Infections associated with glomerular diseases

Infection Glomerular disease

Bacteria of all types MCGN, post-infectious GN,

GLOMERULAR DISEASE

Secondary glomerulardiseaseJeremy Levy

diffuse proliferative GN

Escherichia coli and Shigella

species

HUS

Malaria Post-infectious GN,

membranous GN, MCGN

Syphilis Membranous GN

Leprosy, schistosomiasis, TB AA amyloidosis

Schistosomiasis, filariasis,

strongyloides

MCGN, mesangial proliferative GN

Hepatitis B virus FSGS, MCGN, membranous GN,

vasculitis

Hepatitis C virus FSGS, MCGN, membranous GN

HIV FSGS (collapsing variant),

IgA nephropathy, immune

complex GN, HUS

Erythrovirus (parovirus) FSGS

AA, amyloid A; FSGS, focal segmental glomerulosclerosis; GN, glomerulone-

phritis; HUS, haemolytic uraemic syndrome; MCGN, mesangiocapillary

glomerulonephritis; TB, tuberculosis.

Table 1

AbstractSecondary glomerular diseases are common worldwide and can manifest

in many ways. Bacterial and viral infections, especially hepatitis and HIV,

can cause a variety of patterns of glomerular injury often presenting with

nephrotic syndrome, as can tumours and drugs. Diabetes and systemic

lupus erythematosus are also important causes. Identifying underlying

agents leads to specific treatments and can lead to resolution of the

glomerular injury. In this review we explore the commonest secondary

glomerular diseases and their management.

Keywords focal segmental glomerulosclerosis; glomerulonephritis;

membranous; mesangiocapillary nephritis

Secondary glomerular diseases are conditions with glomerular

pathology in which an underlying cause can be established.

Worldwide they are the commonest forms of glomerulonephritis

(GN), mostly caused by infections and particularly prevalent in

developing countries. Diabetes and systemic lupus erythematosus

(SLE) are also clearly common causes of glomerular disease, and

both have been discussed in previous sections. In this review we

will concentrate on other secondary causes of glomerular disease,

as defined by their cause and by the underlying pattern of renal

injury caused.

Infection-associated glomerular disease

Infections of all types have been associated with various glomer-

ular diseases (Table 1; see Systemic infections and the kidney in

Medicine 35(9): 507e509). Bacterial infections, malaria and

viruses are especially important causes. The classic diffuse

proliferative GN or post-infectious GN is driven by infections,

often but not always streptococcal. Bacterial infection andmalaria

have been particularly associated with mesangiocapillary

glomerulonephritis (MCGN), and viral infections may cause

a number of patterns of injury. Hepatitis B and C can cause focal

and segmental glomerulosclerosis (FSGS), MCGN, and membra-

nous GN,while HIV is especially associatedwith a specific subtype

of FSGS (collapsing variant) but also commonly causes glomerular

immune complex disease.1e3 Since HIV has become a treatable

Jeremy Levy PhD FRCP is a Consultant Nephrologist at the Imperial

College Renal and Transplant Centre, Imperial College Healthcare NHS

Trust, London, UK. He trained in Cambridge, Oxford and London and is

also head of postgraduate medical training in London. His major

clinical interests are in immune-mediated renal disease (especially

vasculitis and systemic lupus erematosus), chronic kidney disease,

haemodialysis and HIV associated renal disease. Competing interests:

none declared.

MEDICINE 39:8 464

chronic disease (with excellent viral suppression inmost patients)

in many patients with HIV any renal problems are more often now

due to drug toxicity, diabetes, hypertension or vascular disease

than HIV infection itself. Bacterial infection, most commonly

Escherichia coli, but also Shigella species, may cause haemolytic

uraemic syndrome (HUS) in which intraglomerular thrombosis is

a key feature. This is most common in children, and epidemics

with clear environmental precedents occur in most years caused

most recently by poorly prepared meat, spinach and infections

derived from children’s zoos or petting farms.4 Chronic infections

can also cause systemic amyloid A amyloidosis (AA amyloidosis)

with glomerular deposition of amyloid.

Tumour-associated glomerular disease

Many different glomerular diseases have been associated with

tumours (Table 2), but it is often unclear whether the associations

are causal or not. There are, however, many case reports of reso-

lution of glomerular disease with removal or treatment of the

tumour without specific intervention aimed at the renal injury.

Well-described examples include nephrotic syndrome caused by

minimal change glomerular disease with an underlying lymphoma,

membranous GN, and MCGN in association with a variety of

cancers including carcinomas and lymphomas.5 It is assumed that

in these cases tumour antigens, either deposited in the kidney or

cross-reacting with renal antigens, drive an autoimmune process.

Lymphomas and myeloma are frequently the cause of cry-

oglobulinaemia, which causes MCGN within the kidney, or alter-

natively can produce a paraprotein causing both glomerular and

tubular damage. Paraproteins may also deposit as amyloidosis in

blood vessels, renal tubules and, most commonly, the glomeruli,

causing nephrotic syndrome.

� 2011 Elsevier Ltd. All rights reserved.

Tumours associated with glomerular diseases

Tumour Glomerular disease

Lymphoma and leukaemia Minimal change disease,

membranous, MCGN,

cryoglobulinaemia

Myeloma Amyloidosis, cryoglobulinaemia

Carcinoma

(lung, gastrointestinal, uterine,

prostate, etc)

Membranous, MCGN, HUS

HUS, haemolytic uraemic syndrome; MCGN, mesangiocapillary

glomerulonephritis.

Table 2

GLOMERULAR DISEASE

Drugs

Many drugs have been associated with glomerular disease6

although classically drugs are usually thought to cause tubular

damage (acute tubular necrosis or acute interstitial nephritis). Non-

steroidal anti-inflammatory drugs (NSAIDs) of all types are the

most commonly recognized as a cause of both minimal change

disease and membranous GN, both presenting as nephrotic

syndrome with or without acute tubular necrosis. Gold, penicilla-

mine and captopril have all been associated with membranous GN.

Chemotherapeutic agents, ciclosporin and tacrolimus have been

thought to cause forms of HUS with intraglomerular thrombosis.

Bisphosphonates are known to cause FSGS and nephrotic

syndrome. Heroin is also a well-described cause of nephrotic

syndrome, and can cause both FSGS and MCGN.

Focal segmental glomerulosclerosis

FSGS is now the most common renal biopsy finding in many renal

centres around the world, especially in the USA. Clinically, patients

present with acute or subacute nephrotic syndrome, or with non-

nephrotic range proteinuria. FSGS can be classified according to

the precise histological pattern, and this may have prognostic

significance and provide clues as to aetiology.7 Although idiopathic

FSGS is probably most commonly seen, secondary causes include

hepatitis B, HIV, erythrovirus (parvovirus), a variety of drugs

including heroin and bisphosphonates, obesity, sickle cell disease

and lymphomas. FSGS can also occur secondary to any condition

leading to a reduction in renal cell mass (e.g. after nephrectomy),

vesico-ureteric reflux, in solitary kidneys, after almost any other

glomerular diseasewith reduced numbers of functioning glomeruli,

and especially in hypertension. Primary FSGS is more likely to

present with severe nephrotic syndrome, although HIV can also

cause very heavy proteinuria. Prognosis is determined mostly by

the extent of irreversible tubular scarring seen in the renal biopsy,

the degree of renal impairment (if any) at presentation, and by the

response to treatment.

Management is obviously aimed at the underlying causewhen

identified. Thus, HIV-associated FSGS should be treated with

anti-retroviral therapy and causative drugs should be stopped.1

Obesity-related FSGS does not usually cause nephrotic-range

proteinuria and may resolve if weight is lost. There is no role

MEDICINE 39:8 465

for immunosuppression in treating secondary FSGS, although

this might be used in primary disease. All patients require

aggressive control of blood pressure aiming for less than 125/75

mmHg, and there is excellent evidence that angiotensin-con-

verting enzyme inhibitors (ACEI) and angiotensin II receptor

blockers (ARB) offer better protection of renal function than

other classes of drugs in proteinuric patients, and may need to be

combined (carefully monitoring serum potassium and renal

function). They also reduce proteinuria by mechanisms inde-

pendent of their blood pressure-lowering effect. Patients are at

increased risk of cardiovascular and cerebrovascular disease and

should therefore have all other vascular risk factors properly

controlled, and be encouraged to stop smoking. Although there

are no direct trial data to support the use of statins, for example,

in this specific case, patients are often hypercholesterolaemic

especially if their proteinuria is heavy. Patients with persistent

heavy proteinuria are at greatest risk of progressive renal failure

and ultimately ending up on dialysis.

Membranous glomerulonephritis

Patients with membranous GN usually present with nephrotic

syndrome or sometimes with non-nephrotic-range proteinuria.

Although most patients will have no identified underlying cause,

SLE is the commonest cause for secondarymembranousGN inmost

centres (see Lupus nephropathy and vasculitis on pp 486e491 of

this issue).Worldwide, hepatitis B and hepatitis C are also common

causes (see Systemic infections and the kidney in Medicine 35(9):

507e509). A number of drugs have been implicated in causing

membranous GN, the most important being NSAIDs. The associa-

tion of tumours with membranous GN has remained somewhat

controversial, and was previously thought to be relatively

uncommon. Recent reports, however, have suggested that cancers

are more common, especially in patients over 60 years old, and in

smokers.8 However, at all ages the risk of malignancy is substan-

tially higher than in the normal population. The cancers are almost

all carcinomas, and can be diagnosed before or after the develop-

ment of nephrotic syndrome. Any patient with a renal biopsy

showing membranous GN should, therefore, have appropriate

serological testing for SLE and hepatitis B andC, and CT scans of the

chest and abdomen, in addition to any investigations driven by

findings from the history or clinical examination (such as endos-

copy, prostate-specific antigen, bronchoscopy).

Treating an identified cause for membranous GN is often not

easy. Membranous GN in association with SLE should be treated

with immunosuppression, and various regimens have been used

(see Lupus nephropathy and vasculitis on pp 486e491 of this

issue). Treating hepatitis B and C can be difficult, and is often

unsuccessful. However, there is increasing evidence that viro-

logical clearance is associated with the resolution of the renal

disease.1 This requires close cooperation with a hepatologist,

identification of viral genotype, and often a liver biopsy to

determine the extent of hepatitis. Choice of drug is made difficult

if patients have significant renal impairment and adverse effects

seem to be commoner in this setting. Where a tumour is identi-

fied, successful treatment may lead to complete resolution of the

membranous GN. Long-term prognosis is determined by renal

function at presentation, and by persistence of heavy proteinuria.

As with FSGS, aggressive control of blood pressure is mandatory

� 2011 Elsevier Ltd. All rights reserved.

GLOMERULAR DISEASE

and the use of ACEIs or ARBs to reduce proteinuria and reduce

secondary renal scarring. There is now good evidence that even

partial remissions of proteinuria confer an advantage in reducing

progression of renal failure and subsequent need for dialysis.

Mesangiocapillary glomerulonephritis

This is one renal disease which is almost always secondary, and

most commonly to an infection, especially hepatitis C virus.

MCGN presents with proteinuria, which may be heavy enough to

cause nephrotic syndrome, often with hypertension and hae-

maturia. All patients with a histological diagnosis of MCGN need

a careful hunt for an underlying cause, especially hepatitis C,

other infections and SLE and serum cryoglobulins. It can also be

associated with inherited or acquired complement disorders, and

many patients have low concentrations of complement C3 or C4.

The association of cryoglobulinaemia, rash, arthralgia, hepato-

megaly, low serum complements, rheumatoid factor and MCGN

is particularly frequent, and in many patients caused by hepatitis

C virus.9 In Northern Europe, lymphomas are common causes.

Treatment is very unsatisfactory in many patients. Infections

should be treated, and SLE managed as described previously.

Trials in children have suggested a marginal benefit of cortico-

steroids, and there are no good data for any specific therapy in

adults. Patients with an underlying cryoglobulinaemia might

benefit from plasma exchange to remove the cryoglobulin, and

from suppression of B cells using azathioprine, mycophenolate,

cyclophosphamide or rituximab (no trials), or with therapy for

hepatitis C virus if this is present. Patients with hepatitis C may

benefit from anti-viral therapy. The prognosis for these condi-

tions is poor with at least 50% of patients requiring dialysis

within 10 years of diagnosis. Furthermore, MCGN recurs

commonly in kidney transplants (in 50e80% of cases).

Post-infectious glomerulonephritis

This condition is now relatively uncommon in developed coun-

tries, and less frequently caused by streptococci. It presents with

oedema, proteinuria, haematuria, hypertension and acute renal

failure, and the renal biopsy shows immune complex deposition

within the glomeruli. An antistreptolysin O (ASO) titre may be

raised and serum complements found to be low. Treatment is

supportive since it is usually a self-limiting condition, and

prognosis very good.

Practice points

C Infectious causes for glomerular diseases are common espe-

cially in developing countries

C Hepatitis B and C viruses and HIV are especially important

causes but can have protean manifestations

C Presentation of secondary disease is often with nephrotic

syndrome

C Tumours and drugs are less common causes of secondary

glomerular disease

C Tumours should be sought especially in membranous

glomerulonephritis

Amyloidosis

Amyloidosis frequently causes glomerular injury manifesting as

nephrotic syndrome. In developed countries, amyloid light chain

amyloidosis (AL amyloidosis) induced by free immunoglobulin

light chains is commonest and often caused by overt myeloma. AA

amyloidosis results from chronic infections and chronic inflam-

mation, for example, bronchiectasis, tuberculosis, schistosomiasis

and leprosy, and rheumatoid arthritis, juvenile arthritis and anky-

losing spondylitis,many ofwhich are less commonnow. In all these

cases the diagnosis is made only with a tissue biopsy, and

management is by treating the underlying condition. Persistent

heavy proteinuria, however, is a poor prognostic sign, and many

patients end up on dialysis (see Paraprotein-related renal disease on

pp 481e485 of this issue).

MEDICINE 39:8 466

Conclusion

Secondary glomerular diseases are common and important.

Making a diagnosis is crucial, and the renal biopsy plays a key

role in determining the nature of the renal damage. Although

conservative measures are common to all (e.g. ACEI, blood

pressure control, etc), specific interventions may be needed to

treat underlying infections, tumours, and remove offending

drugs. A

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FURTHER READING

Chabdan SJ, Atkins RC. Glomerulonephritis. Lancet 2005; 365: 1797e806.

Floege J, Johnson RJ, Feehally J. Comprehensive clinical nephrology.

4th edn. Elsevier, 2010.

� 2011 Elsevier Ltd. All rights reserved.