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RENAL PHYSIOLOGY

Renal Blood Flow (RBF)


RBF is regulated by changes in vascular resistance of all the arteries up to and
including the efferent arteriole, which in turn is regulated by a variety of neurohormonal
signals.
Blood enters the kidney through the renal arteries and divides into progressively
smaller arteries (interlobar, arcuate, and interlobular arteries) until it enters the glomerular
capillary through the afferent arteriole. A portion of the plasma that enters the glomerulus is
filtered across the glomerular membrane; this is called the filtration fraction. The rest of the
blood exits the glomerular capillary through the efferent arteriole. In nephrons located in the
renal cortex, these capillaries travel in close proximity to the tubules and modulate solute and
water reabsorption. In juxtamedullary nephrons (located deeper in the medulla), the efferent
arterioles branch out to form vasa recta, which participate in the countercurrent mechanism
through which urine is highly concentrated and body water conserved.
Under normal resting conditions, RBF is 20% of total cardiac output. Total blood flow
is different for men and women, averaging 982 184 mL/min in women and 1209 256
mL/min in men. Renal plasma flow (RPF) is slightly less, averaging 592 mL/min in women
and 659 mL/min in men, and varies with hematocrit (RPF = RBF [1Hct]). RBF is not
evenly distributed to all parts of the kidney. Flow to the outer cortex is 2 to 3 times greater
than that to the inner cortex, which in turn is two to four times greater than that to the
medulla.
Determinants of Glomerular Filtration
The most important function of the kidney is the process of glomerular filtration.
Through the passive ultrafiltration of plasma across the glomerular membrane, the kidney is
able to regulate total body salt and water content, electrolyte composition, and eliminate
waste products of protein metabolism.
The process of filtration is analogous to fluid movement across any capillary wall, and
is governed by Starling forces. The glomerular filtration rate (GFR) is thus determined by
both hydraulic and oncotic pressure differences between the glomerular capillary and the
Bowman space, as well as by the permeability of the glomerular membrane:
GFR = LpS (hydrostatic pressure oncotic pressure)
where Lp = glomerular permeability and S = glomerular surface area.
The rate at which filtration occurs within an individual nephron is termed the single
nephron GFR (SN-GFR). A more relevant measurement is that of total GFR, which is the
sum of all SN-GFR and is expressed in milliliters per minute. GFR is thus a reflection of
overall renal function. Alterations in GFR can occur either with alterations in any aspect of
Starling forces, or through a change in renal plasma flow (RPF).
1. Transglomerular (hydraulic) pressure (TGP)the most significant determinant of GFR is
the TGP. Although systemic arterial pressures impact on TGP, the glomerular capillary is
unique in that it is interposed between two arterioles (the afferent and efferent arterioles)
and thus can regulate intraglomerular capillary pressure (IGP) independent of systemic
pressures through changes in afferent and efferent arteriolar tone. Under normal
circumstances, the pressure within the Bowman space is essentially zero, and only in
conditions of urinary obstruction does the pressure increase to clinically significant levels.
Thus the TGP = IGP.

2. Renal plasma flowincreases in RPF lead to increases in GFR. Although the filtration
fraction cannot exceed 20% under normal circumstances, an increase in RPF will lead to
an increase in absolute GFR.
3. Glomerular permeabilitygenerally, an increase in permeability does not lead to an
increase in GFR, because the glomerulus is already at maximal permeability for water and
other relevant solutes. It may, however, lead to increased filtration of larger molecules not
normally filtered, such as albumin. Reductions in permeability, or in glomerular surface
area, can lead to reductions in GFR.
4. Oncotic pressurethe least relevant of all the variables. Under normal circumstances,
plasma proteins are not filtered across the glomerular membrane and so oncotic pressure
within the Bowman space is essentially zero.
Regulation of Glomerular Filtration Rate
Under normal circumstances, GFR is tightly maintained at a relatively constant
level, despite large fluctuations in systemic arterial pressures and renal blood flow. This
is accomplished through the processes of autoregulation and tubuloglomerular feedback.
1. Autoregulationwith increases in mean arterial pressure (MAP), afferent arteriolar tone
increases to minimize increases in IGP. Similarly, with reductions in MAP, afferent
arteriolar tone decreases to allow increased flow into the glomerulus to maintain IGP, thus
maintaining GFR. Autoregulation of IGP is effective to a MAP of about 70 mm Hg; below
that, reductions in MAP lead to similar reductions in GFR, and below a MAP of 40 mm
Hg, filtration ceases. The mechanism(s) by which autoregulation is achieved is not well
understood. It is likely mediated through myogenic stretch receptors in the afferent
arteriole wall, possibly mediated by adenosine triphosphate (ATP), but angiotensin II is
also involved with more severe fluctuations.
2. Tubuloglomerular feedback (TGF)tubular ultrafiltrate flow rates are monitored by cells
in the macula densa. If SN-GFRincreases, delivery of sodium cations (Na+) and chloride
anions (Cl) to the distal tubule also increases. This increased Cl delivery triggers a
response by the macula densa, which ultimately leads to an increase in afferent arteriolar
tone and subsequent decrease in RPF, thus returning SN-GFR (and tubular flow) back to
baseline. Thus TGF can be thought of as a mechanism to minimize salt and water losses
through regulation of GFR. The mediators of this response are not well understood, but it
seems that angiotensin II plays a permissive role in TGF. Both adenosine and thromboxane
can cause afferent arteriolar vasoconstriction and have been implicated in TGF. Nitric
oxide is also believed to be important, particularly in minimizing TGF in the setting of
increased NaCl intake.
Under abnormal conditions however, neurohumoral responses become more
important. With significant reductions in effective circulating volume (ECV), both
norepinephrine and angiotensin II play an important role in maintaining GFR through
arteriolar vasoconstriction, often at the expense of reduced RPF. Notably, renal
prostaglandins (PGs) and nitric oxide offset afferent arteriolar vasoconstriction; so, arteriolar
tone is a balance between the vasoconstrictive and vasodilatory effects of the abovementioned hormones. Inhibition of PG synthesis (due to administration of nonsteroidal antiinflammatory drugs), particularly in states of high angiotensin II production, can lead to
severe vasoconstriction and acute reduction in GFR. In contrast, norepinephrine and
angiotensin II levels are diminished in states of volume expansion, while dopamine and atrial
natriuretic peptide levels are increased to facilitate an increase in RPF (dopamine) and
natriuresis (atrial natriuretic peptide [ANP]), thus returning volume status back to normal.

Clinical Assessment of Glomerular Filtration Rate


Unfortunately, GFR cannot be measured directly. It can, however, be estimated by a
variety of methods, some more accurate (but usually more cumbersome) than others.
Renal Clearance. The best estimate of GFR can be obtained by measuring the rate of
clearance of a given substance from the plasma. However, in order to be accurate, the
substance to be measured must meet certain criteria. It must:

Be able to achieve a stable plasma concentration,


Be freely filtered across the glomerulus,
Not be secreted, reabsorbed, synthesized, or otherwise metabolized by the renal
tubules, and
Not be impacted by any other means of removal from the plasma.

If all these criteria are met, then:


Filtered X = excreted X
and since
Filtered X = GFR plasma [X]
and since
Excreted X = urine [X] urine volume (in mL/unit time) we can now see that
GFR P[X] = U[X] urine volume
GFR = U[X] urine volume/P[X]
This is called the clearance of a substance and reflects the amount of plasma that is
completely cleared of the substance per unit time. There are a number of substances that have
been used clinically to estimate GFR.
1. Inulinis a fructose polysaccharide that meets the necessary requirements, and inulin
clearance is felt to be the best measure of GFR. However, it is not clinically useful because it
is difficult to administer (requires an intravenous infusion of inulin), and difficult to measure.
2. Radiolabelled compoundssuch as iothalamate or diethylenetriaminepentaacetic acid
(DTPA). These clearances are also very accurate, but are again limited in clinical use by their
cost and availability.
3. Creatininethe most widely used estimate of GFR is the 24-hour creatinine clearance
(CrCl) (Levey, 1990). It uses endogenous creatinine, which is produced at a constant rate.
The rate of production varies from individual to individual, but for a single individual daily
variability is less than 10%. It has the advantage of being easy to perform (no intravenous
[IV] infusion), is relatively cheap, and readily available. However, it is less accurate than
inulin clearance, because some creatinine is cleared from plasma through proximal tubular
secretion; thus a CrCl overestimates true GFR, on average, by 10% to 20%. This becomes
even more important as GFR declines, because tubular secretion increases in response to
increasing serum creatinine levels and may contribute up to 35% of all creatinine removal at
GFR levels of 40 to 80 mL/min (Shemesh et al, 1985). At best, then, the CrCl should be
considered the upper limit of the true GFR.
Plasma Markers. An even simpler method to estimate GFR is with the use of plasma levels
of substances that can be used as surrogate markers of GFR. To be useful, the substance must
fulfill the criteria outlined above. Three such substances have been used:

1. Plasma creatinine (PCr)the most widely used plasma marker of GFR. While
creatinine production is constant within an individual from day to day, there is marked
variation in production rates between individuals. The absolute rate depends upon muscle
mass, which in turn is influenced by age, sex, and body mass. Thus there is no single
normal PCr that reflects a normal GFR; it must be individualized for every person.
This can be accomplished through mathematical manipulation (see below). However, the
relationship of PCr to GFR is relatively constant (Fig. 381), and thus changes in PCr can be
used to predict corresponding changes in GFR. As a general rule of thumb, every 50%
reduction in GFR results in a doubling of PCr. There are limitations to the use of the PCr that
should be noted:

As GFR falls, tubular secretion of creatinine increases; so, PCr may not change
noticeably until there has been a significant drop in GFR (Shemesh et al, 1985).
Creatinine production may increase in states of increased muscle breakdown (e.g.,
rhabdomyolysis) or with increased dietary protein intake or supplementation, leading
to an underestimation of true GFR.
Creatinine production may decrease with liver cirrhosis, leading to an overestimation
of true GFR.

2. Plasma ureaanother widely used plasma marker. Urea production and excretion is
highly variable, influenced, for instance by dehydration, high-protein diets, and increased
tissue breakdown. As a result, it is a much less reliable marker of GFR than is the PCr and
should not be used as the sole determinant.
3. Plasma cystatin Cis an endogenous protein found in all nucleated cells. It has a constant
rate of production unaffected by diet, and clearance is not influenced by tubular functions
(Filler et al, 2005). This test is not widely available at present, but likely will replace PCr as
the standard test in GFR assessment.
Mathematical Correction. There are a number of mathematical formulas that have been
developed to improve the accuracy of the PCr estimation of GFR (National Kidney
Foundation, 2002). The two most widely used are the Cockcroft-Gault and modification of
diet in renal disease (MDRD) formulas.

1.

Cockcroft-Gaultoriginally developed from data collected from individuals with


normal renal function; it is a simple formula to estimate CrCl (not GFR) that corrects
for age, sex, and body mass (Cockcroft and Gault, 1976). The formula is :

It has the advantage of being very simple, but is not as accurate as other methods
when renal function is impaired.
2.

MDRD formulasa series of formulas derived from data collected in patients with
severe renal impairment; they are more complex but more accurate than the
Cockcroft-Gault. The simplest estimate of GFR is the four-variable equation :

In summary, the GFR is analogous to renal function. Total GFR is a summation of all SNGFR, which in turn are determined primarily by TGP and glomerular permeability of the
individual nephrons, and it is usually tightly regulated. A GFR estimate should be obtained
in all patients with renal impairment (rather than a PCr alone), and the recommended
method is through the use of the four-variable MDRD formula or Cockcroft-Gault
formula.
Key Points: Renal Blood Flow and Glomerular Filtration Rate

GFR reflects total renal function.


GFR can be approximated by creatinine clearance.
Formulas based on patients age, weight, and serum creatinine can best estimate GFR.

GARIS BESAR
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Darah memasuki ginjal melalui arteri renalis dan bercabang menjadi arteri yang lebih
kecil (interlobar, arcuate, interlobular) hingga memasuki kapiler glomerulus melalui
aferen arteriolus.
Fraksi filtrasi adalah bagian dari plasma yang memasuki glomerulus dan disaring oleh
membran glomerulus.
Melalui ultrafiltrasi plasma melewati membran glomerulus, ginjal mampu mengatur
total garam dan kandungan air di tubuh, komposisi elektrolit, dan membuang sisa-sisa
metabolisme protein.
GFR ditentukan oleh perbedaan tekanan hidrolik dan onkotik antara kapiler
glomerulus dan kapsula Bowman, serta permeabilitas membran glomerulus :
GFR = LpS (hydrostatic pressure oncotic pressure)
Lp = glomerular permeability
S = glomerular surface area
Laju filtrasi setiap masing-masing nefron single nephron GFR (SN-GFR).
Penghitungan paling relevan dari total GFR adalah penjumlahan dari seluruh SN-GFR
dalam satuan ml/menit.
GFR menggambarkan keseluruhan fungsi ginjal.
Cara terbaik memperkirakan GFR adalah dengan mengukur laju clearance dari
substansi tertentu di dalma plasma.
Renal clearance, GFR = U[X] urine volume/P[X]

Rumus Cockcroft-Gault

Rumus MDRD