Cecil Alport described a syndrome of hereditary nephritis with haematuria and deafness in a British family in 1927 [3]. He thought the nephritis was due to an infection but we now know that it and the deafness are due to a mutation of one of the type IV collagen genes. The abnormal collagen disrupts the structure of membranes in the glomerulus (see Fig. 7.1) and in the organ of Corti in the cochlea.

Alport reported that: “The male members of a family tend to develop nephritis and deafness and do not as a rule survive. The females have deafness and haematuria and live to old age.” The type IV alpha 5 collagen gene is located on the X-chromosome, explaining why males are severely affected whereas female heterozygotes are less so.

The presentation of nephritis in males can vary. As Alport reported: “The last couple of cases are interesting evidence of the variations in the course of nephritis. The kidneys of two members of the same family were attacked, apparently by the same organism, at the same time, and under exactly the same conditions. The elder brother contracted acute nephritis, which cleared up completely; the younger developed parenchymatous nephritis, passing into small white kidney, and ending in death.”

Alport did not refer to the eye abnormalities that can accompany the syndrome: a misshapen lens (anterior lenticonus ) and abnormal colouration of the retina. These rarely lead to loss of vision [4].

A number of conditions have been described within the Alport syndrome family, involving mutations of genes coding for different protein chains that together form type IV collagen. They are mostly X-linked recessive. Some have autosomal recessive inheritance – homozygotes have the syndrome whereas heterozygote carriers are unaffected or have thin glomerular basement membrane nephropathy (see Patient 11.​1). A small number show autosomal dominant inheritance, heterozygotes being affected.

Numerous genetic abnormalities, both dominant and recessive, have been described in children with congenital nephrotic syndrome. The age of onset depends upon the gene affected and whether one or both alleles are affected. If the presentation is before 3 months of age, the cause is invariably genetic [5]. The nephrotic syndrome is steroid-resistant and often progresses to renal failure (see Patient 9.​1).

The gene mutations lead to abnormal proteins in the basement membrane or the podocytes and have helped to identify the role of these proteins in the glomerular filtration barrier . For example, in the Finnish type of congenital nephrotic syndrome there is an abnormality of nephrin , a transmembrane protein in the slit diaphragm between the podocyte foot processes. Other causes are mutations in the genes coding for laminin and podocin (Fig. 7.2).

The majority of the reabsorption and secretion of solutes occurs in the proximal tubule [7]. The surface area of the tubule is maximised by the brush border microvilli on the epithelial cell surface. The main features of the genetic disorders that disrupt solute transport are polyuria and the loss of electrolytes, sugar or amino acids into the urine. Table 7.1 describes some of the more common disorders.

The loop of Henle is the part of the nephron which enables urine to be concentrated and water conserved [8]. In the thick ascending limb, sodium, potassium and chloride ions are reabsorbed by transporter proteins but water cannot follow [9]. Ions are trapped within the interstitium of the medulla, creating a concentration gradient. The hyperosmolar environment in the deep medulla draws water out of the collecting duct.

Mutations of the genes that code for transporter proteins lead to a condition called Bartter syndrome . The effects are similar to the action of loop diuretics such as furosemide , which blocks the transport of sodium, potassium and chloride into the cells of the thick ascending limb.

Abnormally large amounts of sodium ions flow from the loop of Henle into the distal tubule where they are reabsorbed in exchange for potassium and hydrogen ions. Hence the patient, usually a child, has polyuria, hypovolaemia, hypokalaemia, hypochloraemia and metabolic alkalosis.

Because calcium and magnesium normally are reabsorbed with sodium and chloride in the thick ascending limb, there is also hypercalciuria and hypomagnesaemia.

There are five types of Bartter syndrome with varying renal and extrarenal manifestations [10].

The main function of the distal convoluted tubule is the reabsorption of sodium and chloride, as well as some calcium and magnesium [11]. The sodium/chloride transporter is blocked by thiazide diuretics such as bendroflumethiazide. An autosomal recessive mutation that leads to loss of its function causes similar effects, a condition called Gitelman syndrome [10]. Compared to Bartter syndrome, the salt loss and volume contraction is less severe. The condition usually presents in older children and adults when hypokalaemia and metabolic alkalosis are detected incidentally on a U&E result. In contrast to Bartter syndrome and in line with the effect of thiazides, calcium excretion is reduced.

The opposite of Gitelman syndrome is Gordon’s syndrome (pseudohypoaldosteronism type 2, PHA2 ), an autosomal dominant condition in which the sodium/chloride transporter is overactivated. Excessive sodium reabsorption results in high blood pressure. Reduced potassium and hydrogen ion excretion leads to hyperkalaemia and metabolic acidosis. Thiazide diuretics effectively counteract the abnormalities in Gordon’s syndrome.

The collecting duct has two cell types:

The principal cells contain membrane channels that selectively allow sodium and water to enter the cell and potassium to leave. Sodium is then pumped out through the basal membrane by the Na/K ATPase. An autosomal dominant mutation prevents the epithelial sodium channel being removed from the cell membrane leading to increased absorption of sodium and excretion of potassium and H+. This results in high blood pressure, hypokalaemia and metabolic alkalosis – Liddle syndrome – which is counteracted by amiloride , a potassium-sparing diuretic .

The sodium and potassium channels and the Na/K ATPase in the basal membrane are regulated by aldosterone. Its overall effect is to increase sodium reabsorption and potassium excretion. Mutations of the gene coding for the sodium channel make it unable to respond to aldosterone – pseudohypoaldosteronism type 1 (PHA1) . This results in the opposite of Liddle syndrome – salt wasting, hyperkalaemia and acidosis, like Addison’s disease.

The water channel (aquaporin 2 ) is controlled by the antidiuretic hormone , vasopressin , acting on its receptor. Mutations in the genes that code for the vasopressin receptor or for the water channel lead to hereditary nephrogenic diabetes insipidus . Because the ability to concentrate the urine is lost, the patients have polyuria and nocturia. Urine osmolality is low and plasma osmolality inappropriately raised. This stimulates thirst, leading to polydipsia and preventing severe hypernatraemia.

The intercalated cells break down carbonic acid to H⁺ and bicarbonate via a reaction catalyzed by carbonic anhydrase. The H⁺ ions are actively pumped into the urine by an H⁺ ATPase. The bicarbonate ions are carried to the blood by a Cl⁻/HCO₃ ⁻ anion exchanger. Genetic mutations causing loss of function of either of these mechanisms leads to distal (type 1 RTA). The H⁺ ATPase is also present in the inner ear, hence autosomal recessive mutations cause distal RTA with congenital sensorineural deafness.

The inappropriately alkaline urine in distal RTA leads to the precipitation of calcium in the urine as stones or within the kidney tissue as nephrocalcinosis . In adults, this syndrome is more commonly an acquired defect associated with autoimmune diseases.