RENAL PHYSIOLOGYRenal 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 FiltrationThe 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 RateUnder 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 above-mentioned hormones. Inhibition of PG synthesis (due to administration of nonsteroidal anti-inflammatory 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 RateUnfortunately, 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 Xand sinceFiltered X = GFR plasma [X]and sinceExcreted X = urine [X] urine volume (in mL/unit time) we can now see thatGFR P[X] = U[X] urine volumeGFR = 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 theircost 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 SN-GFR, 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 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 permeabilityS = 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