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Minimal-change nephropathy and focal segmental glomerulosclerosis 

Minimal-change nephropathy and focal segmental glomerulosclerosis
Chapter:
Minimal-change nephropathy and focal segmental glomerulosclerosis
Author(s):

Dwomoa Adu

DOI:
10.1093/med/9780199204854.003.210803

May 25, 2011: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

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Essentials

Minimal-change nephrotic syndrome

Minimal-change nephrotic syndrome (MCNS) is an immune-mediated condition, usually of unknown cause, but which can sometimes be associated with Hodgkin’s disease or the use of nonsteroidal anti-inflammatory drugs. On light microscopy the glomeruli appear normal or small, and on electron microscopy there is effacement of epithelial-cell foot processes over the outer surface of the glomerular basement membrane. MCNS is the cause of about 80% of cases of nephrotic syndrome in children and 20% in adults.

Management and prognosis—treatment in adults is with prednisolone at an initial dose of 60 mg/day (then tapering), with 75% responding by 6 months. Up to 60% of patients who go into a remission have a relapse, and about 40% have frequent relapses, and in these patients treatment with cyclophosphamide induces a sustained remission in 60% over a 5-year period. Ciclosporin is also of benefit in frequent relapsers, but most patients relapse when this is discontinued. Just over 5% of patients remain nephrotic in the long term. Progression to renal failure is not expected and would call the diagnosis of MCNS into question.

Focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is not a specific disease entity but a histological lesion, often of unknown aetiology, which is characterized by segmental areas of glomerular sclerosis. It may be: (1) primary—which is by definition of unknown cause, but in about 30% of cases is associated with a circulating protein factor that causes an increase in glomerular permeability; or (2) secondary—the end product of a variety of pathological processes including glomerular hyperfiltration, healed glomerulonephritis, viral infection (HIV), and genetic mutation. Based on the site of the lesions and other histological features the primary condition can be divided into five variants: (1) perihilar; (2) glomerular tip; (3) collapsing variant; (4) cellular variant; and (5) ‘not otherwise specified’, when the other variants have been excluded. Most patients with FSGS present with nephrotic syndrome (FSGS is the diagnosis in 20% of adults with nephrotic syndrome), some with persistent proteinuria, and a few have haematuria as well as proteinuria.

Management and prognosis—patients with primary FSGS and nephrotic syndrome should be treated with prednisolone for 6 months (initially 60 mg/day, then tapering), and those who are resistant should receive ciclosporin for 26 to 52 weeks. Those who achieve a complete remission have a 5-year survival off dialysis of over 90%, as compared with about 50% of those who do not achieve remission. Patients with the glomerular tip lesion respond best; those with classic FSGS (‘not otherwise specified’) have an intermediate response; and those with collapsing FSGS have the worst prognosis. The nephrotic syndrome recurs—often within days—after renal transplantation in 20 to 40% of patients with primary FSGS, leading to graft failure in approximately 50% of cases.

General considerations in the nephrotic syndrome

Classification of glomerulonephritis

The most helpful classification of glomerulonephritis is one based on histology. Careful clinical and pathological studies have established the histological patterns of glomerulonephritis in patients with a nephrotic syndrome inhabiting temperate regions of the world (Table 21.8.3.1). The aetiology and patterns of glomerulonephritis in tropical countries differ considerably and are considered elsewhere (see Chapter 21.11); discussion in this chapter refers to disease seen in temperate regions. Idiopathic glomerulonephritis accounts for 90% of all childhood cases of the nephrotic syndrome and for approximately 80% in adult patients. Although these histological changes are usually of unknown aetiology, they may also be secondary to well-defined aetiological factors.

Table 21.8.3.1 Histology of the nephrotic syndrome

Histology

Number of childrena (%)

Number of adultsb (%)

Minimal-change nephrotic syndrome

76

17

Mesangiocapillary glomerulonephritis

8

3

Focal segmental glomerulosclerosis

7

17

Proliferative (including diffuse mesangial proliferation)

2

0

Membranous

2

30

Other

5

9

Systemic lupus erythematosus

8

Amyloid

7

Diabetes

9

a From International Study of Kidney Disease in Children (1978). Prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. Kidney Int, 13, 159–65. [Excludes secondary causes of nephrotic syndrome, e.g. systemic lupus erythematosus, Henoch–Schönlein purpura; about 10%.]

b From Howie AJ, Pankhurst T, Sarioglu S, et al. Evolution of nephrotic-associated focal segmental glomerulosclerosis and relation to the glomerular tip lesion. Kidney Int 2005;67(3):987–1001.

General clinical approach

Children

In the original studies of the International Study of Kidney Diseases in Children (ISKDC), the diagnosis of minimal-change nephrotic syndrome (MCNS) was based on renal biopsies. From these and other studies it was established that for a child aged between 1 and 16 years with a nephrotic syndrome and highly selective proteinuria, and who did not have microscopic haematuria, hypertension, or renal impairment, the likely diagnosis was minimal-change nephropathy. When treated with steroids, such children had a greater than 90% chance of going into remission within 4 weeks. Based on these observations, children of this age with the features summarized above are no longer have a renal biopsy, but instead are treated with a trial of steroids. This leads to the term ‘steroid-responsive nephrotic syndrome’ of childhood and most, but not all, of such children will have MCNS. In neonates and in children under 1 year of age there is a high probability of the congenital nephrotic syndrome or diffuse mesangial sclerosis, and therefore renal biopsy should be considered as neither of these lesions respond to steroids.

Adults

Only 20% of adults with a nephrotic syndrome have MCNS and for that reason a renal biopsy is necessary to establish the type of glomerulonephritis. This provides useful information on the likelihood of response to treatment and also the prognosis. In skilled hands the dangers of renal biopsy are small and outweighed by those of steroid treatment given for disorders that will not respond.

General aspects of the management

Although steroids and immunosuppressants have been widely used in the treatment of the nephrotic syndrome, general measures remain an important part of the treatment of these disorders. Initial treatment of oedema is with salt restriction and, if there is hyponatraemia, with fluid restriction. Adults are commonly treated with loop diuretics such as furosemide, but this must be used with care, particularly in children, because of the risk of volume depletion and consequent renal impairment.

Thromboembolic disease

The nephrotic syndrome may be complicated by venous and less commonly by arterial thromboembolism. Many coagulation abnormalities have been described, including raised serum levels of factors V, VII, and X, as well as fibrinogen and von Willebrand factor, and low serum levels of antithrombin III.

In adults the incidence of venous thrombosis has variously been reported in between 10 and 40% of patients, and less commonly in children (2–4%). Venous thrombosis may be complicated by pulmonary emboli. Renal vein thrombosis is now recognized as a complication of the nephrotic syndrome and not its cause, but is particularly common in membranous nephropathy, with a reported prevalence of about 30%, and it is also seen frequently in membranoproliferative glomerulonephritis, but less so in MCNS and focal segmental glomerulosclerosis (FSGS). Thrombosis may also occur in the arterial circulation, with the most common site being the femoral artery, often after this has been punctured.

The high incidence of thromboembolic disease raises the question of whether prophylactic anticoagulation is justified. A decision analysis justified prophylactic anticoagulation in patients with a nephrotic syndrome due to membranous nephropathy, but in the absence of data from randomized controlled trials of anticoagulation in the nephrotic syndrome it is difficult to make any firm recommendations. One could justify prophylactic anticoagulation in patients with an idiopathic nephrotic syndrome that is likely to be resistant to therapy, especially when the serum albumin is less than 20 g/litre. Obviously patients with identified thromboembolic disease should be given anticoagulants, with treatment continuing until the nephrotic syndrome is in remission.

Hypercholesterolaemia

Hypercholesterolaemia is a defining feature of the nephrotic syndrome and is due to increased levels of very low density cholesterol and low-density cholesterol. The mechanisms of this are unclear. One study showed that, as compared with matched controls (for smoking and hypertension), patients with a nephrotic syndrome had a relative risk for myocardial infarction of 5.5 and for death from coronary artery disease of 2.8. Statins (pravastatin or simvastatin) reduce low-density cholesterol and total cholesterol levels by 22 to 33% in patients with a nephrotic syndrome, but there are no studies showing that they confer survival benefit. Effects on triglyceride levels are less marked. Short-term studies report that statins are safe in patients with a nephrotic syndrome, but it is important to note that many statins are metabolized by the cytochrome P450 isoenzyme CYP3A4, and drugs that inhibit this enzyme such as ciclosporin increase drug levels and toxicity. This complication is less likely with pravastatin or fluvastatin.

Angiotensin blockade

Angiotensin converting enzyme (ACE) inhibitors and angiotensin-II receptor antagonists reduce proteinuria in patients with a nephrotic syndrome by up to 40%. There is evidence of an additive effect in proteinuria reduction with combined ACE inhibition and angiotensin-II blockade, but careful monitoring of serum potassium and renal function is required to make this approach safe.

Minimal-change nephropathy

Aetiology and pathogenesis

The responsiveness of the nephrotic syndrome of MCNS to steroids, cyclophosphamide, chlorambucil, and ciclosporin A is strong evidence that this disorder is immune mediated. The pathogenetic mechanisms remain obscure, but recent studies suggest a role for T lymphocytes, as originally suggested by Shaloub. Patients with MCNS show a T-lymphocyte repertoire that is biased towards a TH2 phenotype, with raised serum levels of IgE, interleukin (IL)-13 and IL-4. Subtractive cloning of T lymphocytes in remission and relapse show an increase in transcripts associated with T-cell receptor-mediated signalling. Numerous studies have examined major histocompatibility complex (MHC) associations with MCNS, but these are inconclusive, as are studies of polymorphisms in cytokine genes.

There is a well-recognized association between Hodgkin’s lymphoma and MCNS. Nonsteroidal anti-inflammatory drugs can cause an interstitial nephritis, which in some cases is accompanied by a nephrotic syndrome with renal histology showing the changes of MCNS.

Pathology

The histological features are similar in both children and adults. On light microscopy the glomeruli appear normal or small (Fig. 21.8.3.1), and on electron microscopy there is effacement of epithelial-cell foot processes over the outer surface of the glomerular basement membrane. Some authors accept a minor degree of mesangial IgM deposition and mesangial proliferation as being consistent with this disorder.

Fig. 21.8.3.1 Minimal-change nephropathy. The glomerulus looks normal on light microscopy. Periodic acid–methenamine silver staining, magnification × 64.

Fig. 21.8.3.1
Minimal-change nephropathy. The glomerulus looks normal on light microscopy. Periodic acid–methenamine silver staining, magnification × 64.

By courtesy of Professor A. J. Howie.

Clinical features in children

Although this is textbook of adult medicine, an account of MCNS in children is appropriate because some will continue to be affected in adolescence and adulthood. MCNS is found in approximately 76% of children with an idiopathic nephrotic syndrome. Most affected children are under 6 years of age (80%), with a peak age of onset of 2 to 4 years. The condition is responsible for 59% of cases of nephrotic syndrome in those aged between 6 and 15 years. It is more common in boys than in girls, with a male to female childhood ratio of 2:1. Most cases are responsive to steroids, hence children with a nephrotic syndrome in temperate countries no longer require a renal biopsy and are defined on the basis of their responsiveness to steroids. In children (as in adults) a major problem is relapsing nephrotic syndrome, and recommended second-line treatments for this are (first) cyclophosphamide and (second) ciclosporin. The long-term prognosis for renal function is good in children.

Clinical presentation

The clinical presentation is with a nephrotic syndrome that is characterized by severe hypoalbuminaemia, with a serum albumin level of less than 10 g/litre in approximately 38% of cases. Microscopic haematuria is infrequent (22%), as is hypertension (9%). Renal impairment is infrequent at diagnosis, being found in approximately 10% of cases, and presentation in acute renal failure is rare. These children are prone to infections, in particular cellulitis and pneumococcal peritonitis.

Diagnosis

The role (or not) of renal biopsy has already been discussed. The current approach is to treat all children in temperate countries with a nephrotic syndrome with steroids, and then to define their illness as either steroid responsive or not steroid responsive. In most countries in the tropics, MCNS is uncommon in children and a renal biopsy is needed to establish the diagnosis.

Treatment

Steroids

Meta-analysis showed that treatment with prednisolone for 3 months or more during the first episode of a nephrotic syndrome in children significantly reduced the risk of relapse at 12 to 24 months, as compared with treatment for 2 months (relative risk (RR) 0.70; 95% CI 0.58–0.84). Treatment for 6 months as compared to 3 months reduced the number of subsequent frequent relapsers (RR 0.55; 95% CI 0.38–0.80). It is therefore recommended that children receive at least 6 weeks of treatment with daily oral prednisolone 60 mg/m2, followed by 6 weeks of alternate day prednisolone 40 mg/m2.

Frequent relapsers

In children presenting with a first episode of nephrotic syndrome, about 90% go into remission (meaning that proteinuria disappears) with steroid treatment, but about 30 to 50% will have frequent relapses. An 8-week course of cyclophosphamide (2–3 mg/kg per day) or chlorambucil (0.2 mg/kg per day) significantly reduces the risk of further relapse as compared with prednisolone alone (RR 0.44; 95% CI 0.26–0.73 and RR 0.13; 95% CI 0.03–0.57, respectively). Approximately 50% of treated children are in remission at 2 years and 40% at 5 years. Cyclophosphamide has been carefully evaluated and is the drug of choice. Ciclosporin (6 mg/kg per day) is as effective as cyclophosphamide or chlorambucil, but the effect is maintained only during treatment. Levamisole has also been used and is more effective in reducing relapses than prednisolone alone (RR 0.60; 95% CI 0.45–0.79), but again the effect is restricted to the period of treatment. Levamisole can cause a reversible neutropenia.

Toxicity of cyclophosphamide and chlorambucil

The risk of gonadal toxicity is greater in boys than in girls. Gonadal toxicity occurs with chlorambucil at a cumulative dose of 8 to 10 mg/kg. The borderline dose for permanent gonadal toxicity with cyclophosphamide is a cumulative dose of 200 mg/kg. Bone marrow toxicity with both drugs means that the leucocyte count should be regularly measured during treatment. These drugs also increase the long-term risk of developing cancer. Other toxic side effects of cyclophosphamide include haemorrhagic cystitis and alopecia. At the doses and duration of treatment outlined above it is relatively safe.

Steroid-resistant nephrotic syndrome in children

The 10% or so of children who have steroid-resistant nephrotic syndrome will be found, if biopsied, to have MCNS, mesangioproliferative glomerulonephritis, or FSGS. In these patients ciclosporin is more effective in inducing complete remission than placebo or no treatment (RR for persisting nephrotic syndrome 0.64; 95% CI 0.47–0.88). There is no difference between oral cyclophosphamide and prednisolone compared with prednisolone alone (RR 1.01; 95% CI 0.74–1.36), or intravenous cyclophosphamide compared with oral cyclophosphamide (RR 0.09; 95% CI 0.01–1.39). Azathioprine and prednisolone are no better than prednisolone alone (RR 1.01; 95% CI 0.77–1.32). The ACE inhibitor fosinopril reduces proteinuria by 0.95 g/24 h (95% CI −1.21 to −0.69).

Long-term outcome

The risk of a future relapse is low for those children in whom the nephrotic syndrome goes into remission within 8 weeks of steroid therapy and who do not relapse for 6 months. Early relapse within 6 months is reported to be associated with a risk of relapses for up to 3 years, and approximately 5.5% of affected children continue to relapse into adult life, all of whom have presented with a nephrotic syndrome before the age of 6 years. Children with persistent proteinuria at 8 weeks have a 21% risk of developing endstage renal failure, and this increased to 35% if they still have proteinuria at 6 months. The long-term mortality rate in children ranges from 2.6 to 7.2%.

MCNS as part of a spectrum of glomerular disease

In temperate countries, most children with a nephrotic syndrome have MCNS, FSGS, or a mesangial proliferative glomerulonephritis (Table 21.8.3.1). Repeat renal biopsies performed if the character of illness changes, e.g. if patients become frequent relapsers, steroid dependent, or steroid resistant, sometimes show progression from MCNS or mesangial proliferative glomerulonephritis to FSGS. One study showed that patients with presumed MCNS whose renal biopsies showed large glomeruli were more likely to develop FSGS. In general, those patients with MCNS who develop FSGS but remain steroid responsive have a good prognosis for renal function, while those who are steroid resistant develop progressive renal failure. The prognosis for renal function is therefore determined by the responsiveness to steroids and not by the histological lesion.

Clinical features in adults

About 20% of adults with a nephrotic syndrome have MCNS. The mean age of onset is 40 years, but the condition can occur at any age. The histology is identical to that found in children, with the exception of a higher incidence of globally sclerosed glomeruli that are a feature of ageing.

Clinical presentation

As in children, the clinical presentation is with a nephrotic syndrome, although this is not generally as severe. Profound hypoalbuminaemia (serum albumin level under 10 g/litre) is rare in adults. The disease is slightly more common in men than in women, with a male to female ratio of 1.3:1. More adults than children are hypertensive (30%), have microscopic haematuria (28%), and have renal impairment at diagnosis (60%). These abnormalities are more severe in patients aged over 60 years, who are also at particular risk of developing acute renal failure.

Diagnosis

A renal biopsy is essential to make the diagnosis in adults with a nephrotic syndrome.

Treatment

Treatment is with prednisolone at an initial dose of 60 mg/day, response to which takes longer than in children and is also less complete (75% at 6 months). Up to 60% of patients who go into a remission have a relapse, and about 40% have frequent relapses. In frequent relapsers treatment with cyclophosphamide induces a sustained remission in 60% over a 5-year period. Ciclosporin is also of benefit in frequent relapsers, but most patients relapse when this is discontinued. Patients who are steroid responsive or multiple relapsers are more likely to respond with complete or partial remissions (70–80%) than those who are resistant to steroids (40–50%).

Ciclosporin should be considered in those patients who develop steroid toxicity because they have multiple relapses or who are steroid dependent. However, relapses appear to recur with the same frequency after ciclosporin A has been discontinued as before, and for that reason it is still advisable to use cyclophosphamide as the first-choice treatment in patients with a multiple relapsing or steroid-dependent minimal-change nephropathy in the hope of inducing a sustained remission. Ciclosporin A appears to be effective at blood levels of between 100 and 200 ng/ml, and at these levels significant short-term nephrotoxicity and hypertension are uncommon. In this author’s view, ciclosporin A can best be viewed as a steroid-sparing agent in patients with minimal-change nephropathy.

Mycophenolate mofetil and tacrolimus have also been reported in uncontrolled trials to be effective in inducing and maintaining remission in patients with steroid-resistant or relapsing minimal change disease, and in FSGS.

Long-term outcome

Approximately 6% of adult patients are still nephrotic after a mean follow-up of 7.5 years. The survival in patients over 60 years of age has been reported to be 50% at 10 years, and in those aged 15 to 59 years it was 90%.

Focal segmental glomerulosclerosis

FSGS was first described by Rich in 1957 at autopsy in children who died from a nephrotic syndrome. Fewer terms have generated more disagreement among pathologists and nephrologists as it is not a disease entity but a histological lesion that is often of unknown aetiology.

Types of FSGS

Secondary FSGS

Segmental scarring of glomeruli is the end product of a variety of pathological processes. These include, e.g. sickle cell anaemia, reduced renal mass, HIV infection, inherited mutations of podocyte-related genes, and immune complex nephritis (Table 21.8.3.2). Some of these causes lead to well-defined glomerular lesions, e.g. collapsing glomerulopathy in HIV-associated nephropathy, and prominent hilar segmental lesions in reduced renal mass.

Table 21.8.3.2 Aetiology of FSGS

Cause

Comment

Idiopathic

Genetic

Mutations in α‎-actinin 4, podocin, nephrin, ion-receptor protein transient receptor potential cation channel 6 (TRPC6)

Healed glomerulonephritis

IgA nephropathy, vasculitis

Viral infection

HIV, parvovirus B19

Drugs

Heroin, pamidronate, lithium

Glomerular hyperfiltration (with or without reduced renal mass)

Reduced renal mass, reflux nephropathy, renal agenesis, sickle cell anaemia

Parasitic infection

Schistosoma mansoni

Mutations in genes encoding slit diaphragm proteins are found in up to 20 to 30% of children with steroid-resistant nephrotic syndrome, but not in children with steroid-sensitive nephrotic syndrome, and they are uncommon in adults. Patients with a genetic cause for their nephrotic syndrome show no response to steroids or immunosuppressants, and these should not be used.

Patients with a secondary form of FSGS may have nephrotic or non-nephrotic range proteinuria. FSGS has also been found late on during the clinical course of patients with a nephrotic syndrome who had an initial renal biopsy showing MCNS.

Pathogenesis

Focal segmental sclerosis can develop from different pathogenic mechanisms in different experimental models, including toxic injury (puromycin nephropathy), immunological injury (anti-GBM nephritis), lupus-associated nephritis in NZB/NZW F1 mice, and hyperfiltration injury (five-sixths nephrectomy). Some of these models have clinical counterparts, and the diversity of pathogenic mechanisms may explain the variability in the clinical presentation and response to treatment.

Primary (idiopathic) FSGS

FSGS may be apparently idiopathic and found early on during the clinical course of patients with proteinuria or nephrotic syndrome. About 7% of children and 20% of adults with a nephrotic syndrome have FSGS. Even when FSGS is found early on in the course of a nephrotic syndrome there is no evidence to suggest that it represents a homogenous disease.

Pathogenesis

In about 30% of patients with primary FSGS there is a circulating factor that causes an increase in glomerular permeability in vitro, with the rapid development of heavy proteinuria following renal transplantation in 30 to 40% of patients with primary FSGS, strongly supporting the clinical importance of something in the circulation. The factor appears to be a protein with a molecular weight of between 30 and 50 kDa, and it is not an immunoglobulin. A 70% ammonium sulphate precipitate of serum from patients with recurrent FSGS following renal transplantation is reported to decrease tyrosine phosphorylation of the cytoskeleton-associated proteins focal adhesion kinase and paxillin, which may impair cell–cell interactions in the podocytes slit-pore junction leading to proteinuria.

Pathology

The histological lesions of FSGS comprise segmental areas of glomerular sclerosis with hyalinization of glomerular capillaries, the segmental areas usually being adherent to Bowman’s capsule. In childhood FSGS, these lesions predominantly affect juxtamedullary glomeruli. One suggested classification is the Columbia FSGS classification, shown in Table 21.8.3.3; there is still a lack of agreement over the details, but it provides a useful framework for the management of patients. Several variants are described, based on the site of the segmental sclerosing lesion (perihilar variant and glomerular tip lesion), the presence of glomerular collapse (collapsing variant), and endocapillary cellularity with visceral epithelial cell hyperplasia (cellular variant), leaving ‘FSGS (not otherwise specified)’ when these have been excluded. This latter lesion is equivalent to classic nephrotic-associated FSGS, when the areas of segmental sclerosis are typically randomly distributed within the glomerular tuft, with a predilection for the hilar regions (Figs 21.8.3.2, 21.8.3.3). Focal areas of tubular atrophy and interstitial nephritis are prominent. On immunofluorescence microscopy, deposits of IgM and complement C3 may be seen in the sclerotic areas. Electron microscopy shows diffuse foot-process effacement in apparently unaffected glomeruli.

Table 21.8.3.3 Idiopathic FSGS, classification and treatment

Variant, based on site of segmental sclerosing lesion

Treatment

FSGS, not otherwise specified

Steroids if nephrotic

Perihilar variant

ACE inhibitors

Cellular variant

Steroids if nephrotic

Glomerular tip lesion

Steroids if nephrotic

Collapsing variant

ACE inhibitors

ACE, angiotensin converting enzyme.

Fig. 21.8.3.2 Classic segmental sclerosing glomerulonephritis at an early stage. The glomerulus shows an erratic increase in mesangium with a segmental area of foamy cells and sclerosis opposite the vascular pole, next to the tubular origin. Haematoxylin and eosin staining, magnification ×50.

Fig. 21.8.3.2
Classic segmental sclerosing glomerulonephritis at an early stage. The glomerulus shows an erratic increase in mesangium with a segmental area of foamy cells and sclerosis opposite the vascular pole, next to the tubular origin. Haematoxylin and eosin staining, magnification ×50.

By courtesy of Professor A. J. Howie.

Fig. 21.8.3.3 Classic segmental sclerosing glomerulonephritis at a late stage. Four glomeruli show an erratic increase in mesangium and segmental lesions at various sites. Periodic acid–methenamine silver staining, magnification ×64.

Fig. 21.8.3.3
Classic segmental sclerosing glomerulonephritis at a late stage. Four glomeruli show an erratic increase in mesangium and segmental lesions at various sites. Periodic acid–methenamine silver staining, magnification ×64.

By courtesy of Professor A. J. Howie.

Collapsing glomerulopathy

This is a type of focal segmental sclerosing glomerulonephritis, characterized by segmental or global collapse of glomerular capillaries with basement-membrane wrinkling and crowding of glomerular epithelial cells. These appearances represent a distinct subset of patients with FSGS, and were initially described in patients with HIV-associated nephropathy in the context of a severe nephrotic syndrome and rapid progression to endstage renal failure. Subsequent reports show that the condition may also be idiopathic. Presentation is with a nephrotic syndrome and renal impairment (70% of cases). Treatment with steroids or cytotoxic drugs has been ineffective in inducing remission or preventing the development of endstage renal failure. There is rapid deterioration of renal function and over 70% of patients are in endstage renal failure after a follow-up of 5 years.

Clinical presentation

Children

Approximately 7% of children presenting with an idiopathic nephrotic syndrome have FSGS. Boys and girls are equally affected and the peak age at onset is between 6 and 8 years. Most patients with FSGS (75%) present with a nephrotic syndrome, 20% have persistent proteinuria, and 5% haematuria as well as proteinuria. Clinically, these patients differ from children with MCNS in that two-thirds have microscopic haematuria, one-half have impaired renal function at diagnosis, and one-third are hypertensive. The proteinuria is usually poorly selective.

Adults

The clinical presentation in adults does not differ in any significant respects from that in children. The mean age at onset is between 20 and 30 years, but FSGS has been found in patients aged over 70.

Treatment of primary (‘classic’) FSGS

The prognosis in patients with primary FSGS and proteinuria in the non-nephrotic range is good, and 80% of such patients survive for 10 years without developing endstage renal failure. These patients do not need treatment with either prednisolone or immunosuppressants and should be treated with general measures only.

The main problem is the treatment of patients with FSGS and a nephrotic syndrome. The different histopathological varieties of idiopathic FSGS vary in their clinical presentation, response to treatment, and progression to renal failure (Table 21.8.3.3). Patients with the glomerular tip lesion (probably an early form of classic FSGS) have a good response to prednisolone and only infrequently progress to endstage renal failure. Patients with classic FSGS (‘not otherwise specified’) have an intermediate response to prednisolone and are more likely to progress to renal failure. Patients with collapsing FSGS have the worst prognosis.

Steroids

There have been no randomized controlled trials of steroid therapy in FSGS. Cohort studies report that 40 to 60% of patients treated with a 6-month course of prednisolone go into complete or partial remission. Complete as well as partial remissions are associated with a significant reduction in the risk of developing endstage renal failure as compared with no remission. Adult patients who achieve a complete remission have a 5-year survival off dialysis of 94% as compared with 53% of those who do not achieve remission; children who achieve a complete remission have a 100% renal survival as compared with 92% with a partial remission and 47% with no remission. However, relapses are common and are found in 40 to 56% of patients.

All patients with primary FSGS and a nephrotic syndrome should be treated with prednisolone for 6 months. Children are treated with prednisolone at an initial dose of 60 mg/m2 per day, and adults with a dose of 60 mg/day with tapering of the steroid dose.

Ciclosporin

Patients whose nephrotic syndrome is resistant to 6 months of treatment with prednisolone should receive ciclosporin for 26 to 52 weeks. A meta-analysis of three studies in patients with FSGS who were resistant to an 8-week course of prednisolone indicates that ciclosporin was more effective than prednisolone or placebo in inducing remission (RR for persisting nephrotic syndrome 0.34; 95% CI 0.18–0.69) and in preventing endstage renal failure (RR 0.45; 95% CI 0.21–0.97).

Other immunosuppressants

The evidence supporting the addition to prednisolone of cyclophosphamide or chlorambucil in the treatment of FSGS is not convincing.

ACE inhibition/angiotensin receptor blockade

In one retrospective study of childhood FSGS, angiotensin blockade (hazard rate (HR) 4.96; 95% CI 1.69–9.29) and calcineurin inhibitors (HR 2.54; 95% CI 1.20–5.35) were associated with remission of the nephrotic syndrome by univariate analysis, but by multivariate analysis only angiotensin blockade was significant (HR 3.35; 95% CI 1.42–9.75).

Prognosis

There is no difference in prognosis between adults and children. Adverse prognostic factors include tubulointerstitial fibrosis, renal impairment, and a failure of remission with treatment.

Recurrence after renal transplantation

The nephrotic syndrome recurs in 20 to 40% of patients with primary FSGS, often within days of renal transplantation, and this leads to graft failure in approximately 50% of cases. After recurrence in a first transplant the rate of recurrence in a subsequent transplant approaches 75%. Plasma exchange and protein immunoadsorption have resulted in a reduction of proteinuria or a remission of the nephrotic syndrome in some patients.

Further reading

General

Crew RJ, Radhakrishnan J, Appel G (2004). Complications of the nephrotic syndrome and their treatment. Clin Nephrol, 62, 245–59.Find this resource:

Llach F (1985). Hypercoagulability, renal vein thrombosis, and other thrombotic complications of nephrotic syndrome. Kidney Int, 28, 429–39.Find this resource:

Sarasin FP, Schifferli JA (1994). Prophylactic oral anticoagulation in nephrotic patients with idiopathic membranous nephropathy. Kidney Int, 45, 578–85.Find this resource:

Minimal-change nephropathy

Bargman J (1999). Management of minimal lesion glomerulonephritis: evidence-based recommendations. Kidney Int, 55 Suppl 70, 3–16.Find this resource:

Day CJ, et al. (2002). Mycophenolate mofetil in the treatment of resistant idiopathic nephrotic syndrome. Nephrol Dial Transplant, 17, 2011–13.Find this resource:

Durkan A, et al. (2005). Non-corticosteroid treatment for nephrotic syndrome in children. Cochrane Database Syst Rev, 2, CD002290.Find this resource:

Ghiggeri GM, et al. (2004). Cyclosporine in patients with steroid-resistant nephrotic syndrome: an open-label, nonrandomized, retrospective study. Clin Ther, 26, 1411–18.Find this resource:

Hodson EM, Habashy D, Craig JC (2006). Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane Database Syst Rev, 2, CD003594.Find this resource:

Hodson EM, et al. (2005). Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev, 1, CD001533.Find this resource:

International Study of Kidney Disease in Children (1978). Prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. Kidney Int, 13, 159–65.Find this resource:

    Korbet SM, Schwartz MM, Lewis EJ (1988). Minimal-change glomerulopathy of adulthood. Am J Nephrol, 8, 291–7.Find this resource:

    Mak SK, Short CD, Mallick NP (1996). Long-term outcome of adult-onset minimal-change nephropathy. Nephrol Dial Transplant, 11, 2192–201.Find this resource:

    Mathieson PW (2003). Immune dysregulation in minimal change nephropathy. Nephrol Dial Transplant, 18 Suppl 6, vi26–9.Find this resource:

    Nolasco F, et al. (1986). Adult-onset minimal change nephrotic syndrome: a long term follow-up. Kidney Int, 29, 1215–23.Find this resource:

    Ponticelli C, et al. (1993). Cyclosporin versus cyclophosphamide for patients with steroid-dependent and frequently relapsing idiopathic nephrotic syndrome: a multicentre randomized controlled trial. Nephrol Dial Transplant, 8, 1326–32.Find this resource:

    Tarshish P, et al. (1997). Prognostic significance of the early course of minimal changes nephrotic syndrome: report of the International Study of Kidney Disease in Children. J Am Soc Nephrol, 8, 769–76.Find this resource:

    Ueda N, Kuno K, Ito S (1990). Eight and 12 week courses of cyclophosphamide in nephrotic syndrome. Arch Dis Childhood, 85, 1147–50.Find this resource:

      Focal segmental glomerulosclerosis

      Aucella F, et al. (2005). Molecular analysis of NPHS2 and ACTN4 genes in a series of 33 Italian patients affected by adult-onset nonfamilial focal segmental glomerulosclerosis. Nephron Clin Pract, 99, c31–6.Find this resource:

      Burgess E (1999). Management of focal glomerulosclerosis: evidence based recommendations. Kidney Int, 55 Suppl 70, 26–32.Find this resource:

      D’Agati V (1994). The many masks of focal segmental glomerulosclerosis. Kidney Int, 46, 1223–41.Find this resource:

      D’Agati VD, et al. (2004). Pathologic classification of focal segmental glomerulosclerosis: a working proposal. Am J Kidney Dis, 43, 368–82.Find this resource:

      Detweiler R, et al. (1994). Collapsing glomerulopathy: a clinically and pathologically distinct variant of segmental glomerulosclerosis. Kidney Int, 45, 1734–46.Find this resource:

        Howie A, et al. (1993). Different clinicopathological types of segmental sclerosing glomerular lesions in adults. Nephrol Dial Transplant, 8, 590–9.Find this resource:

        Howie AJ, et al. (2005). Evolution of nephrotic-associated focal segmental glomerulosclerosis and relation to the glomerular tip lesion. Kidney Int, 67, 987–1001.Find this resource:

        Korbet S, Schwartz M, Lewis E (1994). Primary focal segmental glomerulosclerosis: clinical course and response to therapy. Am J Kidney Dis, 23, 773–83.Find this resource:

        Niaudet P, for The French Society of Pediatric Nephrology (1992). Comparison of cyclosporine and chlorambucil in the treatment of idiopathic nephrotic syndrome: a multicenter randomized controlled trial. Pediatr Nephrol, 6, 1–3.Find this resource:

        Rich A (1957). A hitherto undescribed vulnerability of the juxta-medullary glomeruli in lipoid nephrosis. Bull Johns Hopkins Hosp, 100, 173–86.Find this resource:

        Ruf RG, et al. (2004). Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome. J Am Soc Nephrol, 15, 722–32.Find this resource:

        Savin V, et al. (1996). Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N Engl J Med, 334, 878–83.Find this resource:

        Stirling CM, et al. (2005). Treatment and outcome of adult patients with primary focal segmental glomerulosclerosis in five UK renal units. QJM, 98, 443–9.Find this resource:

        Troyanov S, et al. (2005). Focal and segmental glomerulosclerosis: definition and relevance of a partial remission. J Am Soc Nephrol, 16, 1061–8.Find this resource: