• The nephron is the functional unit of kidneys (400,000 to 800,000 nephrons per kidney)
• Each nephron is made of 1 glomerulus and 1 renal tubule, in continuity.
• Each kidney tubule has four different parts, and each part performs a specific function. As the filtered fluid flows through them, substances are added to or removed from it by exchanging materials with the blood, gradually turning it into urine.
• At the end of the tubule, urine composition is final.
• Along the tubule, exchanges are controlled by hormones and mediators either of systemic or local origin.

Reabsorption segment (completes proximal segment):

• 20 to 30% of sodium
• 10 to15% of bicarbonates
• 30% of calcium
• 70% of magnesium

Alteration of exchanges in this tubular segment: Bartter syndrome (major hydro electrolytic loss): metabolic alcalosis with hypokalemia

Distal convoluted tubule:

• Low reabsorption segment in terms of quantity (less than 10% of the filtrated volume)
• Very important exchange step for qualitative hydro-electrolytic adjustment
• An alteration of exchanges in this sub segment: Gitelman syndrome (metabolic alkalosis with hypokalaemia)

Collecting duct:

• Major site of potassium/ acids secretion and sodium/water reabsorption
  • In the event of acid secretion failure, due to proton pump alteration: distal RTA type 1 or Albright acidosis or « classical » RTA (metabolic acidosis with hypokalemia)
  • In the event of NH4+ production mostly due to hypoaldosteronism: distal RTA type 4 (metabolic acidosis with hyperkalaemia)

• pH (power of hydrogen) represents the concentration of hydrogen ions (H⁺) in a solution, which determines its acidity. Under normal physiological conditions, the concentration of H⁺ in blood is extremely low.
• The human body needs to maintain this low acid quantity despite food/ beverage intake (animal proteins bring the highest quantity of acids).
• To do so, the main buffering system is carbonic acid / bicarbonate:

• pH changes when the ratio between PCO₂ and HCO₃- is modified
  • if PCO₂ changes: respiratory acidosis (PCO₂ increase) or alkalosis (PCO₂ decrease)
  • if HCO₃- changes: metabolic acidosis (HCO₃- decrease) or alkalosis (HCO₃- increase)
• One of the function of the lungs is CO2 excretion
  • Hypoventilation=respiratory acidosis
  • Hyperventilation= respiratory alkalosis
• A decrease in blood pH leads to hyperventilation and conversely, an increase in blood pH in blood pH leads to hypoventilation
• One of the functions of the kidneys is filtrated bicarbonate reabsorption (proximal tubule) and acid excretion (distal tubule)

• Due to plasma electro-neutrality, cations concentration is equal to anions concentration.
• When specifically considering Na+ et K+ cations and HCO3- et Cl- anions, their plasma concentration difference is called anion gap.

Normal plasma anion gap =16±4 mmole/L

• In practice, there are physiologically more non measured anions than non measured cations.
• AG changes will allow to determine if the anion compensating the excess of H+ (bicarbonate loss) is Cl- or anion which is non measured .

Metabolic acidosis with normal AG (with hyperchloremia):

Intestinal or renal losses of HCO3-.which is compensated by a proportional increase in Cl- (HCl gain) leading to a metabolic acidosis with hyperchloremia.

Metabolic acidosis with increased AG ( H+ associated to a non measured anion, i.e. lactate) (with normal chloremia)

Presence of another acid than HCl and AG increase as HCO3- decrease is compensated by a non measured anion leading to a metabolic acidosis with normal chloremia.

• dRTA is a rare disease where the distal tubule is unable to secrete protons (H+) in urine in response to a metabolic acidosis, thus leading to an impairment of the acid-base homeostasis.
• dRTA is due to pathogenic variants in genes involved in acid excretion leading to modification of transporters or transcription factors implicated in the renal protons’ secretion. These variants can be either genetic (primary or inherited dRTA) or affected as a consequence of an injury, disease or drug intake, inducing nephrotoxicity leading to tubule damage (secondary or acquired dRTA).

• Retrospective analysis showed that dRTA prevalence in 2017 was estimated to be between 0.46 (recorded cases, of which 22.1% were considered primary) and 1.60 when including suspected cases (7.6% primary) per 10,000 people.
• Prescription and clinical records of diagnosed patients revealed a wide range of comorbidities and a need for pharmacological treatment to manage associated symptoms.
• The study provides new estimates of dRTA prevalence in Europe and suggests that patients may often be unreported or miscoded, potentially confounding appropriate disease management.

• Inherited tubulopathies are secondary to pathogenic mutations in gene coding either for specific transporters of solutes or for their regulating proteins. They are classified according to the concerned solute or segment.
• Inherited dRTA occurs mostly in children, and is diagnosed from the 1st year of life depending upon the mutation
• Primary dRTA is the most frequent form of primary RTA in western countries
• Several gene variants are responsible, and their transmission can be autosomal recessive (AR) or autosomal dominant (AD)
• Analysis of the genetic defects involved is important to define functional consequences and possible genotype-phenotype correlation

• Diagnosed mostly in adulthood
• Associated with:

A systemic disease

• • Auto-immune diseases: Sjögren syndrome (SS), systemic lupus erythematosus (SLE), amyloidosis, thyroiditis, primary biliary cirrhosis, auto-immune hepatitis.

Nephrocalcinosis

• • Medullary sponge kidney (MSK) / Cacchi Ricci disease
  • Hyperparathyroidism

Drugs

• • Toluene, cyclamate

• Auto immune, chronic disease with lymphocyto-plasmocytic infiltration of exocrine glands (predominantly the salivary and lacrimal glands) leading to sicca symptoms.
• Mean age of Sjögren patients: 50 years with majority of female patients (ratio 9/1)
• Extra-glandular disease involving multiple organs may occur, including kidney disease
• Renal complications, in less of 10% of Sjögren patients, are mainly tubulo-interstitial nephritis (due to lymphocyto-plasmocytic infiltration) but also dRTA, diabetes insipidus, Fanconi syndrome…

• Potential presentation clinical symptoms
  • Infants: failure to thrive, growth retardation, polyuria, polydipsia, vomiting, constipation, rickets, hypotonia, nephrocalcinosis, haemolytic anaemia, sensorineural hearing loss
  • Children and adolescents: growth retardation, polyuria, polydipsia, rickets, vomiting, constipation, muscle weakness/hypokalaemic paralysis, haemolytic anaemia, sensorineural hearing loss, nephrocalcinosis/urolithiasis, enamel defects
  • Adults: nephrocalcinosis/urolithiasis, osteomalacia, muscle weakness/hypokalaemia, bone pain, fractures, haemolytic anaemia, sensorineural hearing loss, enamel defects

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