Focal segmental glomerulosclerosis: Treatment beyond corticosteroids
Ms Erin Howells
This case report describes a fourteen year-old male who presented with a relapse of steroid-dependent focal segmental glomerulosclerosis (FSGS). FSGS is responsible for 10-15% of cases of idiopathic nephrotic syndrome (INS) in children, with the majority of cases attributed to minimal change disease. Prednisolone is first line for the induction of remission, with the majority of INS cases responding to initial therapy. Those who fail to achieve remission within four weeks of corticosteroid therapy are labeled “steroid-resistant”. Of those who do remit with corticosteroids, 80% have a relapse, with 50% of these patients having “frequently relapsing disease”. Those patients who relapse while on corticosteroids, or within two weeks of cessation of corticosteroids, are labeled “steroid-dependent”. The aim of this article is to review the literature available on the management of FSGS, particularly steroid-resistant, steroid-dependent, and frequently relapsing disease.
ML, a fourteen year-old male, presented to a rural paediatric department with a one-month history of increasing oedema of his face, sacrum, and lower limbs; lethargy; and oliguria on a background of known steroid-dependent focal segmental glomerulosclerosis (FSGS).
ML first presented with nephrotic syndrome in late 2014, which was initially responsive to corticosteroids, but relapsed following steroid cessation. A renal biopsy was performed in early 2015 and ML was diagnosed with FSGS. At this time, he was started on cyclosporin 125 mg OD and was managed by a general paediatrician and nephrologist.
Approximately one month prior to his admission, ML commenced 50 mg doxycycline at night for acne and the cyclosporin was consequently reduced to 100 mg daily due to concerns that doxycycline may increase the cyclosporin concentration. Soon after, his symptoms of nephrotic syndrome began to return and the cyclosporin was increased to 110 mg daily. ML had also started ramipril 1.25 mg at night prior to his admission.
ML had a history of partial seizures, diagnosed in 2008, which were well controlled by valproate 400 mg twice daily. Developmental history was unremarkable. He had no known allergies and had received his routine childhood vaccinations. Due to the immunosuppressive nature of relapsing nephrotic syndrome, he also received the pneumococcal vaccine and an annual influenza vaccine. There was a family history of epilepsy in his grandmother, but no family history of renal disease. ML was an only child, a non-smoker, and a non-drinker, who lived with his mother in a major regional centre.
On examination, ML was pale and lethargic, with marked periorbital oedema. His vital signs were within normal limits. He had cold peripheries, indicating intravascular depletion but central capillary refill was normal. His jugular venous pressure (JVP) was not elevated, but he had pitting oedema extending to the upper legs, as well as sacral, periorbital, and scalp oedema. His abdomen was distended and ascites was demonstrated by shifting dullness. The abdomen was otherwise non-tender and bowel sounds were present. Heart sounds were dual with no murmurs. His chest was clear with resonant percussion, excluding pulmonary oedema.
Investigations included urine dipstick; urine microscopy, culture, and sensitivity (MCS); spot protein-creatinine ratio; full blood examination (FBE); urea, electrolytes, and creatinine (UEC); liver function tests (LFTs); and a cyclosporin level. Urinary investigations revealed heavy proteinuria, but no haematuria, and all other investigations were unremarkable.
ML was admitted for management of his acute relapse, which included fluid and salt restriction, daily weighs, and daily urine dipstick. The ramipril was ceased. He was administered 75 mg of intravenous 20% albumin over six hours, with 40 mg of intravenous frusemide given at mid-infusion and post-infusion.
ML lost four kilograms overnight and was discharged on a five-day course of oral frusemide, with a 40 mg dose on the first day, then 20 mg for four days.
FSGS is a histopathological pattern of glomerular injury seen under light microscopy, in which sclerosis occurs in segments of only some of the glomeruli . This pattern of injury can occur in all age groups and is the most common cause of adult nephrotic syndrome . FSGS is also identified in 10-15% of cases of idiopathic nephrotic syndrome in children, with the majority of cases attributed to minimal change disease .
In most cases of FSGS, the underlying cause is unknown – termed “primary FSGS” . However, secondary FSGS may develop as a response to previous renal injury. Underlying causes of secondary FSGS include reflux nephropathy, infections (for example, HIV), obesity, medications (for example, interferon), genetic mutations, surgical resection of renal tumours, congenital renal dysplasia, and intrauterine growth restriction .
Primary FSGS presents with a typical nephrotic syndrome, including foamy urine and extensive oedema , particularly periorbital oedema. Nephrotic syndrome is confirmed with a spot urine protein creatinine ratio >0.2 g/mmol . Secondary FSGS is more variable in its presentation, with proteinuria often below nephrotic levels and patients being less likely to present with overt oedema .
In children who present with overt nephrotic syndrome, a renal biopsy is not appropriate, because the majority of these cases will be due to minimal change disease. Only when they are unresponsive to corticosteroids, or develop a frequently relapsing or steroid-dependent pattern of disease, is a renal biopsy justified . For indistinct presentations (for example, proteinuria below nephrotic levels), a renal biopsy may be considered on the initial presentation . The risks and benefits of the renal biopsy must be evaluated, with post-biopsy bleeding being a major risk to consider .
The following discussion will focus on the treatment of primary FSGS. Secondary FSGS is best treated with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers to lower the intraglomerular pressure and treatment of the underlying cause, when possible .
Immunosuppressive treatment: corticosteroid
Corticosteroids are first-line in treatment of idiopathic nephrotic syndrome (INS) for the induction of remission. Between 80-90% of cases of INS are responsive to initial corticosteroid therapy . Those patients who fail to achieve remission within four weeks of corticosteroid therapy are labeled “steroid-resistant”. Of those patients who respond initially, there is an 80% chance of relapse, with 50% of those having frequently relapsing disease, defined as two or more relapses in the first six months or four or more relapses in any twelve-month period [3,8]. Those who relapse while on corticosteroids or within two weeks of cessation of corticosteroids are labeled “steroid-dependent” .
Immunosuppressive treatment: non-corticosteroid
In steroid-resistant, steroid-dependent, and frequently relapsing disease, non-corticosteroid immunosuppressive agents are utilised. The available evidence for each of the commonly used non-corticosteroid immunosuppressive agents will be explored to determine if cyclosporin is the best treatment to prevent relapse in a patient like ML, who has steroid-dependent FSGS.
Calcineurin inhibitors, with or without low dose prednisolone, are first line . The majority of evidence is with cyclosporin. Cochrane Reviews have demonstrated that cyclosporin increases the rate of remission in children with steroid-resistant disease  and reduces relapses in steroid-dependent disease, compared with prednisolone alone . Cyclosporin was superior to intravenous cyclophosphamide in steroid-resistant disease . However, in steroid-dependent disease, relapse was reduced with an eight-week course of alkylating agents, cyclophosphamide, or chlorambucil, while cyclosporin required a prolonged course and its effects were not always sustained following treatment cessation . Therefore, cyclophosphamide plays no role in steroid-resistant disease, but may be used in the treatment of steroid-dependent FSGS when cyclosporin has failed or in patients with higher risk of calcineurin nephrotoxicity due to extensive interstitial fibrosis or vascular disease .
Mycophenolate motefil may be useful as an alternative medication for relapsing disease, however, the evidence is limited to a few smaller trials . It may be used in combination with corticosteroids when calcineurin inhibitors have been unsuccessful or are contraindicated. Rituximab is another alternative, which has had some success in steroid-dependent disease, but the evidence does not support its use in steroid-resistant disease [8,10,11]. Subcutaneous natural adrenocorticotropic hormone (ACTH) therapy has also had some success in pilot studies, however, the treatment is expensive and further randomised trials are required to confirm the results [12,13].
The evidence clearly supports the use of ACE inhibitors or angiotensin receptor blockers in children with steroid-resistant nephrotic syndrome and secondary FSGS . The use of these agents in steroid-dependent or frequently relapsing disease has not been specifically studied. However, guidelines on the use of anti-hypertensive agents in children with chronic kidney disease from any cause suggest that children should be started on an ACE inhibitor or angiotensin receptor blocker when their blood pressure is consistently above the 90th percentile for their age, sex, and height . Treatment should aim to reduce blood pressure to at or below the 50th percentile, unless limited by symptomatic hypotension . Blood pressure-lowering drugs should be used when indicated, irrespective of the level of proteinuria . In primary FSGS, blood pressure-lowering therapy may slow progression to end-stage renal disease, however, it rarely results in remission without concurrent immunosuppressive treatment .
Hyperlipidaemia is a common complication of nephrotic syndrome. Combined with the higher cardiovascular risk of patients with chronic kidney disease, this calls for lipid-lowering therapy with a statin [1,16]. While lipid-lowering agents have been successful in lowering lipids in adults with nephrotic syndrome, no studies have looked at the mortality and morbidity benefits of a statin . The use of statins in children with nephrotic syndrome is controversial, with small studies showing that statins reduce lipid levels and are well tolerated, however, there is a lack of evidence regarding long-term safety of statins in paediatric patients .
Over ten years, 60% of cases of FSGS progress to end-stage renal failure . These patients will need dialysis or renal transplantation. However, there is a high rate of graft failure, with recurrence of FSGS in 30% of allografts [19,20]. The graft survival is lower in children than in adults .
Therapeutic plasmapheresis, used for a number of antibody-mediated conditions, is a process that removes the antibody-containing plasma from the patient’s blood and replaces it with unaffected plasma or a plasma substitute . Therapeutic plasmapheresis may be used in FSGS prophylactically before transplantation or in the treatment of established recurrence in an allograft . Studies show that 49-70% of children with recurrent FSGS who receive plasmapheresis enter complete or partial remission of proteinuria . A small study demonstrated that early and intensive daily plasmapheresis in patients with recurrence was beneficial in obtaining complete remission .
Future novel therapies
Adalimumab and galactose versus conservative therapy with lisinopril, losartan, and atorvastatin is currently being studied in the “Novel therapies for resistant focal segmental glomerulosclerosis (FONT)” trial.  If successful, these treatments may form part of the treatment of FSGS in those patients who have failed other immunosuppressive therapies.
This case report describes a patient with steroid-dependent nephrotic syndrome, diagnosed on renal biopsy as FSGS. The patient was commenced on cyclosporin, which is first-line in steroid-dependent disease. Alternative immunosuppressive agents, rituximab and mycophenolate motefil, require larger-scale trials to confirm their efficacy. Current guidelines suggest that patients’ ramipril should be restarted if their blood pressure is above the 90th percentile for their age, sex and height. However, further research is needed to create specific guidelines for the use of anti-hypertensive agents in children with steroid-dependent nephrotic syndrome. The evidence for the safety of statins in children is insufficient, therefore these drugs should be avoided.
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