What is the probable cause of nephrotic syndrome in an adult patient with subclinical hypothyroidism, recently diagnosed hypertension, and no diabetes?

Probable Cause of Nephrotic Syndrome in This Patient

In an adult patient with subclinical hypothyroidism, newly diagnosed hypertension, and no diabetes, the most probable causes of nephrotic syndrome are focal segmental glomerulosclerosis (FSGS) or membranous nephropathy, with hypertension-related secondary FSGS being particularly likely given the recent hypertension diagnosis. 1, 2

Primary Diagnostic Considerations

Most Common Adult Causes

• Focal segmental glomerulosclerosis (FSGS) and membranous nephropathy are the two most common primary causes of nephrotic syndrome in adults, accounting for the majority of idiopathic cases 3, 4, 5
• In white adults specifically, membranous nephropathy is the most frequent cause, while FSGS predominates in populations of African ancestry 5
• FSGS accounts for 7-20% of nephrotic syndrome cases in children but represents a significantly higher percentage in adults 2

Secondary FSGS from Hypertension

• The recently diagnosed hypertension in this patient raises strong suspicion for secondary FSGS due to hypertensive nephrosclerosis 1
• Chronic hypertension with gradual proteinuria development may indicate hypertensive nephrosclerosis or secondary FSGS, emphasizing the critical importance of blood pressure control in preventing kidney damage 1
• Secondary FSGS can result from decreased glomerular mass due to various systemic conditions, including longstanding hypertension 6

Role of Subclinical Hypothyroidism

Rare but Documented Association

• While uncommon, autoimmune thyroid disease (Hashimoto's disease) has been documented to complicate minimal change disease (MCD) with nephrotic syndrome 7
• The coexistence of severe hypothyroidism and nephrotic syndrome has been reported, though this represents a rare clinical scenario 7
• Actual hypothyroidism complications in nephrotic syndrome are uncommon, though pseudohypothyroidism is well-known in nephrotic pathophysiology 7

Clinical Caveat

• In most nephrotic syndrome cases, acute renal failure coexists with hypertension rather than hypotension 7
• The presence of subclinical (rather than overt) hypothyroidism in this patient makes it less likely to be the primary driver of nephrotic syndrome 7

Critical Distinction: Primary vs Secondary Causes

Why This Matters for Treatment

• Failing to distinguish primary from secondary causes has critical treatment implications, since immunosuppression should NOT be used in secondary FSGS 2
• Secondary causes should be carefully considered because the risks of immunosuppression are more likely to outweigh any potential benefit in these cases 6
• The guideline recommends immunosuppressive therapy only in cases of primary nephrotic syndrome 6

Clues Favoring Secondary FSGS

• History of hypertension (even if recently diagnosed, may have been present subclinically) 1
• Absence of sudden onset nephrotic syndrome (primary FSGS typically presents with sudden onset) 2
• Gradual development of proteinuria alongside hypertension 1

Diagnostic Algorithm

Essential Initial Workup

• Kidney biopsy is mandatory in adults with nephrotic syndrome to determine the underlying cause, except when serum anti-phospholipase A2 receptor antibodies are positive (diagnostic of membranous nephropathy) 1
• Quantify proteinuria using 24-hour urine collection or spot urine albumin-to-creatinine ratio (uACR ≥300 mg/g indicates severely increased albuminuria) 1
• Measure serum albumin to confirm hypoalbuminemia <3.0 g/dL 1
• Urinalysis with microscopy to look for fatty casts/oval fat bodies (nephrotic pattern) 1

Rule Out Other Secondary Causes

• Diabetes mellitus is the most common secondary cause of nephrotic syndrome in adults (already excluded in this patient) 4, 8
• Screen for systemic lupus erythematosus with ANA and complement levels 3, 5
• Review medications for potential drug-induced glomerular injury (NSAIDs, certain cancer therapies) 2, 9
• Consider malignancy screening given the association between solid tumors and paraneoplastic glomerular disease 9

Specific Tests for This Patient

• Evaluate duration and severity of hypertension through review of any prior blood pressure measurements 1
• Assess thyroid function comprehensively (TSH, free T4, thyroid antibodies) to characterize the hypothyroidism 7
• Consider renal artery stenosis evaluation if hypertension is severe or refractory, as this accounts for 24% of resistant hypertension in older patients 6

Prognostic Considerations

Risk Stratification

• Patients with proteinuria >3.8 g/day have a 35% risk of end-stage renal disease within 2 years if left untreated, regardless of underlying histology 2, 9
• Patients with persistent nephrotic syndrome have more than 50% risk of progressing to end-stage renal disease within 5-10 years if untreated 2
• Remission of proteinuria is the most significant predictor of renal survival in FSGS 2

Complications to Monitor

• Thromboembolism risk is significantly elevated, particularly when serum albumin <2.9 g/dL, with consideration of prophylactic anticoagulation in high-risk patients, especially those with membranous nephropathy 1
• Venous thromboembolism occurs in 29% for renal vein thrombosis and 17-28% for pulmonary embolism due to loss of anticoagulant proteins 2
• Increased infection susceptibility due to loss of immunoglobulins and complement factors 2

Common Pitfalls to Avoid

• Do not dismiss the possibility of nephrotic syndrome based solely on normal serum albumin, as early or partial nephrotic syndrome may present atypically 1
• Do not delay kidney biopsy—it should be performed within the first month after onset, preferably before starting immunosuppressive treatment 1
• Do not assume primary FSGS without carefully excluding secondary causes, as this would lead to inappropriate immunosuppression 2
• Do not overlook the need for cardiovascular risk reduction (RAS blockade and statin therapy) in patients with secondary FSGS 6