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Physiology And Pathophysiology text book/Renal physiology and disease

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< Physiology And Pathophysiology text book

Contents

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Study Objectives

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Principles

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Definitions

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Essentials

This paragraph deals with

  1. The nephron
  2. Clearance and three clearance families
  3. Ultrafiltration and the inulin family
  4. Tubular reabsorption and the glucose family
  5. Tubular secretion and the PAH family
  6. Water and solute shunting by vasa recta
  7. Concentration or dilution of urine
  8. Renal bloodflow
  9. Macula densa-tubulo-glomerular feedback
  10. Non-ionic diffusion
  11. Tests for proximal and distal tubular function
  12. Stix testing with dipstics
  13. Diuretics


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The nephron

The kidneys transport substances by three vectorial processes. Vectorial processes are characterized by their direction and size only (Fig. 25-1).


Fig. 25-1: Renal transport. Black arrows indicate three vectorial transporting processes in a nephron: 1. Glomerular ultrafiltration is caused by a hydrostatic/colloid osmotic pressure gradient (the Starling forces), 2. Tubular reabsorption is the net movement of water and solute from the tubular lumen to the tubule cells and to the peritubular capillaries, and 3. Tubular secretion represents the net addition of solute to the tubular fluid.

The final excretion rate of the substance s in the urine is called net-flux, Js, in Fig. 25-1.

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Nephron anatomy

The functional unit is the nephron. Each human kidney contains 1 million units at birth. Each nephron consists of a glomerulus (ie, many glomerular capillaries in a Bowman's capsule), a proximal tubule forming several coils (pars convoluta) before ending in a straight segment (pars recta), the thin part of the Henle loop and a distal tubule also with a pars recta and a pars convoluta. The distal tubule ends in a collecting duct together with tubules from several other nephrons.

The kidney (average normal weight 150 g) consists of a cortex and a medulla. The medulla is composed of renal pyramids, the base of which originates at the corticomedullary junction. Each pyramid consists of an inner zone (the papilla) and an outer zone. The outer zone is divided into the outer medullary ray and the inner ray. The rays consist of collecting ducts and thick ascending limbs of the nephron.

A kidney lobulus is a medullary ray with adjacent cortical tissue. A kidney lobule is a pyramid with adjacent cortical tissue.

The loop of Henle is a regulating unit. Actually, the Henle loop consists of the proximal pars recta, the thin Henle loop and the distal pars recta, which ends at the level of macula densa.

The thin descending limb contains a water channel (called aquaporin 1) in both the luminal and the basolateral membrane. The last segment of the thick ascending limb is called the macula densa. The juxtaglomerular (JG) apparatus include the macula densa and granular cells of the afferent and efferent arterioles. Granular cells are modified smooth muscle cells that produce and release renin.

The distal tubule is convoluted from the macula densa of the JG apparatus (Fig. 25-2). The illustration shows a collecting duct, which receives urine from many neph¬rons. Several collecting ducts join to empty through the duct of Bellini into a renal cup or calyx in the renal pelvis.

The superficial nephron (represented on the left side of Fig. 25-2 A) does not reach the inner zone of the medulla, because its loop of Henle is short. These small, cortical nephrons have a smaller blood flow and glomerular filtration rate (GFR) than the deep, juxtamedullary nephrons (which are located close to the medulla and comprise 15% of all nephrons). The total inner surface area of all the glomerular capillaries is approximately 50-100 m2. Mesangial and endothelial cells in the glomerulus secrete prostaglandins and exhibit phagocytosis. Many vasoconstrictors contract the mesangial cells, reduce the gomerular filtration coefficient (Kf – see later) and thus also GFR.

The proximal tubules have an inner area of 25 m2 due to characteristic microvilli or brush borders (containing carboanhydrase).


Fig. 25-2: A: A superficial and a deep, juxtamedullary nephron leading to the same collecting duct. B: A juxtamedullary nephron with related blood vessels.

The juxtamedullary nephron has a long, U-shaped Henle loop. The bottom of this loop extends towards the tip of the papilla (apex papillae) at the outlet of the collecting duct (Fig. 25-2). The juxtamedullary nephrons have large corpuscles with relatively large bloodflow. These nephrons also receive blood through afferent arterioles with large diameters, and return blood through efferent arterioles with small diameters. When the blood has passed the juxtamedullary glomeruli it continues to a primary capillary network and to the vasa recta in the medulla. The blood collects in vena arcuata, vena interlobaris and finally into vena renalis.

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The glomerular barrier


The filtration barrier of the glomerulus consists of capillary endothelium, basement membrane and the epithelial layer of Bowmans capsule consisting of podocytes with foot processes. The holes or fenestrae of the endothelium have a radius of approximately 40 nm (covered by a thin diaphragm) and are permeable to peptides and small protein molecules. The basement membrane consists of a network of fibrils permeable to water and small solutes. The podocytes cover the basement membrane with foot processes separated by gaps called split-pores through which the filtrate is retarded, because each split is covered by a membrane.

All small ions and molecules with an effective radius below 1.8 nm (water, ions, glucose, inulin etc) filtrate freely. Substances with a radius of 1.8-4.2 nm are less filterable, and substances with a radius above 4.2 nm cannot cross the barrier.

All channels of the glomerular barrier carry negatively charged molecules that facilitate the passage of positively charged molecules (eg, polycationic dextrans, Fig.25-3). Dextran macromolecules can be electrically neutral or they have negative (anionic) or positive (cationic) charges.


Fig. 25-3: Filtration of dextran molecules across the glomerular barrier. The barrier contains glycoproteins with negative charges. Positive charged dextran molecules are attracted by the negative charges and filter easily.

Positive charged molecules with an effective radius of 3 nm filter easier than negative charged molecules of the same size. These molecules can act as effective osmotic diuretics.

Immunological or inflammatory damages of the glomerular barrier reduce the negative charge of the barrier. Hereby, negative protein molecules leave the plasma easier and proteinuria occurs in a number of glomerular disorders.

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Pregnancy and age

The glomeruli grow and the size and weight of the kidneys increase during pregnancy, accompanied by increases in both renal bloodflow and filtration rate.

The number of glomeruli and their tubules decrease with age. Drugs that are excreted by renal mechanisms can easily cause toxic accumulation in the elderly with poor kidney function.

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Clearance


In 1926 Poul Brandt Rehberg, an associate of August Krogh, found the muscle metabolite creatinine extremely concentrated in human urine (CU mg per ml) compared to plasma (CP mg per ml). He also measured the urine flow (urine production per min).

Thus, the concentration index, CU/CP, is large for creatinine. Multiplying this index with the urine flow yields a result greater than¬ similar results derived for most other substances (Eq. 25-1). Brandt Rehberg used this concept (later termed clearance) as his measure of renal filtration rate. The work with these matters developed into the idea of a filtration-reabsorption type of kidney. Rehberg was the first to realise that the reabsorption in the proximal tubules controls the filtration. A few years later Rehberg´s renal filtration rate was called creatinine clearance and used as a measure of the glomerular filtration rate (GFR).

The renal plasma clearance is a cleaning index for blood plasma passing the kidneys. The efficacy of this cleaning process is directly proportional to the excretion rate for the substance and inversely proportional to its plasma concentration (Eq. 25-1).

Clearance is the ratio between excretion rate and plasma concentration for the substance. Renal clearance can also be thought of as the volume of arterial plasma completely cleared of the substance in the kidneys within one min, or the number of ml arterial plasma containing the same amount of substance as contained in the urine flow per minute (Eq. 25-1).

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Glomerular filtration rate

The glomerular filtration rate, GFR, is the volume of glomerular filtrate produced per min.

In healthy adults the GFR is remarkably constant about 180 l each day or 125 ml per min due to intrarenal control mechanisms. In many diseases the renal bloodflow, RBF, and GFR will fall, whereby the ability to eliminate waste products and to regulate body fluid volume and composition will decline. The degree of impaired renal function is shown by the measured GFR.

GFR is routinely measured as the endogenous creatinine clearance.

The endogenous creatinine production is from the creatine metabolism in muscles and proportional to the muscle mass. In a 70-kg person creatinine is produced at a constant rate of 1.2 mg per min (1730 mg daily). This production is remarkably constant from day to day, only slightly affected by a normal protein intake, and equal to the rate of creatinine excretion. Both the serum creatinine and the renal creatinine excretion fluctuate throughout the day. Therefore, it is necessary to collect the urine for 6-24 hours and measure the creatinine excretion rate (ie, the urine flow rate multiplied by the creatinine concentration in the urine). A single venous blood sample analysed for creatinine in plasma is all that is needed to provide the endogenous creatinine clearance (Eq. 25-1).

Theoretically, two small errors disturb the picture, but both are overestimates.

At the normally low plasma concentrations of creatinine, a modest tubular secretion of creatinine from the blood is detectable resulting in up to 15% overestimation of the creatinine excretion flux. Most laboratories measure creatinine in serum instead of plasma, which results in an overestimation of plasma creatinine.

Thus, calculation of a fraction with both an overestimated nominator and denominator results in a value close to that of GFR in almost all situations, where the renal function is near normal.

With progressive renal failure the plasma creatinine rises, and the creatinine secretion increases the nominator in the clearance expression even more, so the measured clearance will overestimate GFR. Still, the clearance provides a fair clinical estimate of the renal filtration capacity (GFR).

In most cases a normal creatinine clearance (above 70 ml plasma per min at any age) is comparable with the normal range for serum creatinine (around 0.09 mM in Fig. 25-4). The serum creatinine concentration is inversely proportional to the creatinine clearance, and also a good estimate of GFR. Renal failure is almost always irreversible, when the serum creatinine is above 0.7 mM.

Fig. 25-4: Creatinine clearance versus serum creatinine. – A low serum creatinine indicates normal kidney function, but not always (see false negative concentrations). – An elevated serum creatinine indicates kidney failure, but not always (see false positive concentrations).

Serum [creatinine] and serum [urea] depend upon both protein turnover and kidney function. The serum [creatinine] and [urea] are large after intake of meals extremely rich in (fried) meat, although the kidney function is normal (false positive concentrations in Fig. 25-4). In some materials up to 15% of measured serum creatinine concentrations are normal, although the kidney function fails (false negative values in Fig. 25-4). Long-term hospitalisation often leads to muscular atrophy, which reduces creatinine production and excretion. The serum creatinine concentration is maintained normal because of a similar fall in kidney function (GFR).

Half the osmolality of normal urine is due to urea, and the other half is mainly due to NaCl. The osmolarity of urine varies tremendously (from 50 to 1400 mOsmol per l).

Physiological changes of the renal bloodflow often parallel changes of GFR. A reduced GFR implies a smaller tubular Na+-reabsorption and thus a smaller O2 demand. When kidneys are perfused by anoxic blood the tubular reabsorption is blocked first, and then the GFR is reduced. As tubular Na+ -reabsorption is the main oxidative energy demanding activity, a high GFR is correlated to high oxygen consumption in the normal kidney.

The size of GFR is determined by the factors shown in Fig. 25-7. The resistance of the glomerular barrier is extremely small in healthy human kidneys.

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Inulin


Inulin is the ideal indicator for determination of GFR, because of the following three relations:

  1. Inulin is a polyfructose (from Jewish artichokes) without effect on GFR. Inulin has a spherical configuration and a molecular weight of 5000. Inulin filters freely through the glomerular barrier. Inulin is uncharged and not bound to proteins in plasma. Inulin crosses freely most capillaries and yet does not traverse the cell membrane (distribution volume is ECV). Since one litre of plasma contains around 0.94 l of water, the ultrafiltrate concentration of inulin is Cp/0.94.
  2. All ultrafiltered inulin molecules pass to the urine. In other words, they are neither reabsorbed nor secreted in the tubules. Inulin is an exogenous substance - not synthesised or broken down in the body.
  3. Inulin is non-toxic and easy to measure.

Thus, under steady-state conditions, the rate of inulin leaving the Bowman's capsulesmust be exactly equal to the rate of inulin arriving in the final urine. The main idea is to measure the amount of inulin excreted in the urine during a timeperiod were the plasma [inulin] is maintained constant by constant infusion of inulin. After one hour the subject urinates, and the urine volume and inulin concentration in the urine and plasma is measured. The amount of inulin filtered through the glo¬merular barrier per min

    is:                             (GFR  Cp/0.94).

All inulin molecules remain in the preurine until the subject urinates. Thus, the amountexcreted is equal to the amount filtered and Eq. 25-4 is developed (see later).

Since the inulin clearance is 180 l per 24 hours for young, healthy males or 125 ml per min, the GFR must be (125  0.94) = 118 ml per min. The inulin clearance is 10% lower for young females than for young males due to the difference in average body weight and body surface area.

The normal values for both sexes decrease with age to 70 ml per min after the age of 70.

Inulin clearance is a precise experimental measure and the ideal standard, but inulin must be infused intravenously, and the method is not necessary in clinical routine.

If the clearance of a substance has the same value as the inulin clearance for the person, then the substance is only subject to ultrafiltration. Theoretically, reabsorption might balance tubular secretion and give the same result.

If the clearance of a substance is greater than the inulin clearance, then clearly this substance is being added to the urine as it flows along the tubules; in other words, it is being secreted.

Similarly, if the clearance of a substance is less than the inulin clearance, it means that the substance is being reabsorbed at a higher rate than any possible secretion.

The extracellular fluid volume (ECV) can be measured with inulin as inulin does not pass the cell membrane (see Chapter 24 and Eq. 24-4). The elimination of inulin is exponential - ie, the fraction (k) of the remaining amount in the body that disappears per time unit is constant (see Chapter 1). Since the filtration family of substances is eliminated from the blood solely by filtration, the elimination depends only on GFR, and the distribution volume is that of inulin (ECV). Thus, the elimination rate constant (k= 0.69/T½) for the inulin family is roughly equal to (GFR*Cp)/(ECV*Cp).

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The three clearance-families


All substances treated by the kidneys can be divided into three groups or families, namely the filtration-, the reabsorption-, and the secretion- family.

The kidney treats the filtration family of substances (see later) just like inulin.

The filtration rate (Jfiltr) for inulin equals the excretion rate (Jexcr), and both increase in direct proportion to the rise in Cp (Fig. 25-5). The clearance is the slope of the curve, and it is obviously a constant value that is independent of Cp.


Fig. 25-5:The straight line shows a direct relationship between the filtration rate and the concentration for the inulin family of substances in plasma.

The reabsorption or glucose family contains many vital substances (see later). For the reabsorption family of compounds, the excretion flux is equal to the filtration flux minus the reabsorption flux. The maximal reabsorption flux (Tmax) is reached above a certain threshold. Above this saturation threshold the clearance for the reabsorption family is equal to (the inulin clearance - Tmax/Cp), according to the mathematical argument in Fig. 25-8.

The secretion or PAH family comprises endogenous substances and drugs (see later). Foreign substances are often distributed in the ECV, but some of them are also entering cells (ICV). At low concentrations their elimination rate constant (k) is roughly equal to renal plasma flow (RPF) divided by ECV: ( RPF*CP/ECV*CP) = RPF/ECV. Thus, k equals RPF/ECV or 1/20 min-1 in most healthy persons. The k value corresponds to a half-life of 14 min (T½ = ln 2/k).

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Excretion rate and clearance.

Excretion rate curves for inulin can be changed into clearance by a simple mathematical procedure:

Differentiating the excretion flux curve for the inulin family with respect to Cp produce the renal plasma clearance curves for these substances. Let us assume that the curves are from a resting person in steady state with a normal inulin clearance (the slope of the line in Fig. 25-6,A).

For the inulin family the excretion flux equals (urine flow × Cu), and by division with Cp we have the inulin clearance.


Fig. 25-6: A, B, and C are the filtration-reabsorption- and se¬cre¬tion-families of substances, respectively. - D shows the clearance curves.

For all substances belonging to the inulin family the excretion flux curves are linear, so the rate of change (which is the clearance) must be constant in a given condition (Fig. 25-6A).

The results of the three excretion fluxes are plotted with Cp as the dependent variable (x-axis of Fig. 25-6, ABC).

The excretion flux curves for the three families of substances, when differentiated (dJexcr/dCp), provide us with the three possible clearance curves (Fig. 25-6, D).

For the reabsorption family, the clearance is zero at first, because the excretion is zero (Fig. 25-6 D). The clearance increases, and finally it approaches the inulin clearance. Therefore, the clearance is steadily increasing towards inulin clearance with increasing Cp.

For the secretion family, the clearance must also be equal to the excretion flux divided by Cp. When the [PAH] increases, more and more PAH is eliminated by filtration, and the secretory elimination is relatively suppressed (so-called auto-suppression). The clearance for the secretion family is falling with increasing Cp, and approaches that of inulin (Fig. 25-6 D).

The composition of urine in Box 25-1 is the basis for simple diagnostics. Anuria or oliguria (<500 ml daily) indicates the presence of hypotension or renal disease. Polyuria (>2500 ml of urine daily) is the sign of diabetes – both diabetes mellitus and diabetes insipidus. Microalbuminuria (ie, 50-150 mg per l) indicates glomerular barrier disorder such as diabetic glomerular disease. Glucosuria with hyperglycaemia is the sign of diabetes mellitus, and without hyperglycaemia it is a sign of a proximal reabsorption defect. High urea excretion is seen in uraemia, and high creatinine excretion indicates a large muscle mass in a healthy person. A low creatinine excretion is the sign of muscular atrophy or ageing.

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Ultrafiltation and the inulin family

Retrieved from "http://www.pharmpedia.com/Physiology_And_Pathophysiology_text_book/Renal_physiology_and_disease"

This page has been accessed 262 times. This page was last modified 15:42, 5 November 2006. All content, except where otherwise noted, is licensed under a Creative Commons Attribution License.

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