Renal tubular disorders

Renal tubular disorders are a heterogeneous group of diseases that involve dysfunctions of transporters and channels in the renal tubular system. These dysfunctions may cause fluid loss and abnormalities in electrolyte and acid-base homeostasis. The disorders are either primary (genetic) or acquired (e.g., drug adverse effects, renal disease). In renal tubular acidosis (RTA), there is normal anion gap (hyperchloremic) metabolic acidosis in a patient with normal or almost normal renal function. Types of RTA include distal tubular acid secretion (type 1), proximal tubular bicarbonate wasting (type 2), very rarely carbonic anhydrase deficiency (type III), and aldosterone deficiency/resistance (type 4). Type 2 can be further classified into isolated proximal tubular bicarbonate wasting and generalized proximal tubular wasting, known as Fanconi syndrome. X-linked hypophosphatemic rickets, the most common form of hereditary hypophosphatemic rickets, is caused by phosphate wasting and manifests with hypophosphatemia and symptoms of rickets. Bartter syndrome, Liddle syndrome, syndrome of apparent mineralocorticoid excess, and Gitelman syndrome are inherited disorders of tubular function characterized by hypokalemia and metabolic alkalosis. Because renal tubular disorders manifest in heterogeneous ways, diagnosis is often challenging; it is based on a combination of clinical features (e.g., rickets, impaired growth, symptoms of electrolyte deficiencies), laboratory analysis of blood and urine, and the results of investigations aimed at determining an underlying cause. The diagnosis of hereditary conditions is usually confirmed with genetic testing. Treatment of type 1 and type 2 RTA involves alkali therapy, while the treatment of type 4 RTA consists of furosemide therapy. X-linked hypophosphatemic rickets requires the supplementation of phosphate and vitamin D, while the mainstay of therapy for Bartter syndrome, Liddle syndrome, syndrome of apparent mineralocorticoid excess, and Gitelman syndrome involves lifelong oral potassium substitution with potassium-sparing diuretics.

• In RTA, there is a normal anion gap metabolic acidosis in patients with normal or almost normal renal function.
• Renal tubular acidosis is caused by defects in the tubular transport of HCO₃^- and/or H⁺.
• Most forms of RTA are asymptomatic; rarely, life-threatening electrolyte imbalances may occur.

Patients with uremic acidosis (metabolic acidosis due to renal failure) have a decreased glomerular filtration rate (increased serum creatinine) and increased anion gap metabolic acidosis. Patients with renal tubular acidosis have relatively normal glomerular filtration rates and normal anion gap metabolic acidosis!

Type 1 RTA: Acid secretion impairment at distal tubule, treatment with Alkali
Type 2 RTA: Bicarbonate wasting at proximal tubule, treatment with Base (alkali)
Type 3 RTA: Carbonic anhydrase deficiency, treatment with Citrate (sodium/potassium)
Type 4 RTA: AlDosterone disorDer, treatment with 4rosemide

Pathophysiology

The α-intercalated cells of the distal tubule are unable to secrete H⁺ (apical) → ↓ intracellular production of HCO₃^-; → ↓ HCO₃^-/Cl^- exchanger activity (basolateral) → decreased concentration of HCO₃^- in the blood → metabolic acidosis

Etiology

• Sporadic type 1 RTA (idiopathic)
• Familial type 1 RTA (inherited genetic defects)
• Autoimmune diseases
  • Systemic lupus erythematosus
  • Sjogren syndrome
  • Rheumatoid arthritis
  • Primary biliary cirrhosis
  • Autoimmune hepatitis
  • Hashimoto thyroiditis
• Nephrocalcinosis (e.g., hyperparathyroidism, vitamin D toxicity, sarcoidosis)
• Medullary sponge kidney
• Chronic obstructive uropathy (e.g., congenital anomalies)
• Sickle cell nephropathy
• Wilson disease
• Drugs: ifosfamide, amphotericin B; , lithium, NSAIDs (analgesic nephropathy)

Clinical features

• Nephrocalcinosis: calcium phosphate stones; (due to an increase in urine pH )
• Polyuria → polydipsia, dehydration
• Bone demineralization; usually without overt rickets or osteomalacia (due to increased bone turnover)
• Impaired growth
• In some cases, features of hypokalemia (e.g., muscle weakness, hyporeflexia, paralysis, U waves and flattened T waves on ECG)

Diagnostics

• Serum
  • Hyperchloremic metabolic acidosis (normal anion gap)
  • Hypokalemia that improves with alkaline therapy
• Urine
  • Urine pH ≥ 5.5
  • Acid load test (ammonium chloride acidification test): Following oral administration of ammonium chloride, the urine does not acidify (pH remains > 5.3).
  • Positive urine anion gap
  • Hypercalciuria
  • Decreased NH₄⁺ excretion
  • Decreased citrate excretion

Treatment

Alkalinization therapy with orally administered sodium bicarbonate or sodium citrate (Shohl solution)

Renal tubular acidosis type 1 causes kidney stONEs.

References:^[1][4]

Type 2 renal tubular acidosis is characterized by a dysfunctional proximal convoluted tubule (PCT) that is unable to reabsorb HCO3-. The defect can either be isolated, affecting only the reabsorption of HCO3- or, more commonly, the PCT has a generalized dysfunction of the PCT, in which case the condition is referred to as Fanconi syndrome.

Clinical features

• Vitamin D-resistant hypophosphatemic rickets/osteomalacia (caused by phosphaturia and hypophosphatemia; individuals with Fanconi syndrome typically have more severe symptoms)
• Short stature
• Polyuria → polydipsia, dehydration
• In some cases, features of hypokalemia (e.g., muscle weakness, hyporeflexia, paralysis, U waves and flattened T waves on ECG)

Diagnostics

• Serum
  • Hyperchloremic metabolic acidosis (i.e., normal anion gap) ^[5]
  • Hypokalemia that worsens with alkali therapy
  • Fanconi syndrome
    • Hypouricemia
    • Hypophosphatemia
• Urine
  • Urine pH
    • If serum HCO₃^- is higher than its reabsorption threshold: pH ≥ 5.5
    • If serum HCO₃^- is depleted: pH < 5.5
  • Bicarbonate infusion test: Urine pH rises to a level higher than 7.5 and the fractional excretion of bicarbonate is > 15% following administration of IV sodium bicarbonate .
  • Negative urine anion gap
  • Fanconi syndrome
    • Aminoaciduria
    • Glucosuria despite normal or low serum glucose
    • Phosphaturia

Treatment

• Alkali therapy with orally administered potassium citrate
• Thiazide diuretics if alkali therapy is not tolerated or effective

Renal tubular acidocis type 2 has two variants (isolated proximal RTA and Fanconi syndrome).

A combination of type 1 and type 2 RTA.

Etiology

• Carbonic anhydrase II deficiency (autosomal recessive disease)

Pathophysiology

• Impaired H⁺ secretion by the distal convoluted tubule and HCO₃^- wasting by the proximal convoluted tubule

Clinical features

• Guibaud-Vainsel syndrome
  • Osteopetrosis
  • Cerebral calcification
  • Intellectual disability

Diagnostics

• Serum
  • Hyperchloremic (normal anion gap) metabolic acidosis
  • Hypokalemia
  • Hypocalcemia
• Urine
  • Urine pH ≥ 5.5
  • Positive urine anion gap
  • Hypercalciuria
  • Decreased NH₄⁺ excretion
  • Decreased citrate excretion

Treatment

• Alkali therapy with orally administered sodium citrate (Shohl solution) or potassium citrate

Etiology

• Hypoaldosteronism
  • Primary adrenal insufficiency (Addison disease)
  • Hyporeninemic hypoaldosteronism
    • Acute glomerulonephritis
    • Diabetic nephropathy (diabetic hyporeninism)
    • SLE
    • AIDS nephropathy
    • Drugs: NSAIDs, cyclosporin
  • Drugs: ARBs, ACE inhibitors, heparin ^[6]
  • Pseudohypoaldosteronism type 2 (Gordon syndrome)
    • An autosomal dominant condition characterized by increased sodium reabsorption and decreased potassium secretion due to dysfunction of ion channels in the kidney.
    • Manifestations include hypertension, hyperkalemia, hyperchloremia, and metabolic acidosis.
• Aldosterone resistance
  • Chronic obstructive nephropathy or interstitial nephropathy
  • Drugs: Potassium-sparing diuretics (e.g., spironolactone, amiloride, eplerenone, triamterene), trimethoprim-sulfamethoxazole, pentamidine
  • Pseudohypoaldosteronism type 1: A form of aldosterone resistance that is a caused by an autosomal dominant loss-of-function mutation in the gene encoding for mineralocorticoid receptor protein or autosomal recessive loss-of-function mutations in the genes encoding the epithelial sodium channel.

Pathophysiology

Aldosterone deficiency and/or resistance in the collecting duct and distal convoluted tubules; → hyperkalemia; and metabolic acidosis → inhibition of ammonia (NH₃) synthesis in the proximal convoluted tubules; → decreased urinary ammonium (NH₄⁺) excretion

Clinical features

• Renal insufficiency: polyuria → polydipsia, dehydration
• Impaired growth in children
• Features of hyperkalemia (e.g., muscle weakness, prolonged PR interval and peaked T waves on ECG)

Diagnostics

• Serum
  • Hyperchloremic metabolic acidosis; (i.e., normal anion gap)
  • Hyperkalemia
• Urine
  • Urine pH < 5.5
  • Positive urine anion gap (persistent sodium excretion)
  • Decreased NH₄⁺ excretion
  • Normal or decreased calcium excretion

Treatment

• Furosemide
• Mineralocorticoid replacement (fludrocortisone)
• Low-potassium diet

Renal tubular acidosis type 4 leads to decreased NH₄⁺ excretion.

Etiology

X-linked dominant disease caused by a mutation in the PHEX gene

Pathophysiology

Mutation in the PHEX gene → increased levels of fibroblast growth factor 23 (FGF23) → indirect inhibition of the sodium-phosphate cotransporter in the proximal renal tubule → impaired reabsorption of phosphate → chronic hypophosphatemia → vitamin D-resistant rickets/osteomalacia

Epidemiology

• X-linked hypophosphatemic rickets accounts for ∼ 80% of all familial causes of hypophosphatemia.
• Age of symptom onset: typically < 3 years

Clinical features

• Features of rickets (e.g., short stature, bowing of legs)
• Dental abscesses
• Calcification of soft tissues (tendons, ligaments, and joint capsules)
• Deafness
• Arnold-Chiari malformation

Diagnostics

• Laboratory tests
  • Pronounced hypophosphatemia
  • Increased alkaline phosphatase
  • Decreased or normal 1,25-dihydroxyvitamin D
  • Normal serum calcium, parathyroid hormone/parathyroid hormone-related peptide, and 25-dihydroxyvitamin D
• X-ray of the wrists, knees, ankles, and long bones, such as the femur (See “Diagnostics” in osteomalacia and rickets.)

Treatment

• Burosumab
  • Drug of choice for children aged ≥ 1 year
  • A monoclonal antibody that targets FGF23
• Phosphate substitution
• Calcitriol (1,25-dihydroxyvitamin D) substitution
• Complications of treatment: hyperparathyroidism, nephrocalcinosis
  • Amiloride and hydrochlorothiazide are used to increase calcium reabsorption and thereby lower the risk of nephrocalcinosis.

References:^[7][8]

Definition

A group of rare genetic disorders (autosomal recessive); that affect chloride reabsorption in the thick ascending limb of the loop of Henle

Epidemiology

• Prevalence: 1/1,000,000

Pathophysiology

Defective Na⁺-K⁺-2Cl^- cotransporter in the thick ascending loop of Henle results in:

• Loss of Cl^-, Na⁺, and K⁺ in urine (as seen in chronic loop diuretic use)
• Failure to reabsorb Na⁺ leading to natriuresis (salt and water loss) and volume depletion, which activates the renin-angiotensin-aldosterone system (RAAS), leading to
  • Renal vasoconstriction; however, a rise in prostaglandin E levels to counter renal vasoconstriction results in growth inhibition
  • Elevated aldosterone levels, leading to increased K⁺ and H⁺ excretion and subsequent hypokalemia and metabolic alkalosis
• Decreased paracellular reabsorption of calcium; → hypercalciuria → hypocalcemia, nephrocalcinosis, and renal stones

Clinical features

• Antenatal symptoms: polyhydramnios, preterm delivery
• Severe polyuria; and polydipsia; → life-threatening volume depletion and hypotension
• Muscle atrophy, weakness, cramps, carpopedal spasm
• Failure to thrive, developmental delay
• Dysmorphic facies , strabismus, sensorineural deafness
• Symptoms of renal colic may occur as a result of calcium stones.

Diagnostics

• Laboratory diagnostics
  • Metabolic alkalosis
  • Hypokalemia
  • Hypercalciuria
  • Hyperuricemia (∼ 50% of cases)
  • Response to thiazide and loop diuretics
    • Normal response to thiazide diuretics
    • Blunted response to loop diuretics
• Confirmatory test: genetic testing

Treatment

• Mainstay of therapy: : lifelong oral potassium substitution with potassium-sparing diuretics (spironolactone, amiloride)

The Na-K-2Cl cotransporter that is defective in Bartter syndrome is a target for loop diuretics!

References:^[9][10]

Epidemiology

• Prevalence: 1/40,000
• Age of symptom onset: ≥ 6 years; diagnosis is usually made in adolescence or adulthood

Etiology

Autosomal recessive; defect in the SLC12A3 gene on chromosome 16p → impaired function of the thiazide-sensitive sodium-chloride cotransporter in the distal convoluted tubule → impaired Na⁺ and Cl^- reabsorption → mild natriuresis → mild volume depletion → mild RAAS activation

Clinical features

• Clinical features are similar to those of chronic thiazide diuretic use:
  • Fatigue, muscle weakness
  • Muscle cramps and/or tetany
  • Mild polyuria
  • Chondrocalcinosis
  • In some cases, mild hypotension

Diagnostics

• Metabolic alkalosis
• Severe hypokalemia
• Hypercalcemia and hypocalciuria
• Hypomagnesemia
• Response to thiazide and loop diuretics
  • Normal response to loop diuretics
  • Blunted response to thiazide diuretics
• Confirmatory test: genetic testing

Treatment

• Mainstay of therapy: : lifelong oral potassium substitution with potassium-sparing diuretics (spironolactone, amiloride)

The effects of Gitelman syndrome are similar to those of a thiazide diuretic!

References:^[10]

Epidemiology

• Extremely rare
• Age of symptom onset: childhood

Etiology

Autosomal dominant gain-of-function mutation; in the SCNN1B and SCNN1G genes on chromosome 16p → structural alteration in the β and γ subunits of the epithelial sodium channel (ENaC) in the collecting duct

Pathophysiology

Structural alteration in the ENaC subunits → inability of these subunits to bind with an intracellular ubiquitin-protein ligase (Nedd4) → decreased degradation of ENaC channels by ubiquitin proteasomes; → increased number of ENaCs in the collecting duct → increased reuptake of water and sodium (pseudohyperaldosteronism) → hypertension with low renin production and hypokalemia

Clinical features

• Hypertension

Diagnostics

• Hypokalemia
• Metabolic alkalosis
• Decreased renin and aldosterone levels
• Confirmatory test: genetic testing

Treatment

Lifelong oral potassium substitution with potassium-sparing diuretics that directly block ENaCs in the collecting duct (e.g., amiloride, triamterene)

The clinical features of Liddle syndrome are similar to those of hyperaldosteronism, except that Liddle syndrome manifests with decreased renin and aldosterone levels!

Epidemiology (hereditary disorder) ^[11]

• Extremely rare
• Age of symptom onset: infancy

Etiology

• Autosomal recessive; , loss-of-function mutations in the 11-beta-hydroxysteroid dehydrogenase type 2 (11-beta-HSD2) gene on chromosome 16q → ↓ 11-beta-HSD2 enzyme.
• Acquired disorder from chronic exposure to glycyrrhetinic acid (e.g., from excessive consumption of black licorice), which inhibits the activity of the 11-beta-HSD2 enzyme.

Pathophysiology

• With normal 11-beta-HSD2 activity: 11-beta-HSD2 converts cortisol into cortisone (cortisone, unlike cortisol, does not activate mineralocorticoid receptors).
• With 11-beta-HSD2 deficiency (or inhibition): ↓ cortisol conversion to cortisone → ↑ cortisol → ↑ mineralocorticoid receptor activity.

Clinical features

• Hypertension
• Low birth weight
• Failure to thrive
• Muscle weakness
• Polyuria and polydipsia due to nephrogenic diabetes insipidus
• Renal failure

Diagnostics

• Best initial test: high ratio of urinary free cortisol to cortisone in a 24-hour urine collection
• Confirmatory test: genetic testing
• Additional findings
  • Hypokalemia
  • Metabolic alkalosis
  • Decreased renin and aldosterone levels
  • Decreased urinary free cortisone excretion
  • Hypercalciuria

Treatment

• Cessation of licorice ingestion
• Lifelong oral potassium substitution with potassium-sparing diuretics (e.g., amiloride or eplerenone) to decrease the mineralocorticoid effects
• Thiazide in hypercalciuria or nephrocalcinosis
• Corticosteroids; : Exogenous corticosteroid decreases endogenous cortisol production and subsequently reduces mineralocorticoid receptor activation.

Spironolactone (an aldosterone receptor antagonist) is effective in treating the syndrome of apparent mineralocorticoid excess but not Liddle syndrome!

In Syndrome of Apparent Mineralocorticoid Excess, cortisol has the SAME action as aldosterone.