GLOMERULAR DISEASE

Secondary glomerular disease

Jeremy Levy

Infections associated with glomerular diseases

Infection Bacteria of all types Escherichia coli and Shigella species Malaria Syphilis Leprosy, schistosomiasis, TB Schistosomiasis, lariasis, strongyloides Hepatitis B virus Hepatitis C virus HIV Glomerular disease MCGN, post-infectious GN, diffuse proliferative GN HUS Post-infectious GN, membranous GN, MCGN Membranous GN AA amyloidosis MCGN, mesangial proliferative GN FSGS, MCGN, membranous GN, vasculitis FSGS, MCGN, membranous GN FSGS (collapsing variant), IgA nephropathy, immune complex GN, HUS FSGS

Abstract
Secondary 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 specic 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

Erythrovirus (parovirus)

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 dened by their cause and by the underlying pattern of renal injury caused.

AA, amyloid A; FSGS, focal segmental glomerulosclerosis; GN, glomerulonephritis; HUS, haemolytic uraemic syndrome; MCGN, mesangiocapillary glomerulonephritis; TB, tuberculosis.

Table 1

Infection-associated glomerular disease

Infections of all types have been associated with various glomerular 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 and malaria 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 membranous GN, while HIV is especially associated with a specic subtype of FSGS (collapsing variant) but also commonly causes glomerular immune complex disease.1e3 Since HIV has become a treatable

chronic disease (with excellent viral suppression in most 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 childrens 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 resolution of glomerular disease with removal or treatment of the tumour without specic 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 cryoglobulinaemia, which causes MCGN within the kidney, or alternatively 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.

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.

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Tumours associated with glomerular diseases

Tumour Lymphoma and leukaemia Glomerular disease Minimal change disease, membranous, MCGN, cryoglobulinaemia Amyloidosis, cryoglobulinaemia Membranous, MCGN, HUS

Myeloma Carcinoma (lung, gastrointestinal, uterine, prostate, etc)

HUS, haemolytic uraemic syndrome; MCGN, mesangiocapillary glomerulonephritis.

Table 2

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-converting 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 independent 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 specic 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.

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). Nonsteroidal anti-inammatory 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, penicillamine 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.

Membranous glomerulonephritis
Patients with membranous GN usually present with nephrotic syndrome or sometimes with non-nephrotic-range proteinuria. Although most patients will have no identied underlying cause, SLE is the commonest cause for secondary membranous GN in most 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 association 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 substantially higher than in the normal population. The cancers are almost all carcinomas, and can be diagnosed before or after the development of nephrotic syndrome. Any patient with a renal biopsy showing membranous GN should, therefore, have appropriate serological testing for SLE and hepatitis B and C, and CT scans of the chest and abdomen, in addition to any investigations driven by ndings from the history or clinical examination (such as endoscopy, prostate-specic antigen, bronchoscopy). Treating an identied 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 difcult, and is often unsuccessful. However, there is increasing evidence that virological clearance is associated with the resolution of the renal disease.1 This requires close cooperation with a hepatologist, identication of viral genotype, and often a liver biopsy to determine the extent of hepatitis. Choice of drug is made difcult if patients have signicant renal impairment and adverse effects seem to be commoner in this setting. Where a tumour is identied, 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

Focal segmental glomerulosclerosis

FSGS is now the most common renal biopsy nding in many renal centres around the world, especially in the USA. Clinically, patients present with acute or subacute nephrotic syndrome, or with nonnephrotic range proteinuria. FSGS can be classied according to the precise histological pattern, and this may have prognostic signicance 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 reux, in solitary kidneys, after almost any other glomerular disease with 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 cause when identied. 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

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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.

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), specic interventions may be needed to treat underlying infections, tumours, and remove offending drugs. A

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 haematuria. 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, hepatomegaly, 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 benet of corticosteroids, and there are no good data for any specic therapy in adults. Patients with an underlying cryoglobulinaemia might benet 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 benet from anti-viral therapy. The prognosis for these conditions 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 countries, 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.

REFERENCES 1 Lai KS, Lai KN. Viral nephropathy. Nat Clin Pract Nephrol 2006; 2: 254e62. 2 Kamar N, Rostaing L, Alric L. Treatment of hepatitis C-virus-related glomerulonephritis. Kidney Int 2006; 69: 436e9. 3 Bhimma R, Coovadia HM. Hepatitis B virus-associated nephropathy. Am J Nephrol 2004 MareApr; 24: 198e211. 4 Centers for Disease Control and Prevention (CDC). Outbreaks of Escherichia coli O157:H7 associated with petting zooseNorth Carolina, Florida, and Arizona, 2004 and 2005. Morb Mortal Wkly Rep 2005; 54: 1277e80. 5 Mallouk A, Pham PT, Pham PC. Concurrent FSGS and Hodgkins lymphoma: case report and literature review on the link between nephrotic glomerulopathies and hematological malignancies. Clin Exp Nephrol 2006; 10: 284e9. 6 Howse MLP, Bell GM. Drugs and toxins that damage the kidney. Medicine 2007; 35: 399e403. 7 Meyrier A. Mechanisms of disease: focal segmental glomerulosclerosis. Nat Clin Pract Nephrol 2005; 1: 44e54. 8 Lefaucheur C, Stengel B, Nochy D, et al. Membranous nephropathy and cancer: epidemiologic evidence and determinants of high-risk cancer association. Kidney Int 2006; 70: 1510e7. 9 Roccatello D, Fornasieri A, Giachina O, et al. Multicentric study on hepatitis C virus-related cryoglobulinaemic glomerulonephritis. Am J Kidney Dis 2007; 49: 69e82.

FURTHER READING Chabdan SJ, Atkins RC. Glomerulonephritis. Lancet 2005; 365: 1797e806. Floege J, Johnson RJ, Feehally J. Comprehensive clinical nephrology. 4th edn. Elsevier, 2010.

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 inammation, for example, bronchiectasis, tuberculosis, schistosomiasis and leprosy, and rheumatoid arthritis, juvenile arthritis and ankylosing spondylitis, many of which are less common now. 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).

Practice points
C

Infectious causes for glomerular diseases are common especially in developing countries Hepatitis B and C viruses and HIV are especially important causes but can have protean manifestations Presentation of secondary disease is often with nephrotic syndrome Tumours and drugs are less common causes of secondary glomerular disease Tumours should be sought especially in membranous glomerulonephritis

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