Nephrotic syndrome, Focal segmental glomerulosclerosis

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Diagnosis and reasoning

This patient has presented with new-onset bilateral pitting edema of the lower limbs; this is a highly concerning presentation that is worrisome of significant systemic disease. Key etiologies to consider include heart failure, acute or chronic liver disease, acute kidney injury or chronic kidney disease, and rarely, pulmonary hypertension. However, the normal jugular venous pressure (JVP) and cardiorespiratory examinations make heart failure clinically less likely. Neither are there signs or symptoms that would suggest pulmonary hypertension. Furthermore, the edema of liver disease typically first manifests as ascites before the lower limbs are affected. Also, the abdominal examination is unremarkable, while the patient is anicteric, with no stigmata of chronic liver cell disease either. All of these argue against a hepatic cause. The presence of frothy urine is a potent clue. This symptom can occur after the rapid passage of urine (in which case the foam clears up quickly) or due to dehydration. However, in the majority of cases this indicates proteinuria, and thus, underlying kidney disease. The presence of periorbital swelling that is maximal during the morning with slow resolution over the course of the day is also suggestive of a renal etiology; subsequent perusal of his investigation results reveals proteinuria, hypoalbuminemia, and dyslipidemia, showing this to be nephrotic syndrome (NS). In adults, focal segmental glomerulosclerosis (FSGS) is the most common cause of NS. Other key causes include IgA nephropathy, membranous nephropathy, diabetic nephropathy, amyloidosis, and minimal change disease. A renal biopsy is the gold standard diagnostic test; here, this shows findings characteristic of FSGS. Note that an autoimmune screen is still useful to definitively exclude immune-mediated conditions. FSGS can be primary or secondary in origin. The former is a diagnosis of exclusion, while the latter can be divided into familial, virus-associated, drug-induced, and adaptive disease. A viral screen excludes the key causes of virus-associated FSGS. He is not on any medications (e.g. lithium) or using recreational drugs (e.g. heroin) that are known to cause drug-induced FSGS. The common causes of adaptive disease include morbid obesity, sleep apnea, a high protein diet, congenital cyanotic heart disease, sickle cell anemia, and androgen abuse, none of which are present here. Familial secondary FSGS is a possibility, especially given his age. Genetic studies are required to establish this, but are not widely available, unfortunately. Follow-up in this respect is essential. Therefore, he has either primary FSGS or secondary familial FSGS. Regardless, his current management should include diuretic therapy to reduce the edema, thromboprophylaxis, and of course, proper fluid and sodium management and suitable nutrition. Whether to use glucocorticoids is tricky, but given the possibility of primary FSGS, this may be considered. Immunosuppression is not warranted right now.


Discussion

Nephrotic syndrome (NS) is a renal disorder defined by the quartet of proteinuria, hypoalbuminemia, dyslipidemia, and peripheral edema. In children, minimal-change disease (MCD) is the most common cause of NS; however, in adults, focal segmental glomerulosclerosis (FSGS) is the most common cause, accounting for ~40% of cases. Note that the remainder of this monograph focuses on FSGS. Similar to MCD, FSGS is a "podocytopathy" (i.e. characterized by podocyte injury that results in effacement of the foot processes). However, while this process is reversible following glucocorticoid therapy in minimal change disease, it is irreversible and progressive in FSGS. These sclerotic lesions occur focally and affect only specific parts of the glomerulus; hence the name of the disease. There are only minimal immune deposits, if at all. Based on etiology, FSGS can be classified as either primary (i.e. without a discernible underlying cause) or secondary. The latter can be further classified into four subtypes: familial, virus-associated, drug-induced, or adaptive. Adaptive secondary FSGS is the most common subtype; this arises after prolonged nephron-level glomerular hyperfiltration and glomerular hypertension causes progressive podocyte hypertrophy, stress, and depletion. Key causes include morbid obesity, sleep apnea, a high protein diet, congenital cyanotic heart disease, sickle cell anemia, and androgen abuse. Following the onset of disease, patients with FSGS tend to become symptomatic relatively rapidly, over a period of weeks to months. Over half of patients have full-blown nephrotic syndrome at presentation; however, others may only manifest nonspecific proteinuria and/or renal failure. Definitive diagnosis requires renal biopsy; the latter will also help identify which of the five histologic variants (as per the Columbia classification) the disease fits into. Once the diagnosis has been established, further investigations are required to differentiate primary from secondary FSGS. Similar to the other forms of NS, the general management of these patients includes proper fluid and electrolyte management; suitable nutrition; treatment of the edema, dyslipidemia, and hypertension; and prevention of complications such as thromboembolism. Secondary FSGS is managed by treating the underlying cause where possible. Primary FSGS is treated via a combination of glucocorticoids and immunosuppressive therapy; plasmapheresis and immunomodulatory agents are other potential therapies. Individuals who manage to achieve remission have a relatively good prognosis, with a 10-year survival rate of over 90%. On the contrary, patients who do not achieve remission have a much poorer prognosis, with a 10-year survival rate of just 35%.


Take home messages

  1. Focal segmental glomerulosclerosis (FSGS) is the most common cause of nephrotic syndrome (NS) in adults, accounting for ~40% of all cases.
  2. FSGS can be primary (i.e. idiopathic), or secondary to a range of conditions. Secondary FSGS can be further divided into several subtypes, of which "adaptive" secondary FSGS is the most common.
  3. The general management of these patients mirrors the general management of NS.
  4. Secondary FSGS is specifically managed by treating or withdrawing the offensive condition; primary FSGS is managed via glucocorticoids and immunosuppression.

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