has systemic
effects. This is shown in animal models
Renal ischemia raises systemic tumor necrosis factor levels.
At the heart, there is increased expression of ICAM-1, one of the adhesion
molecules, that develops in the rats following ischemia, but not in the sham
animals. There is infiltration of the cardiac tissue by inflammatory cells. You
can demonstrate that there is change in cardiac contractility.
That there is an increase in apoptosis of the cardiac myocytes. This is seen
increasing progressively with duration of ischemia that is independent of the
magnitude of azotemia that develops, but is not seen with nephrectomy
despite the more severe degree of azotemia with nephrectomy - so that is
not a factor of the renal failure causing the injury to the heart. It is the renal
ischemic injury, and this can also be seen in cytotoxic injury.
Renal ischemia reperfusion injury alters the expression of sodium channels
and water channels in the lung with a decreased expression of the epithelial
sodium channel and aquaporins, which is associated with a decrease in the
clearance of lung water, so that increased lung water and respiratory
compromise may occur independent of oliguria in patients with acute renal
failure.

Radiocontrast nephropathy.
Is an increase of serum creatinine of 25% at 48 hours or
72 hours; or 50% increase or 100% increase, or is it an
increase of 0.5 or increase of 1 mg/dL?
Increases in serum creatinine are associated with an
increase in mortality, but a decrease in the number of
patients.
Even an increase in serum creatinine of less than 50%,
namely, a 25% to 50% increase in creatinine, is
associated with a doubling in mortality. There is about a
five-fold increase in mortality in patients who have a 50%
to 100% increase in serum creatinine. So small changes
may be important.

The first group received normal saline at 1 mL/kg per hour for 12 hours, pre and post
procedure, a second group that received saline plus mannitol, and a third group that
received the same volume load plus furosemide.

Diuretic Therapy in
ATN

Mehta RL, et al. JAMA 2002; 288:2547-2553

Acute interstitial nephritis. A biopsy from a patient with acute interstitial nephritis
showing the lymphocytic infiltration with many eosinophils in the interstitial.

White cell cast

Hansel stain of the urine


showing eosinophiluria

Acute glomerulonephritis. The characteristic finding that should tip you off to this is the
presence of dysmorphic red cells and red blood cell casts in the urine.

Illustrating the histologic finding in atheroembolic disease of an arteriole with a


characteristic cholesterol plaque in the atheromatous embolus here, and this is
surrounded by a reactive process; and, as time goes on, you get an inflammatory
process and then obliteration of the vasculature.

The renal manifestations of atheroembolic disease may be subacute


renal failure where the renal failure progresses slowly, frequently in
a stuttering fashion over a period of days to weeks, frequently after
an angiographic manipulation.
Sometimes confused with contrast nephropathy. However, contrast
nephropathy will usually have its onset within 24-36 hours and will
have the peak serum creatinine in 3-5 days whereas atheroembolic
disease may not have its onset for several days after the catheter
manipulation.
There may be a fulminant atheroembolism, fulminate showering with
acute renal failure that may be oliguric or anuric.
You may just see exacerbation of hypertension in a patient with
preexisting hypertension.
The patients may develop proteinuria. They may actually develop
nephrotic syndrome, which is associated with a histology of focal
and segmental glomerulosclerosis.
They may present with hematuria or they may have renal infarction.

Anticoagulation may precipitate recurrent


showers of atheroemboli.

Late recovery of renal function may occur.