CHAPTER OUTLINE

Most patients with renal disease have some element of renal tubular involvement, but the other manifestations of the disease tend to be clinically more obvious and important. However, in a small number of patients, the clinical picture results primarily from a disorder of renal tubular function. These disorders can be inherited or acquired, and can affect tubular handling of a limited number of specific substances or encompass more generalized defects.

Renal tubular defects are conveniently considered with renal stone formation, since calculi sometimes form as a result of one of these conditions.

Hereditary renal tubular disease includes certain developmental disorders of the tubules, for example polycystic renal disease and medullary cystic disease. While these can result in disorders of renal function, including renal tubular function, they will not be considered in detail here. Renal tubular physiology will be discussed briefly, followed by a discussion of some well-recognized functional disorders of the renal tubules.

Glucose is absorbed with sodium ions in the early part of the proximal tubules, in a secondary active transport process. Glucose and sodium bind to a common carrier protein (SGLT 2, see later) in the luminal membrane and sodium moves down its electrochemical gradient, carrying glucose into the cell. Na⁺,K⁺-ATPase in the non-luminal (basolateral) membrane of the tubular cells pumps the sodium ions out into the interstitial fluid, while glucose is transported in the same direction by the glucose transporter GLUT 2.

Amino acids are also reabsorbed in the early part of the proximal renal tubules, again by a secondary active transport system linked to sodium reabsorption. There appear to be separate cotransporter proteins for certain groups of amino acids, although some of these probably have overlapping specificities. The process is driven by the Na⁺,K⁺-ATPase in the basolateral membrane pumping sodium out of the cell, with amino acids leaving by passive or facilitated diffusion.

Glucose is freely filtered at the glomeruli, but is normally then reabsorbed in the proximal tubules so that it is undetectable in urine. If plasma glucose concentrations rise to greater than ~ 10 mmol/L or if the glomerular filtration rate increases (as in pregnancy), then the capacity of the proximal tubules to reabsorb filtered glucose is exceeded and glycosuria occurs.

Generalized defects in renal tubular function may also result in glycosuria (see later), but a small group of people appear to have an isolated defect of tubular glucose reabsorption.

Patients with this condition excrete a variable amount of glucose in their urine at normal plasma glucose concentrations. Other aspects of carbohydrate metabolism are not affected: glucose tolerance and plasma insulin concentrations are normal. The condition is inherited in an autosomal recessive manner, and two major phenotypes have been identified (types A and B), based on the exact changes in the kinetics of glucose reabsorption. Hereditary renal glycosuria is rare, and is generally recognized to be a benign condition with no clinical sequelae.

The reabsorption of glucose in the proximal renal tubules is similar to the absorption of glucose in the intestine. There is a Na⁺,D-glucose cotransporter on the luminal cell wall to transport glucose into the cell, with a facilitated glucose transporter (GLUT 2) on the basolateral membrane to enable the glucose to exit. The intestinal form of the Na⁺,D-glucose cotransporter (SGLT 1) and its gene have been well characterized, but, while the corresponding renal cotransporter (SGLT 2) is known to differ from SGLT 1, its identity in humans is less well established. Nevertheless, it is assumed that mutations in the gene for SGLT 2 cause hereditary renal glycosuria by interfering with the uptake of glucose in the proximal tubules.

There is a corresponding condition affecting SGLT 1 in the gut. This cotransporter is involved in both glucose and galactose absorption, and the classic presentation is with life-threatening diarrhoea in early infancy due to glucose and galactose malabsorption (familial glucose–galactose malabsorption). There is often an associated mild renal glycosuria, although in hereditary renal glycosuria there is no corresponding effect on the gut.

Mutations affecting GLUT 2, which facilitates transport of glucose, galactose and fructose across the basolateral membrane, are another rare cause of renal glycosuria (Fanconi–Bickel syndrome).

Amino acids are normally freely filtered at the glomeruli and then almost entirely reabsorbed in the proximal convoluted tubules. There is a maximal capacity to each reabsorptive mechanism and, in most patients with amino aciduria, some extrarenal disorder leads to accumulation of amino acid(s) in the plasma, that exceeds the reabsorptive capacity of the tubules, with consequent ‘overflow’ amino aciduria. However, as with glycosuria, generalized defects in renal tubular function can result in amino aciduria, and there are also some isolated defects in the reabsorption of particular groups of amino acids.

Cystinuria is the classic example of an amino aciduria due to a defect in renal tubular function, in that the amino aciduria occurs at normal or even low plasma concentrations of the amino acids involved.

The only known clinical manifestation of cystinuria is recurrent urinary tract stone formation, the name ‘cystine’ coming from the original (erroneous) assumption that the source of these stones was the bladder. Cystine stones form readily in acidic urine. They are yellow-brown in colour and are radio-opaque because of their sulphur content, although they are less radio-dense than calcium-containing stones. There may also be some calcium deposition if there is infection secondary to the calculi. They tend to occur as staghorn or multiple recurrent stones and often require some form of surgical intervention or lithotripsy (fragmentation of stones by external shock waves). Patients with cystinuria also have a higher incidence of calcium oxalate stones than the general population. All stone formers should, therefore, be screened for cystinuria, preferably by formal amino acid measurement in the urine, as qualitative screening tests are not sufficiently sensitive. The intestinal defect appears to cause no clinical problems.

Cystinuria occurs with equal frequency in both sexes, although males tend to be more severely affected. It may present at any time from the first year of life up to the ninth decade, with a peak incidence in the second and third decades. The prevalence of cystinuria varies between racial groups and according to whether the figures are taken from neonatal amino acid screening programmes or from known cystinuric stone formers (immaturity of the renal tubules in the first few months of life may lead to some heterozygous infants having urinary cystine outputs in the homozygous cystinuria range, leading to misclassification). However, the worldwide prevalence is estimated to be 1 in 7000, making it a relatively common inherited metabolic disorder.

The mode of inheritance is autosomal recessive, although in some families it appears to be incompletely recessive, with heterozygotes excreting more urinary cystine, ornithine, arginine and lysine than normal, although less than in the homozygous state. In the past, this has led to attempts to classify cystinuria into type I (homozygous for the fully recessive form) and types II and III (variants of the incompletely recessive form), based on combinations of the relative amounts of the amino acids excreted in the urine and/or the intestinal uptake of cystine and dibasic amino acids. The discovery of the genes involved in the recessive and the incompletely recessive forms of cystinuria has made this classification clearer, although the situation is not yet completely resolved.

The gene involved in type I cystinuria codes for a protein known as rBAT (a loose acronym for ‘related to the b^0,+ amino acid transporter’, with the term b^0,+ signifying broad specificity for neutral (0) and dibasic (+) amino acids). rBAT is a membrane glycoprotein that is one of the activating components of a heteromultimeric transporter for cystine and dibasic amino acids. The gene for rBAT (SLC3A1) is located at 2p16.3-p21, and, to date, more than 120 different mutations have been identified in it in patients with type I cystinuria.

A second cystinuria locus, accounting for non-type I forms of cystinuria, has been identified by linkage analysis at chromosome 19q13.1–13.2. This gene (SLC7A9) encodes a protein that acts as the amino acid transporting subunit of the membrane complex. More than 95 gene mutations have been identified. Most, but not all cases of cystinuria can be explained by mutations in SLC3A1 and SLC7A9.

Healthy individuals excrete < 10 μmol cystine/mmol of creatinine (< 130 μmol/24 h). Patients with homozygous cystinuria usually excrete > 1700 μmol/24 h and may excrete up to 5000 μmol/24 h. Heterozygotes may have an entirely normal amino acid excretion pattern in the urine or may excrete up to 1700 μmol cystine/24 h, in which case they may produce stones.

Occasionally, in spite of both medical and surgical treatment for stone formation, cystinuria causes sufficient renal damage to result in established renal failure. In this case, renal transplantation may be effective, since the donor kidney should not be affected by the amino acid transport defect and the patient should, therefore, remain disease free.

The original description of Hartnup disease included a pellagra-like skin rash, transient cerebellar ataxia and constant renal amino aciduria. Some affected individuals have also shown psychotic behaviour, while others have learning disabilities. The pellagra-like rash and its response to nicotinamide suggest that the clinical features of the disease may be due to failure to absorb tryptophan in the intestine and reabsorb it in the renal tubules, leading to a deficiency of nicotinamide. However, investigation of siblings of individuals with Hartnup disease and the results of neonatal urine amino acid screening programmes both suggest that the typical amino aciduria (Hartnup disorder) may exist without the features of Hartnup disease. It would appear that Hartnup disorder is an autosomal recessive inherited condition, but that this is not expressed clinically without the presence of certain other genetic or environmental influences, such as poor nutrition. The causative gene, SLC6A19, is located on chromosome 5p15.33 and codes for a sodium-dependent neutral amino acid transporter.

A further example of a specific abnormality in renal tubular reabsorption causing a distinct pattern of amino/imino aciduria occurs in familial renal iminoglycinuria. The primary genetic defect is a mutation in either the SLC36A2 gene, which codes for a high affinity glycine, proline and hydroxyproline transporter, or the SLC36A1 gene, which codes for a low affinity transporter. However, the phenotype is variable as it may be modified by mutations in at least three other genes. Some reabsorption of these amino acids can still occur via the transport system that is not affected in any individual patient.

The condition, which is benign, is autosomal recessive, although some heterozygotes are ‘incomplete’ and have hyperglycinuria. In some but not all homozygotes, impaired intestinal transport of proline can be demonstrated.

Neonatal screening for amino acidurias suggests that familial renal iminoglycinuria occurs in 1 in 15 000 live births in a Caucasian population. However, it should be appreciated that in healthy neonates, the renal tubular reabsorption of proline, hydroxyproline and glycine is less efficient than in adults; imino aciduria normally disappears by three months and hyperglycinuria by six months of age.