Cystinuria

By David S Goldfarb, M.D.
Director, Kidney Stone Prevention Program, St. Vincents Hospital
Professor of Medicine and Physiology, NYU School of Medicine

First published in:
ENCYCLOPEDIA OF LIFE SCIENCES

© Macmillan Reference Ltd

Cystinuria accounts for 1% of kidney stones. Two of the genes responsible for the disorder, SLC3A1 and SLC7A9, have been identified. The identification of SLC3A1 made cystinuria the first disorder of amino acid transport with an identified gene.

Introduction

The physiological organization of the kidney requires that the renal tubules reabsorb significant proportions of the solutes contained in the filtrate formed across the glomerular basement membrane. Cystinuria is a disorder of the proximal tubule’s reabsorption of filtered cystine and dibasic amino acids (lysine, ornithine, arginine). Cystine, first identified as a component of a unique form of urinary tract stone in 1810, is poorly soluble, unlike the other amino acids whose absorption is affected. The inability of cystinuric kidneys to reabsorb cystine leads to the amino acid’s relatively high concentration and subsequent precipitation in the urine and the formation of urinary tract stones. Although kidney stones affect as many as 12% of males and 7% of females in Western societies, most stones are composed of calcium salts; cystinuria accounts for no more than 1% of urinary tract stones. Yet the associated stone formation is often notable for the frequency of recurrence and the large size of the stones. The genetic locus for the classical recessive form of cystinuria has been identified. Mutations of this gene account for defective absorption of cystine and dibasic amino acids in the renal proximal tubule. The identification of this mutation for cystinuria makes it the first abnormal gene that is the basis of a disease of amino acid transport. A second gene, which when mutated accounts for other cases of cystinuria, and may, in rare cases, cause an autosomal dominant form of the disease, has also been discovered.

Pathophysiology of the Disease

Genetics

Cystinuria is a genetic disorder that classically demonstrates autosomal recessive inheritance. This means that an abnormal gene must be inherited from both parents for the disease to be manifested, and that the disorder is not sex-linked. Most cases have been shown to involve mutations in genes called either SLC3A1 or SLC7A9. The parents of a patient with cystinuria are heterozygotes, with one defective gene and one normal one, and do not, in cases with mutations of SLC3A1, have manifestations of the disease. Instead, they are carriers and, should they reproduce with another carrier, will pass the disease on to 25% of their offspring. There are some more unusual families, with mutations in SLC7A9, that manifest autosomal dominant inheritance with one defective gene sufficient for cystine stone formation.

Early studies of families with affected members suggested that there were at least three types of cystinuria (Rosenberg et al., 1966). The three types were based on measurements of urinary cystine excretion in the parents of affected children (obligate heterozygotes for the dysfunctional gene), as well as of the patients themselves. The type I patients were those with the highest urinary cystine excretion. The patients had no increase in plasma levels of cystine following oral intake of cystine, demonstrating that intestinal absorption was also defective. This was also confirmed by studying cystine transport in intestinal epithelial cells taken from biopsies of affected patients. Most patients were in this class. The parents of these type I patients were silent carriers who had normal amounts of cystine in the urine (0 to 100 ?mol of cystine per gram of creatinine). Patients with type II cystinuria had some cystine transport across intestinal epithelial cells, but again, no increase in plasma cystine levels was seen after oral loading. The type III patients had reduced amino acid uptake by intestinal cells compared with unaffected people, but enough remained so that plasma levels rose after oral loading. The parents of type II patients had marked increases in urinary cystine excretion that appeared high enough to cause occasional stone formation (>900 ?mol of cystine per gram of creatinine). These occasional heterozygote cystine stone formers could be considered to have an incompletely recessive, or semi-dominant disease. The type III parents, obligate heterozygotes, had a milder elevation in urinary cystine excretion compared with that of the type II parents (100-900 ?mol of cystine per gram of creatinine). Since the classification preceded identification of the affected genes, the genetic basis for the varying phenotypes was not clear. The continued utility of this classification scheme is currently being reassessed as studies correlating manifestations of the disease, or phenotype, to the genetic abnormalities proceed (Leclerc 2002). It may be more useful to refer to type I and non-type I cases.

Genetic studies, called linkage analyses, of DNA from families with cystinuria were used to identify a defective gene located on human chromosome 2p (Lee et al., 1993). When the DNA from the affected chromosomal location is injected into frog eggs, transport of cystine and dibasic amino acids from outside the egg to the inside occurs more rapidly than before the DNA injection (Palacin et al., 1996). This confirmed that the injected DNA sequence is a gene that codes for a protein important for cystine transport across membranes. The name of the gene that codes for the cystine transporter, originally termed rBAT (‘related to b0,? amino acid transporter’; see below), is now SLC3A1 (SLC3 for solute carrier family 3) in the international Genome Data Base. Some investigators continue to use the rBAT designation for the class of similar genes encoding basic amino acid transporters in other systems, and for the protein products of the genes as well. The normal SLC3A1 gene appears to encode a 663-amino acid heavy subunit of the cystine transporter which is required for the complete transporter to work properly. The protein has sugar groups attached to it, which makes it a “glycoprotein”.

More than 40 mutations have been demonstrated in the SLC3A1 gene to account for cystinuria. The nature of the observed mutations is variable and includes several different mechanisms of disrupting normal protein synthesis. These include both small and large deletions of DNA base pairs from the gene (Saadi et al., 1998). One of the most common genetic alterations in SLC3A1 is called M467T. It codes for an amino acid substitution in the transport protein of threonine for methionine at position 467. This abnormal gene is relatively common in Mediterranean populations. It accounts for 40% of the abnormal genes in a Spanish cohort of families. It is relatively rare, however, in a well-studied group of patients in Quebec, Canada.

From studies designed to correlate specific abnormal genotypes with phenotypic presentation in the Canadian patients, it is evident that type I cystinurics have mutations in both of their SLC3A1 genes (Goodyer et al., 1998). The two mutations each patient inherits may be but are not necessarily the same; a different mutation in the same gene may be inherited from each of the parents to cause the disease.

The Libyan Jews studied in Israel, and some Italian families with a relatively high incidence of cystinuria, have either type II or type III cystinuria and do not have mutations in SLC3A1. Instead, from linkage analyses, these populations were found to have mutations located on the long arm of chromosome 19 (19q). A second mutation coding for cystinuria was found here and called SLC7A9 (Feliubadalo et al., 1999). The normal SLC7A9 gene encodes a 487 amino acid subunit of the cystine transporter called b0,? AT (AT, for amino acid transporter). It therefore appears that mutations in SLC7A9 are responsible for cases previously designated as Type II or Type III. The cause of the differences in the phenotypic manifestations of these two categories with apparently identical genotypes is unclear. More than 30 mutations in this gene have been identified. The most common mutation in the Libyan Jews resulted in a methionine replacing the expected valine amino acid residue (V170M) in the protein.

More recent studies demonstrate that Type I phenotypes are actually caused in some patients by one mutation in SLC3A1 and a simultaneous mutation in SLC7A9 (Leclerc 2002a). Another gene, SLC7A10, on chromosome 19q, may also account for some non-Type I cases (Leclerc 2002b).

Cystine transport

Kidney

Amino acid reabsorption, including that of cystine, is nearly complete by the end of the proximal tubule. Only 0.4% of the filtered cystine appears in the urine. This fractional excretion rises from 0.4% in normal people to 100% of the filtered load or more (implying some cystine secretion) in patients with cystinuria. Cystine transport has been studied in cell membranes taken from the proximal renal tubule of humans, rats and rabbits. There appear to be at least two transport systems for cystine absorption. The one affected in cystinuria is a high-affinity system which mediates uptake of cystine and the dibasic amino acids at the apical, or brushborder membrane of the straight, third segment (S3) of the proximal tubule (figure 1). This high-affinity process is augmented by a low-affinity process which transports only cystine and not the dibasic amino acids. It is present in the earlier convoluted tubule (S1 and S2) of the proximal tubule (Palacin et al., 1996). The gene coding for it has not yet been identified though one suggested possibility is that the SLC7A9 product codes for a subunit of this low-affinity transporter (Goodyer 2000). Its definitive involvement in any cases of cystinuria has not yet been demonstrated. After uptake across the apical membrane each molecule of cystine is reduced intracellularly to two molecules of cysteine (figure 2) which exit the cell across the basolateral membrane.

The mechanism of cystine uptake activated by the SLC3A1 and SLC7A9 products has beenintensively studied in frog egg cells and cultured renal epithelia. The characteristics of the system resemble those of a system, termed b0,?? of neutral (0) and dibasic (?) amino acid transport (denoted by the superscripts) studied in mouse blastocysts. Unlike uptake of other solutes such as glucose, and other amino acids such as glycine, cystine transport is sodium-independent, so that its uptake can proceed without the presence of sodium in the tubular lumen. Instead, it appears to require the exchange of cystine outside the cell, moving into the cell, for neutral amino acids, such as alanine inside the cell, moving out. The transport process is electrogenic, meaning that it generates a charge across the membrane. Since at the pH of the tubular fluid the amino groups of cystine and the basic amino acids are protonated and have a positive charge, the effect of cystine absorption is to depolarize the relatively negative cell interior, i.e. to make the cell interior less negative. The movement of cystine or cysteine out of the tubular cells and into the blood does not appear to be affected in cystinuria.

The DNA sequence of the SLC3A1 gene is predicted to produce a protein that would differ from most other well-studied amino acid transporters in that it would traverse the cell membrane relatively infrequently with only three or four transmembrane domains, or segments. This makes it unlikely to be a typical membrane channel. The protein also has several sites that could have sugar residues attached, a post-translational process called glycosylation that may be important for normal function or regulation. The effect of specific mutations is now being studied. One recent study suggests that the M467T mutation leads to an impairment in glycosylation of the protein after its synthesis in the endoplasmic reticulum of the cell (Chillaron et al., 1997). Interrupted movement of the synthesized protein from the endoplasmic reticulum to the cell membrane has been demonstrated.

The SLC7A9 product b0,? AT is predicted to cross the cell membrane with 12 transmembrane domains. This protein is a member of a class of proteins called glycoprotein-associated amino acid transporters: the gpaAT family (Verry 2003). In this case, the protein interacts via covalent bonds with the normal SLC3A1 product, the glycoprotein rBAT. The two proteins join via a sulfide bridge between them to form a heterodimer composed of light (b0,? AT) and heavy (rBAT) components. Placing both genes into cells in tissue culture leads rBAT to appear at the cell surface instead of being blocked after its synthesis in the endoplasmic reticulum. Uptake of the dibasic amino acid arginine can also be demonstrated when both genes, but not one, are present in cultured cells. The SLC7A9 product b0,? AT is the catalytic subunit, while rBAT is required to place the transporter in the membrane. Other mutations in SLC3A1 and SLC7A9 may more effectively abolish the synthesis of the protein products.

The failure to reabsorb the relatively poorly soluble cystine can lead to stone formation when the concentration of cystine exceeds cystine solubility. Crystals of cystine precipitate from solution and probably adhere at some point to the urinary epithelium, the cells that line the collecting system of the kidney. The mechanisms that cause crystals to adhere and initiate stone formation, rather than pass into the urine without harm, are poorly understood. Only recently have interactions been demonstrated between cell membranes and calcium oxalate crystals (far more common than cystine crystals). Whether these phenomena studied in cell culture are relevant to the human calcium stone disease, and whether they relate to cystine stone formation are not yet known. Another study of calcium oxalate stone formation has shown that crystals may form in the renal interstitium, the tissue in between the nephrons and vasa recta, and then erode through to the urinary space where they presumably grow larger (Evan). Again, the relevance of this interesting phenomenon to cystinuria is not known and not yet studied.

Wherever they first form, or nucleate, crystals may grow, as additional cystine joins at the crystal surface, and they may aggregate, as larger crystals begin to join and stick to each other. Crystal formation, growth and aggregation are more likely when urine is supersaturated with cystine. Supersaturation is a ratio of the activity of cystine in a given urine to the activity of cystine at equilbrium, when no more cystine can be dissolved in a urine sample (Nakagawa 2000). Values greater than 1 represent supersaturated solutions, and presumably a higher risk for stone formation and growth. Values less than 1 represent undersaturated urine and should be associated with less stone activity. Factors affecting supersaturation include the concentration of cystine (so that greater urine volume leads to lower supersaturation) and pH so that high urinary pH (more than 7.0) reduces supersaturation. With a protein-containing diet, urine pH averages about 6.0 for a 24-hour period, and may be as low as 4.5–5.5 between meals. These low values cause higher supersaturation values and can cause cystine precipitation and stone growth.

Eventually crystal aggregates are large enough to be called stones; they can be large enough to be seen without a microscope. Larger stones that break free of their attachments to the cells lining the collecting system can then impair the flow of urine and cause pain when in the urinary tract. It is important to note, however, that disease activity does not correlate perfectly with urinary cystine concentration or pH. Patients may experience stone formation only sporadically and some, despite having two genes for cystinuria, may never form a stone. Other patients with identical genotypes, may have onset of stone disease at different ages and with differing severity. The other variables that influence stone activity are unknown and may include promoters or inhibitors of cystine precipitation, aggregation or adherence to epithelia.

Intestine

The high-affinity cystine transporter composed of the heavy (rBAT) and light subunits (b0,? AT) is also present in the apical brushborder membranes of the jejunum where it mediates absorption of cystine, dibasic amino acids and some neutral amino acids as well. Although cystine absorption by the intestine following an oral cystine feeding is impaired in most patients with cystinuria, cystine deficiency is not clinically significant. This is because the intestine’s absorption of oligopeptides, short amino acid chains, is intact. Adequate cystine, as well as the other affected dibasic amino acids (ornithine, lysine and arginine), can be absorbed in this form, combined with other amino acids. Plasma levels of these amino acids may be normal, or slightly reduced. Dietary methionine, the absorption of which is not affected by cystinuria, serves as a precursor for the body’s cystine requirement. One study of sulfur-containing compounds and sulfate balance in cystinurics demonstrated decreased urinary excretion of sulfates, and decreases in glutathione in white blood cells, suggesting a deficiency in intracellular cystine and cysteine (Martensson et al., 1990). Though glutathione is an important antioxidant, no clinically significant consequence of the abnormal sulfur metabolism and loss of urinary amino acids has been demonstrated in people with cystinuria.

Frequency and Clinical Importance

Cystinuria accounts for no more than 1% of all kidney stones, yet it is one of the most common genetic diseases. It is estimated that the gene is carried by as many as 0.01% of the general population, with the disease occurring in 1 in 7000 people. The Jews of Libyan origin studied in Israel are found to have the disease in as many as 1 in 2500. The United States has a lower incidence of about 1 in 15 000 people. The incidence of stones in patients with cystinuria is not perfectly known since not all people with two genes coding for cystinuria actually form a stone. Patients with type I cystinuria appear much more likely to form stones in their early years but most patients with type II or III usually do not form stones until they are older (Goodyer et al., 1998). The Quebec Genetic Network Neonatal Screening Program screens all newborns for cystinuria. The incidence of persistent cystinuria was 562 cases per million infants, a rate seven times higher than for clinically manifested cystinuria in the adult population of Quebec. This confirms that many cystinurics will not form kidney stones.

Major Clinical Features and Complications

Diagnosis

The only clinically significant feature of cystinuria is recurrent nephrolithiasis. (The disease should be distinguished from cystinosis, which is marked by the intracellular accumulation of cystine in tissues.) The urine in patients with cystinuria usually demonstrates cystine crystals (figure 3), which have a flat, hexagonal appearance in acid urine. The resultant stones are pale yellow in colour (figure 4). In alkaline urine, the crystals are soluble and therefore not seen. They should therefore be sought in the first morning urine, which tends to be the most acid and concentrated. Their appearance in the urine is the simplest way to make the diagnosis since they are not seen in people without the disease. Normal adults excrete less than 25 mg (100 ?mol) of cystine for every gram of creatinine excreted. (Creatinine is a waste product of muscle metabolism, the excretion of which does not vary from day to day). Homozygous Type I cystine stone formers excrete more than 250 mg (1 mmol) per gram of creatinine.

All patients who experience an episode of nephrolithiasis, but particularly children and those with a first episode before the age of 30, should be screened for cystinuria. This is conveniently accomplished by the addition to urine of sodium cyanide and sodium nitroprusside, which in the presence of cystine form a purple-red colour. The test is sensitive to cystine excretion as low as 75 mg per gram of creatinine. The test may therefore detect some asymptomatic heterozygote type II or type III parents, who themselves may very infrequently form a stone. The test may also detect children who are heterozygotic for the defective SLC7A9 gene. These children may have higher levels of cystine excretion in their first year of life so that they resemble type I homozygotes. As they mature, their cystine excretion falls to levels consistent with homozygous type II or III cystinuria, and they are much less likely to form stones (Goodyer 1993).

Clinical course

The age of onset of stone formation appears to depend on the patient’s genotype. In the patients studied in Quebec, more than 50% of untreated type I patients had a first stone episode in the first decade of life (Goodyer et al., 1998). This finding was in contrast to the patients with type II or III cystinuria who did not have stones in their first decades. The type I patients had higher cystine excretion rates, and were more likely to have urinary cystine concentrations that exceeded predicted cystine solubility at the pH of the collected urine.

The frequency of recurrent stones in an individual can range from only a few stones in a lifetime to many stones each year. Similarly the size of stones ranges from ‘gravel’ passed frequently and with little discomfort, to ‘staghorn’ calculi. These relatively massive stones fill the collecting system of the kidney, with branches extending into the calyces to resemble a deer’s antler. Possible complications of all stones include obstruction of the urinary tract, which usually presents with severe, sudden onset of flank pain. Blood in the urine may be noted, and on occasion, obstruction can predispose to infection of the urine as well. In such cases, fever may be apparent, and white blood cells are noted in the urine. Unrelieved obstruction leads to renal dysfunction, but since this rarely affects both kidneys simultaneously, renal failure and the need for dialysis are quite rare. In the most extreme instances, the combination of obstruction and infection may lead to nephrectomy, removal of a kidney. Patients with a single kidney are at greater risk for renal failure should the remaining kidney become obstructed. Many stones may be detected by imaging studies and remain asymptomatic for many years, with the factors causing stones to break off and fall into the urinary tract remaining unknown.

Cystine stones are most often at least partially radioopaque, meaning that they do not allow full penetration of X-rays and do appear on plain radiographs. This is because of the density of the molecule’s disulfide bond. They may be less dense than calcium stones. Occasionally, some cystine stones are better demonstrated by ultrasound of the kidneys or by helical computed tomography (CT). CT is rapidly becoming the imaging procedure of choice for all stones, because of its unmatched diagnostic sensitivity and speed (Dalrymple 1998). Its relatively high cost remains an impediment to its more widespread use. However, cost is falling as the procedure requires no injection and less technician time, and often preempts the need for additional diagnostic testing. Both CT and ultrasound, unlike plain radiographs, may be useful to demonstrate hydronephrosis (dilatation of the urinary tract), when symptoms of obstruction occur. The traditional intravenous pyelogram (IVP), which requires injection of a potentially nephrotoxic radiocontrast agent, is still used for demonstrating the anatomy of the urinary tract, particularly if a surgical procedure is likely to be needed.

Approaches to Management

Medical therapy

There are two goals of the treatment of cystinuria designed to prevent stone formation. The first is to alter the characteristics of the urine so that the large amount of cystine excreted is maintained in a soluble state, in order to avoid its precipitation. The second goal is to reduce the absolute amount of cystine excreted (Barbey 2000). The latter is more difficult to achieve. Increasing urine volume by increasing oral fluid intake may suffice in some cases to lower cystine concentration and avoid stone formation. A standard estimate of cystine solubility is that 250 mg (1 mmol) can be dissolved in 1 litre of urine. Urinary cystine excretion in 24 hours can be measured and oral fluids prescribed to maintain a concentration less than 250 mg L?1. Maintaining higher urine flow rates around the clock should be emphasized. Fluid intake at bedtime is important since increased urinary concentrations of cystine usually accompany sleep with its attendant decrease in fluid intake. Increased sweat losses due to heat and exercise also will reduce urine flow and require an appropriate increase in intake.

A reduction of absolute cystine excretion, not just concentration, requires reduction in the intake of methionine, the amino acid precursor of cystine. The major dietary sources of methionine are animal protein-containing products. However, even vegetarianism does not completely reduce cystine excretion, as some proportion of the cystine that appears in the urine is generated endogenously from normal metabolic processes. Though restriction of animal protein may reduce cystine excretion, it is often not well tolerated by people used to eating various forms of meat and its efficacy as a preventive strategy has not been demonstrated convincingly.

Another major determinant of cystine solubility is urine pH, a measure of the concentration of protons, or hydrogen ions, H?. Addition of acid to a solution leads to increased proton concentration and a decreased pH. Addition of base, or alkali, diminishes H? concentration by buffering, or neutralizing protons and causes increased pH. Normally, in people eating a diet containing animal protein, urine pH tends to be relatively acidic between meals and increases after eating. Cystine solubility increases with increases in urine pH, or urinary alkalinization. This can be achieved through manipulation of diet or by oral supplementation with base.

The major dietary source of protons is animal protein. Reduction of animal protein intake by reduction of ingestion of beef, fowl, pork, eggs and fish is therefore a method of alkalinizing the urine. Less acid is ingested and therefore fewer protons need to be excreted by the kidneys, the organs that maintain the body’s acid–base balance. Restricting intake of animal protein therefore doubly serves to alkalinize the urine and reduce cystine generation. Reduced protein intake is usually accompanied by reciprocal increases in ingestion of fruits and vegetables that are relatively high in organic anion content. These organic anions, such as malate and citrate, contain carboxyl groups which are metabolized by the liver. Their metabolism yields bicarbonate, the blood’s major circulating buffer. Asbicarbonate is synthesized, protons are consumed and fewer protons must be excreted by the kidneys. The net effect is to increase urine pH and improve cystine solubility. The maximal effect occurs at urine pH above 7; maintaining pH in the more alkaline realm of at least 7.5, up to 8, is therefore desirable (figure 5).

Supplementation with oral base may be necessary for urinary alkalinization (Barbey 2000). This supplementation is usually accomplished by oral intake of citrate, an organic anion which represents base, since its metabolism by the liver consumes protons. Sources of citrate include dietary intake of citrus fruit and juices, and pharmacologic supplementation. Citrate can be given as either the sodium or potassium salt or combinations of the two. Potassium citrate is preferred since increases in urinary sodium excretion cause increases in urinary cystine excretion. For this reason, dietary restriction of table salt (sodium chloride) is also recommended to reduce cystine excretion.

Drugs containing thiol (sulfhydryl) groups (figure 2) can accomplish further reduction of cystine excretion. Available agents include penicillamine and tiopronin (also known as ?-mercaptopropionylglycine). These thiol drugs reduce the sulfur bridge in cystine and combine with the resultant cysteines to form soluble drug–cysteine complexes. Both drugs are associated with side effects that may limit long-term use. The angiotensin-converting enzyme inhibitor captopril, often used in the management of heart failure, hypertension and chronic kidney disease, also contains a thiol and may have a modest effect on cystine excretion as well (Sakhaee and Sutton, 1996).

A new approach to the management of cystinuria may come from measurement of cystine supersaturation (see above). The supersaturation reflects urinary concentration of cystine (determined by cystine excretion and urine volume), urinary pH and the presence of thiol drugs. The tendency of crystals to form in the kidney and the contributions of all of these variables, can be expressed by a single value. Values significantly greater than 1 presumably represent supersaturated values likely to be associated with stone formation while values less than 1 represent undersaturated urine and should be associated with a much lesser tendency for stones to form. Whether these values will lead to improved management of the clinical course of patients has not yet been determined (Nakagawa 2000).

Surgical therapy

The likelihood of spontaneous passage of stones out of the urinary tract, regardless of composition, is most dependent on their size. Stones that are more than 5 mm in diameter have a likelihood of spontaneous passage of less than 50%, while stones more than 7–8 mm in diameter rarely pass. Such stones usually require some form of surgical therapy. Staghorn calculi also will not pass without surgical intervention. Options for therapy are now more successful, less invasive and less dangerous than in past years. ‘Open’ surgery, in which the kidney is cut open longitudinally should rarely be performed today for even the largest stones, if the most modern techniques are available (Segura, 1996). For large stones, one choice is percutaneous nephrostolithotomy (PCNL), which requires fibreoptic endoscopes to be placed through the flank and into the kidney through one or more tracts. Lasers are then used to directly fragment the stones (Teichman, 2002). For smaller stones, a less traumatic technique called ureteroscopy (URS) allows these lasers to be passed into the urethra, the bladder, and then up the ureters to find and fragment obstructing stones. Both PCNL and URS may be followed by chemolysis, direct infusion into the urinary tract of alkalinizing chemicals that can further dissolve residual fragments. Another option is extracorporeal shock-wave lithotripsy (ESWL) which uses an electrically generated shock, focused at the stone from outside the body, to shatter it into passable fragments. Popular for management of calcium stones, this therapy is less effective for cystine stones, which are harder and less easy to fragment. This form of lithotripsy often fails to adequately fragment larger stones as well.

In rare instances of cystinuria, stone disease may be so severe that both kidneys could be damaged irreparably, leading to renal failure. With current techniques, devastating renal failure is nearly always avoidable. Should renal failure occur, treatment with renal transplantation would be appropriate after institution of dialysis. Cystinuria would not be expected to recur after renal transplantation since the tubular transport of cystine in the transplanted kidney would be normal.

Summary

Cystine absorption by the kidneys is mediated by transport systems in the proximal tubule that are defective in cystinuria. Several genotypes have been described, with evidence of mutations affecting at least two different genes: one called SLC3A1 located on chromosome 2, and another called SLC7A9 located on chromosome 19. Many mutations in the SLC3A1 gene have been identified which appear to cause similar phenotypes, with recurrent nephrolithiasis, often starting at an early age, the only clinical manifestation. Mutations in SLC7A9, and perhaps in SLC7A10 cause a more mild disease of later onset, but can also rarely cause stones in heterozygotes, an autosomal dominant form of disease. Increasing urine volume and urine pH are the main therapies that reduce stone formation and growth. Pharmacological reduction of cystine to cysteine with thiol drugs is also useful. Since these medical therapies often fail, patients are fortunate that newer surgical therapies have reduced the morbidity of stone removal.

References

  • Barbey F, Joly D, Rieu P, et al. (2000) Medical treatment of cystinuria: critical reappraisal of long-term results. Journal of Urology 163:1419-23.
  • Chillaron J, Estevez R, Samarzija I et al. (1997) An intracellular trafficking defect in type I cystinuria rBAT mutants M467T and M467K. Journal of Biological Chemistry 272: 9543–9549.
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  • Feliubadalo L, Font M, Purroy J et al. (1999) Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (b0,?AT) of rBAT. Nature Genetics 23: 52–57.Goodyer P, Saadi I, Ong P, Elkas G and Rozen R (1998) Cystinuria subtype and the risk of nephrolithiasis. Kidney International 54: 56–61.
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  • Leclerc D, Boutros M, Suh D et al. (2002a) SLC7A9 mutations in all three cystinuria subtypes. Kidney International 62:1550-9.
  • Leclerc D, Wu Q, Ellis JR, Goodyer P, and Rozen R (2002b) Is the SLC7A10 gene on chromosome 19 a candidate locus for cystinuria? Molecular Genetics and Metabolism 73:333-9.
  • Lee W, Wells RG, Sabbag RV, Mohandas TK and Hediger MA (1993) Cloning and chromosomal localization of a human kidney cDNA involved in cystine, dibasic, and neutral amino acid transport. Journal of Clinical Investigation 91: 1959–1963.
  • Martensson J, Denneberg T, Lindell A and Textorius O (1990) Sulfur amino acid metabolism in cystinuria: a biochemical and clinical study of patients. Kidney International 37: 143–149.
  • Nakagawa Y, Asplin JR, Goldfarb DS, et al. (2000) Clinical use of cystine supersaturation measurements. Journal of Urology 164:1481-5.
  • Palacin M, Chillaron J and Mora C (1996) Role of the b0,?-like amino acid-transport system in the renal reabsorption of cystine and dibasic amino acids. Biochemical Society Transactions 24: 856–863.
  • Rosenberg LE, Downing S, Durant JL and Segal L (1966) Cystinuria: biochemical evidence for three genetically distinct diseases. Journal of Clinical Investigation 45: 365–371.
  • Saadi I, Chen X, Hediger M et al. (1998) Molecular genetics of cystinuria: mutation analysis of SLC3A1 and evidence for another gene in the type I (silent) phenotype. Kidney International 54: 48–55.
  • Sakhaee K and Sutton RAL (1996) Pathogenesis and medical management of cystinuria. In: Coe FL, Favus MJ, Pak CYC, Parks JH and Preminger GM (eds) Kidney Stones: Medical and Surgical Management, pp. 1007–1017. New York: Lippincott-Raven.
  • Segura JW (1996) Surgery of cystine stones. In: Coe FL, Favus MJ, Pak CYC, Parks JH and Preminger GM (eds) Kidney Stones: Medical and Surgical Management, pp. 1019–1024. New York: Lippincott-Raven.
  • Teichman JM (2002) Laser lithotripsy. Current Opinion in Urology 12:305-9.
  • Verrey F, Closs EI, Wagner CA, et al (2003) CATs and HATs: the SLC7 family of amino acid transporters. Pflugers Archives epub ahead of print.

Further Reading

  • Auge BK, Preminger GM (2002) Surgical management of urolithiasis. Endocrinology and Metabolism Clinics of North America 31:1065-82.
  • Akakura K, Egoshi K, Ueda T et al. (1998) The long-term outcome of cystinuria in Japan. Urology International 61: 86–89.
  • Bushinsky DA (1998) Nephrolithiasis. Journal of the American Society of Nephrology 9: 917–924.
  • Chow GK and Streem SB (1998) Contemporary urological intervention for cystinuric patients: immediate and long-term impact and implications. Journal of Urology 160: 341–344.
  • Dell KM and Guay-Woodford LM (1999) Inherited tubular transport disorders. Seminars in Nephrology 19: 364–373.
  • Goodyer PR, Clow C, Reade T and Girardin C (1993) Prospective analysis and classification of patients with cystinuria identified in a new born screening program. Journal of Pediatrics 122: 568–572.
  • Leveillee RJ, Lobik L (2003) Intracorporeal lithotripsy: which modality is best? Current Opinion in Urology 13:249-53.
  • Palacin M, Estevez R, Bertran J and Zorzano A (1998a) Molecular biology of mammalian plasma membrane amino acid transporters. Physiological Reviews 78: 969–1054.
  • Palacin M, Estevez R and Zorzano A (1998b) Cystinuria calls for heteromultimeric amino acid transporters. Current Opinions in Cell Biology 10: 455–461.

Figure Legends

Figure 1

cystine transport cartoon

Cartoon of cystine transport. Cystine is filtered across the glomerular capillary membrane into the proximal tubule. Cystine reabsorption from the tubular lumen across the apical membranes of the S3 segments and into the cell is mediated by the amino acid transporter affected in cystinuria. Cystine is exchanged for neutral amino acids like alanine (not shown). The transporter is composed of 2 subunits (making it a heterodimer), the protein products of SLC3A1 (rBAT, the heavy component) and SLC7A9 ((b0,? AT, the light component). Inside the proximal tubule cell, cystine is reduced to 2 molecules of cysteine which exit across the basolateral membrane. Back to article

Figure 2

chemical structure

Chemical structure for cystine, a combination of two molecules of cysteine. Two thiol (-SH) containing drugs used for treatment are penicillamine and ?-mercaptopropionylglycine. Both thiols reduce the disulfide bond in cystine to cysteine and chelate the latter to form a more soluble product. Only the penicillamine–cysteine complex is shown here. Back to article Back to article again

Figure 3

cystine crystal

Typical hexagonal cystine crystal in urine. Courtesy Louis Herring Lab, Orlando, Florida. Back to article

Figure 4

staghorn calculus

A staghorn kidney stone composed of cystine. Courtesy Louis Herring Lab, Orlando, Florida. Back to article

Figure 5

chart

Curve of increasing cystine solubility with increasing urinary pH. Back to article

Glossary

Dibasic amino acid

An amino acid containing two amide groups, both of which can accept a proton at physiological pH, becoming positively charged.

Extracorporeal shock-wave lithotripsy

Procedure in which an electric impulse outside the body creates a shock-wave that can be focused in order to fragment kidney stones.

Glomerular filtration

Process by which plasma is filtered across the relatively permeable glomerular basement membrane by the hydrostatic pressure of the blood.

Heterodimer

A molecule composed of two different subunits.

Lithotripsy

Process of breaking stones via shock wave, laser energy, or pneumatic force.

Proximal tubule

The initial part of the tubule that reabsorbs about two thirds of the glomerular filtrate back into the blood. It consists of a convoluted tubule (segments S1 and S2) and a straight third segment (S3).

Ureteroscopy

Procedure in which a flexible fibreoptic endoscope is passed up the ureter in order to diagnose and treat obstructions and other urologic disorders. Lasers and other instruments may be used through the scope to fragment kidney stones.

Cystinuria and Transplantation

By David S Goldfarb, M.D.
Director, Kidney Stone Prevention Program, St. Vincents Hospital
Professor of Medicine and Physiology, NYU School of Medicine

There is a web-site journal called HDCN you probably know: hypertension, dialysis, clinical nephrology, run by John Daugirdas, a very prominent dialysis expert. Most of the content I believe is limited to health professionals. I’m on the editorial board, and review stone disease especially for John.

There’s an “ask the professor” feature, questions from other nephrologists, and recently a transplant surgeon asked whether cystinuria recurs after transplantation. I took the occasion to discuss some aspects of the disorder, then answered the question. The response is below.

Cystinuria

The question asked is whether cystinuria can recur after renal transplantation. I’ll review the basic pathophysiology with an update on recent investigations of the defective cystine transporter, and then examine this issue.

Cystinuria is an autosomal recessive disorder of transepithelial transport of cystine and other dibasic amino acids. Cystine is relatively insoluble, and its presence in the tubular lumen at concentrations of more than 250 mg/l is associated with precipitation and stone formation. Treatment requires increasing urinary volumes to keep cystine concentrations at or below 250 mg/l, urinary alkalinization with potassium citrate, restriction of dietary sodium, and reduction of cystine to the soluble cysteine with penicillamine, alpha- mercaptoproprionylglycine.

The abnormal gene was mapped via linkage studies to human chromosome 2p (1). At the same time, the mutated gene was demonstrated to be rBAT (basic amino acid transporter) (2), a cystine transporter previously identified in proximal tubular membrane vesicles from humans, rats and rabbits. This transporter mediates sodium-independent, electrogenic, apical membrane uptake of cystine into the cells of the proximal straight tubule (S3). It is also present in the apical brush border membranes of the jejunum where it mediates absorption of cystine.

When expressed in Xenopus oocytes, this transporter also mediates transport of dibasic amino-acids (lysine, ornithine, arginine) and some neutral amino-acids as well (11). This high-affinity process is augmented by a low-affinity process in the proximal convoluted tubule (S1), the mediator of which is not yet identified. After uptake across the apical membrane, cystine, essentially a cysteine dimer, is reduced intracellularly to cysteine which exits the cell across the basolateral membrane.

Studies by Harris (3) and Rosenberg (4) suggested that there were 3 phenotypes of cystinuria.

Type I, the most severe form, appears to be caused most frequently by a mutation of rBAT residue 467 from methionine to threonine. This mutation, called M467T, accounted for 40% of the abnormal chromosomes in the Spanish cohort studied by Calonge et al (2), and 30% of the abnormal chromosomes studied in the entire group (n=36) from Spain and Italy. Heterozygotes for Type I have normal urinary levels of cystine and other amino-acids.

Type II patients have impaired in-vitro intestinal transport of lysine, but cystine transport is present in the homozygote. Type II heterozygotes have increased urinary levels of cystine, ornithine, arginine, and lysine.

Type III patients have some intestinal cystine absorption, and can partially absorb an oral load. Type III heterozygotes also have moderately increased urinary amino-acid excretion.

The molecular correlates for Type II and Type III have not yet been described but presumably represent the manifestations of other mutations in the rBAT gene, or in some cases, combinations of M467T with other abnormal alleles.

In answer to the question about renal transplantation, one would not expect cystinuria to recur after cadaveric renal transplantation since the renal transport of cystine in the graft would be expected to be normal. Intestinal absorption of cystine would be absent in Type I patients and impaired in most Type II and III patients, so cystinuria would not occur. There are no demonstrations of other metabolic abnormalities of proven clinical significance associated with failure of cystine transport.

Deficiency of other amino-acids, like lysine, are not limiting, as their absorption as constituents of oligo-peptides is not impaired (5). One letter describes a patient who received a living-related transplant, though it fails to describe the relationship of the donor to the recipient (6). More than 3 years later, urinary amino- acid levels were normal, with cystine excretion of 37æmol/24 hours, and no recurrence of nephrolithiasis. This letter cites an article purporting to have 3 cases of renal transplantation; in fact, my review of this article finds no mention of transplantation in it (7)!

Another report of stones in renal transplant recipients notes no cases of cystine stones in 88 cases (8). However, cystine stones account for (only) up to 3% of stones in the general population, so not finding a case is not very surprising. One might expect increased urinary cystine levels in recipients of living-related grafts obtained from heterozygotes with Type II- and Type III phenotypes. Since I can find no heterozygotes reported with active cystine stone disease, the clinical significance of the finding would appear to be nil, assuming of course that the prospective donor has no history of nephrolithiasis. In Rosenberg’s reports, levels of cystinuria that occurred in Type II and III heterozygotes were below 250 mg/gm creatinine, levels unlikely to cause nephrolithiasis. The utility therefore of measuring cystine levels would be negligible. The cyanide-nitroprusside test can be used to screen qualitatively for cystinuria with excellent sensitivity (5).

An additional issue is the relative frequency with which patients with cystinuria, and perhaps their relatives, develop calcium or urate stones. Other metabolic abnormalities accounting for this have been described. Sakhaee (9) found that 5 of 27 cystinurics had hypercalciuria, 6 had hyperuricosuria, and 12 had hypocitraturia. These abnormalities may or may not be resolved by renal transplantation and recipients may then be at risk for recurrent stone disease after transplantation. Of course it is also possible that these abnormalities are intrinsic to the native kidneys, or the result of recurrent stone disease (like renal tubular acidosis with hypocitraturia). Morin (10) described a family in which several heterozygotes for cystinuria had hypercalciuria and/or hyperuricosuria.

References
  1. Pras, E. et al. Localization of a gene causing cystinuria to chromosome 2p. Nature Genetics 6:415-419 (94).
  2. Calonge, M.J. et al. Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine. Nature Genetics 6:420- 425 (94).
  3. Harris, H. et al. Phenotypes and genotypes in cystinuria. Ann. Hum. Genet. 20:57 (55).
  4. Rosenberg, L.E. et al. Cystinuria: biochemical evidence of three genetically distinct disease. J. Clin. Invest. 46:365 (66).
  5. Halperin, E.C. and Thier, S.O. “Cystinuria” in Nephrolithiasis, pp 208-230; Eds. Coe, F.L., Brenner, B.M., Stein, J.H., Churchill Livingstone, NY, 1980.
  6. Tuso, P. et al. Cystinuria and renal transplantation. Nephron 63:478 (93).
  7. Crawhall, J.C. Cystinuria: an experience in management over 18 years. Miner Electrolyte Metab 13:286-293 (87).
  8. Urolithiasis after renal transplantation. Transplant. Proc. 21:1960-1 (89).
  9. Sakhaee, K., et al. The spectrum of metabolic abnormalities in patients with cystine nephrolithiasis. J. Urol. 141:819 (89).
  10. Morin, C.L. et al. Biochemical and genetic studies in cystinuria: observations on double heterozygotes of genotype I/II. J. Clin. Invest. 50:1961 (1971).
  11. Bertran, J. et al. Expression cloning of a human renal cDNA that induces high affinity transport of L-cystine shared with dibasic amino acids in Xenopus oocytes. J. Biol. Chem. 268:14842 (93).

New Concepts in Treatment

By Michael Grasso, M.D.
Chief of Urology, St. Vincents Hospital
Professor of Urology at New York Medical College

All ureteral calculi, and in fact many stones throughout the caliceal system, can be accessed and treated in a retrograde fashion with a combination of various fiber optic endoscopes and powerful, precise lithotrites. In the early 1990’s improvements in fiber optic imaging and technical advances in endoscope design have allowed endurologists to place small fiberscopes through the urethra, bladder and into the upper urinary tract atraumatically. Various endoscopic lithotrites, including powerful laser lithotriptors, can be employed throughout the working channel of these endoscopes to treat calculi. In 1993 I began work on a small diameter flexible ureteroscope that measured approximately 2 mm in diameter and allowed access to the entire upper urinary tract. Shortly thereafter, a prospective study was instituted using a new laser energy–the holmium laser. This devise is a thermal laser which destabilizes stones into fine dust. The combination of this endoscope and lithotrite was able to clear 75 consecutive calculi in our most recent series. What is very interesting is that with other laser lithotripters, as the probes become smaller and more precise, the deliverable energy and efficiency decreases. This is not the case with the holmium laser.

Prototypic fibers as small as 2/10ths of a millimeter were designed and employed in this most recent series. As opposed to prior, larger fibers, these small fibers do not inhibit the deflectability of the endoscope and as such I’m able to access the entire caliceal system. Initially, I was only treating somewhat straightforward ureteral calculi. Most recently I’ve addressed a series of larger-branched stones in the caliceal system and I’ve been able to efficiently clear them.

This particular laser lithotriptor fragments all stones equally and efficiently as opposed to other devices including EHL (Electro-Hydrolic Lithotripsy) and the pulse dye laser which are less efficient fragmentors of cystine stones. The holmium laser basically vaporizes or destabilizes cystine stones into a fine powder. It works as efficiently on cystine as it does with other stone compositions.

I’ve recently treated a series of patients with large-branched calculi who had undergone multiple prior open and percutaneous procedures and now were searching for another modality which would obviate the need for long hospitalization and a percutaneous puncture. Most of these patients had undergone multiple courses of ESWL without success. Many of these patients were cystinurics and were quite frustrated with surgical intervention at this point. As excellent example is that of Ben Lokos who is a 33 year old cystinuric who has been suffering for many years.

Ben had undergone three prior percutaneous nephrostolithotomies on the left side and now is suffering with somewhat severe hypertension which most likely reflects perirenal and cortical scarring. I was able to access Ben’s large stone burden in a retrograde fashion and debulk a significant portion of it. We were also able to move the dust and remaining small fragments into portions of the collecting system that clear more easily after treatment.

Lower pole stones, that is those that are in a very dependent portion of the kidney, are less apt to clear after ESWL. With endoscopic therapy we can not only vaporize and remove a good portion of the stone, but are also often able to move or irrigate the remaining small fragments into other portions of the collecting system. It is in these other locations that they are more apt to pass easily. In Ben’s case, we cleared a significant portion of the stone burden in one sitting. As in most cases, this procedure is performed as an out-patient.

In summary, I think that the aforementioned techniques should be put clearly into perspective. The new equipment and the holmium laser are only in the hands of a minority of endurologists in the country. Also, the application requires a certain skill level and there is no question that there is a learning curve to this technique as there is with most minimally invasive surgical procedures. There are a handful of centers throughout the country where prospective studies are being done with these devices. The potential for a treatment that is done as an out-patient, able to clear large stone burdens–including cystine–efficiently, with minimal morbidity and significant efficiency gives promise to those cystinurics who have had multiple surgical interventions with mixed results.

A list of the following centers where retrograde interrenal surgery is performed with the holmium laser and small-diameter actively deflectable, flexible ureteroscopes:

  • Michael Grasso, M.D., Associate Professor of Urology and Director of Stone Treatment and Prevention Center, New York University Medical Center, New York, New York
  • Demetrius Bagley, M.D., Professor of Urology and Radiology at Thomas Jefferson University in Philadelphia, Pennsylvania
  • Michael Conlin, M.D., Assistant Professor of Urology, Oregon Health Science Center, University of Oregon, Portland, Oregon
  • Joseph Segura, M.D., Professor of Urology, Mayo Clinic, Rochester, Minnesota
  • Gerhart Fuchs, M.D., Professor of Urology, UCLA Medical Center, Los Angeles, California
  • Kent Kirby, M.D. at the Cleveland Clinic in Florida.

Update of Cystinuria Research

By John Endsley, M.D.
Vanderbilt University Medical Center
Nashville TN

Medical research can be divided into two categories: “basic science” and “clinical” research. The basic science research asks questions about how organisms (like people) and disease processes work, without a specific plan for how to apply that knowledge to treat disease. Clinical research asks questions about how to develop better treatments for patients, sometimes without knowing all the details of why a treatment works. The two approaches feed off of each other, because understanding how a disease works usually leads to better ideas about how to treat it. In the case of cystinuria research, up until fairly recently there has been little new information from basic science research, and slow progress in clinical research. In the past few years, however, a number of breakthroughs have occurred in basic science research in cystinuria, and I will simplify and summarize the most important ones in the remainder of this article. To those with some background in molecular biology this may seem oversimplified.

Cystinuria is an inherited disease, usually transmitted in what is termed “autosomal recessive” fashion. The disease is manifested by a decreased ability of the kidney to reabsorb certain amino acids from the urine as it is being formed. One of the amino acids, cystine, does not dissolve well in urine, and when too much of it is present it may lead to formation of kidney stones. One of the main aims of basic science research in cystinuria has been to identify the gene or genes which causes the disease.

One of the genes has now been identified. In 1992, two groups1,2 independently isolated (cloned) genes that caused increased transport of cystine when it was expressed in a special type of frog cell (Expression means that the DNA of the gene was injected into the cell and “translated” by the cell to make a protein. The protein in this case then was inserted into the cell membrane and caused cystine to be taken up by the cell.). One gene was isolated in rat (this gene was called D2), the other in rabbit (this gene was called rBAT). When the DNA sequences of the genes were compared, they were extremely similar to each other. This lead to speculation that a similar gene in humans could be one of the genes damaged in patients with cystinuria, and in 1993, a human gene with DNA sequences very similar to the rat and rabbit genes was isolated3. The location of this gene was found to be on chromosome 24. The human gene was designated SLC3A1. The protein produced from this gene is usually referred to as rBAT

The next breakthrough came in 1994, when samples from some patients with cystinuria were found to have abnormalities (or “mutations”) in the DNA sequences of the SLC3A1 gene5. When proteins were produced using these damaged versions of the gene, they were found to have a decreased ability to transport cystine across a cell membrane, which is what one would expect of a gene causing cystinuria. Since then, a number of other investigators have found other abnormalities in this gene in cystinuric patients.

Up until recently, most of the mutations were found by a very labor intensive process which required manipulating the cells obtained from cystinuric patients to make them produce a copy of the gene in a version called “mRNA”. This need to process each patient’s sample shortly after obtaining it and over a period of weeks had limited the ability of investigators to screen many patients for abnormalities. Recently, however, both our group at Vanderbilt and Dr. Pras6 in Israel have independently decoded the “genomic structure (the sequence of “introns” and “exons”) of the SLC3A1 gene. This should allow more efficient screening of patient samples, since it eliminates the need to manipulate the cells to produce mRNA. Several new mutations have been identified using this technique.

It is currently felt that there are probably other genes involved in causing cystinuria in some patients. Future efforts in basic science research in cystinuria will probably focus on continued exploration of the structure and function of SLC3A1 and the rBAT protein as well as finding other genes that can cause cystinuria. Ultimately, the hope is that we can design ways to correct the defect by inserting a corrected copy of the gene into the kidney cells of patients and allow them to begin taking up cystine to prevent further kidney stones. Those of us involved in research appreciate those with the disease who have given samples for these studies, and we also understand the frustration you must feel knowing that this progress in basic science may take years to spill over into clinical trials of new therapies. Thank you for your help, and hang in there.

BIBLIOGRAPHY

1. Wells RG, Heidiger MA: Cloning of a rat kidney cDNA that stimulates dibasic and neutral amino acid transport and has sequence similarity to glucosidases. Proceedings of the National Academy of Sciences of the United States of America 89:5596-5600, 1992

2. Bertran J, et al: Expression cloning of a cDNA from rabbit kidney cortex that induces a single transport system for cystine and dibasic and neutral amino acids. Proceedings of the National Academy of Sciences of the United States of America 89:5601-5605, 1992

3. Bertran J, et al: Expression cloning of a human renal cDNA that induces high affinity transport of L-cystine shared with dibasic amino acids in Xenopur oocytes. Journal of Biological Chemistry 268:14842-14849, 1993

4. Pras E, et al: Localization of a gene causing cystinuria to chromosome 2p. Nature Genetics 6:415-419, 1994

5. Calonge MJ, et al: Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine. . Nature Genetics 6:420-425, 1994

6. Pras E, et al: Genomic organization of SLC3A1, a transporter gene mutated in cystinuria. Genomics 36:163-167, 1996

Urinary Alkalisation

By David S Goldfarb, M.D.
Director, Kidney Stone Prevention Program, St. Vincents Hospital
Professor of Medicine and Physiology, NYU School of Medicine

Alkalization of the urine is important in cystinuria because it increases the solubility of cystine, meaning that more cystine can be dissolved in a given amount of urine. Alkalization means neutralizing the acid in the urine by adding base. When acid is neutralized there are fewer H+ molecules (also called protons) and the pH rises. pH is a measure of the amount of acid in the urine. Human urine can have pH ranging from about 4 (acid) to about 8 (alkaline). When urine pH rises above 7, cystine becomes much more soluble, so achieving a urine pH of 7.5-8 for a good part of the day is desirable. Measuring and recording your urine pH at various times of the day is very helpful to you and your doctor to show whether you are getting to the desired range.

You can alkalinize your urine by decreasing the amount of acid you take in. You can lower the amount of acid you eat (and therefore the amount of acid your kidneys have to get rid of) by eating less animal protein. Protein is what muscle is made of, and includes fish, beef, chicken and pork. These products also contain some cystine, so limiting your intake of these has 2 benefits.

You can also take in more base to alkalinize your urine. If you eat more fruits and vegetables when you reduce your protein intake, you will take in more base. Base comes in the form of molecules called “organic anions”, such as citrate and malate. They are converted to bicarbonate by the liver. Bicarbonate is the blood’s form of base. One citrate is converted to 3 bicarbonates. So taking citrate and bicarbonate are equivalent. Some of the citrate also is found in the urine where it helps prevent calcium stone formation in non-cystinuric people with the more commonly found calcium oxalate stones. Citrus fruits like oranges and lemons and all fruits and vegetables contain these organic anions.

For most people adequate alkalization does not occur without taking in extra base. It comes in many preparations. Potassium (K) citrate is preferable to sodium citrate preparations because sodium may increase cystine excretion. This is also why I don’t usually prescribe baking soda, which is sodium bicarbonate. But the alkalinizing effect, if it works, could override the increase in cystine excretion. If you are doing well with sodium preparations I would not change your prescription.

The major reason why I sometimes prescribe sodium citrate instead of potassium citrate is if there’s too much potassium in the blood, which is rarely a problem in young people with normal overall levels of kidney function. Another reason to use sodium citrate is taste. Some people prefer it. A third reason is gastrointestinal tolerance. Some people find that potassium citrate causes heartburn, or diarrhea, or abdominal cramps. These are not usually serious side effects but can be avoided by changing preparations.

Sodium bicarbonate comes as baking soda and in pill form. Sodium citrate can be taken as Bicitra, Shoal’s solution. Polycitra (NOT the same thing as Polycitra-K!) has both sodium citrate and potassium citrate in it. All three contain sodium citrate and citric acid. Why is it OK to take citric acid if you are trying to avoid acid? Because the citric acid provides both base (citrate) AND acid, which neutralize each other. It has no net effect on urine pH, unlike the citrate in food which has only the base part, not the proton (H+) part. Why is it there then? To help dissolve the sodium citrate.

Potassium citrate comes in various preparations. Polycitra-K comes as a liquid and in crystals (packets) that you mix in water. It comes in several flavors which are worth trying. In either case they can be sufficiently diluted or mixed into other juices to minimize the taste. Another option is K-Lyte which comes as an effervescent tablet that dissolves in water, like an Alka-Seltzer. It also comes in different flavors worth trying on your kids. It’s a combination of potassium citrate and potassium bicarbonate; that’s OK because citrate and bicarbonate are equivalent. It also comes as “DS” or double strength. (You DON’T want K-Lyte/Cl which is potassium chloride and has no alkalinizing property). Another popular form of potassium citrate is Urocit-K, a pill form. They are actually in a wax matrix from which the drug dissolves. People often see the unabsorbed, undissolved wax in their bowel movements; this does not mean the mineral is not being absorbed.

Compare doses of these preparations in milliequivalents (mEq) of bicarbonate equivalents; ignore the number of milligrams. Most people need anywhere from 20 to 120 mEq per day, but measuring the urine pH is the way to determine how much you need. Bicitra and Shohl’s solution are 15 mEq per tablespoon (1 tbsp=15 cc, cubic centimeters), or 1 mEq per cc. Polycitra liquid has 2 mEq per cc (half as sodium, half as potassium). Polycitra-K liquid is 2 mEq per cc, all potassium. Polycitra-K crystals come as 30 mEq per packet. Urocit-K comes in 5 and 10 mEq tablets. K-Lyte comes as 25 mEq per tab, and 50 mEq for the “double-strength” DS. The standard generic sodium bicarbonate tab (325 milligrams, like an adult aspirin) is about 4 mEq.

I know that people often hesitate when a doctor reaches for a prescription pad. I tell my patients that potassium citrate is more like a vitamin, not a drug. Potassium and citrate are in all of your cells, and all the fruits and vegetables you eat. Both are normally found in urine in significant amounts because we take in more than we need. You can’t be allergic to these minerals, though rarely people are allergic to dyes in the preparations. If your blood potassium is in the normal range you should not have a problem: the extra potassium is excreted by the kidneys. The occasional heartburn or other GI symptoms can usually be overcome by taking them with meals, which doesn’t diminish their absorption or effect on the urine. Sodium citrate or bicarbonate may be a problem for people with decreased heart function, kidney function, or high blood pressure, and can increase urinary cystine levels, but like eating salty pretzels should not cause problems for most otherwise healthy people. I wouldn’t be concerned about taking these “supplements” or about giving them to children. I view these medications as safe and effective, though inexplicably expensive.

Surgical Management

By Michael Grasso, M.D.
Chief of Urology, St. Vincents Hospital
Professor of Urology at New York Medical College

In 1996 there are many modalities available to treat upper urinary tract calculi. It is the mission of the American Urologic Association Nephrolithiases Guidelines Panel to develop guidelines for treating upper urinary tract calculi. The first task of this group was to address current treatment of large, staghorn stone burdens. By reviewing the literature en-toto, this non-biased body of the American Urologic Association set guidelines that are now currently in place.

In regards to large stone burdens, that is calculi greater than 2.5 cm in greatest diameter, the governing body felt rather strongly that open surgical intervention–that is, making a large incision to remove a stone–should be strictly prohibited with very few exceptions. Additionally, the feeling was that ESWL (Extracorporeal Shock Wave Lithotripsy) does have a role for the moderately-sized renal calculi. The Guidelines Panel felt strongly, however, that stone burdens greater than 2.5 cm, or those in complex collecting systems, should be treated endoscopically. Percutaneous nephrostolithotomy (placing a tube into the kidney through the skin to fragment and evacuate the stone material) was felt to be the primary treatment for staghorn stones.

The Guidelines Panel also felt rather strongly that a course of watchful waiting for large stone burdens was not acceptable. Additionally, renal function should be assessed prior to treatment. Kidneys with very little recoverable function (less than five to ten percent of total renal function) may be best treated with a primary nephrectomy, depending on other clinical variables including the renal function on the opposite side.

In summation, the American Urologic Association’s Nephrolithiasis Guidelines Panel has set the tone for the 1990’s as far as treating large renal calculi. These stones should be treated endoscopically in most cases, with ESWL being a treatment for smaller stone burdens or as an adjunctive therapy in combination with endoscopic debulking and evacuation of stone fragments. Copies of the AUA Guidelines Panel recommendations are available by writing to the following address: American Urological Association, Inc. Health Policy Department, 1120 North Charles Street, Baltimore MD 21201.

Treatment of Cystine Stones

 

By David A. Zackson, M.D.
Assistant Clinical Professor of Medicine Division of Nephrology
New York Hospital-Cornell Medical Center
New York

INTRODUCTION

Increased urinary dilution (from forced hydration) and strong urinary alkalinization (from oral alkalinizing agents) are two of the most effective methods for the treatment and prevention of cystine kidney stones (calculi). Neither of these modalities reduces the total urinary excretion of cystine; that appears to be relatively stable for each cystinuric individual. Rather, increasing urinary dilution reduces the concentration of urinary cystine (I.e., the amount of cystine contained in each milliliter of urine while the total output of cystine remains unchanged). By contrast, urinary alkalinization increases the solubility of urinary cystine (I.e., the amount of cystine that can be dissolved in each mL of urine without it precipitating out of solution to form cystine crystals, sand, gravel and stones). These therapeutic effects on cystine concentration and solubility are complementary. Not only can they decrease cystine stone formation, but, if applied with sufficient vigor over sufficient time, can even dissolve large cystine calculi–a process accelerated by lithotripsy which cracks cystine calculi and increases their (therapy-exposed) surface area.

The benefits of forced hydration and urinary alkalinization are obtained with wide safety margins. Forced hydration has no serious adverse effects while with urinary alkalinization serious risks are minimal. In treating Cystinuria, a wide safety margin is particularly appreciated because the only other established method of treating Cystinuria is with penicillamine and Thiola, drugs which carry high risks of serious allergy and toxicity. (For simplicity, in this article, the generic drug penicillamine–brand names Cupramine and Depen–will be referred to by their generic appellation. Thiola, the only brand available for the generic variously known as alpha-mercaptoproprionylglycine, tiopronin and MPG, will be referred to by its brand name.) The action of penicillamine and Thiola is to decrease the total urinary excretion of cystine. Since the stone-inhibiting benefits of forced hydration-alkalinization are complementary to the cystine reductions from penicillamine and Thiola, a strongly applied regimen of the former may entirely replace the more toxic agents or at least permit reduction in their dosage. This is of particular importance for patients with proven intolerance of penicillamine or Thiola, or who are in fear of their adverse effects, E.g., patients who already have reduced kidney function, or women who desire pregnancy. In fact, cystinuric women under treatment with penicillamine or Thiola who become pregnant can frequently have these agents discontinued and go through pregnancy treated only by forced hydration and urinary alkalinization–albeit under an extreme burden voiding frequency.

INTENSITIES OF CYSTINURIA

The frequency and severity of kidney-stone formation vary widely in cystinurics. Some patients experience very frequent sand and gravel and form at least two to three cystine stones per year, sometimes huge in size (staghorn calculi). Others form only one or two small calculi over decades. By combining data of 24-hour-urinary cystine excretions, the urine-solubility characteristics of cystine, and clinical experience correlating these parameters with stone formation rates, the following broad classification of Cystinuria intensity can be suggested:
(1) Generally insignificant (I.e., cystine stones rarely form): up to 150 mg/day;
(2) Mild: 150–400 mg/day;
(3) Moderate: 400–800 mg/day;
(4) Moderately severe: 800–1,200 mg/day;
(5) Severe: 1,200–2,000 mg/day;
(6) Very severe: over 2,000 mg/day.

In general, the greater the 24-hour-urine excretion of cystine, the greater the cystine stone problems. Variations from this rule, however, include the following situations:

  1. Obstruction in the urinary tract can induce intense cystine stone formation behind the obstruction even though the total urinary excretion of cystine may be only modest; obstruction has this stone-inducing effect for all types of kidney stones, not just cystine.
  2. (2) Without current explanation, some patients with fairly unimpressive urinary cystine concentrations (E.g.,only 200 mg/liter), who in theory should have ceased forming cystine calculi, nevertheless avidly continue to do so. In contrast, some subjects with urinary cystine concentrations as high as 800 mg/liter only rarely experience stone events.
  3. (3) When numerous retained cystine calculi are present–with an extensive cumulative surface area–percolating high volumes of dilute, strongly alkalinized urine over these stone surfaces dissolves cystine which is then added to the total urinary cystine excretion. Such increments in cystine excretion, however, reflect successful therapy and do not increase the stone formation rate. (However, in such patients it may be impossible to calculate the true baseline urinary cystine excretion until they are rendered stone free, or the regimen of hydration and alkalinization is temporarily discontinued.)

For reasons that are unclear, increased sodium intake can significantly elevate urinary cystine excretion and exacerbate cystine stone formation, in some subjects more than others. Restriction of methionine-containing foods (milk, meat, eggs, etc.) results, in most patients, in a small decrease in total urinary cystine excretion. Usually, the cystine decrement is neither clinically significant nor worth the (considerable) efforts involved; in rapidly growing children the requisite protein restrictions can even lead to nutritional deficiencies. However, because some patients lower their cystine outputs more dramatically than others, advanced protein restriction–with close monitoring of its hoped-for cystine reductions–is worth a brief trial in patients who prove refractory to other measures.

CYSTINE SOLUBILITY IN URINE

It has been observed that if the urinary concentration of cystine is approximately 300 mg/liter, or less, new calculi generally do not arise, nor already formed stones enlarge. If the urinary concentration of cystine is much below 300 mg/liter, calculi may even slowly dissolve (although this usually requires concomitant strong urinary alkalinization.) If the urinary concentration of cystine is above 300 mg/liter, cystine calculi may form, or enlarge–the higher the cystine concentration, the more rapid the process. A urinary concentration of 300 mg/liter may be regarded as the “clinical saturation point” for cystine. The clinical message from this data is that, if at all possible, the urinary concentration of cystine should be kept at, or below, 300 mg/liter. For the rare patients who continue to form cystine calculi at unexpectedly low cystine concentrations (E.g., even as low as 200 mg/liter), therapy should be directed at strong urinary alkalinization and keeping urinary cystine concentrations at even lower levels.

URINARY DILUTION AND FORCED HYDRATION

Clearly, it is not the total cystine excretion which determines whether or not cystine calculi will form but the urinary cystine concentration. E.g., even if the cystine output of a patient were (a huge) 2,000 mg per day, if the concentration of cystine in the urine could be diluted down to 200 mg/liter–I.e., by forcing enough water ingestion to form 10 liters of urine per day–cystine calculi would be unlikely to form. In contrast, if the urinary cystine output of a patient were only 400 mg/day, but only 1 liter of urine per day were formed, the resultant urinary cystine concentration (I.e., 400 mg per liter, or twice that in the previous example) might be sufficient to initiate stone formation.

Since to stop cystine calculi in most patients it is sufficient to dilute urinary cystine concentration down to 300 mg/liter, for a patient with a daily cystine excretion of 600 mg this would mean forcing a 24-hour urine volume of 2 liters (2,000 ml, or about 2 quarts). For a patient with a daily cystine excretion of 1,200 mg, achieving the protective cystine concentration would necessitate a 24-hour urine volume of 4 liters, etc. In such a subject, to achieve the even safer (lower) cystine concentration of 200 mg/liter, a daily urine volume of 6 liters would be required–a formidable undertaking!

For cystinurics who require such huge daily urine volumes, it is advisable to consume at least 2 large glasses of water every 2 hours during the day, with 2 more glasses upon retiring to force voiding at least twice during the night, coupled with ingestion of another glass of water at each nocturnal awakening. It may take several months of patient effort until such an onerous regimen is adapted to–with an ability to readily fall back to sleep being a significant asset in this regard. As a rule of thumb, the urine should be kept “very light in color,” approaching that of tap water, making it a habit to observe this aspect with each voiding–and increasing the amount and/or rate of water consumption no matter what it might already be if the urine color remains too dark. (Maintain awareness that coloring dyes in medications, or capsules, may also darken urine.)

INSENSIBLE WATER LOSSES

Protection against cystine stone formation comes not from how much liquid is drunk, but from how much urine is passed. Under different circumstances, different amounts of liquid will be required to achieve protective volumes. Most ingested water is excreted from the body as urine. However, significant additional losses of water from the body occur via sweating, evaporation from skin surfaces, excretion as liquid stool, and as moist air exhaled during respiration. These are called “insensible losses,” and can readily mount to 1,500 ml/day–or much more if environmental temperatures are high, or fever, heavy sweating, diarrhea, or deep rapid respirations are present (as during illness.) Thus a cystinuric who requires a daily urine volume of 4,000 mL might readily have to drink 5,500 ml of water per day to reach this goal and perhaps double this amount if insensible water losses are very pronounced (e.g., as in vigorously playing tennis, with heavy associated sweating, during very warm weather.)

POTENTIAL ADVERSE EFFECTS FROM FORCED HYDRATION

Adverse effects from forced hydration are primarily of a nuisance type, but may be very perplexing. Large urine volumes force frequent, highly inconveniencing voidings. Indeed, certain professions may be rendered almost impossible by this aspect, e.g., mailmen, policemen, sterile-gowned surgeons, etc. Commuting via public transportation without adequate bathroom facilities can become nightmarish. Nocturnal voiding forces frequent awakening and some patients cannot fall back to sleep, resulting at times in near ruinous daytime fatigue, with job loss or falling asleep at the wheel. The small bladder capacities of men with prostatism, and women in their last trimester of pregnancy, exact particularly cruel penalties. However, serious medical risks from forced hydration are vanishingly rare. In general, one need not fear drinking “too much water” since normal kidneys can excrete up to 20–22 liters per day of an ingested water load. Rarely, a patient ingesting a large water load who is also on thiazide diuretics, high dosages of nonsteroidal anti inflammatory drugs (e.g., Naprosyn, Advil, Aleve, etc.), or a very-low sodium diet, may retain water and experience a drop in serum sodium with resultant muscle cramps and headache. Patients with advanced renal disease should also observe special precautions. On balance, however, the advantages of forced hydration in preventing cystine stones far outweigh any downside risks especially when the alternatives are a concentrated stone-forming urine, or potentially toxic drugs such as penicillamine or Thiola.

SIGNIFICANCE OF URINARY PH

Urinary pH signifies the degree of acidity or alkalinity of the urine: the lower the number, the more acidic the urine; the higher the number, the more alkaline the urine. Because of limits on the degree of urinary acidity or alkalinity which can be generated by human kidneys, urine pH ranges only from 4.5 to 8.0. As approximate definitions, urine pHs of 4.5–5.5 are regarded as highly acid; 5.5–6.5 as mildly acid to neutral; 6.5–7.0 as neutral to mildly alkaline; and 7.0–8.0 as strongly alkaline. All pH measurements are based upon a logarithmic scale (i.e., a mathematical system of 10 being multiplied upon itself) as in an earthquake-measuring scale. In a logarithmic system, small-appearing differences signify huge mathematical increments: E.g., with a pH increment of only 2 units, a urine pH of 7.0 is one-hundred times more alkaline than a pH of 5.0, and with a further pH increment of only 0.3 units, a urine pH of 7.5 is twice again as alkaline as a urine pH of 7.2.

EFFECTS OF PH ON CYSTINE SOLUBILITY

At urine pHs below 6.5, the solubility of cystine is only 300 mg/liter. At pH 6.5, cystine solubility starts a very slow rise–barely perceptible until pH reaches 7.0 when it has risen to 400 mg/liter. By pH 7.5, however, cystine solubility has climbed to 600 mg/liter and starts to elevate even more rapidly. By pH 8.0 it has climbed to over 1,000 mg/liter, with some graphed results suggesting even more dramatic elevations. (Note: at urine pH 9.0, the solubility of cystine reaches 1,400 mg/liter which would be incredibly useful for dissolving cystine stones. Although urine pH cannot rise above 8.0 via any oral alkalinizing regimen, certain chemicals at pH 9.0–10.0 (solutions of THAM and sodium hydroxide) can be infused directly into the collecting system of the kidneys–where cystine stones collect–via percutaneously introduced catheters. At medical centers specializing in these techniques, such “super alkalinization” can be safely maintained for several days at a time, rapidly dissolving cystine stone fragments.) Cystine calculi dissolve only very slowly when exposed to dilute-alkaline urine because dissolution only occurs from stone surfaces, which are limited. Even though lithotripsy commonly is not successful in breaking up cystine stones so that they pass from the urinary tract, lithotripsy treatments can introduce myriads of cracks into a large cystine stone. This vastly increases the total surface area of the stone over which dilute-alkaline urine can percolate, grossly accelerating the rate of stone dissolution.

Viewing the benefits of urinary alkalinization benefits in reverse, at urine pH 8.0, marked solubilization of cystine is present; at pH 7.5, cystine solubilization is rising rapidly; at pH 7.2, although the solubility increments from alkalinization are measurable, they are of only minimal clinical significance; at pH 6.8–7.0, urinary alkalinization is largely a waste of time for cystinurics. Physicians who are not familiar with the ultra-steep slope of cystine’s solubility curve at pH 7.5 may not counsel cystinuric patients correctly about pH matters. One reason for this is that for the much more common (and familiar-to-physicians) condition of uric acid kidney stones, a urine pH of 6.0–6.5 is all that is required for protective solubilization, and a sustained urine pH of 8.0 is deemed undesirable.

MEASURING URINE

pH: To monitor urine pH in cystinurics, a fine grade of urine pH-testing strip paper should be used that can distinguish readings in the 7.0–8.0 range. Nitrazine pH-testing paper has the advantage of being widely available. Its drawbacks, however, include its considerable expense (frequently over $30.00 per roll), and a top pH reading of only 7.5. An inexpensive but high quality urine pH-testing paper, which has proven sufficiently accurate clinically, is available from Micro Essential Laboratories in New York. This pH paper starts its readings at 6.0 and progresses, by increments of 0.2–0.4 pH units, to a top reading of pH 8.0. (Write for: pH paper; range 6.0–8.0; Catalog# 345; Micro Essentials Laboratories, Inc.; 4224 Avenue H; Brooklyn, New York 11210; $12.00 for two rolls. Management requests no telephone orders, please.)

HOW INGESTED ALKALI ALKALINIZES URINE

Alkalinizing agents (“alkali” ) work by neutralizing body-fluid acids, with the excess alkali spilling out through the kidneys to alkalinize the urine. The acids in body fluids arise both from dietary sources (i.e., ingesting acidifying foods, e.g., red meats, or acidic liquids) and from the body’s internal metabolism (i.e., cellular activities, e.g., muscle cells during exercise). Alkali can be ingested as alkalinizing foods (e.g., vegetables), ingested as drug store-origin chemicals (e.g., sodium bicarbonate, or Alka-Seltza), produced internally by the kidneys, or “borrowed” from the alkali-rich skeleton.

Both acids and alkali are measured in units termed milliequivalents (mEq). One mEq of any alkali neutralizes one mEq of any acid, and vice versa, whether in a test tube or the body. An average adult produces internally about 70 mEq of acids per day. Since this acid is generally more than is needed to neutralize the body’s usual alkali load, the “excess acid” spills into the urine, acidifying it down to a pH 4.5–5.5 Therefore, to strongly alkalinize such urine (raise its pH to 8.0) this individual would have to introduce into his/her body about 70 mEq of alkali, either ingested as alkalinizing food or drug store-origin sodium bicarbonate. (Renal and bone originating alkali are not calculated in this simplified example.) Although such an alkali load would neutralize the body’s acid load, it would not yet alkalinize the urine. To do this, the subject would have to ingest slightly more alkali (i.e., in “excess” of what was required to neutralize the acid load) which would then “spill” into the urine, alkalinizing it. The more excess alkali taken, the more rapid the urinary alkalinization, and the higher the resultant urine pH, until the maximum of 8.0 was reached.

The amount of alkali required for this “alkali-acid titration” is not fixed. Rather, it will vary with rates of cellular metabolism, diet (e.g., vegetarian vs. meat-eating), loss of alkaline fluids from the body (e.g., as in alkali-rich diarrhea), or the ingestion of drug store-origin alkali over the preceding several days. Therefore, for a cystinuric to attain the desired degree of urine alkalinity, a “guesstimated” amount of alkali is taken and urine pH measured after about 30–60 minutes (to allow for absorption, metabolic processing and urinary excretion of the “excess” alkali). If the chosen dosage of alkali does not sufficiently elevate urine pH, a larger amount is chosen for the next dose. Frequently, over time, less and less alkali is required to produce the desired degree of urinary alkalinization as alkali stores within the body (probably in the skeleton) progressively build up.

Acetazolamide (Diamox) alkalinizes the urine by a different mechanism: Acetazolamide blocks the kidneys’ reabsorption of bicarbonate causing bicarbonate to spill into the urine, strongly alkalinizing it. Acetazolamide also blocks the kidneys’ reabsorption of sodium, water and potassium causing large losses of these substances–I.e., acetazolamide is a strong diuretic. Acetazolamide is particularly useful for nocturnal alkalinization of urine in patients who cannot, or do not want to, awaken to maintain forced hydration, and in patients who cannot tolerate high sodium loads E.g., patients with hypertension, edema, or heart problems.

AVAILABLE URINARY ALKALINIZING AGENTS

Urinary alkalinizing agents include:

(1) those that are sodium-based;
(2) those that are potassium-based;
(3) the drug acetazolamide.

Examples of sodium-based alkalinizing agents, and their common dosage forms, include:

(1) sodium bicarbonate tablets, (generic only, 0.324 gm or 3.7 mEq; 0.648 gm or 7.5 mEq);
(2) BICITRA oral solution (sodium citrate and citric acid; each mL is equivalent to 1 mEq of bicarbonate).

Examples of potassium-based alkalinizing agent include:

(1) POLYCITRA-K CRYSTALS (potassium citrate and citric acid, 30 mEq per packet for solution in water);
(2) K-Lyte tablets (potassium citrate-bicarbonate, 25 mEq or 50 mEq per tablet for solution in water);
(3) UROCIT-K (slow-release potassium citrate in a wax-matrix tablet, 5 mEq and 10 mEq per tablet). Diamox (acetazolamide) is available in extended-release caplets of 125, 250 and 500 mg.

REGULATING THE ALKALINIZATION REGIMEN

An average cystinuric patient, under average conditions of diet and exercise, requires about 15–20 mEq of an alkalinizing agent to elevate urine pH to 7.5, perhaps 25–30 mEq to reach 8.0. If this amount of alkalinizing agent does not elevate the urine pH to the requisite range (I.e., probably signifying that the body had a larger-than-expected acid load to be neutralized), a larger dose should be administered at the next chosen dosing interval and/or the interval between dosages should be shortened. After an alkalinizing agent elevates urine pH, that elevation will remain for a highly variable duration (E.g., 15 minutes to 6 hours), depending, again, upon the rate of the body’s acid loading from diet and internal metabolic acid production.

For some examples, if the alkalinization target were an 8.0 urine pH for merely a 2 hour period, then a single dose of about 15–20 mEq of the chosen alkalinizing agent would likely be sufficient. If the alkalinization target were a urine pH of 8.0 on an around-the-clock basis, then 25–30 mEq three or four times per day would likely be required.The exemplified dosages are on the light side. If a target urine pH elevation is not achieved, be prepared to increase the dose of alkalinizing agent (perhaps markedly), or shorten dosing intervals, or both. Conversely, if a target urine pH is readily achieved, test if the amount of alkalinizing agent utilized was really necessary by lessening its dose or lengthening dosing intervals, etc. Lastly, recall that the longer, and more frequently, a subject takes alkalinizing agents, the easier alkalinizing the urine becomes (as internal alkaline stores build up).

HOW LONG AND HOW FREQUENT THERAPY?

Although approximate guidelines can be suggested, clinical results are the final judge. If over a 6 to 12 month period a given hydration-alkalinization regimen prevents cystine stone formation, or actually dissolves stones, it is likely sufficient and, if the regimen were burdensome, can perhaps (gingerly) be lightened. If stones are not prevented, or dissolved, the hydration-alkalinization regimen must be intensified, or, if the regimen were already maximized, complementary therapy should probably be added (E.g., penicillamine or Thiola), probably on a permanent basis. E.g., for a patient with mild-moderate-intensity Cystinuria (E.g., cystine excretion of about 400 mg/day), with no cystine calculi, where the goals of therapy are primarily prophylactic, maintaining the hydration-alkalinization regimen for merely 2 to 4 hours per day, or perhaps even every other day, is probably sufficient. (This may be analogized to a prophylactic “Roto-Rooter” treatment.) However, if numerous or large cystine calculi are present, and the goal of hydration-alkalinization is stone dissolution, the regimen should optimally be maintained around-the-clock for months at a time, perhaps even permanently. This would be especially true, E.g., for a woman planning pregnancy, or a stone-forming cystinuric planning a trip abroad to undeveloped regions, both being instances where it would be desirable to enter the endeavor with a stone-free urinary tract.

POTENTIAL ADVERSE EFFECTS FROM URINARY ALKALINIZATION

Serious adverse effects from alkalinizing agents are very uncommon provided some minimal precautions are observed. Minor adverse effects are common but can be minimized by appropriate monitoring and regimen modifications.

POTENTIAL ADVERSE EFFECTS FROM SODIUM PREPARATIONS

Sodium bicarbonate frequently gives rise to increased gas formation in the stomach which may lead to excessive belching and chest discomfort. It can also induce lower intestinal bloating and diarrhea. Because of its buffered characteristics, Bicitra is far less problematic than sodium bicarbonate in terms of gastrointestinal tolerance. (Indeed, it is also far less irritating to the gastrointestinal tract than any of the potassium-based agents.) In patients with heart problems or advanced kidney disease, however, sodium-containing agents can induce sodium retention resulting in edema or lung congestion. Sodium loading can also exacerbate hypertension and induce excessive thirst. And all alkalinizing agents can induce over accumulation of bicarbonate in the body (I.e., metabolic alkalosis) with confusion, cramps, weakness, and symptoms of low blood calcium (muscle spasms)–especially in the face of any dehydration and renal disease. Close physician’s guidance is necessary if any of these conditions are present, suspected, or develop.

At sustained high urine pH, starting at about 7.3, and becoming more pronounced at 8.0, calcium phosphate salts (apatite) in the urine are much less soluble. Apatite stones can form in the urinary tract and “ring calcifications,” I.e., calcium encrustations can form around foreign bodies including catheters, stents and cystine kidney stones. These complications occur more readily in patients who already have low urine citrate values (urinary citrate helps keeps calcium in solution and helps prevent calcium stones or encrustations from forming or enlarging).

Although apatite stone formation, and ring calcifications, are a theoretical risk from any intense, sustained alkaluria, in our experience we have noted it only in association with sodium-based alkalinizing agents. Although we don’t fully understand the basis for this advantage of potassium over sodium-based agents, it may be because potassium citrate elevates protective urinary citrate more than does sodium bicarbonate. Also, sodium loading sweeps calcium out through the kidneys elevating urinary calcium–much more in some subjects than others–while potassium-based alkalinizing agents do not possess this disadvantage. Elevated urinary calcium (hypercalciuria) increases the potential for calcium stones formation, and ring calcifications at high urine pHs. (The action of sodium citrate in this regard is not known; as a sodium-based agent it likely also induces hypercalciuria; but, as a citrate salt, it may elevate protective urinary citrate as much as the potassium citrate preparations.)

To monitor whether intense alkalinization therapy is inducing the complication of calcium kidney stones, or calcium encrustations in the urinary tract, it is wise to obtain X-rays of the abdomen every 1–2 months when starting the regimen, then, if no problem has arisen, less frequently; radiation-free sonographic evaluations, although more expensive, may be substituted. If calcification-type complications do not develop within the first 6 months of intense urinary alkalinization, it is unlikely that they will do so in the future provided the regimen is not significantly altered. If calcium stones, or calcium encrustations, are induced by urinary alkalinization, it is best to switch to a potassium-based alkalinizing agent, if tolerated. If this cannot be effected, one might consider drastically lowering dietary phosphate intake, probably coupled with the use of oral aluminum-based phosphate binders, I.e., a Schorr regimen. The Schorr regimen decreases apatite stone formation in the urinary tract, perhaps by grossly lowering urinary phosphate concentrations, or perhaps by the apatite-inhibiting effects of aluminum being excreted in the urine. Lastly, since sodium loading can increase urinary cystine excretion, in patients with refractory, problematic cystine stones, sodium loading should be avoided unless it has been demonstrated not to significantly elevate urinary cystine.

POTENTIAL ADVERSE EFFECTS FROM POTASSIUM PREPARATIONS

Potassium-based alkalinizing agents also can cause stomach and intestinal gas formation but far less frequently than sodium-based agents. However, potassium agents frequently irritate the gastrointestinal lining causing gastritis, “heartburn,” and diarrhea, especially in patients with an underlying G.I. sensitivity. These bothersome GI side effects can be mitigated somewhat by taking the preparations only at mealtimes, or by taking lower dosages at more frequent intervals.

The only potentially serious adverse effect from potassium-based alkalinizing agents is potassium retention (I.e., hyperkalemia.) When marked, or arising suddenly, potassium retention can be fatal. Potassium retention from potassium alkalinizing agents is a risk in the following situations:

(1) Whenever kidney function is very depressed, or when urinary tract obstruction is present;
(2) Rarely, some older diabetics may unexpectedly experience difficulty with excreting potassium;
(3) When a potassium-taking patient is concurrently being treated with drugs that inhibit renal excretion of potassium. These include certain diuretics (E.g.,Dyazide, Aldactone, Midamor), and “ACE inhibitors” (E.g., Vasotec, Capoten, etc.) In this regard, the ACE-inhibitor, captopril (Capoten) is to be particularly feared because it is sometimes used, and in very high dosage, to treat Cystinuria as a substitute for penicillamine and Thiola (in subjects allergic to the latter.) Captopril can be a very effective drug to lower urinary cystine, at least for a few months, but any cystinuric subject taking daily dosages of more than 50 mEq potassium, and more than 50 mg of captopril, should have it proven that a potentially dangerous degree of potassium retention has not occurred. Because peak potassium retention may not occur until 1-2 hours after the alkalinizing agent has been taken, the serum potassium should be checked then, rather than a fasting state preceding medication administration.
(4) Rarely, when a patient taking very high dosages of potassium is also taking very high dosages of a beta blocker (E.g., Inderal, Lopressor, etc.) since beta blockers may retard the rate at which potassium enters systemic cells.

POTENTIAL ADVERSE EFFECTS FROM ACETAZOLAMIDE

Although acetazolamide sounds like an ideal agent, it has major drawbacks in that in chronic use, at high dosage, it causes too much accumulation of acid in the body (metabolic acidosis), markedly lowers (stone-protective) urinary citrate and elevates urinary calcium (from skeletal leaching.) This combination, in the face of urine at pH 8.0, grossly favors the formation of calcium encrustations and calcium stones in the urinary tract. For these reasons, acetazolamide is frequently used only intermittently, during phases of sodium intolerance. In selected individuals, however, it can be excellently tolerated and may prevent a cystinuric patient from requiring penicillamine or Thiola. In our experience, it also greatly aids nocturnal alkalinization and can be a vital force in cystine stone dissolution (when losses of potassium and bicarbonate are judiciously replaced.)

CONCLUSIONS AND SUMMARY

For the treatment and prevention of cystine calculi, a regimen of urinary dilution and urinary alkalinization provides the best combination of efficacy and safety. Since the components of this regimen are complementary in their actions (decreasing urinary cystine concentration and increasing urinary cystine solubility), they should always be used together. Penicillamine and Thiola lower urinary cystine excretion but they possess a much greater risk of toxicity. Since forced hydration and urinary alkalinization are also complementary in purpose to penicillamine and Thiola, they should always be added to a regimen of the latter. Forced hydration and urinary alkalinization may reduce the requirements of penicillamine and Thiola and, in milder cases, even substitute for them. Significant urinary cystine solubility begins at urine pH 7.5 and peaks at 8.0. Therefore, sufficient alkalinizing agent should be given to always reach this target pH range. Intensity of treatment with alkalinizing agents and hydration, should be determined empirically: intermittent and/or low-intensity regimens are likely sufficient for mild cystinurics whereas high intensity, around-the-clock, long-term regimens will likely be required for severe cystinurics. Penicillamine or Thiola should be initiated only after an optimal regimen of forced hydration and urinary alkalinization has proved insufficient. The intensity of Cystinuria can be defined on the basis of 24-hour-urine cystine excretions, with some exceptions. Potassium-based alkalinizing agents are probably superior to sodium-based ones because they do not elevate urinary cystine or urinary calcium, nor at high urine pH as strongly favor the formation of calcium stones and calcium encrustations in the urinary tract. Acetazolamide is a very useful drug for urinary alkalinization, especially for nocturnal use, sodium retainers and rapid stone dissolution. However, because of its unique adverse effects profile it should be reserved for special situations. Focused and vigorous application of forced hydration and urinary alkalinization are a major modality for the treatment and prevention of cystine calculi.

David A. Zackson, M.D.
Medical Treatment & Prevention of Kidney Stones
450 East 69th Street
New York, N.Y., 10021
(212) 744-4400 (Office)
(212) 535-6932 (Fax)