C14.Renal system

Renal disease and its ultimate consequence - renal failure - represent important issues in the

health debate. Although it is now technically feasible to relieve or reverse renal failure, limits to

what can be done in practice arise from ethical issues surrounding the allocation of healthcare

resources and the organization of organ donation, issues that are under constant debate.

Chronic renal failure is potentially fatal and may condemn a patient to years of dialysis with a substantially reduced quality of life. Successful renal transplantation provides an almost complete solution and now has an extremely good outcome; however, society has not yet fully adjusted to the implications of organ donation. Regular controversies on the persistent vegetative state and ‘brain death’ testify to this.

This chapter first reviews the normal function of the kidney. Subsequently, the consequences of impairment of these functions, i.e. homeostatic imbalances and renal failure, are explained. Finally, the common clinical conditions that cause these abnormalities are discussed.

Physiological principles of the renal system

The kidney is both structurally and function-

ally complex, and plays a central role in home-

ostasis.  Thus,  many  possible  forms  of  renal

malfunction can cause a wide range of clinical

conditions.  Manifestations  of  renal  disorder

include  fluid,  electrolyte  and  pH  imbalances,

haemodynamic imbalance, the accumulation of

drugs,  toxins  and  waste  metabolic  products,

loss  of  essential  metabolites,  and  endocrine

abnormalities  such  as  anaemia  and  bone

disease.

Pathological   processes   such   as   infection,

inflammation,  auto-immunity,  neoplasia  and toxins  can  cause  structural  damage  to  the

glomeruli,  the  tubules  or  the  urinary  tract. Systemic or local circulatory insufficiency can also seriously compromise renal function. The most   common   pathologies   are   glomerular inflammation, urinary-tract infection and drug-

induced   nephrotoxicity.   In   this   section   we review the physiological principles of normal renal function, so that abnormalities of the renal system may be better understood.

Anatomy

The gross anatomy of the renal system is shown

in Figure 14.1. It is important to distinguish

between  the  kidneys,  which  are  structurally

complex, and the urinary tract, the function of

which is essentially the storage and transport of

urine.  Three  main  regions  are  distinguished

within the kidney: the cortex, the medulla and

the pelvis. The cortex contains the glomeruli

and the proximal and distal tubules, and the

medulla contains the loops of Henle. Glomeruli

in different areas have different-length loops of

Henle to permit differential control over urine

concentration. The loops of the juxtamedullary

nephrons (nearest the medulla) extend almost to

the pelvis, the area into which the formed urine

drains from the collecting ducts. Throughout the

kidney   there   are   interstitial   cells,   probably

concerned with endocrine functions.

Although kidney disorders are almost always

serious,  disorders  in  the  lower  urinary  tract

are  seldom  serious  in  themselves  but  often

symptomatically troublesome. However, chronic

obstructive problems in the lower urinary tract

may eventually cause damage to the kidneys.

The importance of the kidneys may be judged

from the fact that although they together weigh

just 500 g (less than 1% of body weight) they

receive 25% of the cardiac output. Thus renal

blood flow is about 1.2 L/min. Like many other

organs, the kidneys are modular, each having

about    1   million   functional   subunits   or

nephrons, each of which performs all the major

renal functions and which together provide a

total  filtration  area  of 1 m2.  This  represents considerable  functional  over-capacity  because

life can continue quite normally with one-half of

a single functioning kidney, i.e. only 25% of

nephrons functioning. Thus when the kidneys

are diseased, serious symptoms do not appear

until there has been over 90% damage; more-

over, such damage is often irreversible, making

treatment difficult.

Summary of renal functions

The kidney is the body’s key organ of overall

homeostatic control and its functions may be

considered in three main groups (Table 14.1).

Elimination of waste is usually the main func-

tion associated with the kidney, but the regula-

tory functions are equally important, and the

kidneys  are  also  involved  in  several  major

endocrine systems.

Elimination

The potentially toxic by-products of metabolism

must be excreted, along with excess nutrients and

any exogenous toxins absorbed from the gut and

their subsequent metabolites. Generally, elimina-

tion is passive, although certain substances are

actively secreted.

Carbohydrate metabolism, the major energy

pathway of the body, produces carbon dioxide

and water. Most carbon dioxide is eliminated

passively by the lungs, but the kidneys have far

more control in secreting it, in small but crucial

amounts, as acid. Although much of the water

produced by metabolism, along with that taken

in the diet, is lost through sweating, respiration

and insensible losses, once again the kidney

exercises  selective  control  to  maintain  water

balance.

The predominant nitrogenous waste product

is urea from protein metabolism and its level in

the blood provides a useful approximate index of

renal function. Nucleic acid breakdown produces

urate, which is actively secreted, and muscle

metabolism produces creatinine, which is also

used  as  an  index  of  kidney  function.  Some

sulphate  and  phosphate  are  also  released  by

protein metabolism. Urea is not as harmful as is

commonly  believed,  guanidine,  amines  and

other metabolites (phenols, hydroxyacids, etc.)

being more toxic.

The kidney also has a role in the catabolism of peptides, notably insulin.

Fluid and electrolyte balance

The kidney plays a crucial, active role in main-

taining the correct ionic, osmotic, pH and fluid

balances throughout the body. It detects imbal-

ances, secretes local regulatory hormones, and

actively excretes or retains substances as neces-

sary. One of the drawbacks of its interaction with

so many different systems is that there may occa-

sionally be conflicting demands, which can be

resolved  only  by  compromises.  For  example,

chloride may be variously regarded as an anion,

an acid or simply an osmotically active particle,

depending on circumstances. Controlling chlor-

ide to preserve electrical neutrality or osmotic

balance may compromise pH balance.

Water balance

The body is normally in positive water balance,

the kidney adjusting for varying intakes and

losses by altering water clearance. Certain irre-

ducible constraints enforce a minimum average

daily  intake  of  about 1 L   (Table 14.2).  The

kidneys  require  at  least 500 mL  of  water  to

excrete the average daily load of osmotically

active   waste   products   at   maximal   urinary

concentration, i.e. under maximal ADH stimula-

tion. This is just about balanced by the water

produced from the metabolic oxidation of carbo-

hydrates.  Thus  the  minimum  dietary  intake

needed  is  that  which  will  replace  insensible

losses   in   breath,   faeces   and   perspiration

(excluding additional or exertional perspiration).

Fluid compartments

The main fluid compartments of the body are

given  in  Figure 14.2.  The  intravascular  and

extravascular  components  of  the  extracellular

fluid (ECF) are in equilibrium by free diffusion,

except  that  plasma  proteins  cannot  usually

leave the blood. Although water diffuses across

cell  walls  passively  under  osmotic  forces,

there  are  membrane  pumps  effecting  the

flow of most other substances to and from the

intracellular  fluid (ICF).  However,  the  activity

of  these  pumps  is  largely  dependent  on

concentration  gradients.  Thus  the  kidney,  by

controlling  ECF  composition,  influences  all

compartments.

There  is  a  complex  and  subtle  interplay

between the maintenance of ECF osmotic pres-

sure, mainly through control of sodium concen-

tration,  and  the  total  volume  and  relative

distribution of fluid between the compartments.

The kidney also controls the plasma potassium

level and thus total body potassium. By selec-

tively varying the secretion of hydrogen ions

and reabsorption or regeneration of bicarbonate

the kidney can significantly alter plasma pH, and

thus body pH.

Endocrine functions

The  kidney  is  involved  in  three  important

systemic hormonal systems.

Blood pressure

Renal  involvement  in  blood  pressure  control

operates  via  a  number  of  mechanisms (p.

880).  This  is  partly ‘enlightened  self-interest’

because  the  kidney  cannot  operate  without

an  adequate  perfusion  pressure,  but  it  also

contributes  to  the  systemic  blood  pressure

control mechanisms.

Calcium            •  Size-elective    but    otherwise    indiscrimi-

The kidney is vital to calcium and bone metabo-            nate   ultrafiltration   across   the   glomerular

lism. In addition to being a target organ for

vitamin  D  and  parathormone,  the  kidney  is

responsible for the final stage in the activation of

vitamin D by hydroxylating 25-hydroxychole-

calciferol to 1,25-dihydroxycholecalciferol. An

overview of vitamin D metabolism is given in

Chapter 3, p. 150.

Erythropoiesis

In response to hypoxaemia, the kidney secretes

erythropoietin, which promotes RBC production

in the bone marrow. Without erythropoietin,

erythropoiesis cannot proceed efficiently and Hb

levels   stay   below       6-8 g/100 mL,   producing

anaemia. In certain less common renal diseases,

e.g. polycystic kidney and renal tumour, there is

erythropoietin over-production, with consequent

polycythaemia.

It can now be appreciated why renal failure is

so  serious.  In  acute  renal  failure (ARF)  it  is

mainly elimination and fluid/electrolyte regula-

tion that are affected. The patient suffers partic-

ularly from retention of excess water, acid and

potassium. In chronic renal failure, endocrine

malfunction  adds  other  problems,  including

hypertension,  bone  disease  and  iron-resistant

anaemia.

Mechanisms of elimination

The kidney goes about elimination in a seem-

ingly perverse and inefficient manner. Instead of

selectively  excreting  unwanted  substances  it

filters almost everything, and then selectively

reabsorbs what needs to be conserved. About

10%   of   the   total   renal   blood   flow,   i.e.

120 mL/min, is filtered at the glomeruli, along

with most low-molecular weight constituents:

this is the glomerular filtration rate (GFR). Some

99% of this 180 L/day is then actively reab-

sorbed, leaving an average daily urine volume of

only about 1.5 L. (This system may be a relic of

the aquatic era of the evolution of life, when the

large amounts of fluid and sodium that were lost

could easily be replaced.)

There are three main phases of elimination

(Figure 14.3):

membrane  from  plasma  into  the  tubular lumen to produce filtrate.

•  Active  reabsorption  into  plasma  of  useful

            substances in bulk, mostly from the proximal

tubule.

•  Selective secretion from plasma or reabsorp-

            tion into plasma of certain critical substances

in small amounts to maintain the fluid and

electrolyte  balances,  mainly  in  the  distal tubule and collecting duct.

To understand how certain diseases affect renal function, the factors that affect filtration and

the  patterns  of  reabsorption  and  secretion

must  be  briefly  reviewed.  This  simple  discus-

sion  will not distinguish between the cortical and juxtamedullary nephrons; unless otherwise stated, the former are usually implied.

Filtration

During glomerular ultrafiltration blood cells and

colloidal macromolecules, i.e. plasma proteins,

are retained but smaller molecules (crystalloids)

are carried through the glomerular basement

membrane (GBM) under hydrostatic pressure by

solvent  drag (convection).  Substances  with  a

molecular weight ÷5000 Da pass freely. Passage

decreases with increasing molecular size, espe-

cially  above  about 25 kDa;  only 3%  of  Hb

(64 kDa) would pass if it were free in plasma, and

less than 1% of albumin (minimum size approx.

70 kDa)  passes.  Anions  pass  less  easily  than

cations because the GBM is negatively charged,

but again this effect is only significant for larger

molecules.

Factors affecting glomerular filtration rate

The GFR is the key index of renal function

because if there is no filtration then none of

the  regulatory  mechanisms  that  act  on  the filtrate can operate. Figure 14.3 is a functional diagram of a nephron, which identifies the sites where factors which influence the GFR operate. Table 14.3 summarizes the clinical conditions under which these factors can become altered. This usually happens due to changes in filtra-

tion  pressure (especially  the  systemic  arterial pressure).  The   integrity   of   the   basement membrane is another important factor.

Perfusion.   The  kidney  strives  to  maintain

systemic arterial blood pressure, but failing that,

filtration pressure at the glomerulus is defended

by intrarenal mechanisms. Probably the most

common cause of ARF is when such mechanisms

are overwhelmed by severe systemic hypoten-

sion,  e.g.  from  haemorrhagic  or  cardiogenic

shock. Long-term damage to renal arteries, e.g.

arteriosclerosis   and/or   atherosclerosis   from

untreated hypertension, can cause chronic renal failure.

Renal autoregulation maintains renal blood

flow, filtration pressure and GFR over wide vari-

ations in renal perfusion pressure, principally by

alterations in the calibre of afferent and efferent

glomerular arteries. The afferent arterioles are

dilated by intrarenal PGs, while the efferent ones

are constricted by intrarenal angiotensin. In this

way the transmembrane hydrostatic pressure,

and hence GFR, is defended. One input to this

system is tubulo-glomerular feedback. If the GFR is altered, the consequent changes in the solute load of the glomerular filtrate are detected in the distal tubule by the juxtaglomerular apparatus (p. 879),   which   is   involved   in   intrarenal hormone systems.

Another   important   intrarenal   regulatory

mechanism is the potentially confusingly named

glomerulotubular balance. This is a second line

of defence if GFR is compromised beyond the

ability  of  the  primary  compensatory  mecha-

nisms to cope. It serves to preserve excretion of

water, sodium and other solutes in the face of

reduced GFR. It thus provides one aspect of renal

reserve,  delaying  the  onset  of  symptomatic

uraemia if renal function declines chronically.

The operation of these control mechanisms is

illustrated  by  the  adverse  effect  of  ACEIs  in

patients with obstructive lesions in both renal

arteries (bilateral   renal   artery   stenosis),   or

patients in whom renal perfusion is otherwise

compromised   by   hypovolaemia (low   blood

volume) or cardiac failure. In such cases optimal

renal perfusion is being maintained partly by

raised  levels  of  angiotensin  originating  from

the   renal   response   to   the   hypoperfusion.

Angiotensin  maintains  renal  blood  flow  by

causing intrarenal efferent arteriolar constriction

and  also,  possibly,  by  elevating  systemic  BP.

ACEIs, by blocking this protective mechanism,

may precipitate renal failure by causing a signif-

icant reduction in renal perfusion. Similarly, PG inhibitors, e.g. NSAIDs, can have an adverse

effect on renal haemodynamics, causing renal impairment and fluid retention.

Glomerular basement membrane.   The GBM

is a sensitive structure that is exposed to high

flow rates and high concentrations of potential

toxins and mediators. It can be damaged by

numerous   pathological   processes,   and   this

underlies many chronic renal diseases. If the

GBM is damaged, its permeability to large parti-

cles, especially smaller colloids such as albumin,

may be increased, causing proteinuria. In more

severe cases there may also be, paradoxically,

retention of water and sodium owing to a degree

of renal impairment (reduced GFR).

Simple variations in pore size cannot account

for these changes; porosity may be partly related

to  a  loss  of  the  negative  membrane  charge,

which  normally  repels  the  similarly  charged

plasma   albumin.   Normally   some   proteins

smaller than about 60-100 kDa are filtered, but

almost all are completely reabsorbed. However,

the   reabsorptive   capacity   is   low   and   soon

exceeded if there is an increase in tubular protein

concentration. The catabolism of filtered protein

within  the  renal  tubules,  which  is  normally

minimal, may be increased in the presence of

proteinuria to compensate.

Glomerular number.   In chronic renal failure,

diminishing renal function is believed to result

from a reduced number of fully active nephrons

rather than to a general decline in the function

of all nephrons (the ‘intact nephron hypoth-

esis’). A progressive loss of functional nephrons

is the main reason why the elderly have reduced

renal   function -   a   process   that   continues

throughout adult life. Normally about half of the

nephrons are lost by the age of 80 years.

Tubular back pressure.   Obstruction anywhere

along the urinary tract will inhibit filtration by

increasing the pressure within the tubule, which

reduces the filtration pressure across the GBM.

Such obstruction can occur within the tubules

themselves if they are damaged; in the renal

pelvis (in  pyelonephritis  and  some  forms