new human physiology ch 25

N e w H u m a n P h y s i o l o g y | P a u l e v - Z u b i e t a 2 n d E d i t i o n

C h a p t e r 2 5 : R e n a l P h y s i o l o g y a n d D i s e a s e

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C h a p t e r2 5

S t u d y O b j e c t i v e s· To define the c oncepts: Nephron, glomerular f i ltration, tubular sec retion and reabsorption, renal

lobulus, renal plasma c learance, osmolar c learance, tubular passage f rac tion, reabsor ption

f rac tion, exc retion f rac tion, f i ltration f rac tion, plasma extrac tion f rac tion, proximal and distal

sy stem, glomerular propulsion pressure, net f i ltration pressure, renal threshold, and the maximal

transfer (Tmax) for tubular sec retion and reabsorption.

· To desc r ibe the renal c i r culation and measurement of renal bloodf low, a super f i c ia l and a

juxtamedullary nephron, the juxtaglomerular apparatus, and the concentrating mec hanism of the

kidney.

· To calculate the relation between half - li fe, elimination rate constant, c learance and distr ibution

volume of a substance treated in the kidneys.

· To ex plain the normal renal func tion inc luding the c ontrol func tions, use of endogenous

c reatinine c learance as a renal test, the renal treatment of the f i ltration- reabsorption- and

New Human Physiology Ch 25 http://www.zuniv.net/physiology/book/chapter25.html

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sec retion- fami lies of substances, the glomerular f i ltration rate (GFR) , the angiotensin- renin-

aldosterone casc ade, the tubulo-glomerular feedbac k, the proximal and distal transpor t processes,

and mic tur i tion. To explain the pathophysiology of common renal disorders inc luding r enal

oedema.

· To us e the above concepts in problem solving and in case histor ies.

P r i n c i p l e s· The glomerulus and the prox imal tubule are respons ible for f i l t rat ion of plasma and f or major

reabsorpt ion of water and solutes . Glomerular f i l t rat ion is due to a hydros tat i c /col l oid os mot ic

pressure gradient .

· Tubular reabs orpt ion is the movement of water and solute f rom the tubular lumen to the tubule

cel l s and of ten fur ther on to the per i tubular capi l lary network .

· Tubular sec ret ion represents the net addi t ion of solute to the tubular f luid in the l umen.

· Al l subs tances t reated by the k idneys can be divided into three groups or famil ies , namely the

f i l t rat ion group, the reabs orpt ion group and the sec ret ion group.

D e f i n i t i o n s· Anur ia refers to a total stop of ur ine produc tion f requently caused by c i rculatory fai lure wi th

anoxic damage of the tubular system.

· (Renal plasma) Clear ance i s a c leaning index for b lood plasma passing the kidney s. The

ef f icacy of this c leaning process is d irec tly propor tional to the exc retion rate for the substance,

and inversely propor tional to i ts p lasma concentration.

· Diuresis is an i nc reased ur ine f low ( ie, volume of ur ine produc ed per time uni t) .

· Excret ion fract ion (EF) for a substance is the f rac tion of i ts g lomerular f i ltration rate, which

passes to and is exc reted in the ur ine.

· Extract ion fract ion (E) for a substance is the f rac tion ex t rac ted by glomerular f i ltration f rom


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the total amount of substance delivered to the kidney dur ing one passage of the ar ter ia l blood

plasma.

· Free water clearance i s the di f ferenc e between ur ine f low and osmolar c learance (see below) .

The f ree water c learance is an indicator of the exc retion of solute- f ree water by the k idneys.

Excess water i s exc reted compared to solutes, when f ree-water c learance is posi ti ve. Excess

solutes are exc reted c ompared to water, when free-water c learanc e is negative. – Free water

c learance is an estimate of the renal capac i ty for exc retion of solute- f ree water.

· Glomerular filt rat ion i s due to a hydrostati c /colloid osmotic pressure gradient - the Star ling

forces.

· Glomerular filt rat ion fract ion (GFF) i s the f rac tion of the plasma f lowing to the kidneys that is

ultraf i ltered (GFR/RPF) . GFF is normally 0.20 or 1/5. - The GFF is reduc ed dur ing acu te

glomerulonephr i ti s.

· Glomerulonephr it is i s an autoimmune in jury of the glomeruli of both kidneys.

· Glomerular filt rat ion rate (GFR) is the volume of glomerular f i ltrate produc ed per min.

· Glomerular propulsion pressure in the blood of the glomerular capi llar ies i s the hydrostati c

minus the colloid osmotic pressure of the blood ( ie, 2-3 kPa in a healthy resting per son) .

· Glomerulo-tubular balance refers to the simultaneous inc rease in NaCl and water reabsorption

in the proximal tubules as a result of an inc rease in GFR and f i ltration rate of NaCl. An almost

constant f rac tion of salt and water i s thus reabsorbed regardless of the size of GFR.

· Nephron : A nephron c onsists of a glomerulus, a proximal tubule forming several c oi ls (pars

convoluta) before ending in a straight segment (pars rec ta) , the thin par t of the Hen le loop and a

distal tubule also wi th a pars rec ta and a pars convoluta.

· The nephrot ic syndrome refers to a serious inc rease in the permeabi li ty of the glomerular

bar r ier to albumin, resulting in a marked loss of albumin in the ur ine. The albuminur ia (more than

3 g per day ) causes hypoalbuminaemia and generali zed oedema.

· Net ult rafilt rat ion pressure i s the pressure gradient governing the glomerular f i ltration - the net


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result of the so-called Star l ing forces ( see Fig. 25-7) .

· Osmolar clearance i s the plasma volume c leared of osmoles (solutes) each minute. – Osmolar

c learance is also def ined as the f i c ti ve ur ine f low that would have rendered the ur ine isosmolar

with plasma. - Osmolar c learance is the di f ference between the ur ine f low and the f ree water

c learance, and osmolar c learance estimates the renal capac i ty to exc rete solutes.

· Osmolar ity i s the amount of osmotically ac ti ve par ti c les dissolved in a li tre of solution.

· Proximal tubule c onsists of the proximal convoluted tubule and pars rec ta.

· Renal threshold for glucose is the blood glucose concentration at which the gluc ose can be

f i r st detec ted in the ur ine (appearance threshold) or at which the reabsorption capac ities of all

tubules are saturated (saturation threshold) .

· Renal ult rafilt rate i s also compared to plas ma water , because i t i s composed li ke plasma minus

proteins. The f rac tion of one li tre of plasma that is pure water i s ty pically 0.94. Thus, the

concentration of many substances in the ultraf i ltrate, C f i l t r , i s equal to Cp /0.94.

· Single effect gradient i s a transepi thelial concentration gradient between the tubular f luid and

the medullary intersti tial f luid establi shed at each level of the thick ascending limb by ac tive NaCl

reabsorption.

· Tmax refers to the maximal net transfer rate of substance by tubular sec retion or reabsorption.

· Tubular passage fract ion. The f rac tion of the amount ultraf i ltered of substance passing a c ross

sec tion of the nephron is the pas sage f rac t ion. The passage f rac tion for inulin does not vary at a ll

throughout the nephron. The passage f rac tion for inulin i s one and remains so.

· Tubular reabsorpt ion fract ion. The reabsorpt ion f rac t ion i s the reverse of the passage f rac tion

(1 minus the passage f rac tion) .

· Tubular reabsorpt ion (ac ti ve or passive) i s the net movement of water and solute f rom the

tubular lumen to the tubule cells and of ten fur ther on into the per i tubular capi llary network.

· Tubular secret ion (ac ti ve or passive) represents the net addi tion of solute to the tubular lumen.


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· Tubulo-glomerular feedback (TGF) c ontrols the glomerular capi llary pressure and the proximal

tubular pressure – thus stabi li sing delivery of solute and volume to the distal nephr on. The macula

densa-TGF mec hanism responds to disturbances in distal tubular f luid f low passing the macula

densa. - Renal autoregulation is caused by myogenic feedbac k and by the macula densa- TGF

mechanism.

E s s e n t i a l sThis paragraph deals wi th 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 ur ine, 8. Renal bloodflow , 9. M acula densa- tubulo-glomerular feedback, 10. Non- ionic

diffusion, 11. Tests for proximal and distal tubular function , 12. Stix testing with dipstics , and

13. Diuretics.

1. The nephron

The kidneys transpor t substances by three vec tor ial processes. Vec tor ial processes ar e

charac ter ized by their di rec tion and size only (Fig. 25-1) .

Fig. 25-1: Renal t ranspor t . Black ar rows indicate three vector ial t ranspor t ing processes in a

nephron: 1. Glomerular ult rafilt rat ion is caused by a hydrostat ic/colloid osmot ic pressure


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gradient ( the Star ling forces) , 2. Tubular reabsorpt ion is the net movement of water and solute

from the tubular lumen to the tubule cells and to the per itubular capillar ies, and 3. Tubular

secret ion represents the net addit ion of solute to the tubular fluid.

The f inal exc retion rate of the substance s in the ur ine is called net- f lux, J s , in Fig. 25-1.

1a. Nephron anatomy

The func tional uni t is the nephron. Each human kidney c ontains 1 mi l l ion uni ts at bi r th. Each

nephron consists of a glomerulus ( ie, many glomerular capi llar ies in a Bowman's capsule) , a proximal

tubule forming several coi ls (pars convoluta) before ending in a straight segment (pars rec ta) , the

thin par t of the Henle loop and a distal tubule also wi th a pars rec ta and a pars convoluta. The distal

tubule ends in a col lec t ing duc t together with tubules f rom several other nephrons.

The kidney (average normal weight 150 g) consists of a c or tex and a medulla. The medulla i s

composed of renal py ramids, the base of whic h or ig inates at the cor tic omedullary junc tion. Each

py ramid consists of an inner zone ( the papi lla) and an outer zone. The outer zone is divided into the

outer medullary ray and the inner ray. The rays consist of collec ting duc ts and thick ascending limbs

of the nephron.

A k idney lobulus i s a medullary ray wi th adjacent c or ti cal ti ssue. A kidney lobule is a py ramid with

adjacent cor ti cal ti ssue.

The loop of Henle i s a regulating unit. Ac tually, the Henle loop consists of the proximal pars rec ta,

the thin Henle loop and the distal pars rec ta, which ends at the level of macula densa.

The th in descending limb contains a water c hannel (called aquapor in 1) in both the luminal and the

basolateral membrane. The last segment of the thick ascending limb is called the mac ula densa. The

juxtaglomerular (JG) apparatus inc lude the macula densa and granular c ells of the aff erent and

ef ferent ar ter io les. Granular cells are modif ied smooth musc le cells that produce and release renin.

The distal tubule i s convoluted f rom the macula densa of the J G apparatus ( Fig. 25-2) . The

i llustration shows a collec ting duc t, whic h receives ur ine f rom many nephrons. Several collec ting

duc ts join to empty through the duc t of Bellini into a renal cup or calyx in the rena l pelvis.

The super f i c ial nephron ( represented on the lef t side of Fig. 25-2 A) does not reac h the inner zone


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of the medulla, because i ts loop of Henle is shor t. These small, cor ti cal nephrons have a smaller

blood f low and glomerular f i ltration rate (GFR) than the deep , jux tamedul lary nephrons (which are

located c lose to the medulla and c omprise 15% of all nephrons) . The total inner sur face area of all

the glomerular capi llar ies is approximately 50-100 m2 . Mesangial and endothelial cells in the

glomerulus sec rete prostaglandins and exhibi t phagocy tosis. Many vasoconstr i c tors contrac t the

mesangial cells, reduce the gomerular f i ltration coeff i c ient (K f – see later ) and thus also GFR.

The prox imal tubules have an inner area of 25 m2 due to charac ter isti c mic rovi lli or brush borders

(containing carboanhydrase) .

Fig. 25-2: A: A super ficial and a deep, juxtamedullary nephron leading to the same collect ing

duct . B: A juxtamedullary nephron with related blood vessels.

The juxtamedullary nephron has a l ong, U-shaped Henle loop. The bottom of this loop extends towards

the tip of the papi lla (apex papi llae) at the outlet of the collec ting duc t (Fig. 25- 2) . The juxtamedullary

nephrons have large corpusc les wi th relati vely large bloodf low. These nephrons also r eceive blood

through afferent ar ter ioles wi th large diameters, and return blood through efferent ar ter ioles wi th

small d iameters. W hen the blood has passed the juxtamedullary glomeruli i t continues to a pr imary

capi llary network and to the vasa rec ta in the medulla. The blood c ollec ts in vena ar cuata, vena

inter lobar is and f inally into vena renali s.

1b. The glomerular bar r ier


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The f i ltration bar r ier of the glomerulus consists of c api llary endothelium, basement membrane and the

epithelial layer of Bowmans c apsule consisting of podocy tes with foot proc esses. 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 molec ules. The basement membrane consists of a

network of f ibr i ls permeable to water and small solutes. The podocy tes cover the basement membrane

with foot proc esses separated by gaps called spl i t-pores through which the f i ltrate i s retarded,

because each spli t i s covered by a membrane.

All small ions and molecules with an effec ti ve radius below 1.8 nm (water, ions, gluc ose, inulin etc )

f i ltrate f reely. Substanc es wi th a radius of 1.8-4.2 nm are less f i lterable, and substances wi th a

radius above 4.2 nm cannot c ross the bar r ier.

All channels of the glomerular bar r ier car ry negat ively charged molecules that fac i li tate the passage

of positi vely charged molec ules (eg, polycationic dextrans, Fig.25-3) . Dextran macromolecules can

be elec tr i cally neutral or they have negative (anionic ) or positi ve (cationic ) charges.

Fig. 25-3: Filt ration of dext ran molecules across the glomerular barr ier. The barr ier contains

glycoproteins with negat ive charges. Positive charged dextran molecules are at t racted by the

negat ive charges and filter easily.

Posi ti ve charged molecules wi th an ef fec tive radius of 3 nm f i lter easier than negative charged

molecules of the same size. These molecules can ac t as effec ti ve osmotic diuretic s.


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Immunological or inf lammatory damages of the glomerular bar r ier reduce the negative c harge of the

bar r ier. Hereby , negative protein molecules leave the plasma easier and proteinur ia occurs in a

number of glomerular disorders.

1c . Pregnancy and age

The glomeruli grow and the size and weight of the kidneys inc rease dur ing pregnancy , acc ompanied

by inc reases in both renal bloodf low and f i ltration rate.

The number of glomeruli and thei r tubules decrease with age. Drugs that are exc reted by renal

mechanisms can easi ly c ause toxic acc umulation in the elder ly wi th poor kidney func tion.

2. Clearance

In 1926 Poul Brandt Rehberg, an assoc iate of August Krogh, found the musc le metaboli te c reat inine

extremely conc entrated in human ur ine (CU mg per ml) compared to plasma (CP mg per ml) . He also

measured the ur ine f low (ur ine produc tion per min) .

Thus, the concentration index, CU/CP , i s large for c reatinine. Multiply ing this index wi th the ur ine

f low y ields a result greater than simi lar results der ived for most other substances ( Eq. 25-1 ) . Brandt

Rehberg used this concept ( later termed c learance) as his measure of renal f i l t rat ion rate. The work

with these matters developed into the idea of a f i l t rat ion- reabs orpt ion type of kidney. Rehberg was

the f i r st to reali se that the reabsorption in the proximal tubules controls the f i ltr ation. A few y ears

later Rehberg´s renal f i l t rat ion rate was called c reat inine c learance and used as a measure of the

glomerular f i l t rat ion rate (GFR) .

The renal plasma c learanc e is a c leaning index for blood plasma passing the kidneys. The eff i cacy

of this c leaning process is di rec tly propor tional to the exc retion rate for the substanc e and inversely

propor tional to i ts plasma concentration ( Eq. 25-1) .

Clearance i s the ratio between exc retion rate and plasma concentration for the substanc e. Renal

c learance can also be thought of as the volume of ar ter ia l plasma completely c leared of the

substance in the kidney s wi thin one min, or the number of ml ar ter ial plasma containing the same

amount of substance as contained in the ur ine f low per minute (Eq. 25-1) .


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2a. Glomerular f i l t rat ion rate

The glomerular f i ltration rate, GFR, i s the volume of glomerular f i ltrate produc ed 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 b loodf low, RBF, and GFR wi l l fall, whereby

the abi li ty to eliminate waste produc ts and to regulate body f luid volume and c omposi tion wi ll dec line.

The degree of impai red renal func tion is shown by the measured GFR.

GFR is routinely measured as the endogenous c reatinine c learance.

The endogenous c reatin ine produc tion is f rom the c reatine metabolism in musc les and propor tional to

the musc le mass. In a 70-kg person c reatinine is produc ed at a constant rate of 1.2 mg per min

(1730 mg dai ly ) . This produc tion is remarkably constant f rom day to day, only slightly affec ted by a

normal protein intake, and equal to the rate of c reatinine exc retion. Both the serum c reatinine and

the renal c reatin ine exc retion f luc tuate throughout the day. Therefore, i t i s necessary to collec t the

ur ine for 6-24 hours and measure the c reatinine exc retion rate ( ie, the ur ine f low rate multiplied by

the c reatin ine concentration in the ur ine) . A single venous blood sample analysed for c reatinine in

plasma is all that i s needed to provide the endogenous c reatin ine c learance (Eq. 25-1) .

Theoretically, two small er rors disturb the pic ture, but both are overestimates.

At the normally low plasma concentrations of c reatin ine, a modest tubular sec retion of c reatinine

f rom the blood is detec table resulting in up to 15% overestimation of the c reatinine exc retion f lux.

Most laborator ies measure c reatinine in serum instead of plasma, which results in an overestimation

of plasma c reatinine.

Thus, calculation of a f rac tion wi th both an overestimated nominator and denominator results in avalue c lose to that of GFR in almost all si tuations, where the renal func tion is near normal.

W i th progressive renal fai lure the plasma c reatinine r i ses, and the c reatin ine sec ret ion inc reases the

nominator in the c learanc e expression even more, so the measured c learanc e wi ll overestimate GFR.

Sti ll, the c learance provides a fa ir c linical estimate of the renal f i ltration capac i ty (GFR) .

In most cases a normal c reatinine c learance (above 70 ml plasma per min at any age) i s comparable

with the normal range for serum c reatinine (around 0.09 mM in Fig. 25-4) . The serum c reatinine

concentration is inversely propor tional to the c reatinine c learance, and also a good estimate of GFR.


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Renal fai lure i s almost a lways i r revers ible, when the serum c reatin ine is above 0.7 mM.

Fig. 25-4: Creat inine clearance versus serum creat inine. – A low serum creat inine indicates

normal kidney funct ion, but not always (see false negat ive concentrat ions) . – An elevated

serum creat inine indicates kidney failure, but not always (see false posit ive concent rat ions).

Serum [c reatinine] and serum [urea] depend upon both protein turnover and k idney func t ion. The

serum [c reatinine] and [urea] are large af ter intake of meals extremely r i ch in ( f r ied) meat, a lthough

the kidney func tion is normal ( false positi ve conc entrations in Fig. 25-4) . In some mater ials up to

15% of measured serum c reatinine c oncentrations are normal, although the kidney func t ion fai ls

( false negative values in Fig. 25-4) . Long- term hospi talisation often leads to musc ular atrophy, whic h

reduces c reatinine produc tion and exc retion. The serum c reatinine concentration is maintained

normal because of a simi lar fall in kidney func tion (GFR) .

Half the osmolali ty of normal ur ine is due to urea, and the other half i s mainly due to NaCl . The

osmolar i ty of ur ine var ies tremendously ( f rom 50 to 1400 mOsmol per l) .

Physiological changes of the renal bloodf low of ten parallel changes of GFR. A reduc ed GFR implies a

smaller tubular Na+- reabsorption and thus a smaller O2 demand. W hen kidneys are per fused by

anoxic blood the tubular reabsorption is b loc ked f i r st, and then the GFR is reduced. As tubular Na+

- reabsorption is the main oxidative energy demanding ac tivi ty, a high GFR is cor related to high

ox ygen consumpt ion i n the normal kidney.


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The size of GFR is determined by the fac tors shown in Fig. 25-7. The resistance of the glomerular

bar r ier i s extremely small in healthy human kidneys.

2b. Inul in

Inul in i s the ideal indicator for determination of GFR, bec ause of the following three relat ions:

1. Inulin i s a poly f ruc tose ( f rom J ewish ar ti chokes) wi thout effec t on GFR. Inulin has a

spher ical conf iguration and a molecular weight of 5000. Inulin f i lters f reely through the

glomerular bar r ier. Inulin i s uncharged and not bound to proteins in plasma. Inulin c rosses

f reely most capi llar ies and yet does not traverse the c ell membrane (distr ibution volume is

ECV) . Sinc e one li tre of plasma contains around 0.94 l of water, the ultraf i ltrate

concentration of inulin is Cp /0.94.

2 All ultraf i ltered inulin molecules pass to the ur ine. In other words, they are neithe r

reabsorbed nor sec reted in the tubules. Inulin i s an exogenous substance - not synthesised

or broken down in the body.

3. Inulin i s non- toxic and easy to measure.

Thus, under steady -state condi tions, the rate of inulin leaving the Bowman's capsulesmust be exac tly

equal to the rate of inulin ar r i ving in the f inal ur ine. The main idea is to measure the amount of inulin

exc reted in the ur ine dur ing a timeper iod were the plasma [ inulin] i s maintained constant by c onstant

infusion of inulin. Af ter one hour the subjec t ur inates, and the ur ine volume and inu lin concentration

in the ur ine and plasma is measured. The amount of inulin f i ltered through the glomerular bar r ier per

min is: (GFR × Cp /0.94) .

All inulin molecules remain in the preur ine unti l the subjec t ur inates. Thus, the amountexc reted is

equal to the amount f i ltered and Eq. 25-4 i s developed (see later) .

Since the i nul in c learance i s 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 c learance is 10% lower for young females than for

young males due to the di f ferenc e in average body weight and body sur fac e area.

The normal values for both sexes dec rease wi th age to 70 ml per min af ter the age of 70 .


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Inul in c learance i s a prec ise exper imental measure and the ideal standard, but inulin must be infused

intravenously, and the method is not nec essary in c linical routine.

I f the c learanc e of a substance has the same value as the inulin c learance for the person, then the

substance is only subjec t to ul t raf i l t rat ion. Theoretic ally, reabsorption might balance tubular

sec retion and give the same result.

I f the c learance of a substance is greater than the inulin c learance, then c lear ly this substanc e is

being added to the ur ine as i t f lows along the tubules; in other words, i t i s being sec reted.

Simi lar ly, i f the c learance of a substanc e is l es s than the inulin c learance, i t means that the

substance is being reabsorbed at a higher rate than any possible sec retion.

The extracellular f luid volume (ECV) c an be measured wi th inulin as inulin does not p ass the cell

membrane (see Chapter 24 and Eq. 24-4) . The elimination of inulin is exponential - ie, the f rac tion

(k) of the remaining amount in the body that disappears per time uni t i s constant (see Chapter 1 ) .

Since the f i ltration fami ly of substanc es is eliminated f rom the blood solely by f i lt ration, the

elimination depends only on GFR, and the distr ibution volume is that of inulin (ECV) . Thus, the

elimination rate constant (k= 0.69/T½) for the inulin fami ly i s roughly equal to (GFR*Cp ) / (ECV*Cp ) .

2c . The three c learance- famil ies

All substances treated by the kidneys can be divided into three groups or fami l ies , namely the

f i ltration- , the reabsorption- , and the sec retion- fami ly.

The kidney treats the f i l t rat ion fami ly of substances (see later) just like i nulin.

The f i ltration rate (J f i l t r ) for inulin equals the exc retion rate ( J excr) , and both inc rease in di rec t

propor tion to the r i se in Cp (F ig. 25-5) . The c learanc e is the slope of the c urve, and i t is obviously a

constant value that is independent of Cp .


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Fig. 25-5:The straight line shows a direct relat ionship between the filt rat ion rate and the

concentrat ion for the inulin family of substances in plasma.

The reabsorpt ion or glucose fami ly contains many vi ta l substances (see later ) . For the reabsorption

fami ly of compounds, the exc retion f lux i s equal to the f i ltration f lux minus the reabsorption f lux. The

maximal reabsorption f lux (Tmax) is reached above a cer tain threshold. Above this saturation

threshold the c learance for the reabsorption fami ly i s equal to ( the inulin c learance - Tma x/Cp ) ,

ac cording to the mathematical argument in Fig. 25-8.

The sec ret ion or PAH fami ly compr ises endogenous substanc es and drugs (see later ) . Foreign

substances are of ten distr ibuted in the ECV, but some of them are also enter ing cells ( ICV) . At low

concentrations thei r elimination rate constant (k) i s roughly equal to renal p lasma f low (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 c or responds to a half- li fe of 14 min (T½ = ln 2/k) .

2d. Exc ret ion rate and c learance.

Exc ret ion rate curves for inulin can be changed into c learance by a simple mathematical proc edure:

Dif ferentiating the exc retion f lux c urve for the inulin fami ly wi th respec t to Cp produce the renal

plasma c learance curves for these substances. Let us assume that the c urves are f rom a resting

person in steady state wi th a normal inulin c learance ( the slope of the line in Fig. 25-6,A) .

For the inul in fami ly the exc retion f lux equals (ur ine f low × Cu ) , and by divis ion wi th Cp we have the


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i nulin c learanc e.

Fig. 25-6: A, B, and C are the filt rat ion- reabsorpt ion- and secret ion- families of substances,

respect ively. - D shows the clearance curves.

For all substances belonging to the inulin family the exc retion f lux curves are linear, so the rate of

change (whic h is the c learance) must be constant in a given condi tion (Fig. 25-6A) .

The results of the three exc retion f luxes are plotted wi th Cp as the dependent variable (x-axis of Fig.

25-6, ABC) .

The exc retion f lux curves for the three families of substances, when di f ferentiated ( dJ excr /dCp ) ,

provide us wi th the three possible c learance curves (Fig. 25-6, D) .

For the reabsorpt ion fami ly, the c learanc e is zero at f i r st, because the exc retion is zero (Fig. 25-6

D) . The c learanc e inc reases, and f inally i t approaches the inulin c learance. Therefore, the

c learance is steadi ly inc reasing towards inulin c learance with inc reasing Cp .

For the sec ret ion family, the c learance must also be equal to the exc retion f lux divided by C p . W hen

the [PAH] inc reases, more and more PAH is eliminated by f i ltration, and the sec retory elimination is

relati vely suppressed (so-called auto-s uppres s ion) . The c learance for the sec retion family i s falling

with inc reasing Cp , and approac hes that of inulin (Fig. 25-6 D) .

Table 25-1: Composit ion of ur ine


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Component Concentrat ion Daily renalexcret ion Finding/Disease

Water 500-2500 ml<500 ml/Nephropathy, shock

>2500 ml/Diabetes

Potassium 60-70 mM 90 mmol dai ly<20 mmol dai ly /Low diet

>150 mmol dai ly /Ric h diet

Sodium 50-120 mM 150 mmol dai ly

Protein 20 mg* l-1 30-150 mg dai ly Mic roalbuminur ia/Diabetes

Proteinur ia/Nephropathy

Glucose zero Neglig ib leGluc osur ia/Diabetes melli tus

Gluc osur ia/Proximal defec t

Urea 200-400mM 500 mmol dai ly High exc retion/Uraemia

Creatinine 0.1 1500-2000 mg dai ly High exc retion/Large m. mass

Low exc retion/Muscul. atrophy

Osmolali ty >600 mOsmol*kg-1 Acceptable conc . capac ity

The composi tion of ur ine in Table 25-1 is the basis for simple diagnostics. Anur ia or oligur ia (<500

ml dai ly ) indicates the presence of hy potension or renal disease. Polyur ia ( >2500 ml of ur ine dai ly )

i s the sign of diabetes – both diabetes melli tus and diabetes insipidus. Mic roalbuminur ia ( ie, 50-150

mg per l) indic ates glomerular bar r ier disorder such as diabetic g lomerular disease. Glucosur ia wi th

hy perglycaemia is the sign of diabetes melli tus, and wi thout hy perglycaemia i t i s a s ign of a proximal

reabsorption defec t. High urea exc retion is seen in uraemia, and high c reatin ine exc r etion indicates

a large musc le mass in a healthy person. A low c reatinine exc retion is the sign of muscular atrophy

or ageing.

3. Ult rafiltat ion and the inulin family

In a healthy person at rest almost 25% of cardiac output passes the two kidneys (1200 ml each min) .


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The blood reaches the f i r st par t of the nephron through the afferent ar ter iole to the glomerular

capi llar ies. In the glomerular capi l lar ies the hydrostati c pressure is approximately 60 mmHg at the

star t and 55 mmHg at the end (Fig. 25-7 ) . The inul in or f i l t rat ion fami ly consists of inulin,

radioac tive indic ators( 51Cr-EDTA, 57Co- marked B12 , 1 4C-marked inulin, 3H-marked inulin,

iothalamate marked wi th 125 I or 131 I ) , mannitol, raff inose, suc rose, th iocyanate, and th iosulfate.

These substances are more or less evenly distr ibuted in the ECV.

3a. The Star l ing forces

The pressures governing the glomerular ultraf i ltration rate (GFR) are c alled the Star l ing forc es (see

equation in Fig. 25-7) . Normally, f i ltration continues throughout the enti re length o f the glomerular

capi llar ies in humans, because the net ultraf i ltration pressure (P ne t ) is positi ve also at the efferent

ar ter iole. The average values for determinants of GFR are given in the f i rst equation of Fig. 25-7. The

hy drostati c pressure gradient is an impor tant determinant of GFR. The glomerular f i l t rat ion

coef f ic ient i s called K f . The K f i s equal to the f i ltration sur face area divided by the resistanc e of the

glomerular bar r ier and thus a c onstant for a given bar r ier (Fig. 25-7) . The value of K f (also called

the rec iprocal glomerular hydrodynamic res is tance) i s reduced in diabetes, glomerulonephr i tis and

hy per tension. Vasoac tive substances c onstr ic t or di latate the glomerular mesangial c e lls and c hange

the value of K f .

In other condi tions, the forces opposing f i ltration become equal to the forces favour ing f i ltration at

some point along the glomerular capi llar ies. This is c alled f i l t rat ion equi l ibr ium.

The hydrostati c pressure in Bowmans space below the glomerular bar r ier i s about 15 mmHg or 2 kPa

(PBow in Fig. 25-7) . This pressure is a lmost equal to the proximal tubule pressure, since there is no

measurable pressure fall a long this segment.


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Fig. 25-7: Net ult rafilt rat ion pressures in afferent and efferent end of glomerular capillar ies.

The Star ling forces determine the final ult rafilt rat ion pressure ( Pn e t ) across the glomerular

barr ier.

There is almost no colloid-osmotic pressure in Bowmans space, but an oncotic pressure of

approximately 25 mmHg in the incoming plasma, mainly due to proteins, which are up-conc entrated,

when f luid leaves the the plasma for Bowmans space. Hereby, the protein-onc otic pressure (pgc ) may

inc rease f rom 25 to 35 mmHg at the end of the glomerular capi llary (Fig. 25-7) . The h igher the renal

plasma f low (RPF) , the lower is the r i se in pgc .

A selec tive inc rease in the resistance of the af ferent ar ter io le reduces both the RPF and the

glomerular hydrostati c pressure (Pgc ) , but GFR dec reases more than RPF, so the f i ltration f rac tion (=

GFR/RPF) falls. In contrast, a r i se in the resistance of the ef ferent ar ter io le reduc es RPF but

inc reases Pgc (F ig. 25-7) . Instantly, GFR inc reases slightly, but GFR eventually dec reases due to the

r ise in pgc . As RPF falls more than GFR the f i ltration f rac tion inc reases. A combined inc rease in

both the afferent and the ef ferent ar ter io lar resistance (as caused by most vasoconstr i c tors) may

also reduce RPF more than GFR, and inc rease the f i ltration frac tion.

3b. The net ul t raf i l t rat ion pres sure

The net ul t raf i l t rat ion press ure (Pne t ) var ies f rom 20 to 5 mmHg through the glomerular capi llar ies,

and provides the force for ultraf i ltration of a fat- and protein- f ree f lu id ac ross the glomerular bar r ier


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i nto Bowmans space and f low through the renal tubules ( Fig. 25-7) .

The ultraf i ltrate i s i sosmolar wi th plasma, almost protein f ree, and contains low molecular substances

in almost the same concentration as in plasma water.

The proximal tubular reabsorption takes place through para- and trans-cellu lar pathways. In the

per i tubular c api llar ies, the Star ling forces are seemingly adequate for capi llary uptake of intersti tia l

f luid (Fig. 25-7) .

The hydrostati c net pres sure in the proximal tubules – and wi th i t the GFR - i s remarkably well

maintained in spi te of changes in proximal reabsorption of salt and water.

An acute defec t in the proximal reabsorption mechanism results in an in i tial r ise in proximal

hy drostati c pressure and the GFR is reduced. Due to autoregulat ion (see paragraph 9) , the proximal

hy drostati c pressure is rapidly normalised at a new steady state. Sympathetic stimulation inc reases

both the proximal reabsorption rate and the per i tubular capi llary uptake (Fig. 25-7) . Hereby, the

hy drostati c pressure falls in the proximal tubules and Bowman's capsule so GFR may inc rease. In

reverse, angiotensin I I sec retion inhibi ts the proximal reabsorption rate, inc reases the proximal

pressure and may reduce GFR. The total dis tal f low res is tance below the proximal tubules ( ie, in the

distal system) is large and impor tant. The distal resistance has two major components namely a high

resistance in the Henle loop and an even higher resistance in the remaining distal sy stem inc luding

the collec ting duc ts.

The res is tance of the glomerular barr ier i s calculated in Fig. 25-7 to be extremely small.

Normally, there is hardly any hy drodynamic resistance to glomerular ultraf i ltration.

4. Tubular reabsorpt ion and the glucose family

The reabsorpt ion or glucose fami ly c ontains vi ta l substances such as glucose, amino ac ids, albumin,

ac etoacetates, asc orbic ac id, beta-hydroxybuty rate, carboxy late, vi tamins, lac tate, py ruvate, Na+ ,

Cl- , HCO3- , phosphate, sulphate and urea.

4a. Tubular handl ing of glucose

Tmax is the maximum transfer or net reabsorption f lux ( J r ea bs ) for gluc ose (mol.wt. 180 g per mol) in

the proximal tubules. The optimal value for this glucos e transpor ter i s 300 mg/min or 300/180 = 1.7


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mmol/min for healthy, young subjec ts wi th a body weight of 70 kg.

For the reabsorption fami ly of substances, the exc retion is zero at f i r st s ince the enti re f i ltered load

is reabsorbed (all glucose is reabsorbed, see Fig. 25-8) . The exc retion f lux inc reases then linear ly

with inc reasing f i ltration f lux.

Fig. 25-8: Renal Glucose rates as a funct ion of the plasma concentr at ion (Cp ) .

The appearance thres hold is the blood plasma [gluc ose] at which the glucose can be f i r st detec ted in

the ur ine (normally 8.3 mM or 150 mg%). This oc curs when most but not all nephrons are saturated

(Fig. 25-8) .

The ac tual saturat ion thres hold, the point where all nephrons are glucose-saturated, is much higher

(normally above 13.3 mM) . The concentration dif ference (13.3 - 8.3 = 5 mM) represents a simi lar

reabsorption rate di f ferenc e (1.7 - 1.0 = 0.7 mmol/min at normal GFR) called splay . The reabsorption

capac i ty for glucose in the proximal tubule c ells becomes saturated at these high blood

concentrations (Fig. 25-8).

4b. Urea t ranspor t

The water reabsorption in the proximal tubules inc reases the urea concentration in th e f luid. Sinc e

urea is uncharged and di f fuses easi ly, i t wi ll di f fuse passively to the per i tubular c api llary blood. The

passage f rac tion at the outlet of the proximal tubule i s around 0.5 (50% of the f i lte red load) .


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Urea is thus reabsorbed in the proximal tubules and also in the inner medullary collec ting duc ts and

sec reted in the th in descending and asc ending limb of the Henle loop (see later ) .

The kidney reuses urea by rec irc ulation in the intrarenal urea rec yc ling c i rcui t: Inner medullary

collec ting duc ts – medullary intersti tium – loop of Henle – distal tubules – collec ti ng duc ts.

The net reabsorption f lux i s around 50% of the f i ltration f lux at normal ur ine f low. The normal urea

concentration in plasma is 5mM, and the exc retion f lux for urea is propor tional to th is urea

concentration.

4c . Prox imal tubular reabsorpt ion

Healthy proximal tubules reabsorb approximately 70% of the f i ltered water, Na+ , Cl- , K+ and other

substances. The tubular passage frac tion for these substanc es at the outlet of the pr oximal tubule is

0.3 (30%) . The reabsorption of f luid is i sosmotic . Almost all f i ltered glucose, peptides and amino

ac ids are also reabsorbed by the proximal tubules. The Cl- reabsorption is passive. This ion fo llows

the secondary ac tive reabsorption of Na+ in order to maintain elec tr i cal neutrali ty. Reabsorption of

water is passive as a result of the osmotic force c reated by the reabsorption of NaCl. All reabsorption

processes are linked to the func tion of the basolateral Na+-K+ -pump. The extremely high water

permeabili ty of the proximal tubule i s essential for i ts near ly i sosmotic volume reabsorption. The

ac tive reabsorption of solutes makes the f lu id s lightly di lute and the intersti tial f luid slightly

hy per tonic . I f inulin and PAH molecules are present thei r conc entration in the f luid wi ll r i se (PAH also

because of proximal sec retion) . The ac tively reabsorbed solutes have lower permeabi li ties (higher

ref lec tion coeff i c ients) than NaCl.

In the f i r s t hal f of the prox imal tubule , Na+- is reabsorbed wi th c arbonic ac id and organicmolecules

belonging to the reabsorption fami ly. - The proximal and distal reabsorption ofbicarbonate is already

desc r ibed in Chapter 17.


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Fig. 25-9: Reabsorpt ion of NaCl in the ear ly and the late par t of the proximal tubule. CA stands

for carboanhydrase in the brush borders of the cell.

The reabsorption fami ly of substances (X) enters the tubule cells by spec i f i c sympor ter proteins

coupled to the Na+ - reabsorption (1. in Fig. 25-9) . This i s secondary ac tive transpor t showing

saturation k inetics. Na+ - reabsorption is also coupled to H+ - sec retion f rom the c ell by the func tion of

the Na+ -H+-ant ipor ter protein (2. in Fig. 25-9) . This H+ -sec retion is linked to bic arbonate

reabsorption in the upper par t of the proximal tubules. The dr iving force for the Na+ -entry i s the Na+

-K+-pump loc ated in the basolateral membrane, which extrudes the Na+ to the intercellular spac e and

the blood (3. in Fig. 25-9) . Glucose is a typical example. The luminal membrane conta ins a sodium-

gluc ose-cotranspor ter (SGLT 2) . A genetic defec t in this protein produces familial renal glucosur ia –

just as a genetic defec t in a s imi lar intestinal protein (SGLT 1) produces glucose-ga lac tose

malabsorption. - The passage of glucose ac ross the basolateral membrane is by car r ier -mediated

( fac i li tated) di f fusion.

In the second half of the prox imal tubule , Na+ is reabsorbed together wi th Cl- ac ross the cell

membrane or through paracellular routes ( Fig. 25-9, below) . In this segment the tubular f lu id c ontains

a high concentration of Cl- and a minimum of organic molecules. Na+ c rosses the luminal membrane

by the operation of Na+ -H+-ant ipor ters and Cl - -anion ant ipor ters . In the tubular lumen the sec reted

H+ and anion form a H+-anion complex. The accumulation of a lipid-soluble H+-anion-complex

establi shes a concentration gradient that a llows H+-anion-c omplex recyc ling (Fig. 25-9) . Transfer of


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the Cl- - ion f rom the tubular f luid to the blood causes the tubular f lu id to become posi tive ly charged

relati ve to the blood.

4d. Reabs orpt ion in the th ic k ascending l imb

The Na+-K+-pump maintains a low intracellular Na+ , which dr ives the simultaneous, e lec troneutral

reabsorpt ion of 1 Na+ , 1 K+ , and 2 Cl- by the l uminal Na+‑K+-2Cl - -sympor ter . The Cl- -channels are

only located in the basolateral membrane, so accumulated Cl - reaches the ISF. The K+ -c hannels are

located in all membranes and K+ rec irc ulates (Fig. 25-10) . Paracellular reabsorption of posi tive ions

by dif fusion is augmented by the posi ti ve charge of the tubular f luid (Fig. 25-10) .

The secondary ac tive reabs orpt ion of Na+ (and Cl - ) is the bas is for the t ransepithel ial s ingle ef fec t

gradient at each transverse level of the thick ascending limb (see later ) .

Fig. 25-10: Reabsorpt ion of NaCl in the thick ascending limb of the Henle loop. There is a

luminal Na+ K+-2Cl- -symporter and a basolateral Na+ K+-pump. This mechanism is essential for

development of medullary hyper tonicity by NaCl and thus for counter current mut iplicat ion

(see later ) .

The elec trochemical energy for the func tion of the basolateral Na+ K+-pump is provided by i ts

Na+-K+-ATPase. The pump throws Na+ into the per i tubular f luid. The K+ and Cl- ions leak out

passively. The thick asc ending limb is impermeable to water in the absence of ADH, and reabsorbs

Na+ ac tively.


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Loop diureti cs, which abolish the entire osmolar gradient in the outer renal medulla, inhibit the

l uminal Na+ K+-2Cl - -sympor ter of the thick ascending limb.

4e. Reabs orpt ion in the dis tal tubule and col lec t ing duc t

The distal tubule i s divided into an ear ly and a late segment, sinc e the ear ly segment reabsorbs NaCl

and is impermeable to water (as the thick ascending limb) , whereas the late segment func tions more

li ke the collec ting duc t. In the ear ly segment, the NaCl transfer i s mediated by a NaCl -sympor ter

(Fig. 25-11) . Na+ leaves the c ell through the basolateral Na+‑K+-pump, and Cl- leaves the cell by

di f fusion ac ross the basolateral Cl- -channels. Only a small f rac tion of the glomerular f i ltrate reaches

the distal tubules. Thiazide diureti cs inhibi t the NaCl-sy mporter.

Fig. 25-11: Cellular t ranspor t processes in the distal tubule and collect ing duct .

The late segment i s composed of two cell types just as the c ollec ting duc ts. The light princ ipal c el ls

reabsorb Na+ and sec rete K+ . The Na+-K+-pump in the basolateral membrane draws Na+ out into the

ISF and K+ into the pr inc ipal cells (Fig. 25-11) . These cells have spec ial ion c hannels in the luminal

membrane, which is permeable to Na+ , but a lso to K+ . The Na+ -uptake depolar ises the luminal

membrane ( -70 mV) and makes the lumen elec tronegative ( -12 mV) compared to the inters ti tia l f luid

( reference potential zero) . K+ rapidly di f fuses into the tubular f luid. This sec retion of K+ into the

tubular f luid f rom the pr inc ipal cell i s thus linked to the Na+- reabsorption. The amount of Na+

reabsorbed in the distal tubule system is much less than in the proximal, but i t can be inc reased by


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the adrenocorti cal hormone, aldosterone. Aldosterone is a mineralocor ti coid, which pr omotes the

reabsorption of Na+ (and thus Cl- ) and the sec retion of K+ (and H+) in pr inc ipal cells. Aldosterone

enters the cell f rom the blood and binds to an intrac ellular receptor to form a complex. The complex

inc reases the formation of membrane proteins inc luding the Na+-K+ -pump and the luminal

Na+-channels. This is the essential c ontrol mechanism for [K+ ] in the ECV. Sec retion mainly occurs

when the [K+ ] in the ECV is higher than normal.

Aldosterone also promotes the reabsorption of Na+ (and thus Cl- ) and the sec retion of K+ (and H+) in

the collec ting duc ts of sweat and sali vary glands just as in the pr inc ipal cells of the distal tubules of

the kidney. Aldosterone-antagonists inhibit all a ldosterone effec ts. The dark i ntercalated cel l s

sec rete H+ across the luminal membrane and reabsorb K+ .

Intercalated c ells are mi tochondrial- r i ch and most ac ti ve in persons wi th a low K +-pool. The H+

-sec retion by the H+-pump is prec isely determined by the [H+ ] in the ECV.

The col lec t ing duc t contains pr inc ipal and intercalated cells just as the late distal segment, but the

intercalated c ell disappears in the inner medullary c ollec ting duc ts.

The luminal membrane of the pr inc ipal c ells in the collec ting duc ts can be regulated f rom near ly

water - impermeable ( in the absence of antidiureti c hormone, ADH) to water -permeable ( i n the

presence of ADH) . The hormone inc reases the water -permeabi li ty by inser tion of water - channels

called aquapor in 2. The water -channels are stored in cy toplasmic vesic les that fuse wi th the luminal

membrane. The basolateral membrane of the pr inc ipal cell contains other aquapor ins an d they remain

water -permeable even in the absence of ADH. Mutations in the genes for these channel proteins

cause nephrogenic diabetes ins ipidus .

5. Tubular secret ion and the PAH family

Substances sec reted li ke PAH consti tute the sec retion or PAH fami ly. The f i ltration f lux (J f i l t r ) as

usual inc reases in di rec t propor tion to the r i se in Cp (Fig. 25-12) . Dividing the exc retion f lux for PAH

with Cp provides us with the PAH c learance . The c learance is the slope of the exc retion f lux curve

(Fig. 25-12) . The sec retion f lux approaches a maximum (Tmax) . Most of the PAH molecules are f ree,

but 10-20% are bound to plasma proteins.


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Fig. 25-12: Renal PAH net rates (fluxes or J) as a funct ion of plasma concentrat ion, Cp .

Organic ac ids and bases sec reted in the proximal tubules inc lude endogenous substances and drugs.

The endogenous substances inc lude adrenaline, bi le salts, c AMP, c reatinine, dopamine, hippurates,

noradrenaline, organic ac ids and bases, oxalate, prostaglandins, steroids and urate. The drugs

compr ise ac etazolamine, ami lor ide, atropine, bumetanide, chlorothiazide, c imetidine, diodrast,

furosemide, hydrochlorothiazide, morphine, ni trofurantoin, para-aminohippur ic ac id (PAH) , penic i lli n,

phenol red, probenec id, sulphonamides, and acety lsalic y lic ac id. The sec retion is of ten competi tive.

All these substances have vary ing but high af f ini ty to an organic ac id-base s ec retory sys tem i n the

proximal tubule cells showing saturation kinetics with a Tmax. The organic cation sec retion is

analogous to the anion sec retion.

5a. Tubular handl ing of PAH

Tmax is the maximum sec retion rate for PAH in the tubules ( Fig. 25-13) . Normally, the Tmax i s 0.40

mmol per min (80 mg/min) for PAH.

At low PAH concentrations in the plasma (Fig. 25-13), the slope of the exc retion rate c urve is high

( the c learance for PAH is high) . Here the PAH c learance is an acceptable estimate of the minimal

renal p lasma f low (see ef fec tive RPF later ) , because the blood is almost c leared by one transi t.

The sec retion f lux is maximal, when the plasma- [PAH] is h igh enough to achieve saturation. The weak

organic ac ids and bases mentioned above are simi lar ly sec reted into the proximal tubu le, and have


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sec retory Tmax - values just like PAH (Fig. 25-14 ) . In humans of average size (wi th an average body

sur face area of 1.7 m2 ) , the Tmax for diodrast and phenol red average 57 and 36 mg/min,

respec tively.

5b. Tubular handl ing of urate

The ac t ive reabs orpt ion of urate ions is accomplished in the proximal tubules by an elec troneutral

Na+-cotranspor t. The tubular reabsorptive capac i ty is normally far greater than the amount deli vered

in the glomerular f i ltrate. Above a c r i ti cal concentration in the ECV of about 0.42 mM, the urate

prec ipi tates in the form of ur ic ac id c rystals, provided the envi ronment i s ac id. Prec ipi tation in the

joints i s termed gout (arthr i ti s ur ica) , of ten affec ting several joints. Urate ions are ac cumulated in the

ECV of gout patients, and of ten also in patients wi th uraemia. High doses of probenec id compete with

urate for the proximal reabsorption mechanism. Use of this drug to patients wi th acute gout inc reases

the exc retion of urate in the ur ine.

The ac t ive sec retion of urate ions occurs f rom the blood plasma to the tubular f luid by the organic

ac id-base sec retory sys tem , which has a low capac ity for urate.

Thus, the renal tubules have a c apac i ty of both ac tively reabsorbing urate ions and a c tively sec reting

them.

5c . Tubular handl ing of c reat inine

Essentially a ll c reatinine in the glomerular f i ltrate passes on and is exc reted in the ur ine. The

molecule i s larger than that of urea, and none of i t i s reabsorbed. Contrary, c reatinine is sec reted

into the proximal tubules, so that the c reatin ine concentration in the ur ine inc reases more than

100- fold.

5d. The sec ret ion mechanism

The molecules of the sec retion fami ly leave the blood plasma of the per i tubular capi l lar ies and binds

to basolateral rec eptors wi th sympor ters on the tubule cell (Fig. 25-13) . These channels are dr iven by

energy f rom the basolateral Na+-K+ -pump transpor ting the molecules against thei r c hemic al gradient

ac ross the basolateral membrane. Inside the cell the molecules ac cumulate unti l they can dif fuse

towards the luminal membrane. Here, an antipor ter transfers the ions into the tubular f luid. All these


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molecules compete for transport, so intake of the drug probenec id c an reduc e the peni c i lli n sec retion

loss.

Fig. 25-13: Secret ion of organic anions across the proximal tubules

The luminal membrane contains spec i f i c receptor proteins for nut r i t i ve mono- and di -carboxy lates .

These receptor func tions are also coupled to Na+ - transfer.

6 . W ater and solute shunt ing by vasa recta

The normal per fusion of the renal medulla i s typically 5-10% of RBF. This bloodf low i s larger than the

f luid f low through the loop of Henle. Both the vasa rec ta and the c losely located loops of Henle ( f rom

juxtamedullary nephrons) consists of two parallel limbs wi th counter -cur rent f luid f low in the medulla.

Vasa rec ta are designed as a counter cur rent b loodf low and ac t as water-solute shunts that protec t

the medullary hyperosmotic gradient. The endothelial li ning of vasa rec ta i s highly permeable for

small molecules (water, urea, NaCl, oxygen and carbon dioxide) . Vasa rec ta also serve as a nutr i ti ve

source to the medulla.

Vasa rec ta receive blood f rom the efferent ar ter ioles and consequently have an elevated colloid

osmotic pressure and reduc ed hydrostati c pressure ( Fig. 25-14 ) . The net force in these vascular

loops favours net f luid reabsorpt ion .

Let us c onsider the si tuation wi th a hyperosmotic medullary gradient and ADH present, so a


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concentrated ur ine is produced. The blood in the descending limb of vasa rec ta i s f i r st passed on in

the di rec tion of inc reasing medullary osmolar i ty. Ac cordingly, this blood must gradua lly supply water

to the hyperosmolar, intersti tia l f luid by passive osmosis, and passively reabsorb so lutes (NaCl and

urea) by di f fusion. Hereby, the intersti tium is temporar i ly di luted and the blood is concentrated. In

the ascending por tion the blood passes regions wi th falling osmolar i ty, and the blood gradually

absorbs water osmotically and deli vers solutes to the intersti tium by di f fusion. The f low in the

ascending vasa rec ta i s larger than in the descending limb, because water f rom the Henle loop is also

reabsorbed.

Fig. 25-14: A: Passive counter -current exchange occurs in vasa recta, with diffusion of solutes

along black ar rows. Passive osmotic flux of water from the blood to the hyperosmolar

interst it ium occurs along st ippled, blue ar rows. – B: The act ive counter -current mult iplier in

the thick ascending limb with a single effect at each hor izontal level.

The gross effec t of the passive counter -cur rent exchange in the vasa rec ta i s that of a water shunt

passing the medullary ti ssue, whereas solutes recyc le and thus are maintained in medulla. W ater i s

shunted f rom limb to limb without disturbing the inner medulla. The passive counter -c ur rent exchange

and low bloodf low through the vasa rec ta curtai l the medullary hyperosmotic gradient (Fig. 25-14) .

The meagreness of the medullary blood f low, reduc ed by ADH, contr ibute to the maintenance of the

medullary hyperosmotic gradient, but reduce the nutr i tive supply to the inner medulla .

7 . Concentrat ion or dilut ion of ur ine


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The thin ascending limb of Henle i s impermeable for water, but highly permeable for NaCl and less so

for urea. The thic k ascending limb is a lso impermeable for water and also for urea. The water

permeabili ty of the cor tic al and medullary c ollec ting duc ts inc rease with inc reasing concentrations of

antidiureti c hormone (ADH) in the per i tubular blood. Concentrat ion of ur ine. Ini tially, the osmolar i ty

of the tubular f luid, the vasa rec ta blood, and the intersti tial f luid i s 300 mOsmol * l- 1 . The asc ending

limb of the Henle loop is impermeable to water and ac tively transpor ts NaCl f rom the preur ine into the

sur rounding intersti tium. Thus solute and f luid i s separated and the tubular f luid becomes di luted. At

each hor izontal level of the thick ascending limb, a hy perosmotic gradient (a s ingle ef fec t ) of

typically 200 mOsmol * l- 1 i s establi shed (Fig. 25-14B) . Energy is necessary to establish the

hy perosmotic gradient. The energy is from Skou´s basolateral Na+-K+-pump, working in conjunc tion

with the Na+-K+-2Cl—sympor ter of the thick ascending limb (Fig. 25-10) .

The total osmolar i ty in the inner medullary intersti tial tissue can be as high as 1400 mOsmol per l,

when the ur ine is maximally concentrated.

The renal cor tex f lu id i s i sotonic with the plasma. W hen the isotonic f luid from the proximal tubules

passes down through the hy per tonic medulla in the descending th in l imb of the Henle loop, water

moves out into the medullary intersti tium by osmosis, making the tubular f lu id c oncen trated. This i s

because the epi thelial cells of the thin descending limb are highly permeable to water but less so to

solutes (NaCl and urea) . W ater i s reabsorbed and returned to the body via vasa rec ta and the renal

veins. At the bend of the loop the f lu id has an osmolar i ty equal to that of the sur rounding medullary

intersti tia l f luid. However, the tubular f luid has a greater concentration of NaCl and a smaller

concentration of urea than the sur roundings.

In contrast to the thin and thick ascending limb, most cell membranes inc luding those of the proximal

tubules and the thin descending limb of the Henle loop, are water -permeable under all c i r cumstances.

This i s bec ause these c ell membranes contain water -channel proteins called aquapor ins .

As new f luid enters the desc ending limb of the Henle loop, the hyperosmotic f lu id in the bottom of the

loop is pushed into the ascending limb, where NaCl i s separated f rom water.

The osmolar i ty of the isosmotic tubular f luid running into the thin descending loop o f the outer

medulla i s 300 mOsmol* l- 1 and the output to the distal tubule i s 100 mOsmol* l- 1 (Fig. 25-14, B ) . At


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the bottom of the Henle loop the osmolar i ty can inc rease to at least 1300 mOsmol* l - 1 . In a steady

state with continuous f lu id f low the total osmotic gradient along the enti re system i s thus (1300 - 100)

= 1200. The gradient along the enti re system is 6 mul t ip les of the 200 mOsmol* l- 1 single effec t

gradient. The thick ascending limb is a counter -cur rent mult ipl ier wi th a high multipli cation capac ity.

The NaCl i s reabsorbed repeatedly in the thick ascending limb of the Henle loop. The passive

counter -cur rent exc hange in the vasa rec ta and the ac tive counter -cur rent NaCl reabsorption in the

thick asc ending limb combine into a solute-water separator , when ADH is present.

Another component in the maintenanc e of the medullary hy perosmotic gradient is addi ti on of urea to

the tubular f luid in the th in segment of the Henle loop. Urea is then trapped in the lumen, bec ause all

nephron segments, f rom the thick ascending limb through the outer medullary collec ting duc t, are

impermeable to urea.

As the tubular f luid f lows through the distal tubules, cor ti cal collec ting duc ts and outer medullary

collec ting duc ts, i ts urea concentration r i ses progressively, because these segments are essentially

urea- impermeable whether or not ADH is present. In the presenc e of ADH, water i s reabsorbed but

urea is not and the osmolar i ty of the f luid inc reases. The maximal osmolar i ty in the cor t ic al c ollec ting

duc t i s up to 300 mOsmol* l- 1 , which is equal to the sur rounding intersti tial f luid.

The distal f luid contains much urea and less NaCl. In reverse, the inner medullary co llec ting duc t

cells have urea- transpor ters that are ADH-sensi ti ve. Thus large amounts of urea are r eabsorbed at

low urine f lows, and the inner medullary intersti tial f luid i s loaded wi th urea that di f fuses back to the

tubular f luid through the thin descending and ascending limb in th is urea recyc ling proc ess. Urea

covers 700 and NaCl also 700 mOsmol* l- 1 out of the total 1400. W i thout passive urea recyc ling, the

medullary intersti tial osmolar i ty contr ibuted by NaCl would have to double and thus the energy

demand. W i thout the medullary hyper tonic gradient we would be unable to produce conc entrated

ur ine when water depleted.

A high osmolar i ty in the medullary intersti tium enhances passive water reabsorption when ADH is

present. ADH inc reases the concentration of solutes in the collec ting duc ts, and reduces the loss of

water. A hyperosmotic conc entration – moving f rom 300 up to 1400 mOsmol* l- 1 i n the inner medulla -

has establi shed a large concentration gradient between the tubular and the intersti ti al f luid.


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In man, the maximal ur ine osmolar i ty – when ADH is high - is 1400 mOsmol* l - 1 , which in a dai ly ur ine

volume of 500 ml c or responds to a dai ly solute loss of up to 700 mOsmol. The small ur ine volume

contains high conc entrations of urea and nonreabsorbed or sec reted solutes.

Dilut ion of ur ine ( large ur ine f low)

In the absence of ADH, the distal tubules, cor tic al c ollec ting duc ts and outer medullary collec ting

duc ts are impermeable to water. The osmolar i ty of the passing tubular f luid i s reduce d ( towards 100

mOsmol* l- 1 ) when we need a di luted ur ine. The medullary collec ting duc t reabsorbs NaCl (ac ti vely )

and is s lightly permeable to water and urea in the absence of ADH. The f inal ur ine – wi th small

concentrations of NaCl and urea - has an osmolar i ty of 50-150 mOsmol* l - 1 , wi th a volume of up to

10% of the dai ly GFR.

W hen ADH is absent, the f luid leaving the distal tubules remains hypotonic . Large amounts of

hy potonic ur ine would then f low into the renal pelvis (with an osmolar i ty down towards 50

mOsmol* l - 1 ) . A dai ly solute loss of 700 mOsmol, under these c ondi tions, implies a dai ly water loss of

at least 14 l .

8. Renal bloodflow (RBF)

The Fick's pr inc iple (mass balance pr inc iple) i s used to measure the renal plasma c learanc e at low

plasma [PAH] , since at low conc entrations - the blood is almost c leared by one trans i t. Thus, the

renal p lasma c learance for PAH is almost equal to the renal plasma f low RPF in Eq. 25-5. The law of

mass balanc e states that the infusion rate of PAH is equal to i ts exc retion rate at s teady state.

Only one passage through the kidneys ef fec t i vely eliminates PAH f rom the venous blood plasma at

low [PAH] . A methodological shor t c ut i s to measure the [PAH] in the medial c ubi tal vein only, instead

of the true ar ter ial [PAH] by ar ter ial c atheter isation. PAH c learanc e is an acceptable approximation

called the ef fec t i ve renal p lasma f low (ERPF) . In a healthy, resting person the ERPF is 600-700 ml of

plasma per min and lower than the RPF. The ERPF pr inc iple avoids complex invasive procedures suc h

as c atheter isations.

The Tmax for PAH is also a valuable measure of the sec reting tubular mass, because the proximal

tubule c ells are saturated wi th PAH at high plasma- [PAH] .


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The RBF falls drastically, when the mean ar ter ia l pressure is below 9.3 kPa (70 mmHg) . The

medul lary bloodflow is always small in both absolute and relati ve terms. Any severe RBF reduc ti on as

in shock, easi ly leads to isc haemic damage of the medullary ti ssues resulting in papi llary nec rosis

and ultimately to fai lure of renal func tion.

Dur ing such pathophysiologic al condi tions, prostaglandins (PGE2 and PGI2 ) are sec reted f rom the

mesangial and endothelial cells due to sympathetic stimulation. These prostaglandins di latate the

af ferent and ef ferent g lomerular ar ter ioles and dampen the renal ischaemia caused by sympatho-

adrenergic vasoconstr i c tion.

Both RBF and GFR show autoregulat ion following acute c hanges in the per fusion pressure wi th in the

physiological pressure range (Fig. 25-15 ) . The renal autoregulation is mediated by my ogenic

feedback and by the macula densa-tubulo-glomerular feedback mechanism. Myogenic feedback i s an

intr insic property of the smooth musc le cells of the af ferent and ef ferent ar ter ioles. The myogenic

response allows preglomerular ar ter ioles to sense c hanges in vessel wall tension (T) and respond wi th

appropr iate adjustments in ar ter iolar tone. Stretching of the c ells by a r i se in ar ter ial transmural

pressure (DP) eli c i ts smooth musc le c ontrac tion in inter lobular arter ies and afferent ar ter ioles (Fig.

25-15) . Dur ing sleep the mean arter ial pressure dec reases 1-2 kPa, whic h would lower Pgc and GFR

without autoregulation. Autoregulation with maintained RBF and GFR means that also the f i ltered load

and the sodium exc retion is maintained dur ing sleep and var iations in dai ly ac ti vi ties. The macula

densa- TGF mechanism i s desc r ibed below.

W hen the renal per fusion pressure r ises, the cor tic al b loodf low is effec ti vely autoregulated. However,

dur ing cer tain c i rcumstances the papi llary bloodf low may inc rease due to release of NO,

prostaglandins, kinins or other fac tors. The inc reased medullary bloodf low inc reases the intersti tial

hy drostati c pressure and thus the resistance towards Na+ -reabsorption, whereby the Na+-exc retion

inc reases.

Sympathetic vasoconstr i c tion reduces the renal per fusion pressure and thus the restin g RBF.

Inc reased renal sympathetic tone releases renin and enhances Na+- reabsorption in the proximal and

distal tubules via nerve f ibres. At maximum exerc ise RBF falls to half the resting le vel. - RBF also

drops dur ing emotional stress and dur ing haemor rhage.


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Fig. 25-15: Pressure- flow relat ions in the kidney. The RBF curve shows autoregulat ion, and

GFR follows the bloodflow.

Noradrenaline/dopamine from adrenergic f ibres and c i rculating adrenaline from the adr enal medulla,

constr ic t the af ferent and efferent g lomerular ar ter ioles, when the hormones are bound to

a1 -adrenergic receptors. This constr i c tion dec reases both RBF and GFR. Sy mpathetic stimulation

releases renin f rom the granular JG-cells of the ar ter ioles via b1 -adrenergic rec eptors. Ac tivation of

the adrenergic f ibres enhanches the Na+- reabsorption along the whole nephron.

The normal 300-g's of k idney ti ssue receive a total bloodf low (RBF) of 1200 ml per min, which is

20-25% of the c ardiac output at rest. Thus, on an average, RBF is 400 ml of blood per min and per

100-g kidney ti ssue. These uni ts are ac tually called Flow Uni ts (FU) or per fusion c oeff i c ients. The

renal b lood f low per weight uni t i s higher than any other major organ in the body. The renal cor tex

rec eives 90% of the total RBF, and only 5-10% reaches the outer medulla. The blood supply i s at a

minimum in the inner medulla, and the oxygen tensions fa lls off sharply in the papi llary ti ssue. The

medullary bloodf low can be reduc ed towards 1% by vasopressin.

The counter cur rent exchange of oxygen in vasa rec ta i s a disadvantage to the renal papi llae

because their cells are last fed wi th oxygen by the blood. The inner cells meet their energy

requi rements pr imar i ly by anaerobic breakdown of glucose by gly colysis. The amount of energy

obtained here is only 1/10 of the oxidative breakdown of 1 mol of glucose (2 888 kJ f ree energy ) .


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The cor t i cal bloodf low i s much larger than the medullary bloodf low. Here, 1/5 of the whole plasma

stream passes the glomerular barr ier by ultraf i ltration and becomes preur ine . For tunately, we obtain

the greater par t of the energy required for c or ti cal tubular transpor t by oxidative metabolism.

9. Macula densa- tubulo-glomerular feed-back (TGF)

The mac ula densa-TGF mechanism responds to disturbances in distal tubular f luid f low passing the

macula densa.

The JG-apparatus inc ludes 1) the renin-produc ing granular cells of the afferent and ef ferent

ar ter ioles, 2) the macula densa of the thick ascending limb, and 3) the extraglomerular mesangial

cells connec ting the afferent and the efferent ar ter iole ( Fig. 25-16) .

Renin is desc r ibed in paragraph 6 of Chapter 24.

Fig. 25-16: The juxtaglomerular apparatus with renin secret ion.

Regulation of renal sodium exc retion is desc r ibed in paragraph 9 of Chapter 24.

The TGF mechanism thus inc ludes the renin-angiotensin I I -aldosterone cascade ( Fig. 24-5) .

Prostaglandins, adenosine and NO can modulate the response. These renin responses are part of the

autoregulation to maintain RBF and GFR normal.

10. Non- ionic diffusion


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Non- ionic di f fus ion i s a passive tubular reabsorption of weak organic ac ids and bases, whic h are

lipid-soluble in the undissoc iated or non- ionised state. In this state these compound s penetrate the

lipid membrane of the tubule c ell by di f fusion. The tubule cells, however, are prac ti cally impermeable

to the dissoc iated form of these compounds. Therefore, the i onic form of the weak ac id or base is

f i xed in the tubular f luid and favoured for ur inary exc retion.

A weak organic ac id i s mainly undissoc iated at low ur inary pH, whereas an organic base is more

dissoc iated. In ac id ur ine the reabsorption rate of weak organic ac ids i s inc reased, whereas the

reabsorption rate of weak organic bases is reduced. In alkaline ur ine the opposi te s i tuation prevai ls.

Examples of weak ac ids showing this phenomenon are phenobarbi tal and proc ain (both wi th pK just

below 7) , NH4+ , ac ety lsali cy li c ac id, and many other therapeutics. W eak bases are the doping

substance, amphetamine, and many therapeutic s.

In rare cases of poisoning wi th weak bases, the patients are treated wi th infusions of ammonium

chlor ide solutions or amino ac id-HCl solutions, which ac idif ies the ur ine (see Chapter 17) . In cases

of poisoning wi th weak ac ids, some patients receive infusions of bicarbonate solutions, whereby

alkali sation of the ur ine is insti tuted.

11. Tests for proximal and distal tubular funct ion

Several proximal tests are avai lable.

1. About 30 g of plasma albumin passes through the glomerular bar r ier each day. For tunately,

most of th is albumin is absorbed through the brush border of the proximal tubules by pinocy tosis.

Inside the c ell the protein molecule i s digested into amino ac ids, which are then absorbed by

fac i l i tated di f fus ion through the basolateral membrane. Proteins der ived f rom proximal tubule

cells, such as ß2 -mic roglobul in , are reabsorbed by the proximal tubules. I f this protein is

demonstrated by ur ine elec trophoresis, a proximal reabsorption defec t i s present. Thi s i s also the

case, when general i zed aminoac iduria i s present.

2. Glucosur ia in the abs ence of hy perglycaemia indicates a proximal reabsorption defec t of

gluc ose, since all g luc ose is reabsorbed before the f luid reaches the end of the proximal tubules

in the normal state.


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3. The l i thium c learanc e . The li thium ion, L i+ , i s f i ltered f reely ac ross the glomerular bar r ier, and

i ts conc entration in the ultraf i ltrate i s equal to that in plasma water. L i thium carbonate is used in

the treatment of manic phases (catec holamine over - reac tion) of manic depress ive psychos is . A

plasma concentration of 0.5-1 mM provides enough Li + to block membrane receptors on the

neurons involved for catec holamine binding.

Fig. 25-17: Lithium clearance used as a measure of the proximal reabsorpt ion capacity in the

nephron.

Li+ i s reabsorbed isosmotic ally in the proximal tubules together wi th water and Na+ (Fig. 25-17) .

The amount of Li + that leaves the proximal tubules (pars rec ta) i s equal to i ts exc retion rate in the

f inal ur ine. This i s because there is prac tically no reabsorption or sec retion of Li + distal to this

loc ation. Accordingly, a large li thium c learance depic ts a low proximal li thium reabsorption, and

thus a poor proximal tubular func tion at a given GFR. Normally, the passage f rac tion of Li+ i s

0.25-0.3 at the end of the proximal tubules and almost the same f rac tion passes into the ur ine.

4 Hy pokalaemia combined wi th normal or inc reased renal K+ -exc ret ion suggests a defec tive

proximal K+ - reabsorption (see Chapter 24 or Table 25-1 ) .

5 Sec retion ac ross the proximal tubules (PAH c learanc e) .

Tests of d istal tubular func tion:


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Renal concentrating capac i ty i s easi ly estimated as osmolali ties in morning plasma and ur ine.

Normal plasma osmolali ty ranges over 275-290 mOsmol per kg, and a ur ine osmolali ty above

600 mOsmol per kg suggests an ac ceptable renal concentrating capac i ty (more acc urate is a

standardized water depr ivation test) .

1.

Inabi li ty to lower ur ine pH below 5.3 despi te a metabolic ac idosis i s indicative of d istal renal

tubular ac idosis ( ie, a bicarbonate reabsorption defec t) . This i s a rare inher i ted condition wi th

fai lure of bicarbonate reabsorption in the distal tubules and the c ollec ting duc ts. The metabolic

ac idosis is insti tuted by the oral intake of 100 mg ammonium chlor ide per kg and conf i rmed by

a pHa less than 7.35 with a negative base exc ess and [bicarbonate] below 21 mM.

2.

NaCl reabsorption in the ear ly par t of the distal tubule di lutes the tubular f luid, bec ause this

segment i s impermeable to water (Fig. 25-11) . Thiazide diureti cs inhibi t the Na+-Cl- sympor ter

protein that causes a measurable inc rease in NaCl exc retion and in diuresis (Fig. 25- 11) .

3.

12. St ix test ing with dipst ics

Rout ine s t i x tes t ing for blood, glucose, protein etc . i s necessary for the c lin ic al evaluation of renal

patients. Reagent s t r ips for red blood c ells are extremely sensi ti ve. Even a tr i vial bleeding f rom a

small c api llary results in a posi ti ve answer indic ating the presenc e of a few red cel ls. In such cases

mic roscopy is necessary. Mic rosc opy of f resh ur ine reveals red c ells in cases of bleeding f rom the

ur inary trac t, and red-cell c asts in c ases of kidney bleeding as in glomerulonephr i ti s.

Since the conc entration threshold in ur ine for most reagent str ips i s 150 mg albumin per li tre ( l) ,

there is no reac tion to the normal albumin concentration of 20 mg l - 1 . Even 50-100 mg of protein i s

of ten exc reted dai ly due to the upr ight posture and exerc ise.

An ear ly sign of diabetic glomerular leakage or nephropathy is mic roalbuminur ia, whic h is def ined as

an albumin concentration of 50-150 mg per l of ur ine, and measured by radioimmunoassay (RIA) .

Some laborator ies measure the Tamm-Horsefal l gly coprotein, which is sec reted f rom the cells of the

thick asc ending limb of Henle, and thus a normal consti tuent of ur ine.

Bac ter ia in the ur ine produce ni tr i te f rom the ur inary ni trate, and dipstic ks easi ly demonstrate the

ni tr i te. Ur inary trac t infec tion also results in white blood cells in the ur ine, and more than 10 cells per


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µ l are abnormal.

13. Diuret ics

Diuret ic s are therapeutic agents that inc rease the produc tion of ur ine. Diureti cs are employed to

enhance the exc retion of salt and water in cases of cardiac oedema or ar ter ial hyper tension. The

so-called nat r iuret ic s inhibit tubular Na+- reabsorption, but since the sec retion of K+ and H+ i s also

inc reased, the patient must have compensatory treatment. The si tes of ac tion for di f f erent groups of

diureti cs are shown in Fig. 25-18.

13 a. Carboanhydras e inhibi tors (eg, acetazolamide) ac t on the carboanhydrase (CA) in the brush

borders and inside the c ells of the proximal tubules. Inhibition of the metallo-enzyme reduces the

conversion of f i ltered bic arbonate to carbon dioxide. As a result, there is a high conc entration of

bicarbonate and sodium in the tubular f luid of the proximal tubules. Up to half of the bicarbonate

normally reabsorbed is eliminated in the ur ine causing a high ur ine f low and a metabolic ac idosis.

Thus, these inhibi tors are diureti cs. They are mainly used in the treatment of open-angle glaucoma

( ie, an intraocular pressure above 22 mmHg) . Ac etazolamide promotes the outf low of the aqueous

humour and probably diminishes i ts isosmotic sec retion.

Fig. 25-18: Sites of act ion on the nephron of different groups of diuret ics

13 b. Loop diureti cs (bumetanide and furosemide) inhibit pr imar i ly the reabsorption of NaC l in the


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thick ascending l imb of Henle by blocking the luminal Na+-K+-2Cl- -sympor ter. The reabsorption of

NaCl, K+ and divalent cations is reduced, and also the medullary hyper tonic i ty i s dec reased. Hereby,

the distal system receives a much higher rate of NaCl, water in isotonic f luid, and K + . The overall

result i s an inc reased exc retion of NaCl, water, K + and divalent cations. The patient’s plasma- [K+ ]

should be chec ked regular ly.

13 c. Thiazide diuret i cs (bendrof lurazide, hydroc hlorothiazide) ac t on the ear ly par t of the distal

tubule by inhibiting the (Na+- Cl- ) -sympor ter. They inc rease K+ exc retion by inc reased tubular f low

rate. Thiazide and many other diureti cs are sec reted in the proximal tubules. This sec retion inhibits

the sec retion of ur ic ac id, so th iazide is c ontraindicated by gout .

13 d. Potass ium-spar ing diuret i cs (eg, ami lor ide) inhibi t Na+- reabsorption by inhibi tion of sensiti ve

Na+-channels in the pr inc ipal c ells of the distal tubules and collec ting duc ts. Hereby, they reduce the

negative charge in the lumen and thus the K+-sec retion. Ami lor ide c auses natr iuresis and reduces

ur inary H+- and K+-exc retion

13 e. Aldos terone-antagonis ts (eg, spironolac tone) compete with aldosterone for receptor si tes on

pr inc ipal cells. As aldosterone promotes Na+- reabsorption and H+ / K+ - sec retion, aldosterone-

antagonists cause a natr iuresis and reduc e ur inary H+ - and K+ -exc retion. Aldosterone-antagonists

are weak potassium-spar ing diuretic s, mainly used to reduce K+ -exc retion caused by thiazide or

loop diureti cs.

13 f. Angiotens in-conver t ing-enzyme (ACE) - inhibi tors (captopr i l, enapr i l and lis inopr i l) reversibly

inhibi t the produc tion of angiotensin I I , reduce systemic blood pressure, renal vascu lar resistance

and K+ -sec retion. ACE- inhibi tors promote NaCl and water exc retion. ACE- inhibi tors inc rease RBF

without much inc rease in GFR, because of a dec rease in both afferent and efferent ar ter iolar

resistance. The development of diabetic nephropathy c an be markedly delayed by ear ly reduc tion of

blood pressure with ACE- inhibi tors and by careful diabetic management.

13 g. Osmot ical ly ac tive d iuret ic s are substanc es such as mannitol and dextrans. These substances

retard the normal passive reabsorption of water in the proximal tubules. Osmotic ther apy wi th

manni tol is used in the treatment of cerebral oedema.

Manni tol is a hexahydric alcohol re lated to mannose and an isomer of sorbi tol. Manni tol passes f reely


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through the glomerular bar r ier and has hardly any reabsorption in the renal tubules. I ts presence in

the tubular f luid inc reases f low according to the concentration of osmotic ally ac ti ve parti c les, which

inhibi t reabsorption of water. The high f low of tubular f luid means that the exc retio n of Na+ i s great -

despi te the rather low Na+ concentration. Manni to l may help to f lush out tubular debr is in shock wi th

ac ute renal fai lure, but the results are controversial.

Dextrans ( ie, polysacchar ides) have a power ful osmotic and diureti c effec t. - The lar ger, molec ules

(macrodex) are seldom used as volume expanders dur ing shoc k because of allergic reac tions.

P a t h o p h y s i o l o g yThis paragraph deals wi th 1. Glomerulonephr itis , 2. Renal insufficiency, 3. Acute tubular

necrosis, 4. Diabetic nephropathy, 5. Nephrotic syndrome, 6. Ur inary tract infection , 7. Tubulo-

interstitial nephr itis , 8. Gouty nephropathy , 9. Renal hyper tension , 10. Ur inary tract obstruction ,

and 11. Tumours of the kidney.

The sever i ty and cause of kidney disease is evaluated by measurement of the GFR.

1. Glomerulonephr it is

Glomerulonephr i tis i s an immunologic ally mediated injury of the glomeruli of both kidneys.

The major i ty of patients suffer f rom postinfec tious glomerulonephr i ti s or immune complex nephr i ti s.

This i s a disorder, where c i rculating antigen-antibody complexes are deposi ted in the glomeruli or

f ree antigen is bound to antibodies trapped in the capi llary network. Typic ally , the antigen is der ived

f rom Lancefield group Aß- haemoly ti c streptococ c i, but also other bac ter ia, vi ruses, parasi tes

(malar ia) , and drugs may be the or igin. A few patients produce antibodies against the i r own antigens

(eg, host DNA in sy stemic lupus ery thematosus, malignant tumour antigen, or anti -glomerular

basement antibody, anti -GBM) . The inf lammation is an abnormal immune reac tion of ten caused by

repeated streptococ cal tonsi lli tis. An insoluble antigen-antibody c omplex prec ipi tates in the basement

membrane of the glomerular capi llar ies.

The cells of the glomeruli proli ferate, and disease wi ll of c ourse reduce GFR and to some extent, the

RBF (measured as PAH c learanc e) . Thus the infec tion depresses the glomerular f i ltrati on frac tion

(GFF = GFR/RPF) . The ac ute postinfec tious glomerulonephri ti s occurs typically in a chi ld, who has


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suffered f rom streptococcal tonsi lli ti s a few weeks before.

Haematur ia, proteinur ia, and oligur ia c harac ter ise ac ute nephr i ti s wi th salt-water re tention c ausing

oedemas and hyper tension. Pulmonary oedema and hyper tensive encephalopathy with f i ts is li fe

threatening.

Uraemia is a c linical syndrome dominated by retention of non-protein ni trogen (eg, ur ea, ur ic ac id,

NH4+ c reatinine and c reatine) . Uraemic patients generally exhibi t hyperkalaemia (plasma- [K+ ] above

5.5 mM) and metabolic ac idosis (pH below 7.35 and a negative base excess) . This i s due to the

inadequate sec retion of K+ , NH4+ and H+ . In complete renal shutdown, the patient d ies wi th in 1-2

weeks wi thout dialysis.

Dialy sis i s mandatory with severe uraemia. W hen serum c reatinine r ises above 0.7 mM, renalinsuff ic iency is usually terminal (Fig. 25-4) .

Recording of blood pressure and f luid balance wi th weighing is impor tant in order to preventhy per tension and pulmonary oedema to develop into a li fe- threatening condi tion.

Fig. 25-19: Post -st reptococcal glomerulonephr it is.

The par ietal and visceral epi thelial cells of the glomeruli grow and proli ferate, jus t as the mesangial

cells (Fig. 25-19). This proli feration and the damage of the basement membrane wi th accumulation of

insoluble c omplexes all impair the glomerular bar r ier and reduce the glomerular f i ltr ation rate (GFR) .

Produc tion of cy tokines and autocoids enhance the inf lammation. Capi llary injur ies wi th reduc tion of

the lumen also reduc e the renal bloodf low (RBF) to some extent (Fig. 25-19) .


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Chi ldren wi th poststreptococ cal glomerulonephr i tis are treated wi th a c ourse of penic i llin - of ten with

an excellent prognosis.

Glomerulonephr i tis as a par t of sy stemic lupus ery thematosus (SLE) i s f requent in female lupus

patients - in par ti cular dur ing pregnancy, where hyper tension may prec ipitate glomerular in jur ies.

Oestrogens accelerate progression of SLE, and there is a genetic predisposi tion. In SLE there is

hy perac tivi ty of the B-cell sy stem, which may involve any organ, but typically affec ts the kidney s,

joints, serosal membranes and the skin ( Chapter 32) . The B-cell system releases many antibodies to

host antigens both in and outside the c ell nuc lei ( single- and double-stranded DNA, RNA, plasma

proteins, c ell sur face antigens, and nuc leoproteins) . Lymphocy totoxic antibodies are also liberated,

which may explain the inhibi tion of the T-c ell system. The most impor tant autoantibod ies are those

against nuc lear antigens. Accumulation of immune complexes wi th double-stranded DNA probably

causes the glomerular lesions as well as vasculi tis and synoviti s.

Fig. 25-20: Ant i-GBM glomer ulonephr it is with ant i-GBM of the IgG type. Complement is shown

as a small circle.

Ant i-GBM glomerulonephr i t i s i s a seldom disorder, where the patient produces antibodies (IgG type)

against his own basement membrane. The antibody is known as anti-GBM or anti-Glomerular

Basement Membrane antibody. The antigen is localised both in the glomerular basement membrane

and in the basement membrane of the alveolar capi llar ies. The histological pic ture i s charac ter ized


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by proli feration of both par ietal epi thelial cells, and mesangial c ells (Fig. 25-20) .

The capi llary basement membrane is disrupted, and there is red cells and f ibr in in Bowmans space.

The diagnosis i s confi rmed by identi f i cation of c i r culating anti-GBM (Y-shape in Fig. 25-20) .

Glomerulonephr i tis with pulmonary haemor rhage is termed Goodpastures syndrome. The recur rent

haemoptyses can be li fe threatening.

2. Renal Insufficiency

Renal insuff i c iency is a c linical condi tion, where the glomerular f i ltration rate i s inadequate to c lear

the blood of n i trogenous substances c lassif ied as non-protein ni trogen (urea, ur ic ac id, c reatin ine,

and c reatine) . The retention of nonprotein ni trogen in the plasma water i s called azotemia, and the

c linical syndrome is called uraemia. The number of f i ltrating nephrons falls below 1/ 3 of normal, as

determined by measurement of a GFR below 40 ml/min.

Acute renal insuff i c iency accompanies extremely severe states of c i r culatory shock (prerenal cause) .

The prerenal causes are hypovolaemia wi th hypotension or impai red cardiac pump func ti on or the

combination.

Also a large group of renal causes to fai lure occurs (Table 25-2) . F inally, the postr enal causes are all

types of ur inary trac t obstruc tion.

Acute renal fai lure is a ser ious disorder, which leads to progressive uraemia and c hronic renal

insuff ic iency .

Table 25-2. Causes of renal failure

Prerenal Causes: Cardiogenic and hy povolaemic shock

Renal Causes: ACE- inhibitors and NSAID´s impair renal autoregulation

Fulminant hy per tension.

Renal ar tery stenosis and embolism

Vasculi ti s in glomerular c api llar ies

Renal vein thrombosis

Toxic tubular damage (organic solvents, myoglobin, aminoglyc osides, and X- raycontrast) .


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Postrenal Causes: Ur inary trac t obstruc tion is caused by obstruc tions of the lumen, the wall andby pressure f rom outside

Lumen: Tumours, calculus and blood c lots wi th in the lumen of the renal pelvis, ureter,and bladder

Wall: Str ic tures of the ureter, the ureterovesical region, urethra, and pinhole meatus.

Congeni tal d isorders such as megaureter, b ladder neck obstruc tion, and urethral valve.

Neuromusc ular dysfunc tion in the ur inary trac t

Pressure: Compression by tumours, aor ti c aneurysm, retroper i toneal f ibrosis or g landenlargement, retrocaval ureter, prostate hyper trophy, phimosis, and diver ti culi ti s.

Two complic ations to c hronic renal fai lure must be c onsidered:

1. Renal osteodystrophy develops in patients with severe renal fai lure. The kidneys f ai l in produc ing

suff i c ient 1,25-dihydroxy -cholecalc i ferol. This i s ac tive vi tamin D or a potent stero id hormone.

The ac tive vi tamin D metaboli te stimulates the Ca2+ - transpor t ac ross the cell and mitoc hondr ial

membranes.

Lack of ac ti ve vi tamin D has the fo llowing two effec ts:

a. Poor gut absorption of dietary Ca2+ , so that plasma [Ca2+] falls.

b.The PTH release is stimulated, because the normal inhibi tory ef fec t of ac ti ve vi tamin D is lost.

Af ter some time a secondary hyperparathy roidism develops wi th inc reased resorption of calc ium

f rom bone and inc reased proximal tubular reabsorption of calc ium in an attempt to cor rec t the low

serum calc ium. The calc ium release f rom bone results in osteomalac ia and in osteoporosis.

Osteomalac ia or sof t bones is the result of deminerali sation of the osteoid matr ix usually caused

by insuff i c ient ac ti ve vi tamin D. Osteoporosis or thin bones is charac ter ized by a reduc tion in all

c omponents of the bones.

2. Normoc hromic , normocy tic anaemia. W hen normal kidneys are per fused with hy poxaemic blood,

the per i tubular intersti tial cells produce large amounts of the glycoprotein hormone,

ery thropoietin, wi th strong effec t on ery throgenesis.

Chronic renal fai lure leads to ery thropoietin def ic iency, and thus to anaemia, which is of the

normoc hromic , normocy tic type.


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Haemodialysis

The aim of haemodialysis i s to eliminate ni trogenous wastes in patients wi th renal fa i lure, and

maintain normal elec troly te concentrations, serum glucose and normal ECV. In other words, the

haemodialy zer or ar ti f i c ial kidney mimics the normal renal exc retion of waste produc ts (Fig. 25-21)

Fig. 25-21: An ar t ificial kidney (dialyser ) with an area of 1 m2 and a membrane thickness of 10

µm.

Blood f rom the patient i s pumped through a container wi th ser ies of semi -permeable membranes

separating the blood f rom dialy sate (Fig. 25-21) .

Dialy sate is a mixture of pur i f ied water wi th salts, and glucose in a composition comparable to normal

fasting plasma apar t f rom proteins. Bicarbonate or acetate buffer i s present at a concentration about

35 mM.

Haemodialysis is per formed with a bloodf low of 200-300 ml per min. The patient i s of ten connec ted to

the dialyzer by an ar ter iovenous shunt made by plasti c cannulae between the radial ar tery and an

adjacent vein. The ar ter ial blood f lows into the ar ti f i c ial kidney and af ter dialysis the blood is

returned to the venous sy stem (Fig. 25-21 ) . Dialy sate is pumped through the container at a rate of

500 ml each min.

A plasti c shunt connec ts the two cannulae on the forearm between dialysis sessions, and the large


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ar ter ial bloodf low is suff i c ient to avoid coagulation in the plast shunt. Also dual- lumen venous

catheters placed centrally are in use.

I f the sodium concentration of the dialysate i s too high, the patient complains of th i rst and the

ar ter ial pressure starts to r i se. Low dialysate c alc ium may result eventually in secondary

hy perparathy roidism, whereas a high dialysate calc ium concentration causes hypercalcaemia.

An adult patient wi th acute renal fai lure (so-called shock kidney ) requi res 4 -5 hour s dia ly sis 3 times

a week.

Renal Transplantation

Fit patients wi th chronic renal fai lure are of fered renal transplantation. Rejec tion of the transplant i s

due to complement- f i xing antibodies in the blood, or later caused by cellular or humoral immuni ty.

Rejec tion years af ter the transplantation is f requently caused by ischaemic damages o f the kidney.

Donation of a kidney leaves the donor with one kidney only.

Immediately af ter the removal, the GFR of the patient falls to half i ts or iginal value, because half the

func tioning nephrons have been removed.

Soon, most individuals wi ll inc rease thei r GFR towards normal values by c ompensatory work

hy per trophia of the remaining kidney. The hyper trophia- fac tor is not known. Each remaining nephron

must f i lter and exc rete more osmotically ac tive par tic les than before.

3. Acute Tubular Necrosis

This disorder has haemodynamic or toxic causes.

Cardiogenic and hypovolaemic shock cause acute renal fai lures just as renal vasoconstr i c tion. Renal

ischaemia leads to hy poxic damage, in par ti cular damage of the renal medulla, which i s espec ially

susceptible to isc haemia, because of the normally relatively poor oxygenation. I schaemic tubular

damage also reduces the GFR fur ther, because of ref lex spasms of the afferent ar ter io les, and due to

tubular bloc kage wi th acc umulation of f i ltrate in the ear ly par t of the proximal tubu les, and hypoxic

damage of the proximal tubular reabsorption capac i ty.

Loss of appeti te and energy, nausea and vomi ting, noc tur ia and polyur ia c harac ter ise the condi tion.


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Only when the GFR is severely depressed there is o ligur ia. Even a GFR of only 1 ml each min, as a

contrast to the normal 125 ml per min, may result in a dai ly ur ine f low of 1440 ml (1 *1440 min dai ly ) ,

i f there is a total loss of tubular reabsorption and no luminal obstruc tion. This ur i ne f low is normal,

but unfor tunately based on an almost total loss of g lomerular and tubular func tion. S uff i c ient

regeneration of the tubular epi thelium allows c linical recovery.

Sometimes also the renal cor tex i s nec rotic , and following healing of the injur ies, the result is

sc ar r ing wi th glomerulosc lerosis. This c ondi tion is a lso found following radiation nephr i ti s.

4. Diabet ic nephropathy

Diabetic nephropathy inc ludes glomerulosc leros is , wi th thickening of the basement membrane and

damage of the glomerular f i lter by disruption of the protein c ross- linkages and glomerular

hy per f i ltration. Excess NO produc tion reduc es the afferent ar ter iolar resistance and inc reases the

glomerular capi llary pressure. The ear liest evidence of glomerular damage may occur 5-15 years

following diagnosis in the form of mic roalbuminur ia . The patient later develops intermi ttent

albuminur ia followed by persistent a lbuminur ia. Diabet ic nephropathy inc ludes hyper tension,

persistent a lbuminur ia, and a dec line in GFR. One thi rd of a ll insulin-dependent diabetics develop

nephropathy. The mor tali ty rate i s high. The metabolic disturbance in diabetic s causes hyper tension

and leaky renal glomeruli , but the mechanism remains uncer tain.

Ascending infec tions result in intersti tial lesions and diabetes typically show hy per trophy and

hy alinization of af ferent and efferent ar ter ioles. Obstruc tion of the renal bloodf low ( ischaemia) leads

to hypoxic damage of the renal tissue. The tenuous bloodf low to the renal papi llae vi a the vasa rec ta

explains why renal papi llary nec rosis i s f requent in diabetic s.

Treatment wi th ACE- inhibi tors reduce ur inary albumin exc retion. Prophy lac tic therapy also

postpones the development of diabetic nephropathy and hyper tension wi th persistent

mic roalbuminur ia. The effec ti veness of th is treatment suggests that relati ve oversec r etion of

angiotensin may be involved in the pathogenesis of diabetic nephropathy.

5. Nephrot ic syndrome

The nephrotic syndrome refers to a ser ious inc rease in the permeabili ty of the glomer ular bar r ier to

albumin, resulting in a marked loss of albumin in the ur ine.


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The albuminur ia (more than 3 g per day ) causes hypoalbuminaemia and generali zed oedema. The

number and size of pores in the glomerular bar r ier inc rease due to disruption of protein- linkages.

Negatively charged gly coproteins in the glomerular bar r ier repel negatively charged proteins. The

amount of negatively charged glycoproteins i s reduced in glomerular disease.

Oedema is visible in the face - espec ially around the eyes. A ser ious but rare complication may

develop when a large volume of f luid accumulates in the abdominal cavi ty as asc i tes.

6. Ur inary Tract Infect ion

Ur ination (mic tur i tion) i s controlled by the mic tur i tion ref lex. Stretch or contrac ti on of the smooth

musc les in the bladder wall i s sensed by mechanoreceptors and signalled via the pelvi c nerve to the

sac ral spinal c ord. Inc reased parasympathetic tone (via pelvic nerves and musc ar inic receptors)

cause sustained bladder contrac tion. Normally, contrac tion of the bladder musc les by mic tur i tion

almost completely empties the bladder.

Recur rent infec tions of the ur inary trac t are f requent among females. Faecal bac ter ia are transfer red

to the per iurethral region, and f inally to the bladder via the shor t female urethra. Bladder ur ine is

normally ster i le owing to bladder mucosal fac tors and other loc al defence mechanisms. Bac ter ia

adhere to the bladder epithelium and multipli cate, when defence mechanisms func tion i nsuf f ic iently.

Prolonged bladder catheter isation predisposes to bladder infec tion, and even a few day s can be

c r i ti cal.

The diagnosis bladder infec tion is based on more than 100 000 bac ter ia per ml of c lea n-catch

mid-stream ur ine. Qui te a few patients wi th signi f ic ant bac ter iur ia do not develop ni tr i te enough to be

shown by dipsti ck tests.

Ty pical symptoms are f requent mic tur i tion (poly ur ia) , painful voiding (dysur ia) , supr apubic pain and

smelly ur ine perhaps wi th haematur ia.

Echer ichia coli and other c oli form bac ter ia cause the major i ty of ur inary trac t infec tions; these

infec tions are treated successfully wi th antibioti cs (amoxy llin, tr imethopr im etc ) e i ther as a single

shot or for longer per iods.

7. Tubulo- Interst it ial Nephr it is


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Bac ter ial pyelonephr i t i s typically causes intersti tial inf lammation of the kidneys, but the intersti tial

inf lammation is more often c aused by a hypersensi ti vi ty reac tion to drugs (antibioti cs, phenaceti n

and non-steroid anti - inf lammatory drugs, NSAIDs) .

Pyelonephr i ti s begins in the renal pelvis, and then progresses into the renal medullary tissue.

The essential func tion of the medulla i s to conc entrate the ur ine dur ing water deplet ion. Therefore, in

patients with py elonephr i ti s, the abi li ty to concentrate the ur ine is abolished/dec reased

( isosthenur ia/hyposthenur ia) . The abi li ty to di lute the ur ine deter iorates also. Thus, in i sosthenur ia

the ur ine is always isotonic wi th the plasma.

The patient wi th acute nephr i ti s has fever, skin rashes and ac ute renal fa i lure with eosinophi lur ia and

eosinophi lia. F irst of all the offending drug must be withdrawn, and the renal fai lur e may requi re

dialysis.

Chronic tubulo- intersti tial nephr i ti s i s caused by pyelonephr i ti s, NSAIDs, diabetes melli tus,

hy perur icaemia, i r radiation damage etc . The major problem is that long lasting c onsumption of large

amounts of analgesics leads to terminal renal fai lure. Nephrotoxic analgesics must be abandoned.The

patient presents wi th uraemia, a lbuminur ia, polyur ia, haematur ia, anaemia, and most o f ten a history

of analgesic abuse. Papi llary nec rosis can be present wi th papi llary ti ssue passed in the ur ine or

obstruc ting the ureter or urethra. In patients wi th tubular damage of the renal medul la, the abi li ty to

concentrate the ur ine is aboli shed together wi th the abi li ty to di lute the ur ine. Thus, the ur ine is

always isotonic wi th the plasma ( isosthenur ia) .

The result i s polyur ia and salt wasting. As the inf lammation progresses to the c or tex also the

glomerular f i ltration deter iorates wi th acc umulation of non-protein ni trogen in the p lasma water

(azotaemia) , and the c linical syndrome uraemia.

An isolated damage of the Na+ - reabsorption (salt- losing nephr i ti s) i s a condi tion in which the

disease processes are mainly due to dysfunc tion in the renal medulla. There is a marked loss of Na+

i n the ur ine and ser iously low ECV and blood volume (hy povolaemia wi th threat of immi nent shock) .

Thus the patient must have a high salt intake to prevent shock and keep ali ve.

8. Gouty Nephropathy


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Acute hyperuraemic nephropathy occurs in patients, where the condition leads to rapid destruc tion

of cell nuc lei (at the star t of treatment for malignant disorders or obesi ty ) . Large quanti ties of

nuc leoproteins are released, and the produc tion of ur ic ac id is inc reased. The urate concentration

inc reases in the extracellular volume (ECV) . Above a c r i ti cal concentration of 420 mM, the urate

prec ipi tates in the form of ur ic ac id c rystals, provided the f luid is ac id. This c onc entration threshold

def ines hyperur icaemia.

Prec ipi tation in the joints wi th pain i s termed gout (ar thr i ti s ur ica) , and prec ipi ta tion of ur ic ac id

c ry stals also occurs in the tubules, the collec ting duc ts and the ur inary trac t. Normally, urate ions

are ac tively reabsorbed in the proximal tubules by a Na+-cotranspor t. Urate ions c an also be ac tively

sec reted f rom the blood to the tubular f luid.

Allopur inol i s presc ribed dur ing radiotherapy or cy totoxic therapy. Acute cases are a lso treated wi th

allopur inol and forc ed alkaline diuresis.

Ur ic ac id stones are found in patients wi th hyperur icaemia, and in patients sec reting suff ic ient urate

without hyperur icaemia. Calc ium stones may be formed around a nuc leus of ur ic ac id c r ystals.

9. Renal Hyper tension

Bilateral renal disease such as chronic glomerulonephr i t i s i s a frequent cause of hyper tension

(Chapter 12) , whereas uni lateral renal disease, such as renal ar tery stenosis, i s a fai r ly seldom

cause of hyper tension. Stenosis (narrowing of the lumen) of one renal ar tery leads to renal

hy potension with exc ess renin produc tion (see below) and systemic (secondary ) hyper tension.

Exposure to f luid loss, reduced glomerular propulsion pressure, and inc reased sympathetic ac ti vi ty

releases renin f rom the juxtaglomerular cells in the af ferent glomerular ar ter iole, so the renin-

angiotensin-aldosterone cascade is tr iggered ( Fig. 24-5) . Angiotensin I I stimulates the aldosterone

liberation f rom zona glomerulosa of the adrenal cor tex, and thus stimulates Na+ - reabsorption and K+

-sec retion in the distal tubules. The result i s salt and water retention with inc rease in blood volume

and blood pressure.

Angiotensin I I also constr i c ts ar ter io les, with an espec ially strong effec t on the ef ferent renal

ar ter iole. This reduc es the renal bloodf low fur ther and also the proximal reabsorptio n. The


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development of hyper tension in high renin states is mainly due to salt- retention and systemic

vasoconstr i c tion.Stenosis of one renal ar tery does not a lways lead to inc reased ery throgenesis.

Stenosis of the renal ar tery implies a small renal bloodf low, a small g lomerular f i lt ration and a small

NaCl- reabsorption wi th a related small oxygen c onsumption on the affec ted side. As long as the renal

oxy genation is suff i c ient, the ery thropoietin produc tion is normal.

Severe renal ar tery stenosis implies renal isc haemia and hypoxia, which is probably a lways

consequentia l with complications. A hypoxic kidney has a low c reatinine and PAH c lear ance.

A long- term inc rease in sodium intake results in changes of the kidney func tion. Surpr isingly, the

changes are simi lar in hy per tensive and normotensive humans! Most people inc rease thei r ECV and

GFR without changing the absolute reabsorption rate of Na + and water in the proximal tubules.

Therefore, the r i se in f i ltration rate of Na+ and water wi ll reach the loop of Henle and the distal

tubule. The ar ter ia l blood pressure and hear t rate is unaffec ted by the amount of sodium in the diet.

The plasma c oncentrations of ac ti ve renin ( Fig. 24-7) , angiotensin I I and aldosterone dec rease wi th

inc reasing Na+ intake, but atr ial natr iuretic fac tor (ANF) and cyc li c GMP inc rease. Arginine

vasopressin (ADH) in plasma does not change.

The reason why this inc rease in NaCl load to the loop of Henle i s not counterbalanced by the

TGF-system is due to resetting of the TGF-mechanism, so a contrac tion is avoided in spi te of the

inc reased salt load.These homeostatic reac tions are all appropr iate phy siologic al responses in both

healthy and hyper tensive humans.

A rare cause of renal hy per tension is due to Liddles sy ndrome. This is an autosomal d ominant defec t

charac ter ised by severe hyper tension, hypokalaemia and metabolic alkalosis. The syndr ome is

similar to pr imary hyperaldosteronism, but the renin-aldosterone conc entration in plasma is not

inc reased. Liddles syndrome is caused by mutation of the gene for the ami lor ide-sensi tive

Na+-channel (Fig. 25-11) , whereby the channel is wide open. The Na+-entry depolar ises the

membrane and favours sec retion of K+ and H+ .

10. Ur inary Tract Obstruct ion

Obst ruc t ion of the ur inary trac t may occur at any loc ation, and cause di latation of the above

struc tures. The obstruc tion is locali sed wi thin the lumen (stone, s loughed papi lla, or tumour ) , within


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the wall (neuromusc ular dysfunc tion, str i c ture, congeni tal urethral valve, or pin hole meatus) , or

pressure f rom the outside obstruc t the trac t (eg, tumours, diver ti culi ti s, aor ti c aneury sm, prostati c

obstruc tion, retroc aval ureter ) .

Stretching of the renal calyces as they collec t ur ine promotes thei r pac emaker ac tivi ty and ini tiate a

per istalti c contrac tion along the smooth musc le sync y tium of the ur inary trac t.

Obstruc tion of the ur inary trac t for weeks may lead to i r reversible damage of the renal func tion in

par ti cular when combined with infec tion. Obstruc tion of the upper ur inary trac t wi th backpressure

damage of the kidney is espec ially dangerous.

Kidney stone disease (nephroli thiasis) attacks only a few percent of the W estern population at any

time. Most stones in male patients are composed of calc ium complexed wi th oxalate and phosphate,

whereas magnesium ammonium phosphate/acetate stones are more common in females. Only a few

percent of all renal stones are composed of ur ic ac id c ry stals or c ysteine (mainly in chi ldren) .

Calc ium-containing and cysteine stones are radiopaque, whereas stones of pure ur ic ac id are

radioluc ent.

In the presence of infec tion wi th urea-spli tting bac ter ia, urea is hydrolysed to form the strong base

ammonium hy droxide:

CO (NH2 )2 + H2O è 2 NH3 + CO2 ; NH3 + H2O è NH4+ + OH- .

Alkaline ur ine favours stone formation by c rystalli zation in the supersaturated f luid . Magnes ium

ammonium phosphate stones are also termed mixed in fec tion stones.

Obst ruc t ion or spasm of the ureter c auses ref lex constr i c tion around the stone wi th ureter ic or renal

col i c pain . The pain i s an exc ruc iating f lank pain, with radiation to the i li ac fossa and the genitals.

The wall of the ureter i s innervated wi th sensory nerve f ibres running in the pelvic nerves. Renal colic

is considered to be one of the most severe pain exper ience known.

Exc retion urography and plain X- ray examination are impor tant in the diagnosis of renal stone

disease.Perc utaneous nephroli thotomy, pyeloli thotomy or ureteroli thotomy can avoid many cutti ng

operations. Also shoc k-wave disintegration is in use ( li thotr ipsy ) .

Nephroc alc inos is refers to di f fuse renal calc i f i cation that i s detec table on a plain abdominal X- ray.


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Patients wi th hypercalcaemia (eg, pr imary hyperparathy roidism, hy pervi taminosis D, and

sarcoidosis) or wi th hyperoxalur ia prec ipi tate c alc ium oxalate and calc ium phosphate in the renal

parenchy ma. Patients wi th renal tubular ac idosis fa i l to ac idi f y thei r ur ine, which f avour prec ipitation

of calc ium oxalate and phosphate.

Abdominal radiography

A plain X- ray can identi f y calc i f i cation at any si te inc luding the renal system.

Int ravenous py elography

An organic iodine-c ontaining contrast substance is in jec ted slowly. Serial X- ray s are taken, whi le

compression bands are applied to the abdomen in order to obstruc t ureteral empty ing. Hereby, the

upper renal trac t is distended by the exc reted contrast medium. Following removal of the compression

bands, the rate of exc retion of contrast i s studied wi th f i lms before and af ter voiding.

11. Tumours of the Kidney

Benign and malignant tumours occur in the kidney.

Benign renal f ibroma, c or ti cal adenomas or simple cysts seldom cause symptoms and signs. Those of

no c linical impor tance are found inc identally at autopsy. Jux taglomerular cel l tumours are seldom.

They produce large amounts of renin, which causes hyper tension.

Haemangiomas may bleed following trauma and cause fatal blood loss.

Mal ignant renal tumours are nephroblastoma and renal cell carc inoma.

Nephroblas toma (W i lms´ tumour ) is the most f requent intraabdominal tumour in both gi r ls and boys.

I t usually presents within the f i r st three years of li fe. A l arge abdominal mas s is found sometimes

with signs of intestinal obstruc tion. The tumour grows rapidly and spread to the lungs. The diagnosis

is confi rmed wi th exc retion urography, ar ter iography or scanning.

Radiotherapy and chemotherapy, combined with nephrec tomy have improved the long- term survivalrate.

Renal cel l carc inoma (hypernephroma) acc ounts for more than 90% of a ll the malignant renal

tumours in adults - in par ticular smokers. There is a strong assoc iation with a rare autosomal

dominant inher i ted disease called Von Hippel -Lindau´ syndrome (haemangioblastomas in the


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cerebellum and the retina). The genetic locus is on chromos ome 3p.The tumour ar ises f rom proximal

tubular epithelium, and lies wi th in the kidney, but the prognosis i s worse, i f the tumour penetrates the

renal c apsule. The tumour i s of ten protruding and the neoplastic cells have an unusually c lear

cy toplasm.

Renal cell c arc inoma is a li kely source of ec topic hormone produc tion. Inc reased produc tion of

ery thropoietin leads to ery throcy tosis and polycy thaemia. Release of a parathy roid-hormone- li ke

substance leads to hy perparathy roidism and hypercalcaemia. Release of abnormal quanti ties of renin

tr iggers the renin-angiotensin-aldosterone cascade and leads to sy stemic hyper tension.

Metastases to distant regions are f requently found in the lungs and in the bones (osteoly ti c

metastases) . Soli tary tumours are treated by par tial or total nephrec tomy or wi th inter feron.

E q u a t i o n s · The plasma clearance is def ined as follows:

Eq. 25-1: Clearance = (Cu × V°u ) /Cp [ (mg/ml)× (ml/min) / (mg/ml)= ml/min] .

Clearance c an also be thought of as the volume of ar ter ial p lasma containing the same amount ofsubstance as c ontained in the ur ine f low per minute.

· Excret ion fract ion (EF) . EF for a substance is the f rac tion of i ts glomerular f i ltration f lux,

which passes to and is exc reted in the ur ine.

EF = J excr /J f i l t r

Since J excr = (Cu × V°u ) and J f i l t r =(GFR × C f i l t r ) i t follows that:

Eq. 25-2: EF = (Cu ×V°u ) / (GFR × C f i l t r )

C f i l t r i s the c oncentration of the substance in the ultraf i ltrate. The exc retion f rac tion f or inulin is one

(1) . Substances with an EF above one are subjec t to net s ec ret ion. Substances wi th an EF below one

are subjec t to net reabsorpt ion.

· Extract ion fract ion (E) . E for a substance is the f rac tion ex t rac ted by glomerular f i ltration

f rom the total substance deli very to the kidney via renal blood plasma.

Eq. 25-3: E = J f i l t r /J t o ta l = (Ca - Cvr ) /Ca .


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Substances wi th an E of one are c leared totally f rom the plasma dur ing thei r f i r st passage of the

kidneys. Inulin has an extrac tion f rac tion of 1/5. PAH has an extrac tion f rac tion of 0.9.

· Inulin clearance. The f lux of inulin f i ltered through the glomerular bar r ier per min is:

(GFR × Cp /0.94) . All inulin molecules remain in the preur ine and is exc reted in the f inal ur ine.

Thus, the amount exc reted is equal to the amount f i ltered:

GFR × Cp /0,94 = (Cu × V°u ) mmol/min

Eq. 25-4: GFR = ( (Cu ×V°u ) /Cp ) × 0.94 = CLEARANCE inu l in × 0.94.

· The Fick's pr inciple (mass balance pr inc iple) is used to measure the renal plasma c learance

at low plasma [PAH] , since at low concentrations the blood is almost c leared (90%) by one

transi t. Thus the renal plasma c learance is equal to the effec ti ve renal plasma f low (ERPF) :

Eq. 25-5 : ERPF = J excr /Cp ; RPF = ERPF/EPAH

· The law of mass balance states that the deli very of PAH to the kidney is equal to i ts exc retion

rate at steady state. The Ef fec t ive Renal Blood Flow (ERBF) is c alc ulated by the help of a total

body haematoc r i t (normally 0.45) . I f ERPF is measured to be 600 ml plasma per min, we can

calc ulate ERBF: 600/ (1 - 0.45) = 1090 ml whole blood per min at rest. This is 20-25 % of cardiac

output. The true RBF is 10% higher than the measured ERBF ( ie, 1200 c ompared to 1090 ml

whole blood) .

S e l f - A s s e s s m e n tMult iple Choice Quest ions

The following five statements have True/False opt ions:

A: The B-cell system releases antibodies to host antigens.

B: The glomerular barr ier fac i li tates the passage of negatively charged polyanionic macr omolecules.

C: Thiazide diureti cs may have ser ious side ef fec ts such as hypercholesterolaemia, hyper gly caemia

(eg, gluc ose intolerance) , hyperur icaemia, hypokalaemia, and impotence.


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D: Loop diureti cs inhibi t the reabsorption of NaCl in the thick asc ending limb of Henle – and

proximal pars rec ta - by blocking the cotranspor t proc ess in the luminal entry membrane.

E: Aldosterone antagonists, such as spi ronolac tone, ac t on the aldosterone receptors on the late

distal tubule cell and inhibi t the K+-exc retion.

Case History A

A male of f i ce worker, 58 years of age, body weight 70 kg, suf fers f rom ins ul in-dependent diabetes

mel l i tus . The disorder i s compl icated with arter ial hyper tens ion, hypercholes terolaemia,

albuminur ia and open-angle glaucoma. The patient i s in ant i -hypertens ive therapy wi th a

ß -adrenergic antagonis t . The open-angle glaucoma is t reated wi th acetazolamide (a

carboanhydrase- inhibi tor used as a diuret i c to reduce the intra-ocular pressure) .

Scanning of the k idneys show a normal pic ture wi th an es t imated normal k idney weight of 300 g.

Dur ing renal catheter isat ion, a renal ar ter iovenous oxygen c ontent di f ference is measured to 15 ml

per l of blood, and the renal bloodf low is 1.2 l (normal ) . – The f ir s t 3 ques t ions nec ess i tate

pharmacological knowledge.

I s i t recommendable to treat hy per tensive complications to diabetes wi th ß-blockers?1.

Desc r ibe the ef fec ts of c arboanhydrase- inhibi tor - treatment.2.

Are th iazide diuretic s wi thout r isks when presc r ibed to diabetics?3.

Calculate the renal oxygen uptake. Calculate the renal oxy gen uptake in percentage of the total

oxy gen uptake of 250 ml per min.

4.

Calc ulate the kidney weight in perc entage of the total body weight.5.

I s the renal bloodf low redundant compared to the renal oxygen c onsumption?6.

Case History B

A female pat ient (weight 57-kg) of 23 years , wi th an inher i ted defec t in renal tubula r func t ion, has a

lowered tubular thres hold for glucose reabsorpt ion. The pat ient has a blood- [gluc ose] of 1000 mg

per l i t re, and jus t above this level gluc ose appears in the ur ine (her appearanc e thr eshold) . The


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diures is is 1.5 ml per min, the plas ma - [c reat inine] i s 0.09 mM, and the ur ine [c reat inine] i s 6

mM. The normal b lood-glucos e level i s 5-6 mM.

1. I s the above blood - [glucose ] normal?

2. Calculate the c reatinine c learance?

3. Calculate the glucose reabsorption at this glucose level and compare i t to the normal maximal

capac i ty : 1.78 mmol min - 1 .

4. I s the appearanc e threshold def ined above equal to the saturation threshold?

Case History C

A 14-year old gi r l has a his tory of previous upper res pi ratory t rac t infec t ions , and is now treated

for another sore throat ( ie, tons i l l i t i s and high fever ) wi th ampic i l l i n for 10 days . Two weeks later

she returns to her general prac t i t ioner (GP) complaining of tender knee joints f rom p lay ing

handbal l . There is abdominal pain.

The gi r l i s obvious ly i l l and has a higher blood pressure than normally (145/90 mmHg or 19.3/12.7

kPa) . The tons i l l i t is i s cured and there is no fever. The upper abdomen is tender. A freshly pass es

ur ine s ample is ex amined wi th a combined quant i tat i ve s t i ck tes t. There is found haematur ia and

albuminur ia (300 mg l - 1 ) .

1. W hat i s the cause of the arthr i ti s?

2. W hat are the causes of the haematur ia and albuminur ia?

3. Does the GP admi t the gi r l to a hospital?

Case History D

Dur ing her work ing hours a 24-y ear old nurse del ivered an ar ter ial sample for b lood gas tens ions .

She had no symptoms or s igns of dis ease, but doubted that an ar ter ial sample could be taken

without caus ing pain. The sample was taken f rom a radial ar tery wi th a f ine needle fo l lowing local

anaes thes ia and she ex per ienced no pain. The ar ter ial blood gas values were: CO 2 par t ia l pressure

24 mmHg, O2 par t ia l pressure 102 mmHg, pHa 7.36, and Base Exc ess - 8 mM. The nurse had been


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s tarving for 24 hours .

1. W hat was the explanation of her ac id-base disturbance?

2. W hat was the rational treatment?

Case History E

A y oung female (body weight 56 kg) with an inul in c learance of 125 ml of p lasma per min is tes ted

with para‑amino‑hippur ic ac id (PAH) . The f ree f rac t ion of PAH in the plas ma is 0.80, and the res t

binds to plasma proteins .

Her ur ine is col lec ted in a per iod and the exc ret ion f lux of PAH is measured to 100 m g each min.

The average concent rat ion of PAH in plasma from the renal ar ter ial and venous blood i s 0.2 and

0.02 g per l , respec t ively. The haematoc r i t is 43%.

1. Calc ulate the c learance for PAH.

2. Calc ulate the tubular sec retion f lux for PAH at the blood plasma c oncentration concer ned.

3. Calc ulate the renal b lood f low (RBF) .

The patient collec ts the ur ine in a second per iod, where the average concentration of PAH in

plasma f rom the arter ial blood is 1 g per l. The maximal tubular sec retion rate for PAH is

def ined as Tmax for PAH and is 80 mg per min.

4. Calc ulate the exc retion f lux for PAH in the ur ine.

5. Calc ulate the new c learance for PAH.

Try to s olve the problems before look ing up the answers

H i g h l i g h t s · Creat in ine c learance provides a fai r c l in ic al es t imate of the renal f i l t rat ion c apac i ty.

· The renal c ont rol of body f luid osmolal i t y maintains the normal cel l volume (ICV) by changes

of renal water exc ret ion.


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· Normal ly, we exc rete 1500 ( range: 1200-1800) ml of water and 2-5 g of Na+ (= 5-12 g NaCl )

dai l y.

· Renal exc ret ion of was te produc ts . Urea f rom amino ac ids is exc reted with about 30 g or hal f

a mol of urea per day. The dai l y renal exc ret ion of ur ic ac id, c reat inine, hormone metabol i tes

and haemoglobin der ivat ives matches thei r dai ly produc t ion.

· The dai l y renal exc ret ion of metabol ic intermediates and foreign molecules (drugs , tox ins ,

chemicals , and pes t ic ides ) i s careful l y matched to the intake or produc t ion.

· Sec ret ion of hormones : The k idney sec retes ery thropoiet in, renin, k inins , pros taglandins and

1,25-dihydroxy -cholecalc i ferol .

· Acute Tubular Necros is has haemodynamic or tox ic causes . Cardiogenic and hypovolaemic

shock cause acute renal fai lures jus t as renal vasocons t r i c t ion. Renal i schaemia lead s to

hy pox ic damage, in par t i cular damage of the renal medul la. I schaemic tubular damage a lso

reduces the GFR fur ther, because of ref lex spasms of the af ferent ar ter ioles , and due to tubular

bloc kage with ac cumulat ion of f i l t rate in the ear ly par t of the prox imal tubules .

· Bac ter ial pyelonephr i t i s t ypical l y causes inters t i t ia l inf lammat ion of the k idneys , but the

inters t i t ial inf lammation is more of ten caused by a hypersens i t i vi t y reac t ion to drugs

(antibiot i cs , phenacet in and non-s teroid ant i - inf lammatory drugs , NSAIDs) .

· Diabet ic nephropathy inc ludes hyper tens ion, albuminur ia and low GFR wi th

glomerulosc leros is ( th ic kening of the bas ement membrane and damage of the glomerular f i l ter

by dis rupt ion of the protein c ross - l inkages) . The ear l ies t evidence may be mic roalbum inur ia.

The pat ient later develops intermi t tent albuminur ia fol lowed by pers is tent a lbuminuri a.

· Nephroblas toma (W i lms ´ tumour ) i s the mos t frequent int raabdominal tumour in both gi r l s and

boys . A large abdominal mass is found s ometimes wi th s igns of intes t inal obs t ruc t ion. The

tumour grows rapidly and spread to the lungs . The diagnos is i s confi rmed wi th exc ret i on

urography and ar ter iography.

· Renal cel l carc inoma (hy pernephroma) accounts for more than 90% of al l the mal ignant renaltumours in adults (smokers ) . There is a s t rong as soc iat ion wi th a rare autosomal domi nant


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i nher i ted dis ease cal led Von Hippel -Lindau syndrome (haemangioblas tomas in the cerebe l lumand the ret ina) . The genet ic locus is on chromosome 3p.

F u r t h e r R e a d i n gNephron . Monthly journal publi shed by the International Soc iety of Neprology. S Karger AG,

Allschwi lerstrasse 10, PO Box CH-4009 Basel, Swi tzer land.

Rehberg, P. Brandt. "Studies on kidney func tion: I . The rate of f i ltration and reabsorption in the

human kidney. " Biochem. J . 20: 447, 1926.

Schafer, JA. Renal water and ion transpor t systems. Am. J . Phys iol . 275 (Adv. Phys iol . Educ . 20):

S119-S131, 1998.

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