• Information
  1. Symptoms
  2. Disease Classifications
  3. Renal Tubular Acidosis
  4. Characteristics of RTA
  5. Renal Fanconi Syndrome
  6. Cystinosis
  7. Liddle's Syndrome

A. Symptoms

1. Polyuria
2. Nocturia
3. Electrolyte Disorders
   1. Always present
   2. Renal tubular acidosis or alkalosis
   3. Hyperkalemia more common than hypokalemia
   4. Hypocalcemia, hypomagnesemia variably present
4. Tubular Necrosis
   1. Oliguria / anuria ccurs in 25%
   2. Remainder have normal urine volume

B. Disease Classifications

1. Medullary Cystic Kidney
2. Tubular Function Disease
   1. Familial nephrogenic diabetes insipidus
   2. Renal Tubular Acidoses (RTA) - proximal (Type II), distal (Type I), and Type IV
   3. Fanconi Syndrome (usually from cystinosis with cystinuria) [1,2]
   4. Lead nephropathy
3. Acute Tubular Necrosis
   1. Usually due to ischemia (eg. hypotension) and/or toxin mediated
   2. Note that tubular cells are highly sensitive to low perfusion
   3. This is because they are fed by "venous" blood (which has passed glomeruli)
4. Inherited Disorders
   1. Liddle's Syndrome - pseudoaldosteronism (see below) [3]
   2. Hypokalemic metabolic alkaloses [4]

C. Renal Tubular Acidosis (RTA) [5,6]

1. Types
   1. Proximal (Type 2)
   2. Distal (Type 1)
   3. Defective Ammoniagenesis (Hyperkalemic; Type 4)
   4. Type 3 disease is a combination of others and is no longer distinguished
2. Symptoms and Laboratory Abnormalities
   1. Unexplained acidosis (especially in distal disease)
   2. Failure to thrive
   3. Electrolyte disorders
   4. Persistent hyperchloremic (non-anion gap) acidosis
   5. Abnormal Potassium Regulation is common
3. Cell Types
   [Figure] "Renal Tubular Cells"
   1. alpha-Intercalated Cell (~40% of distal tubule cells) - major acid excretion
   2. Principal Cell (~60% of distal tubule cells) - Na/K (aldosterone dependent) regulation
   3. ß-Intercalated Cell (few) - HCO3- production
4. Proximal (Type 2) RTA
   1. Defect in proximal tubular resorption of HCO3-
   2. Defect in Na+/H+ exchange in proximal tubule
   3. Part of Fanconi Syndrome
5. Distal (Type 1 Classical) RTA [9]
   1. Mild to moderate HCO3- wasting with urine pH not <6.0, regardless of blood acidosis
   2. Probably due to abnormal alpha-intercalated cell secretion of H+
   3. Albright's Disease, Sjogren's Syndrome, renal tranplant rejection, osteopetrosis
   4. Also caused by amphotericin, rheumatoid arthritis, systemic lupus erythematosus
   5. Diagnosis: infusion of arginine hydrochloride (acid load) with urine pH >5.5 after loading
   6. Patients are usually hypokalemic with high urine calcium
   7. Pseudofractures, osteoporosis may be present
   8. Treatment with bicarbonate loading, potassium citrate, calcium supplements
6. Defective Ammoniagenesis (Hyperkalemic; Type 4) RTA
   1. Most common form of Distal RTA
   2. Serum hyperkalemia with acidosis suppresses ammonia production
   3. Urine pH is also acidic with low urine potassium
   4. Due to both alpha-Intercalated Cell and Principal Cell abnormalities
   5. Most of these center around low aldosterone or aldosterone resistance
7. Subsets of Type 4 RTA
   1. Primary hyporeninemia, secondary hypoaldosteronism (most common)
   2. Usually with intrinsic renal disease
      1. Diabetes mellitus is most common cause
   3. Mineralocorticoid deficiency, without intrinsic renal disease
   4. Aldosterone Resistance - usually associated with obstruction or interstitial disease
   5. Amphotericin B - permeability increase allowing back-diffusion of H+ ions
   6. Restricted to Principle cell abnormalities
8. Principal Cell Abnormalities (Type 4 RTA Subtype)
   1. Chloride shunt (Gordon's Syndrome)
   2. Drug Effect: amiloride, triamterene, lithium, trimethopterin
   3. Pseudohypoaldosteronism
   4. Early childhood type, neonatal renal disease, usually unilateral
9. Pseudohypoaldosteronism Type 1 [1]
   1. End organ resistance to aldosterone
   2. Present in first week of life with dehydration, hyponatremia, hyperkalemia
   3. Associated with mineralocorticoid (mainly aldosterone) resistance
   4. Type 1 has autosomal dominant and recessive forms
   5. Recessive form due to defects in alpha, beta, and/or gamma subunits of Na+ channel
   6. Dominant form due to mutations in the mineralocorticoid type I receptor
   7. Four distinct mutations have been described in each of the recessive and dominant forms
   8. Airway epithelial Na+ transport abnormal, with increased fluid in lungs found [7]
10. Pseudohypoaldosteronism Type 2 [8]
    1. Also called familial hyperkalemic hypertension or Gordon syndrome
    2. Rare, autosomal dominant form of hyperkalemia
    3. Deletions in WNK1 or missense mutations in WNK4 genes demonstrated
    4. Impaired renal potassium excretion
    5. Hyperchloremic metabolic acidosis
    6. Hypertension
    7. Normal glomerular filtration rate
    8. Respond to thiazide diuretics
11. Complications
    1. Nephrolithiasis and nephrocalcinosis
    2. Rickets
    3. Potassium level disorders (may be severe)
    4. Osteoporosis (Renal Osteodystrophy)

D. Characteristics of RTA

1. Generalized proximal renal tubular dysfunction
2. Inherited as autosomal dominant, autosomal recessive, or X-linked trait
3. Effects on Kidney
   1. Hypophosphatemia due to hyperphosphaturia
   2. Renal glycosuria
   3. Generalized aminoaciduria
   4. Hypouricemia
   5. Hypokalemia also common
   6. Type 2 RTA also present (failure to resorb HCO3-)
4. Causes
   1. Inherited much more common than sporadic cases
   2. Cystinosis (see below)
   3. Wilson's Disease
   4. Galactosemia
   5. Tyrosinemia
   6. Fructose intolerance
   7. Lowe's oculocerebral syndrome
   8. Multiple Myeloma (uncommon)
   9. Amyloid
   10. Heavy metal (mainly lead or platinum) toxicity
5. Bone Effects
   1. Due to phosphate wasting (hypophosphatemia)
   2. Rickets and osteomalacia commonly seen
   3. Pathologic fractures can occur
6. Treatment
   1. Phosphate supplements and calcitriol for bone lesions
   2. Alkali (particularly potassium salts) for acidosis
   3. Liberal intake of salt and water

F. Cystinosis [2,11]

1. Most common cause of renal Fanconi Syndrome in childhood
2. Autosomal Recessive Disease
   1. Lysosomal storage disease
   2. Defective transport of cystine out of lysosomes
   3. Usually due to 57kb DNA deletion of CTNS
3. Function of CTNS
   1. CTNS on chromosome 17p encodes cystinosin
   2. Cystinosin is a 7 transmembrane protein of 367 amino acids
   3. Cystinosin transports disulfide amino acid cystine out of lysosomes to cytoplasm
   4. In cytoplasm, cystine is reduced to two molecules of the amino acid cysteine
   5. Transport process is defective in cystinosis, causing intralysosomal accumulation
   6. In most cells, crystals also form
4. Symptoms and Signs
   1. Renal tubular damage, usually begins 6-12 months of age, progresses to renal failure
   2. Polyuria, polydipsia, dehydration, acidosis, cystinuria
   3. Hypophosphatemic rickets, hypokalemia, hypocalcemia, hypocarnitinemia
   4. Growth retardation
   5. Nonrenal: photophobia, retinal blindness, hypothyroidism, mypoathy, diabetes, others
5. Treatment [11]
   1. All patients progress to renal failure and renal transplantation is required
   2. Long term treatment with oral cysteamine therapy is clearly beneficial
   3. Cysteamine improves growth, delays renal failure, reduces death rate

G. Liddle's Syndrome [1,3,5]

1. Clinical Description
   1. Inherited disorder with variable phenotypic penetration
   2. Classic phenotype of hypertension (HTN), hypokalemia, metabolic alkalosis
   3. Classic phenotype is not expressed in all patients, even within a family
   4. Hypokalemia is found in ~50% of patients, and HTN in most patients
   5. Metabolic alkalosis is also variable
   6. HTN occurs in the presence of suppressed plasma renin and serum aldosterone levels
   7. Contrast with Bartter Syndrome (normotensive hypokalemic metabolic alkalosis)
2. Etiology [10]
   1. Due to mutations in renal epithelial collecting duct Na+ channels (ß-ENaC)
   2. This renal channel has alpha, ß, and gamma subunits
   3. Each polypeptide has two membrane spanning alpha-helices with large loop between each
   4. alpha subunits have intrinsic pore-forming activities
   5. Gamma and ß subunits modulate activity and increase currents
   6. Mutations in Liddle Syndrome ß-ENaC affect interaction with the Nedd4 gene
   7. Nedd4 protein normally recognizes ion channel and targets for degradation by proteasome
   8. Mutant ß-ENaC cannot be degraded and accumulates
   9. Excess ENaC leads to increased Na+ and H20 reabsorption
3. These channels are found primarily in the principal cells
   1. Normal principal cell membrane potential is -60mV
   2. In Liddle's Syndrome, membrane potential is -80mV
4. Consequences of Mutations in Sodium (Na+) Channel
   1. Constitutive activation/opening of the Na+ channel (on urine side)
   2. Mutations in ß or gamma subunits of this channel cause Liddle's syndrome
   3. Na+ absorption is increased and fluid retention with HTN results
   4. However, extracellular (clinical) edema does not develop due to compensatory changes
   5. Alkalosis is due to an increase in H+ secretion in the initial cortical collecting ducts
   6. An H+ ATPase is located on the apical membrane of alpha intercalated cells in the ducts
   7. In Liddle's syndrome, H+ secretion into urine is increased, resulting in alkalosis
   8. The major driver for this increase appears to be changes in voltage potential
5. Treatment
   1. Clinical manifestations are reversed with triampterene
   2. Triampterene is a potassium sparing diuretic
   3. Triampterene functions by direct sodium channel blocking activity
   4. Amiloride may also be used
   5. Therefore, the constitutive activating mutations in Liddle's Syndrome are modulated

References

1. Scheinman SJ, Guay-Woodford L, Thakker RV, Warnock DG. 1999. NEJM. 340(15):1177
2. Gahl WA, Thoene JG, Schneider JA. 2002. NEJM. 347(2):111
3. Oparil S, Zaman A, Calhoun DA. 2003. Ann Intern Med. 139(9):761
4. Peters M, Jeck N, Reinalter S, et al. 2002. Am J Med. 112(3):183
5. Palmer BF and Alpern RJ. 1998. Am J Med. 104(3):301
6. Gluck SL. 1998. Lancet. 352(9126):474
7. Kerem E, Bistritzer T, Hanukoglu A, et al. 1999. NEJM. 341(3):156
8. Achard JM, Warnock DG, Disse-Nicodeme S, et al. 2003. Am J Med. 114(6):495
9. Cukierman T, Gatt ME, Hiller N, Chajek-Shaul T. 2005. NEJM. 353(5):509 (Case Discussion)
10. Reinstein E and Ciechanover A. 2006. Ann Intern Med. 145(9):676
11. Gahl WA, Balog JZ, Kieta R. 2007. Ann Intern Med. 147(4):242