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Depositionof PAS-stained material, hyalinization, fibrous crescentformation, tubular atrophy, interstitial fibrosisChronic Glomerulonephritis The upper panel illustrates key features of chronic glomerular damage,including swollen epithelial cells, a grossly thickened basement membrane, fused foot processes, andincreased matrix proteins. These abnormalities destroy the normal filtration barriers.
The lower left paneldepicts the effects of severe glomerulonephritis on the whole kidney, and the lower right panel gives a representative micrograph of damaged glomeruli.202Renal PhysiologyBasementmembraneof capillaryAfferent arterioleEndotheliumEndotheliumBasementmembraneBasement membraneParietal epitheliumBowman’scapsuleVisceral epithelium(podocytes)JuxtaglomerularcellsFenestratedendotheliumSmoothmuscleProximaltubuleMesangialmatrixand cellDistalconvolutedtubuleMacula densaEfferentarterioleFigure 16.3 Anatomy of the Glomerulus Plasma is filtered at the glomerular capillaries into Bowman’s space, and the ultrafiltrate then flows into the proximal tubule. The glomerular endothelial barrierprevents filtration of the cellular elements of the blood, so the ultrafiltrate does not contain blood cells orplasma proteins.
The cells of the macula densa are in contact with the afferent arteriole through the juxtaglomerular cells, forming the juxtaglomerular apparatus. The macula densa monitors NaCl delivery to thedistal tubule and regulates renal plasma flow (autoregulation).Renal Plasma FlowWhile whole blood enters the renal arteries, only plasma isfiltered at the glomerular capillaries, and thus, when discussing glomerular filtration, renal plasma flow (RPF) is animportant factor. RPF can be determined by the followingequation:RPF = RBF × (1 − HCT)In the normal adult male, RBF = ∼1 L/min, and hematocrit(HCT) is ∼40% (0.4).
Thus,RPF = 1 L/min × 0.6 = 600 mL/minTo determine the effective renal plasma flow (EPRF), whichis the plasma flow entering the glomeruli and available forfiltration, the plasma clearance of the inorganic acid paraaminohippurate (PAH) is used. PAH is filtered at the glom-eruli, and under normal circumstances the remaining PAH inthe peritubular capillaries is secreted into the proximal tubule,so that essentially no PAH enters the renal vein (Fig.
16.4 andsee “Analysis of Renal Function” Clinical Correlate).GLOMERULAR FILTRATION: PHYSICALFACTORS AND STARLING FORCESGlomerular filtration is determined by the Starling forces andthe permeability of the glomerular capillaries to the solutes inthe plasma. In general, with the exception of formed elements(red blood cells, white blood cells, platelets) and most proteins, plasma is available for filtration at the glomerular capillaries. Because the molecules must travel through severalbarriers to move from the capillary lumen to Bowman’s spaceOverview, Glomerular Filtration, and Renal Clearance203PRINCIPLE OF TUBULAR SECRETION LIMITATION (TM) USING PARA-AMINO HIPPURATE (PAH) AS EXAMPLEBelow TMConcentration of PAH in plasmais less than secretory capacity oftubule; plasma passing throughfunctional kidney tissue isentirely cleared of PAHAt TMConcentration of PAH in plasmais just sufficient to saturatesecretory capacity of tubule120etedExcr80Amount ⫽ Amount ⫹ AmountexcretedfilteredsecretedSecreted60TMPAH (mg/min)100Above TMConcentration of PAH inplasma exceeds secretorycapacity of tubule; plasmapassing through functionalkidney tissue is not entirelycleared of PAH40redFilte20010203040Plasma PAH (mg/dL)506070Figure 16.4 Renal Handling of Para-amino Hippurate (PAH) PAH is filtered at the glomerulusand also secreted into the proximal tubule.
When the plasma concentration of PAH is below the tubulartransport maximum (TM), PAH is effectively cleared from the blood entering the kidney. However, if theplasma concentration exceeds the TM, PAH is not entirely removed and is found in the renal vein.(fenestrated epithelium → basement membrane → betweenpodocytes → filtration slit → Bowman’s space), there are sizelimitations, and ultimately the effective pore size is ~30 Å.Small molecules such as water, glucose, sucrose, creatinine,and urea are freely filtered.
As molecular size increases, or netnegative charge of molecules increases (for example, amongproteins), filtration becomes increasingly restricted.Starling forces govern fluid movement into or out of thecapillaries (see Chapter 1).
The pressures that determine glomerular filtration dynamics are glomerular capillary hydrostatic pressure (HPGC) forcing fluid out of the capillary,glomerular capillary oncotic pressure (πGC) attracting fluidinto the glomerular capillary, Bowman’s space hydrostaticMyoglobin, a small protein that is released from musclefollowing damage, is only 20 Å, but its shape restrictsfree passage, and only about 75% is filtered. Most proteins arenegatively charged or of high molecular weight and will not befiltered unless there is damage to the glomerular barriers, or thenegative charge of the protein is affected by viral or bacterialprocesses. In those cases, protein will enter the renal tubule andbe excreted in urine (proteinuria).pressure (HPBS) opposing capillary hydrostatic pressure, andBowman’s space oncotic pressure (πBS) attracting fluid intoBowman’s space (typically there is negligible protein in the204Renal PhysiologyFiltrationcoefficient(Kf)⫻IntraIntracapillarycapsular⫺hydrostatichydrostaticpressurepressureSystemiccirculationColloidosmotic⫺pressureof plasmaproteinsGlomerular⫽ filtrationrate (GFR)Smooth muscleAfferent arterioleAutonomicnervesEfferent arterioleFlow rate (mL/min)Smooth muscleRBF(Pin)Plasma inulinconcentrationⴛ⫻(GFR)Glomerularfiltration rateⴝGFRⴝ⫽(Uin)Urine inulinconcentrationⴛ⫻(V)Urinevolume/minUin ⴛ VPinGFR050100150200Arterial blood pressure (mm Hg)Figure 16.5 Glomerular Filtration Blood enters the glomerular capillaries from the afferent arterioles,and ∼20% of the fluid is filtered into the nephrons (filtration fraction).
The glomerular filtration rate (GFR) canbe described on the basis of the forces governing filtration (upper equation), or from the clearance of inulin(lower equation). The graph illustrates that renal blood flow (RBF) and GFR remain fairly constant over awide range of mean arterial blood pressures (MAP)—this occurs in part through autoregulation and tubuloglomerular feedback.Bowman’s space, so πBS is not significant). Thus, assuming πBSis zero,merular filtration by both intrarenal and extrarenalmechanisms.Net filtration pressure = (HPGC − HPBS) − πGCThe glomerular capillaries are different from other capillaries(which have significantly reduced pressures at the distalend of the capillary), because the efferent arteriole (at theother end of the glomerulus) can constrict and maintain pressure in the glomerular capillary.
Thus, there is very littlereduction in HPGC through the capillary, and filtration can bemaintained along its entire length. Afferent and efferent arteriolar resistance can be controlled by neural influences, circulating hormones (angiotensin II), myogenic regulation, andtubuloglomerular feedback signals, allowing control of glo-Glomerular Filtration RateGlomerular filtration rate (GFR) is considered the benchmark of renal function. GFR is the amount of plasma (withoutprotein and cells) that is filtered across all of the glomeruli inthe kidneys, per unit time. In a normal adult, GFR is ∼100 to125 mL/min, with men having higher GFR than women.Many factors contribute to the regulation of GFR, which canbe maintained at a fairly constant rate, despite fluctuations inmean arterial blood pressure (MAP) from 80 to 180 mm Hg(Fig. 16.5).Overview, Glomerular Filtration, and Renal ClearanceGFR is determined by the net filtration pressure, as well asphysical factors associated with the glomeruli, or Kf (hydraulic permeability and total surface area, which reflects nephronnumber and size).
The equation is:GFR = Kf [(HPGC − HPBS) − πGC]Maintaining normal GFR is critical for eliminating excessfluid and electrolytes from the blood and maintaining overallhomeostasis. Significant alteration of any of the parameters inthe equation above can affect GFR. For example, a hemorrhage that reduces MAP below 80 mm Hg may decrease HPGCenough to dramatically decrease or stop filtration.
Filtrationcan also be reduced if the HPBS is increased (for example,during distal blockage by kidney stones), or if Kf is reduced(for example, in glomerulosclerosis).In general, the nephrons are associated with filtration, reabsorption, secretion, and excretion:■The filtered load (FLx) of a substance (the amount of aspecific substance filtered per unit time) is equal to theplasma concentration of the substance (Px) times GFR:FLx = Px × GFR■The urinary excretion (Ex) of a substance is the urineconcentration of the substance (Ux). times the volumeof urine produced per unit time (V):.Ex = Ux × V■Most substances are reabsorbed (to some extent); reabsorption rate of a substance (Rx) is equal to the filteredload (FLx) of the substance minus the urinary excretionof a substance (Ex):Rx = FLx − Ex■Select substances are actively secreted (e.g., creatinine,PAH, H+, K+).
The secretion rate of a substance (Sx) isequivalent to the excretion rate minus the filtered loadof the substance:205.Cx = (Ux × V)/PxThis equation can be used to easily determine the GFR: theclearance of a substance is equated to the GFR if the substanceis freely filtered, but not reabsorbed or secreted. In this case,the amount filtered will equal the amount excreted [FLx = Ex],and thus:.since FLx = Px × GFR and Ex = Ux × Vwhen Flx = Exthen,.Px × GFR = Ux × Vand, rearranging the equation,.GFR = (Ux × V)/PxThus, for such a substance, GFR = Cx.Although there is no endogenous substance that exactly meetsthese requirements (i.e., the substance is freely filtered, but notreabsorbed or secreted, and, therefore, FLx = Ex), the polyfructose molecule inulin does meet these criteria.
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