Tubulopathies

Renal tubulopathies comprise a spectrum of disorders that affect one or multiple tubular segments of the nephrons that involve cellular functions for electrolyte balance, acid-base homeostasis, free water handling, and reabsorption of substances from the glomerular filtrate.

Symptoms/Red Flags

Tubular disorders should be suspected in the presence of one or more of the following factors:

prenatal history of polyhydramnios (e.g., antenatal Bartter syndrome)
failure to thrive (e.g., cystinosis)
muscle weakness or paresthesias
primary polyuria, increased thirst, or salt craving
recurrent kidney stones or nephrocalcinosis (e.g., cystinuria, hyperoxaluria)
frequent hospitalizations for dehydration (e.g., nephrogenic diabetes insipidus)
unexplained electrolyte derangements with non-anion-gap metabolic acidosis or metabolic alkalosis (e.g., renal tubular acidosis)
strong family history of congenital deafness or hearing loss (can be associated with distal renal tubular acidosis)

Causes of Renal Tubulopathies

Type	Key Clinical Features	Etiology
Proximal Tubule
Cystinosis	Fanconi syndrome* Failure to thrive Photophobia with positive exam for corneal cystine crystals	CTNS gene mutation results in lysosomal accumulation of cystine
Iatrogenic (e.g., chemotherapeutic agents such as ifosfamide or carbonic anhydrase inhibitor)	Fanconi syndrome marked with glycosuria	Toxicity of proximal tubular function
Lowe syndrome	Glaucoma/cataracts Developmental delay Fanconi syndrome with possible rickets	OCRL1 mutations
Dent disease	Tubular proteinuria Hypercalciuria Kidney stones	OCRL1/CLCN5 mutations
Metabolic disorders		Wilson disease Glycogen storage disease type 1 Galactosemia Hereditary fructose intolerance
Loop of Henle (LOH)/ Distal convoluted tubule (DCT)
Bartter syndrome	Metabolic alkalosis Hypokalemia Low/normal magnesium Hypercalciuria	Classic form mimics loop diuretic: 5 types (mutations resulting in aberrant transporter proteins: NKCC, ROMK, barttin, ClC-Kb, ClC-Ka)
Gitelman syndrome	Metabolic alkalosis Hypokalemia Low magnesium Hypocalciuria	Mimics thiazide diuretic effect (mutant SLC12A3)
Distal/Collecting Duct
Diabetes insipidus	Failure to thrive Extreme thirst for free water May present with hypernatremia (if under free water restriction or if patient has an impaired thirst mechanism)
Hyperaldosteronism	Hypertension Hypokalemia Metabolic alkalosis	Primary hyperaldosteronism Congenital adrenal hyperplasia Apparent mineralocorticoid excess Glucocorticoid-remediable aldosteronism (GRA) Liddle syndrome (AD)
Hypoaldosteronism/pseudohypoaldosteronism (PHA)		(See type IV renal tubular acidosis in table below) Type I PHA (AD or AR) Type II PHA (AD)

Types of Renal Tubular Acidosis

Renal Tubular Acidosis	Symptoms
Type I (distal)	Inability to acidify urine in distal nephron; some patients have sensorineural deafness
Type II (proximal)	Inability to reabsorb bicarbonate in proximal tubule
Type IV (hypoaldosteronism)	Hypoaldosteronism resulting in hyperkalemia and metabolic acidosis.

Diagnostic Workup

serum electrolytes, renal function, venous blood gas (to confirm metabolic etiology of acidosis)
- In the absence of diarrhea or high chloride load (e.g., from 0.9% saline bolus or infusion), hyperchloremic metabolic acidosis is strongly suggestive of renal tubular acidosis.
serum and urine osmolality (to assess for diabetes insipidus)
urinalysis (to assess for proteinuria, glycosuria, or both)
urine electrolytes, calcium, phosphorus, and magnesium
- To calculate fractional excretion of solutes and determine if renal handling is appropriate: For example, hypocalcemia with elevated urinary calcium excretion (hypercalciuria) is suggestive of tubular dysfunction.
- The calculation for fractional excretion of a solute in the urine is:

FE_solute = (U_solute x P_creatinine)/(P_solute x U_creatinine) x 100%

(where U_solute is the urine concentration and P_solute is the plasma concentration of a given solute)

To calculate urine anion gap: A positive urine anion gap suggests impaired acidification of the urine and renal tubular acidosis. Urine NH4+ excretion is accompanied by urine Cl, and in this case, urine Cl is an indirect measure for NH4+ because of the difficulty of measuring NH4+.
- The formula for calculating urine anion gap:

(urine [Na⁺] + urine [K⁺] - urine anions [Cl ^-])

genetic testing and metabolic screening (e.g., leukocyte cystine levels for cystinosis)

Research

Landmark clinical trials and other important studies

Research

A Novel Gene Encoding an Integral Membrane Protein Is Mutated in Nephropathic Cystinosis

Town M et al. Nat Genet 1998.

In this landmark article, investigators isolated and identified a novel gene, CTNS, to cause cystinosis, a disease in which cystine cannot be transported properly, leading to renal Fanconi syndrome and crystal deposition in the eye.