What is the best course of action for a patient presenting with hilar lymphadenopathy, low Thyroid-Stimulating Hormone (TSH), hypercalcemia, and Acute Kidney Injury (AKI)?

Diagnostic Approach: Sarcoidosis Until Proven Otherwise

This constellation of hilar lymphadenopathy, low TSH, hypercalcemia, and AKI strongly suggests sarcoidosis with multisystem involvement, and you must immediately discontinue all nephrotoxic medications, aggressively hydrate with isotonic crystalloids, and initiate corticosteroid therapy while ruling out malignancy. 1, 2

Immediate Diagnostic Priorities

Rule Out Malignancy First

• Obtain chest CT with contrast to characterize the hilar lymphadenopathy and assess for mediastinal involvement or lung parenchymal disease 1
• Perform diagnostic paracentesis if ascites present to exclude spontaneous bacterial peritonitis, as infection is the most common precipitant of multiorgan failure 3
• Send blood cultures, urine cultures, and obtain chest radiography immediately to screen for infection 3
• Measure serum intact PTH to distinguish PTH-dependent (primary hyperparathyroidism) from PTH-independent causes (malignancy, sarcoidosis) of hypercalcemia—a suppressed PTH (<20 pg/mL) indicates malignancy or granulomatous disease 1

Assess Sarcoidosis Likelihood

• Check serum ACE level and 1,25-dihydroxyvitamin D (not 25-OH vitamin D), as sarcoidosis causes hypercalcemia through excessive intestinal calcium absorption from granulomatous production of 1,25-dihydroxyvitamin D 1, 4
• The low TSH may represent thyroid involvement by sarcoidosis or a separate autoimmune process 5
• Hilar lymphadenopathy with hypercalcemia and suppressed PTH is pathognomonic for either sarcoidosis or lymphoma 6, 5

Immediate Management of AKI and Hypercalcemia

Nephrotoxin Elimination (First Priority)

• Discontinue ALL nephrotoxic medications immediately: NSAIDs, aminoglycosides, ACE inhibitors, ARBs, diuretics, beta-blockers, and any iodinated contrast 7, 2
• Hold thyroid replacement if the patient is on it, as the low TSH suggests hyperthyroidism or overreplacement 1
• Each additional nephrotoxin increases AKI odds by 53% 7

Aggressive Fluid Resuscitation

• Administer isotonic crystalloids (lactated Ringer's preferred over normal saline) to achieve euvolemia and restore urine output to approximately 2 L/day 8, 2
• Target mean arterial pressure ≥65 mmHg to ensure adequate renal perfusion 7
• Avoid overhydration, especially if cardiac dysfunction is present, but vigorous saline hydration is integral to hypercalcemia therapy 8, 1
• Monitor urine output hourly and assess fluid balance meticulously 2

Hypercalcemia-Specific Treatment

For Severe Hypercalcemia (≥14 mg/dL or symptomatic):

• Administer IV zoledronic acid 4 mg as a single dose over no less than 15 minutes after adequate hydration is achieved 8, 1
• Ensure serum creatinine is assessed prior to bisphosphonate administration 8
• If renal function is severely impaired (CrCl <30 mL/min), reduce zoledronic acid dose to 3 mg 8
• Bisphosphonates typically reduce serum calcium within 3-6 days 4

If Sarcoidosis is Confirmed or Highly Suspected:

• Initiate glucocorticoids (prednisone 40-60 mg daily) as primary treatment, as they are highly effective for hypercalcemia due to excessive intestinal calcium absorption from granulomatous disorders 1, 4
• Glucocorticoids work by reducing 1,25-dihydroxyvitamin D production by granulomas 1
• Consider infliximab if hypercalcemia is refractory to steroids, as case reports demonstrate prompt resolution of severe hypercalcemia with progressive renal insufficiency 6

Renal Replacement Therapy Considerations

• Initiate RRT for life-threatening hyperkalemia, severe metabolic acidosis, uremic complications, or refractory fluid overload 2, 7
• Continuous RRT (CRRT) is preferred if the patient is hemodynamically unstable 2
• In patients with kidney failure, denosumab and dialysis may be indicated for hypercalcemia management 1

Monitoring Requirements

Short-Term (First 48-72 Hours)

• Measure serum creatinine, calcium, and electrolytes every 12-24 hours during acute management 7, 2
• Monitor urine output hourly 2
• Assess volume status and vital signs continuously 2
• Recheck serum calcium 3-4 days after bisphosphonate administration 8

Medium-Term Follow-Up

• Evaluate kidney function at 3 months post-AKI to assess for resolution, new onset, or worsening of CKD 9
• Continue monitoring serum creatinine every 2-4 weeks during the first 6 months after discharge 7
• If CKD develops, refer to nephrology 9

Critical Pitfalls to Avoid

• Do NOT use diuretics to treat oliguria or prevent AKI progression—they are ineffective and worsen renal perfusion 2, 7
• Do NOT administer bisphosphonates before adequate hydration—this increases nephrotoxicity risk 8
• Do NOT delay corticosteroid therapy if sarcoidosis is suspected—hypercalcemia from granulomatous disease responds poorly to bisphosphonates alone 1, 4
• Do NOT use dopamine, N-acetylcysteine, or furosemide for AKI treatment—these are proven ineffective 7, 2
• Do NOT overlook infection as a precipitant—bacterial infections commonly trigger multiorgan failure in this presentation 3

Definitive Diagnosis

• Tissue diagnosis via mediastinoscopy or endobronchial ultrasound-guided biopsy of hilar lymph nodes is required to confirm sarcoidosis and exclude lymphoma or metastatic malignancy 6
• Non-caseating granulomas on histology confirm sarcoidosis 6, 5
• If malignancy is identified, the prognosis is significantly worse, as hypercalcemia of malignancy is associated with poor survival 1