when

considering   a   particular   patient.   Thus,   for

example,  diabetes  is  usually  associated  with

chronically progressive glomerulosclerosis and a

poor outcome. On the other hand, acute post-

infective nephritis showing diffuse proliferative

change has an excellent prognosis with minimal

treatment being required.

Presenting syndromes

The  histopathological  classification  is  becom-

ing   the   standard   among   nephrologists   but

glomerular disease remains perplexing for the

non-specialist. It is best tackled by first under-

standing that there are four main ways in which

it may present, ranging in severity from asymp-

tomatic proteinuria through nephritic syndrome

and nephrotic syndrome to irreversible renal

failure.   This   is   illustrated   in   Figure 14.22,

although this scheme must not be taken to

imply an inevitable or direct progression. Each

syndrome  can  have  various  aetiologies  and

outcomes, so the likely cause should be identi-

fied if possible and the pathology described. It is

then possible to decide treatment and judge

prognosis.

The clinical features and management options

for  these  syndromes  will  be  summarized  in

general terms, including a brief description of

the  main  varieties  of  nephritic  syndrome  as

commonly classified by prognostic categories.

The  syndrome  of  chronic  renal  failure  was

described above.

Asymptomatic proteinuria

Normal urine contains only trace amounts of

protein, usually less than 100 mg excreted over

24 h. Most plasma proteins are too large for

filtration; smaller ones such as microglobulin are

filtered to some extent, but most is reabsorbed in

the tubules. Proteinuria means the presence of

more than 500 mg protein in 24 h. If these are

smaller proteins it implies a tubular defect, i.e. a

failure of reabsorption (a ‘tubular pattern’).

Albumin is larger, and its presence in signifi-

cant amount suggests a ‘glomerular pattern’, i.e.

a failure of filtration. Thus it is more correctly

called albuminuria. Albumin is usually discov-

ered as an incidental finding during a general

medical examination or during investigation of

some other disease. Albumin loss below about

2 g/24 h may be benign, but such patients are

always investigated and regularly monitored for

the possible development of conditions such as

glomerulonephritis, diabetes and hypertension.

A medication history is also important. Intermit-

tent  proteinuria  is  quite  a  common  normal

finding after exercise or after prolonged standing

or walking.

Microalbuminuria (÷200 mg albumin per 24 h)

is a prognostic marker of the possible develop-

ment   of   nephropathy   in   diabetes.   Urine

dipsticks  can  currently  detect  this  level  of

proteinuria.  Microscopic  haematuria  may  be

benign. Even macroscopic haematuria need not

be a sinister sign although it is obviously very

alarming. Of course, both conditions also require

thorough investigation.

Nephritic syndrome

Definition

The hallmarks of nephritis are renal impairment

with   oliguria,   sodium   and   fluid   retention,

peripheral oedema, mild to moderate proteinuria

and possibly haematuria. Urinary RBC ‘casts’ are

diagnostic; these are clumps of cells that have

been shaped by the tubular lumen. Frequently

there are no further complications, but hyper-

tension,   hypertensive   encephalopathy   and

pulmonary oedema may occur. Serum creatinine

is moderately elevated, but only rarely does olig-

uric  ARF  supervene.  The  pathophysiological

basis of these features is illustrated in Figure

14.23.

Aetiology and pathogenesis

Acute nephritis following a non-renal strepto-

coccal infection, e.g. streptococcal sore throat, is the most common form although other infections may be responsible, e.g. malaria, bacterial endo-

carditis.  Drug  reactions  and  connective  tissue disorders, e.g. SLE and Wegener’s granulomatosis, are other possible causes.

Most cases are extra-renal in origin, involving

immune complex (IC) deposition on the GBM.

These complexes may be Ig plus, for example,

streptococcal  antigen  or  a  drug  acting  as  a

hapten.  In  connective  tissue  disorder,  anti-

nuclear antibodies may be involved. Why some

patients react in this way, and why the ICs are

deposited in the glomeruli rather than being

cleared  by  the  reticuloendothelial  system  as

usual, is not known. Low plasma complement

levels may be implicated, although this may be effect rather than cause, complement having

been precipitated on the GBM.

Course and prognosis

Usually nephritis runs an acute florid course

with excellent recovery, especially in children.

Some older patients may have benign persistent

or intermittent proteinuria for many months or

years. A significant number progress slowly to

CRF  and  a  few  follow  a  rapidly  progressive

decline.

Management

The aims of management are to:

•  identify any specific cause (e.g. infection) and

            treat that,

•  institute simple symptomatic and supportive

            measures until the patient recovers.

The   range   of   therapies   used   include   the

following (see Table 14.24), although the precise

combinations that are effective will depend on

precise histological assessment following biopsy.

Immunosuppression.   This can include corti-

costeroids, often in combination with antiprolif-

eratives such as cyclophosphamide, azathioprine,

mycophenolate  mofetil,  sirolimus  and  ciclosporin. Surprisingly, it is not universally effective.

Plasma exchange (plasmapheresis).   The aim

of this is to remove circulating auto-antibodies

and ICs from the blood. Whole blood is removed

and   centrifuged:   the   supernatant   plasma,

containing  the  harmful  immune  products,  is

discarded and the cellular components are then

re-injected.  Fluid,  electrolytes  and  albumin

must  also  be  administered  to  compensate  for

losses.

Renoprotection.   As   discussed   above   when

consdering CRF, protein restriction needs to be

used  with  caution,  for  fear  of  malnutrition.

ACEIs, possibly in combination with ARAs, offer

reduced progression and blood pressure control.

In  addition,  antihypertensive  agents,  anti-

microbials, diuretics, fluid restriction and dietary protein  manipulation  may  be  necessary,  as appropriate.

Common presentations

Acute glomerulonephritis.   This is the classic

post-streptococcal form usually seen in children

or young adults. A very abrupt and severe renal

inflammatory   response   might   develop   for

example a few weeks after a severe throat infec-

tion. Disease severity usually correlates with the

patient’s titre of ASO. In children particularly,

the prognosis is excellent with resolution in a

week or less, and only supportive therapy is

required. Anti-inflammatory therapy is usually

ineffective.

Rapidly  progressive  glomerulonephritis.   In

about 1% of patients who develop acute GN

there  is  rapid  progression  to  acute  oliguric

failure. If this occurs the outlook is poor, with

progression to ESRD within 2 years. Progressive

GN may be associated with the presence of anti-

GBM    auto-antibodies            (e.g.     Goodpasture’s

disease), or arise in association with vasculitic

connective   tissue   diseases (e.g.   polyarteritis

nodosa,  PAN).  The  renal  damage  caused  by

malignant hypertension usually presents as a

rapidly progressive GN although in this case the

damage is not immunological.

Treatment and prognosis depend on the aeti-

ology. For the connective tissue diseases early

aggressive  immunosuppressive  therapy  with

cytotoxic drugs and steroids may induce a remis-

sion or retard progression. In idiopathic forms or

in Goodpasture’s disease this is rarely successful,

but plasmapheresis may be helpful. Nevertheless,

eventual progression to CRF and renal replace-

ment therapy is common. Following transplanta-

tion a recurrence of the disease is still possible,

but  the  tendency  nowadays  is  to  transplant

anyway.

Chronic glomerulonephritis.   About 10% of

GN patients, usually adults, progress to chronic

illness.   It   is   this   slowly   progressive,   late-

presenting form of GN that is the most common

cause of CRF. Invariably there are co-existent

hypertension  and  proteinuria.  The  cause  of

chronic   GN   is   usually   unknown.   Diabetic

nephropathy could be considered to be one form

of the condition, although strictly speaking this

is glomerular sclerosis rather than inflammation,

and nephrotic syndrome is a more common

presentation.

Specific treatment is rarely possible and the

patient   must   enter   a   renal   replacement

programme. Certain forms of chronic GN with

less  glomerular  damage (‘membranous’  and

‘minimal change’ GN) may respond to immuno-

suppressant therapy, but this is still controversial.

Nephrotic syndrome

The nephrotic syndrome can occur in associa-

tion with many forms of nephritis or may arise

independently. It is defined by the symptom

triad:

•  Heavy proteinuria.

•  Hypoalbuminaemia.

•  Gross pitting oedema.

The hallmark of nephrotic syndrome is extensive

urinary protein loss associated with hypopro-

teinaemia sufficient to cause severe generalized

oedema. The liver can synthesize albumin up to

a maximum of about 15 g/24 h in an attempt to

maintain plasma albumin levels, but paradoxi-

cally proteinuria no greater than 4-6 g/24 h may

be sufficient to cause nephrotic syndrome. Thus

there is probably another avenue of protein loss

involved. This is may be an increase in the renal

tubular   catabolism   of   albumin,   such   that

measurement of urinary protein loss underesti-

mates the total deficit. These combined losses

exceed hepatic capacity to synthesize protein

and   lead   to   progressive   hypoproteinaemia,

regardless   of   dietary   protein   intake (Figure

14.24).

Aetiology

The nephrotic syndrome may be a complication

or progression of GN or it may present de novo.

Specific aetiologies include diabetes, drugs (e.g.

penicillamine,   captopril,   heavy   metals)   and infections (e.g. malaria, endocarditis).

Pathophysiology

The  apparently  paradoxical  combination  of  a

reduced  GFR  with  a  ‘leak’  sufficient  to  pass

albumin molecules of molecular weight   60 kDa

may arise because the reduced plasma volume

causes a mild pre-renal impairment of filtration,

while changes in the GBM electrostatic charge

allow smaller proteins, that are normally repelled,

to pass through. In mixed nephritic-nephrotic

syndromes there is also some glomerular obstruc-

tion. The phenomenon of proteinuria is still not

understood.

The oedema forms by a quite different mecha-

nism to that of simple nephritis or heart failure.

In the latter cases there is redistribution of the

raised total body water with increased volumes

in  all  compartments,  plasma  hypervolaemia

causing hypertension and tissue hypervolaemia

causing the oedema. By contrast, in nephrotic

syndrome there is a reduced plasma volume and

often  hypotension.  The  hypovolaemia  results

from  the  reduced  plasma  oncotic  pressure

brought about by the hypoproteinaemia, which

permits a loss of plasma water to the extravascular

compartment (Figure 14.23).

In  nephrotic  syndrome  the  RAAS  acts  to

restore BP by increasing renal sodium and water

reabsorption. However, blood volume cannot be

expanded while plasma protein is low because

the   resultant   low   plasma   oncotic   pressure

permits renally retained fluid to pass straight to

the  tissue.  This  exacerbates  the  oedema  and

causes further fluid and electrolyte retention.

This vicious cycle may result in gross oedema,

and the presence of over 20 L of oedema fluid

has been reported. Nevertheless, many patients

are not overtly hypotensive, possibly owing to

the direct vasoconstrictor action of persistently

raised angiotensin levels. Postural hypotension

is usual, however. This classical account of the

pathophysiology   of   oedema   in   nephrotic

syndrome has been challenged and may not

represent the whole picture.

Course and prognosis

The prognosis will depend on the age of the

patient and the underlying lesion. In children

the cause is usually acute GN and the outlook is good, with an 80% remission rate. In adults the underlying pathology is more likely to be a

chronic  progressive  disease  and  the  average remission rate is nearer 20-30%.

Clinical features

The clinical picture is usually very distinctive.

Nephrotic  syndrome  may  have  an  acute  or

insidious onset and resembles acute GN, except

that the oedema is usually greater, including

pulmonary oedema and ascites, and the patient

Important renal diseases            941

is not hypertensive and may be hypotensive. The

patient is usually very ill, weak, anorexic and

oliguric.  A  common  unexplained  finding  is

hyperlipidaemia, possibly related to disordered

protein metabolism (an attempt to synthesize

new amino acids). High aldosterone levels often

cause hypokalaemia.

Management

The aims of management are:

•  To investigate and treat the cause (e.g. an

            underlying disease).

•  To  correct  haemodynamic  and  metabolic

            abnormalities.

•  To reduce glomerular inflammation.

Table 14.25 summarizes the treatment options.

The  effectiveness  of  immunosuppressant  ther-

apy, initially high-dose steroids, will depend on

the  cause,  but  in  general  steroid  therapy  is

more  beneficial  than  in  simple  GN.  Patients

who  relapse  after  steroid  withdrawal,  i.e.  are

steroid-dependent, may benefit from cytotoxic

drugs.

Reversal   of   the   hypoproteinaemia   must

usually   await   resolution   of   the   glomerular

damage, but high-protein diets are traditional.

The principal clinical problems are oedema and

sodium  and  fluid  retention.  Salt  and  water

restriction and loop diuretics are used and high

doses may be needed, e.g. 50 mg furosemide. Care

must be taken not to exacerbate hypovolaemia

and precipitate pre-renal failure by too rapid a

diuresis; thus the use of diuretics may be delayed

until there is a recovery in urine output. This

can be prevented by subsequent infusion of a

plasma  expander  such  as  salt-free  albumin.

Hypokalaemia, which would be exacerbated by

loop diuretics, can be treated with high-dose

spironolactone and potassium supplements.

Polycystic disease

Adult polycystic disease is the most common

inherited renal disease. Both kidneys become

enlarged up to two or three times normal size,

owing to the development of many fluid-filled,

inert cysts. These gradually crush adjacent renal

structures.

The more common autosomal dominant form

has a prevalence of 1/1000. The age of onset

and progression are highly variable. Progression

to end-stage renal failure usually occurs within

10-20 years of diagnosis, so patients who first

present late in life may avoid this. Nevertheless,

10% of ESRD patients have polycystic disease.

In  the  rarer  recessive  form,  onset  and  rapid

progression to renal failure occur in childhood.

Clinical features are similar to those of other

forms of RF. Hypertension is common, there

may be loin or lumbar pain, and haematuria if a

cyst ruptures. Diagnosis is based on ultrasound

imaging.

There is no specific treatment beyond the stan-

dard procedures for CRF; control of BP will slow progress.   Regular   screening   of   siblings   and offspring is important.