The improvement of our knowledge of the functioning of the renal tubules, the identification of the transporters expressed in the different tubular segments and the appearance of animal models invalidated or overexpressing these transporters or regulatory molecules have allowed a better understanding of physiology and pathophysiology tubular in man.
The molecular substratum of the majority of renal tubular abnormalities is thus known. In practice, knowledge of the physiology of the renal tubules allows a clinical picture and biological anomalies to orientate towards the tubular segment potentially responsible and facilitates the identification of abnormalities. In this article, we will briefly recall the physiology of each tubular segment, and then describe the tubular pathologies known to man apart from diabetes insipidus, treated in another article. Whenever possible, the numbering assigned by MacKusick for each hereditary condition is mentioned.
In humans, normal glomeruli filter the plasma, producing about 120 ml of ultrafiltrate per minute.
It is easy to understand that, in the absence of modifications of this initial urine by the tubules, the large losses incurred would be rapidly incompatible with life.
Tubulopathies reflecting proximal tubular dysfunction:
Approximately 60% of the initial ultrafiltrate is reabsorbed into the proximal tubule and the composition of the primary urine is heavily modified; most glucose, most amino acids, 80% phosphate and bicarbonate, more than 60% of the chlorine, potassium and sodium filtered are reabsorbed into the proximal tubule.
Glucose reabsorption:
The reabsorption of glucose is done exclusively in the proximal tubule. Entry of glucose to the apical (urinary) pole of the proximal tubular cell is an active process that requires the presence of sodium; the glucose exit at the basolateral pole, which allows the return of glucose in the blood, is a facilitated transport that requires neither sodium nor energy.Two apical glucose carriers are expressed in proximal cells; this is explained by the modification of the composition of the urine along the tubule. At the beginning of the proximal tubule, the primary urine is rich in glucose; the apical transporter thus has a low affinity for glucose and a high transport capacity; the concentration and amount of glucose decreasing, the carrier’s affinity for glucose should increase while transport capacity may decrease. The low affinity and high capacity apical transporter, called SGLT2, transports a sodium ion with a glucose molecule and is coupled on the basolateral pole to the “facilitated” low affinity transporter GLUT2.
The high affinity apical transporter SGLT1 carries two sodium ions for one glucose molecule and is associated with the GLUT1 high affinity basolateral transporter.
SGLT1 also transports galactose.
The presence of glycosuria reflects the inability of the renal tubule to completely reabsorb the filtered glucose. In view of this anomaly it is necessary to determine whether the presence of glucose in the urine reflects a saturation of the renal glucose reabsorption system due in practice to hyperglycemia or if there is a decrease in the capacity of the proximal tubules to reabsorb the glucose glucose, defining renal glycosuria. Apart from diabetes patents, the increase in blood glucose can be transient and is sometimes difficult to objectify.
The measurement of glucose Tm, which measures the maximum capacity of the kidneys to reabsorb glucose, is then an important diagnostic element. If the glucose Tm is lowered, it is then necessary to determine whether this abnormality is isolated or associated with other renal abnormalities, in particular tubular proximal abnormalities.
Several causes of glycosuria have been identified, focusing on the expression level of renal glucose carriers.
Reabsorption defects involving the SGLT2 transporter:
The SGLT2 transporter reabsorbs the majority of the filtered glucose, so that a defect in expression of this transporter, essentially expressed in the proximal tubule, effectively leads to glycosuria by two identified mechanisms: mutation of the transporter or mutation of a transcription factor.
A few dozen mutations of the SGLT2 transporter (also referred to as SLC5A2) have been reported (OMIM 233100), associating missense, nonsense mutations, deletions or splicing modifications. There does not seem to be any foundation mutation. The subjects identified initially were either homozygous for the mutation, or most often composite heterozygotes, that is to say carriers of a different mutation on each allele. In these subjects, glycosuria is generally significant, often greater than 10 g / day in adults. There is no polyuropolydipsic syndrome. A more detailed analysis of the heterozygous subjects, carrying a healthy allele and a mutated allele, showed the possibility of a low to moderate glycosuria. No other abnormalities, particularly renal, have been reported in these subjects and the tolerance of glycosuria is generally good. One study reported levels of glycosylated hemoglobin (HbA1c) and plasma insulin concentrations below the usual values, suggesting that these mutations could protect against the onset of diabetes.The gene of this transporter is carried by chromosome 16.
More surprisingly, mutations of the transcription factor HNF1alpha (gene located on chromosome 12), responsible for the occurrence of MODY3 type diabetes (OMIM 600496), are also associated with a significant reduction in the capacity of the kidneys to be reabsorbed glucose in humans.
This anomaly seems to precede diabetes, sometimes several years, and glycosuria with normal blood sugar is then inaugurating.
Diabetes often begins after adolescence and it has been suggested that this late onset may be related to the protective role of glycosuria. Some subjects with a decrease in glucose Tm do not develop diabetes according to the WHO criteria. Patients carry a heterozygous mutation and the anomaly is transmitted in the autosomal dominant mode. The mechanism of this glycosuria could be clarified by studying the phenotype of homozygous mice invalidated for the HNF1alpha gene. In these mice, there was a very marked decrease in the expression of the SGLT2 transporter in the proximal tubule. The decrease in transcription of the gene coding for SGLT2 is due to the presence of HNF1alpha binding sites in its promoter. Homozygous mice also exhibit aminoaciduria, renal phosphate leakage and hyperphenylalaninemia. In humans, glycosuria appears to be isolated, although we have observed a decrease in phosphate Tm (D. Prié, unpublished personal results).
Changes affecting the SGLT1 cotransporter (OMIM 606824):
The SGLT1 transporter is expressed not only in the proximal renal tubule but also in the intestine. The mutations of the SGLT1 cotransporter (SLC5A1) are responsible for intolerance to glucose and galactose. The diagnosis of this disease is usually made in the first days of life before diarrhea and severe dehydration requiring the eradication of glucose and galactose from the diet. This table is accompanied by glycosuria. This is an autosomal recessive pathology. The phenotype of the heterozygous subjects is not strictly normal: a defect in glucose transport has been demonstrated.
Transfers of GLUT2 Carrier:
Although the GLUT2 transporter is expressed in the same tubular segments as SGLT2, the phenotypes generated by the mutations of these transporters are very different. Because the GLUT2 transporter is expressed in the liver and kidney, inactivating mutations in this transporter result in a Fanconi-Bickel syndrome overload disease that associates glycogen accumulation in the liver, fasting hypoglycemia, and postprandial hyperglycemia reflecting pancreatic involvement, glycosuria, aminoaciduria, and hypophosphatemia. It is an autosomal recessive disease. Depending on mutations, heterozygous subjects may or may not have isolated glycosuria; this could be related to a negative dominant effect of the mutated proteins.
Mutations of the GLUT1 transporter have been described, but these appear to be responsible only for hypoglycorachic cometal seizures. However, the publications do not mention the specific search for glycosuria. These mutations are generally present in the heterozygous state.
Phosphate reabsorption:
Like glucose, phosphate is reabsorbed almost exclusively in the proximal tubule, but the reabsorption of the filtered phosphate is not necessarily complete. The amount of phosphate reabsorbed depends on digestive intake and the needs of the body; it varies over the course of life, which is greater in children during growth than in adults.
The reabsorption of phosphate at the apical pole of the cell from the primary urine is an active phenomenon which requires the presence of sodium. Three phosphate transporters were identified in the proximal tubule: cotransporters NPT1, NPT2a and NPT2c. The relative importance of each of these carriers in phosphate homeostasis appears to vary over the lifetime. Only the role of NPT2a in phosphate homeostasis has been clearly established in humans. The mechanism by which the phosphate leaves the cell at its basolateral pole is still incompletely understood. Recently, the pathophysiology of several hereditary causes of renal leakage of phosphate has been identified.
Transporter Changes NPT2a:
Mutations responsible for a decrease in the function of the NPT2a transporter have been identified in humans. Patients with these mutations have recurrent calcium renal lithiasis and / or bone demineralization.
The exploration revealed hypophosphatemia due to a decrease in kidney capacity to reabsorb phosphate. This deficiency is objectified by the calculation of the phosphate Tm obtained from phosphatemia, the fractional excretion of phosphate, and the nomogram of Walton and Bijvoet.
Plasma concentrations of parathyroid hormone and calcium in these patients are normal. Calcitriolaemia is in normal high or increased values, and is explained by hypophosphatemia. Calcium is often elevated and reflects the increase in digestive calcium absorption induced by calcitriol. The invalidation of the NPT2a transporter in mice leads to a phenotype close to that observed in humans. The physiopathology of the formation of lithiasis and bone demineralization during these pathologies has been discussed in a recent article.
Invalidation of the NHERF1 adaptive protein in mice results in a phenotype similar to that observed in mice invalidated for NPT2a. In this model, there is a decrease in the expression of NPT2a on the surface of the proximal renal tubular cells. It is likely that mutations in the NHERF1 protein may be responsible for renal leakage of phosphate in humans, although these have not yet been published.
Chlorine channel mutations ClC5, Tooth disease, X-linked renal lithiasis (OMIM 300009):
This pathology combines calcium renal lithiasis, renal failure nephrocalcinosis, hypophosphatemia due to a lack of tubular proximal reabsorption of phosphate, an increase in plasma calcitriol, hypercalciuria, a proteinuria of low molecular weight particularly affecting the retinol binding protein and b 2-microglobulin, and sometimes glycosuria or aminoaciduria.
Rickets is present in some individuals. This pathology is due to an inactivating mutation in the ClC5 chloride channel, expressed in the endosomes of the proximal tubular cells. The mechanisms by which these mutations lead to proximal tubular abnormalities are still partially hypothetical. The absence of a chlorine channel in the endosomes would prevent their acidification with an H + / ATPase, the protons being able to be transported only with an anion. This blocking of the endosome function would prevent endocytosis by the proximal tubule of the proteins filtered in the glomerulus. The renal leakage of phosphate is due to a lack of expression of the transporter NPT2a at the apical pole of the cells.
This protein is located in intracellular vesicles.
The explanations for this anomaly remain hypothetical.
The mechanisms of hypercalciuria are even less well understood and may be multiple: lack of proximal reabsorption due to less reabsorption of chloride ions; role of ClC5 in the loop of Henlé or the distal tubule; increased digestive absorption of calcium as a result of the increase in circulating calcitriol …
The gene encoding ClC5 is located on the X chromosome and the transmission of the abnormality is actually linked to the X chromosome. Heterozygous women may have low molecular weight proteinuria, and sometimes nephrocalcinosis and renal insufficiency.
All patients with the table described above have no mutations in the gene coding for ClC5, and it is almost certain that this syndrome is heterogeneous and possibly due to mutations in other genes.
Tubular reabsorption defects of phosphate secondary to an extrarenal factor:
Parathyroid hormone is not the only factor that modulates reabsorption of phosphate through the proximal tubule.Fibroblast growth factor 23 (FGF-23) is one of these recently identified factors. It decreases the expression of NPT2a on the surface of proximal tubular cells, strongly inhibits synthesis and stimulates the degradation of calcitriol. An overexpression or an increase in activity of this factor thus lead to a renal leakage of phosphate and a hypophosphatemia that does not induce an increase in plasma calcitriol. The autosomic dominant hypophosphatemic rickets [ADHR], OMIM 193100) are observed in the autosomal dominant hypophosphatemic rickets (OMIM 193100) due to a mutation in the gene encoding FGF-23 located on chromosome 12. These mutations could stabilize the circulating FGF-23 rendering it resistant to enzymatic degradation or being responsible for an affinity gain for its receptor that has not yet been identified. Diagnosis is usually carried out during childhood in the presence of hypophosphatemic rickets. In adults, a similar picture can be observed, associating bone demineralization of osteomalacia type, hypophosphatemia with decreased Tm of phosphate and a polyalgic syndrome. This table, acquired, is due to a hypersecretion of FGF-23 of tumoral origin. The tumor, usually benign (hemangiopericytoma in particular), is sometimes difficult to locate. The table regresses completely after removal of the tumor.
There is also a hypophosphatemic rickets that is linked to the X chromosome. This pathology, identical to ADHR on the clinical and biological level, is due to a mutation in a gene encoding a protein, PHEX, one of whose functions would be to participate in the degradation of the circulating FGF-23. The gene encoding PHEX is located on chromosome X. These mutations would therefore result in a decrease in PHEX activity: an accumulation of FGF-23 in the plasma of these patients has actually been reported.
Reabsorption of amino acids:
The proximal tubule is the almost exclusive place of reabsorption of amino acids. There are different types of carriers which generally allow the reabsorption of several amino acids to the neighboring properties.
Cystinuria:
Cystinuria, not to be confused with cystinosis, is a pathology which is revealed by the occurrence of yellowish-colored kidney stones, rich in sulfur because of their high cysteine content. Cysteine (and cystine, which is a cysteine dimer) is an amino acid which is sparingly soluble in an aqueous medium, and an excess of urinary excretion causes it to precipitate. Cystinuria is the most common cause of aminoaciduria. It affects about one in every 7,000 people and is accompanied by an increased elimination of dibasic, lysine, arginine and ornithine amino acids using the same transport routes. Cystinuria is a heterogeneous pathology. Three forms of cystinuria have been defined on biological data. In type I cystinuria, aminoaciduria is normal in heterozygotes, while it is moderately elevated in Forms II and III.Blood cystinaemia after cystine oral loading only increases in form III. Two mutations on two distinct genes but concurrent to the same function have been identified to date. Type I cystinuria is due to a mutation of one of the subunits of the rBAT / SLC3A1 transporter, whose gene is located on chromosome 2 (OMIM 104614). Cystinuria that is not type I (types II and III, OMIM 600918) is caused by a mutation of another carrier subunit, the gene of which is located on chromosome 19. All these mutations are responsible for a decreased activity of the heterodimeric carrier.
The prevention of lithiasis consists in providing abundant diuresis, alkalizing the urine (pH> 7.5) with sodium bicarbonate or potassium citrate, and optionally adding D-penicillamine in order to improve the solubilization of cysteine.
Cystinosis:
Cystinosis (OMIM 219800) is caused by a mutation of a cystine transporter, cystinosine, expressed in the lysosome membrane. The dysfunction of this transporter causes the accumulation of cystine in the cells, in particular renal cells.Proximal tubular involvement resulting in complete Fanconi syndrome is often prominent. Renal disease progresses to renal failure. Through dialysis and kidney transplantation, the life expectancy of these patients has increased, and signs of overload in other organs appear: pancreas, thyroid, gonads, eye, brain, muscles, aorta.
It is a pathology of autosomal recessive transmission, but an increase in cystine concentration in leukocytes has been observed in heterozygotes. In France, the incidence of this disease is higher in Brittany (1/26 000) than in the rest of the country.
There are forms of late-onset cystinosis in adolescence. In these forms, renal involvement is not usually manifested by Fanconi syndrome but by a glomerular syndrome evolving towards renal insufficiency. There are also forms of cystinosis without renal involvement.
The differences in phenotype seem to depend on the mutation.
Treatment is based on diet, cystamine use and transplantation. Prenatal diagnosis is available.
Other renal causes of hereditary aminoaciduria:
Hartnup’s disease:
A mutation in the cotransporter of neutral amino acids and sodium has recently been made responsible for Hartnup’s disease (OMIM 234500). This autosomal recessive condition associates to varying degrees skin signs reminiscent of pellagra, cerebellar ataxia, psychosis, aminoaciduria affecting neutral amino acids and a selective defect of digestive absorption of these amino acids.
The association of increased urinary excretion of lysine, ornithine and arginine without increased cystinuria, retarded mental development and signs of digestive intolerance to lysine (diarrhea, vomiting) has been reported by various authors. This condition appears to be more prevalent in Finland. Mutations in the SLC7A7 gene, which encodes a subunit of the basolateral transporter of lysine, have been identified and made responsible for the disease.
An aminoaciduria selectively affecting glutamate and aspartate, accompanied by neurological damage, has been described (see OMIM 222730 and 133550), but no abnormalities of the transporter of these amino acids in the kidney have been identified.
Lowe syndrome:
Lowe syndrome (OMIM 309000), associates an aminoaciduria, hyperchloremic acidosis, ammonium renal failure, increased phosphaturia, vitamin D-resistant rickets, renal insufficiency, mental retardation, blindness, nystagmus, hydrophthalmia, cataracts, and postural delays. Transmission is linked to chromosome X. The mutation affects a gene encoding a lipid phosphatase allowing the conversion of phosphatidylinositol 4,5-biphosphate to phosphatidyl 4-phosphate. The deficiency of activity of this enzyme results in the accumulation of phosphatidylinositol 4,5-biphosphate and its toxicity.
Aminoacidides of various causes:
The causes of aminoaciduria affecting all the amino acids, and not a single class, are numerous and reflect a toxic affection of the proximal tubule (overloading disease, toxicity …). They are generally associated with other tubular dysfunctions.
An increase in selective urinary excretion of one or a few amino acids outside tubulopathy may also be observed in metabolic abnormalities affecting the synthetic or degradative pathways of these amino acids.
Anomalies of reabsorption of bicarbonates:
Unlike the substances described above, the acid-base equilibrium involves several tubular segments. More than 80% of the filtered bicarbonates are reabsorbed into the proximal tubule through a complex process that requires the coordination of several steps. The protons are secreted in the tubular lumen by the NHE3 sodium-proton exchanger (for two thirds) and by a proton-ATPase for one third. H + ions combine with bicarbonates to form carbon dioxide; this reaction is catalyzed by the type IV carbonic anhydrase expressed at the apical pole of the cells. Carbon dioxide diffuses into the cell according to its pressure gradient and binds to water molecules under the effect of cytoplasmic carbonic anhydrase type II. At the basolateral pole of the cell, bicarbonate is secreted into the interstitium by a sodium bicarbonate cotransporter NBC1 (SLC4A4) which carries three bicarbonate ions with a sodium ion.
The bicarbonates which have not been reabsorbed in the proximal tubule are reabsorbed in the loop of Henlé and in the collecting duct following a similar procedure (see below).
Proximal tubular acidosis is characterized by a decrease in the maximum capacity of the proximal tubule to reabsorb the bicarbonates, which results in a decrease in the threshold for the appearance of bicarbonates in the urine or Tm of the bicarbonates. This type of acidosis is not due to a defect of acidification of the urine, but to a renal loss of bicarbonate.
However, in the basal state, the urine does not contain bicarbonates because the value of bicarbonate is lower than the Tm / DFG value (bicarbonate reabsorption capacity / glomerular filtration rate); a bicarbonatura appears only if the subject is loaded with bicarbonate. Urinary pH is acidic under basal conditions. The decrease in the Tm of the bicarbonates can be demonstrated by an intravenous bicarbonate loading. Two major forms of proximal tubular acidosis, also known as type 2 renal acidosis, have been described, an autosomal recessive form and a probably autosomal dominant form.
Isolated proximal tubular acids (type 2):
The autosomal recessive form (OMIM 604278) is due to a mutation of the basalateral sodium-bicarbonate cotransporter NBC1 / SLC4A4, whose gene is located on chromosome 4. Clinically, this acidosis is associated with cataract, bilateral glaucoma and keratopathy in bands. These ocular signs are explained by the expression of NBC1 / SLC4A4 in the cornea, the lens and the trabeculum. There are pancreatic and cardiac isoforms of NBC1 due to alternative splicing.
A form of proximal tubular acidosis with probably autosomal dominant transmission (OMIM 179830) has been described in humans. The cause of this pathology is unknown.
A mutation affecting the gene coding for NHE3 could be responsible for this disease, the mice invalidated for this gene having a phenotype close to that of the patients.
However, to date, no mutations of NHE3 have been identified in humans.
Mixed proximal and distal tubular acidosis (type 3) (OMIM 259730):
This pathology manifests itself early in childhood, associating mental retardation, cerebral calcifications, osteopetrosis, sometimes fractures, a proximal mixed renal acidosis (decrease in the Tm of the bicarbonates) and distal (defect of proton secretion) . It is an autosomal recessive disease due to an inactivating mutation in the gene coding for carbonic anhydrase type 2. The sites of expression of this enzyme (proximal renal tubule, collector duct and brain interceptor cells ) explain the phenotype of the patients.
Mutations of carbonic anhydrase type 4 have been described (OMIM 114760). They are responsible for retinitis pigmentosa, but patients do not appear to have tubular proximal acidosis.
The causes of hereditary distal tubular acidosis are presented below.
Anomalies of transport of uric acid (OMIM 210150):
Renal elimination of uric acid is a complex process involving both reabsorption mechanisms and secretion mechanisms in the proximal tubule. Four molecules carrying urate have been described to date, two are expressed at the apical pole of the renal cell and two at the basolateral pole.
A mutation on one of the carriers named SLC22A12 / URAT1 is responsible for a tubular urate reabsorption defect, resulting in hypo-uricemia, increased uraturia, and the appearance of renal lithiasis of uric acid.
SLC22A12 / URAT1 is a urate / anion cotransporter expressed at the apical pole of the proximal tubular cell which allows urate reabsorption. The fractional excretions of uric acid, normally between 5 and 10%, can reach 95% in these patients. Episodes of acute renal failure resulting from intense effort have been reported.
The inhibitors of secretion (pyrazinamide) and inhibitors of tubular reabsorption of uric acid (probenecid) do not modify or little the high clearance of uric acid. Subjects with these abnormalities are homozygous for the mutation; however, heterozygous subjects had a higher urine / creatinine ratio in the urine than subjects not carrying the mutation.
Tubulopathies related to malfunction of the cove of Henle:
The cove of Henle is a place of reabsorption of sodium, potassium, chlorine, calcium and magnesium. Sodium, potassium and chlorine are reabsorbed by the Na-K-2Cl cotransporter (SLC12A1) expressed at the apical pole of the loop cells. Potassium is recycled into the tubular lumen through a potassium channel (ROM-K / Kir1,1 / KCNJ1), generating a positive transepithelial potential difference in the lumen.
Sodium leaves the cell at the basolateral pole by Na-KATPase; the chlorine ion is accompanied by chlorine channels (ClC-Ka and CLC-Kb) whose expression is regulated by bartine.
At the basolateral pole of the cell is expressed the calcium receptor (CaSR), which regulates the activity of the Na-K-2C1 and ROM-K transporter. Calcium and magnesium are reabsorbed by the paracellular route under the effect of the potential difference generated by the recycling of potassium. Calcium and magnesium borrow a channel made up of paracellin, a protein of the claudine family, which constitutes intercellular junctions.
Bartter Syndrome:
Bartter syndrome is an autosomal recessive disorder with: hypokalaemia; increased urinary excretion of chlorine, potassium, sodium, calcium, magnesium; normal blood pressure (eliminating primary hypermineralocorticism);hyperaldosteronism with increased renin activity in the plasma; a tendency to metabolic alkalosis. Nephrocalcinosis may occur over time. This table is close to that observed during the chronic intake of loop diuretics (furosemide, bumetanide).
Diagnosis is usually carried in childhood or adolescence. Antenatal form has been described, which additionally combines hydramnios, prematurity, postnatal polyuria, and sometimes changes in facial morphology and an increase in prostaglandin E 2 in blood and urine.
An additional clinical entity with perceptual deafness (sensory neurosensory) was then described.
The pathophysiology of this syndrome is well known now.
A lack of reabsorption of sodium, potassium and chlorine in the cove of Henle leads to the appearance of a secondary hyperaldosteronism which makes it possible to maintain sodium homeostasis but aggravates the loss of potassium.The lack of recycling of potassium due to the reduction in sodium, potassium and chlorine reabsorption prevents the occurrence of a positive luminal potential difference and therefore the reabsorption of calcium and magnesium.
The different forms of the Bartter syndrome correspond to mutations in various genes expressed in the cove of Henlé.
The classical form and the antenatal form are due to inactivating mutations affecting the Na-K-2Cl co-carrier (type 1 OMIM 601678; 600839) located on chromosome 15, the ROM-K potassium channel (type 2 OMIM 241200) chromosome 11, or ClC-K a or b chloride channel (type 3 OMIM 607364) carried by chromosome 1. If the antenatal form was initially associated with mutations of ROM-K, mutations of Na-K-2Cl and ClCK were then observed in this clinical form.
Form 4 (OMIM 602522), which is characterized by perceptual deafness, is due to an inactivating mutation of a regulatory subunit of the ClC-Ka and b channels: bartlet. Bartlet is necessary for proper membrane addressing of these two channels; the deafness is explained by the expression of the ClC-K and the bartlet in the inner ear: the two channels are necessary for the proper functioning of the inner ear. The severity of the clinical picture observed in the mutations of bartine (growth retardation, significant kidney losses) reflects the loss of simultaneous function of the two chlorine channels in the cove of Henle.
A fifth gene may be responsible for a Bartter syndrome when mutated: it is CaSR, located on chromosome 3 (OMIM 601199). The mutation in this case is activating; the activation of the calcium sensor is responsible for an inhibition of the ROM-K channel and of the cotransporter Na-K-2Cl which thus reproduces a Bartter’s syndrome. CaSR activating mutations (see below) are responsible for hypocalcaemia associated with inadequate calciuria. The subjects are heterozygous, the transmission is autosomal dominant.
Primary hypomagnesemia with hypercalciuria (OMIM 603959):
Using a positional cloning method, the cause of hypercalciuric hypomagnesemia with nephrocalcinosis, an autosomal recessive disease, could be linked to a mutation in a gene on chromosome 3, encoding a claudine protein: paracellin or claudine 16. This protein of 305 amino acids is expressed exclusively in the tight junctions of the loop of Henlé and the distal tubule. Patients with this condition, which can lead to renal insufficiency, are homozygous or heterozygous composites. Some authors suggest that the heterozygous state may favor the occurrence of hypercalciuria and renal lithiasis.
Paracellin is a transmembrane protein that, like other claudines, forms paracellular channels that permeabilize tight junctions to specifically pass certain ionic species, magnesium and calcium for paracellin. The consequences of certain mutations on the function of the protein have been studied. These mutations abolish the interaction of paracellin with other proteins, thus preventing the formation of the channel. The tight junctions become impermeable to calcium and magnesium, which can no longer be reabsorbed in the handle.
Calcium receptor mutations CaSR (OMIM 601199):
Calcium receptor CaSR is expressed in the parathyroid glands where it allows the coupling of parathyroid hormone secretion to calcemia. But this receptor is also expressed in different segments of the nephron where it manages inter alia renal reabsorption of calcium. CaSR mutations therefore modify tubular reabsorption. Activating mutations are responsible for hypocalcaemia without the collapse of calciuria. They can lead to Bartter syndrome (see above).Inactivating mutations are accompanied by hypercalcemia without hypercalciuria. The homozygous forms of these mutations give rise to severe phenotypes of neonatal hypo- or hyperparathyroidism. The full description of these pathologies is beyond the scope of this article.
The reader is invited to refer to recent reviews and work.
Hereditary Tubulopathies Affecting the Distal Tubule:
The distal tubule reabsorbs sodium through the Na-Cl cotransporter (SCL12A3 / NCCT), which is inhibited by thiazide diuretics, and calcium. Contrary to what happens in the loop of Henlé, calcium is reabsorbed transcellularly via calcium channels called CaT / Ecac. The amount of calcium reabsorbed is negatively correlated with sodium absorption, and the excretions of calcium and magnesium are dissociated.
Mutations associated with decreased sodium reabsorption in the distal tubule:
Inhibiting mutations of the SCL12A3 / NCCT transporter are responsible for a table evoking the chronic intake of thiazide diuretic: Gitelman’s syndrome (OMIM 263800). This syndrome, close to Bartter’s syndrome, is distinguished by the existence of hypocalciuria and hypomagnesaemia due to increased urinary excretion of magnesium. The association with chondrocalcinosis has been reported.
The SCL12A3 / NCCT gene is located on chromosome 16; the transmission is autosomal recessive.
Transporter Function Gain SCL12A3 / NCCT:
Type 2 pseudohypoaldosteronism, also known as Gordon’s syndrome, is characterized by hyperkalaemia, hypertension, metabolic acidosis, decreased renin and plasma aldosterone (OMIM 145260). All these disorders are corrected by thiazide diuretics, suggesting hyperactivity of the SCL12A3 / NCCT cotransporter. Transporter activator mutations have not been described in this syndrome, but mutations in two genes regulating the activity and expression of SCL12A3 / NCCT have been identified. The mutations affect the WNK1 gene on chromosome 12 and the WNK4 gene on chromosome 17. The role of these two serine threonine kinases is now better understood. WNK4 inhibits the SCL12A3 / NCCT cotransporter in the distal tubule and a ROM-K potassium channel in the collecting channel. WNK4 mutations resulted in a loss of function of this protein and an increase in SCL12A3 / NCCT cotransporter activity and the ROM-K potassium channel. WNK1 is a WNK4 inhibitor. Mutations affecting WNK1 result in a gain in function of this protein, increasing the inhibitory effect on WNK4. Metabolic acidosis in this table is a consequence of hyperkalemia, which inhibits ammoniogenesis in the proximal tubule, preventing proper proton elimination.
Binding studies suggest that a third gene, located on chromosome 1, may also be responsible for some forms of type 2 pseudohypoaldosteronism.
Tubulopathies due to dysfunction of the collecting canal (apart from diabetes insipidus):
Apart from balancing the water balance, the collecting channel plays a central role in the homeostasis of sodium, potassium and protons. Sodium is reabsorbed at the apical pole of the main cells by a sodium channel, ENaC, and exits at the basolateral pole of the cell by Na-K-ATPase, thus coupling this reabsorption with the secretion of potassium ions through a channel apical potassium. The expression of all these proteins is regulated by aldosterone.Type A intercalated cells secrete protons in the tubular lumen and allow the reabsorption of bicarbonates that have not been reabsorbed into the proximal tubule or into the Henlé loop by expression of a proton ATPase and to a chlorine-bicarbonate exchanger.
Changes affecting the sodium channel or its regulatory elements:
The ENaC sodium channel consists of three subunits a , b , c , whose genes are present on chromosome 12 (subunit a ) and 16 (subunits b and c ). Activating and inhibitory mutations of these proteins have been identified.
Mutations with gain of function:
The activating mutations affect subunits b and c . They are responsible for the Liddle syndrome (OMIM 177200), which presents itself as an array of pseudohyperaldosteronism, associating arterial hypertension, hypokalemic alkalosis with low aldosteronemia. Amiloride and triamterene, sodium channel inhibitors, are used to control abnormalities.Spironolactone has no effect.
Mutations with loss of function:
The inhibitory mutations can affect each of the three sub-units of the sodium channel and then give a type 1 pseudohypoaldosteronism of autosomal recessive transmission (OMIM 264350). It is a severe loss of salt syndrome that is insensitive to mineralocorticoids. The amounts of sodium in the urine, sweat and stool are high. The serum potassium is increased, aldosterone and renin are elevated. Evolution is characterized by episodes of vomiting, hyponatremia and respiratory distress.
Inhibitory mutations of the mineralocorticoid receptor give a picture of pseudohypoaldosteronism type 1 similar to the previous one but less severe, of autosomal dominant transmission (OMIM 177735).
Mutations affecting enzymes expressed in the collecting duct:
Given the relative concentrations of mineralo- and glucocorticoids and the respective affinities of the mineralocorticoid receptor for these species, this receptor in the collecting duct should be permanently occupied by glucocorticoids.
The specificity of the action of mineralocorticoids is given by the expression of an enzyme, 11- b- hydroxysteroid dehydrogenase type 1 (gene located on chromosome 16), which converts cortisol to cortisone and whose affinity for the mineralocorticoid receptor is very weak. Inhibitory mutations of this enzyme are responsible for a permanent stimulation of the mineralocorticoid receptors by glucocorticoids, giving rise to a syndrome of apparent excess of mineralocorticoids responsible for hypertension with low hypokalemia, renin and aldosterone (OMIM 218030).
Distal tubular acids:
These acidases are characterized by a defect in the secretion of protons in the collecting duct. They are due to mutations in various proton-proton-ATPase subunits or in bicarbonate transporters (chlorine-bicarbonate exchanger).
The metabolic acidosis table is usually patent in the basal state. An acidification or bicarbonate loading test may eventually uncover the disorders.
These tests are of interest only in the absence of kidney failure.
Autosomal recessive distal tubular acids:
Two forms have been described. The first is accompanied by deafness of perception (OMIM 267300). It is due to a mutation on the ATP6B1 subunit gene of a proton-ATPase located on chromosome 2, expressed in the inner ear and in the collecting duct. The second is not accompanied by deafness (OMIM 602722). It is due to a mutation on the gene of another proton-ATPase subunit (ATP6N1B) located on chromosome 7. Hearing losses during evolution have been described in this latter form. In addition to acidosis, which requires alkaline intake, these patients may have renal lithiasis and a progression to renal insufficiency.
Autosomal dominant distal tubular acidosis (OMIM 179800):
This type of acidosis is due to an inhibitory mutation of the basolateral chlorine-bicarbonate exchanger (SLC4A1) identified as part of the proteins of the band 3 of the red blood cell. The renal and erythrocytic isoforms are encoded by the same gene, but from different promoters.
Some mutations are thus responsible for abnormalities in the shape of the red blood cell (spherocytosis). The gene is located on chromosome 17.