Salt-losing nephropathy

Causes

• Advanced CKD, especially chronic tubulointerstitial nephritis/interstitial disease
• Tubulointerstitial disorders, such as:
  • Analgesic nephropathy
  • Reflux nephropathy/chronic pyelonephritis
  • Obstructive uropathy
  • Medullary cystic kidney disease
  • Polycystic kidney disease in some patients
• Proximal renal tubular acidosis (type 2 RTA) or Fanconi syndrome
• Post-obstructive diuresis during recovery from urinary obstruction

• Diuretics, especially thiazides
• Mineralocorticoid deficiency or resistance, such as adrenal insufficiency
• Osmotic diuresis: glycosuria, mannitol, urea diuresis
• Nephrotoxic tubulopathy, for example cisplatin, ifosfamide, aminoglycosides
• Cerebral salt wasting in patients with major intracranial disease

Pathophysiology

1. Loss of functioning nephrons and tubular damage
   • Diseased renal tubules, especially in tubulointerstitial disease, lose their ability to reabsorb sodium chloride and to adapt sodium excretion to low dietary sodium intake.
   • The remaining nephrons may receive a large solute load per nephron, promoting natriuresis.
2. Persistent urinary NaCl loss
   • Sodium and water are lost in urine.
   • Unlike normal hypovolemia, the kidney fails to reduce urinary sodium appropriately. Urinary Na is often >20-30 mmol/L in the absence of diuretics.
3. Extracellular-fluid volume contraction
   • Reduced effective circulating volume causes dehydration and hypotension.
   • Renin, angiotensin II, aldosterone, sympathetic activity, and thirst increase, but the injured tubules cannot adequately conserve salt.
4. Hyponatremia
   • Volume depletion stimulates non-osmotic secretion of vasopressin (ADH).
   • ADH retains water, while sodium continues to be lost, producing or aggravating dilutional hyponatremia.
   • Thus, the patient has a deficit of both sodium and water, but the sodium deficit is proportionately greater. - Comprehensive Clinical Nephrology, 7th Edition, p. 144
5. Associated tubular abnormalities
   • With proximal RTA, bicarbonate loss causes bicarbonaturia, which obligates further urinary sodium loss; potassium wasting may coexist even when GFR is only moderately reduced. - Comprehensive Clinical Nephrology, 7th Edition, p. 145

Clinical features

Symptoms and signs of volume depletion

• Thirst, dry mouth
• Weakness, fatigue, lethargy
• Dizziness, especially postural dizziness
• Orthostatic hypotension, tachycardia
• Reduced skin turgor, dry mucosae
• Weight loss
• Oliguria may occur, though urine volume can be relatively high if concentrating ability is impaired
• Severe cases: syncope, confusion, shock

Features of hyponatremia

• Nausea, headache, malaise
• Drowsiness, irritability, confusion
• Seizures or coma in profound or rapidly developing hyponatremia

Typical biochemical findings

• Low serum sodium and low serum osmolality
• Evidence of hypovolemia: raised urea/creatinine ratio may be present, although interpretation is limited in CKD
• Inappropriately high urinary sodium, commonly >20 mmol/L despite volume depletion
• Urine may not be maximally dilute because ADH is increased
• Potassium may be low if there is tubular potassium wasting, diuretic exposure, or proximal RTA
• Acid-base status depends on cause:
  • Normal-anion-gap metabolic acidosis with proximal RTA/Fanconi syndrome
  • Other patterns may occur with CKD or concurrent disorders

Diagnosis and key differential diagnosis

1. Hypotonic hyponatremia, if hyponatremia is present
2. Clinical evidence of reduced extracellular volume
3. Renal sodium loss that is inappropriate for the degree of volume depletion
4. A compatible renal disorder, particularly advanced tubulointerstitial CKD
5. Exclusion of mimics

Important differentiation from SIADH

• Low serum sodium
• Concentrated urine
• Urine sodium >30 mmol/L

Management

1. Treat urgent symptomatic hyponatremia first

• Check serum sodium frequently.
• Avoid overly rapid correction, since this can cause osmotic demyelination.
• The exact saline regimen and correction target must be individualized by the treating team, particularly in CKD.

2. Restore intravascular volume and sodium

• 0.9% sodium chloride is generally used to correct volume depletion and replace ongoing sodium losses.
• Once circulation is restored, non-osmotic ADH secretion falls and water excretion improves.
• In stable patients, use oral salt supplementation and adequate oral fluid intake where feasible.

3. Replace other losses

• Correct potassium depletion, usually with potassium chloride when appropriate.
• Correct magnesium and phosphate if tubular dysfunction causes losses.
• In proximal RTA, alkali therapy is often required, but sodium bicarbonate can increase urinary potassium losses, so potassium must be monitored and replaced.

4. Identify and remove the cause

• Stop or reduce causative diuretics if possible.
• Stop nephrotoxins and review medications.
• Treat obstruction promptly.
• Investigate and treat active interstitial nephritis or systemic disease when applicable.
• Assess for adrenal insufficiency if hyperkalemia, hypotension, or suggestive clinical features are present.

5. Long-term CKD care

• Individualize dietary sodium: patients with true salt-wasting CKD may need a liberalized sodium intake, unlike many other CKD patients.
• Monitor body weight, postural blood pressure, urine output, serum sodium, potassium, bicarbonate, creatinine/eGFR, and magnesium.
• Avoid indiscriminate sodium restriction and excessive diuresis.
• Refer to nephrology. Progressive advanced CKD may ultimately require renal replacement therapy.

Exam-style summary