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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2003  |  Volume : 14  |  Issue : 3  |  Page : 351-357
Cystinosis and Cystinuria: Differences in Outcome

1 Departments of Pediatrics, Creighton University, Omaha, NE, USA
2 Barbara Bush Children's Hospital, Maine Medical Center, Portland, ME and University of Vermont, Burlington, VT, USA

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Cystinosis and cystinuria, both recessive genetic disorders, are fundamentally different in their pathophysiologic mechanisms. Cystinosis is a disease of cystine storage in which the kidney is the initial, but not the sole target organ. Cystinuria is a disease of renal tubular cystine transport in which excessive loss of this insoluble amino acid causes precipitation at physiologic urine pH and concentration. The former disorder uniformly results in the need for renal allograft despite recent advances in medical therapy. Cystinuria has a variable severity of expression and may be amenable to long-term medical treatment in some patients. Others may have frequent stone recurrence and infection and progress to chronic renal failure in the long term. It is the purpose of this review to provide the reader with an understanding of the respective diseases and the reasons for the differences in their prognoses and long-term outcomes.

Keywords: Cystinosis, Cystinuria, End-Stage, Renal, Stones.

How to cite this article:
Roth KS, Chan JC. Cystinosis and Cystinuria: Differences in Outcome. Saudi J Kidney Dis Transpl 2003;14:351-7

How to cite this URL:
Roth KS, Chan JC. Cystinosis and Cystinuria: Differences in Outcome. Saudi J Kidney Dis Transpl [serial online] 2003 [cited 2021 Mar 4];14:351-7. Available from: https://www.sjkdt.org/text.asp?2003/14/3/351/33014

   Introduction Top

Both cystinosis and cystinuria are autosomal recessive disorders with the potential for adverse impact on renal function. Cystinuria, first reported in 1810 by Wollaston, [1] holds a very special place in the history of medicine since it was one of the four original diseases recognized 100 years later by Garrod [2] as an "inborn error of metabolism." Wollaston's original description was of the calculus itself, which he named "cystic oxide," inten­ding it to convey the meaning of an oxide stone in the bladder. In the intervening century before Garrod, it was recognized that the calculus was not an oxide and the compound renamed cystine, but the chemical nature of the material was defined only 6 years [3] before Garrod's presentation. There are three clinical forms of cystinuria, as defined by Rosenberg, et al, [4] carriers for which are generally unaffected, although some may manifest a tendency toward urolithiasis. It is important to point out that as a dimeric amino acid with two sulfhy­dryl side chains, reduction of cystine yields two monomers of cysteine.

Almost immediately after the chemical definition of cystine was published, Abder­halden [5] reported finding cystine crystals in liver and spleen of a 21 month old infant whose death was due to inanition. The case was considered to be an example of a familial cystine storage diathesis because two siblings had also died of inanition with very similar symptoms. Three first-degree relatives of these children were also reported to have increased urinary cystine excretion. [5] This circumstance may be explained by concur­rence of the mutations for both cystinuria and cystinosis. However, it led to almost half a century of confusion until cystinosis was clearly defined by Dent and Harris in 1951. [6] In this disease, carriers have no clinical symptoms, although leukocytes contain about 6-fold normal cystine concen­trations. In contrast, homozygotes have concentrations 50-100 fold normal, so that distinction is easily made between the two groups. Since there are three major clinical types of cystinosis now described, we will confine ourselves in this discussion to the type known as nephropathic cystinosis.

It is our intent in the present report to briefly and clearly delineate the different aspects of pathophysiologic and molecular biology of the two disorders, and to demonstrate how these differences should result in very different long-term outcomes.

   Pathophysiology Top


As suggested by Abderhalden's patholo­gical description of the first reported case, [5] a fundamental clinical aspect of cystinosis is the storage of cystine throughout the body of an affected individual. Microscopic examination of virtually all body tissues will show the presence of birefringent crystals. In all cases of cystinosis the plasma concentration of cysteine-cystine is normal, suggesting that the intracellular storage is secondary to a defect located within the cell itself. In 1968, Patrick and Lake [7] reported evidence that the intracellular storage locus was the lysosome, opening a new perspective on the cellular mechanisms of disease. This discovery lent itself to a number of possible mechanisms: increased uptake, diminished ability to reduce cystine to cysteine, dimini­shed capacity for cysteine/cystine utilization, decreased rate of efflux of cysteine/cystine from the cell or various combinations of these. The reversible oxidation-reduction reactions of the two amino acids conside­rably complicated progress toward an understanding of the mechanisms involved. It should be mentioned that cysteine is the predominant intracellular species. Moreover, the integral place occupied by cysteine in synthesis of the major intracellular reducing agent, glutathione, made investigation even more complex. A major leap forward in our understanding of cystinosis was provided by the report of Jonas, et al [8] that lysosomal efflux of cystine is proton pump-ATPase dependent. The significance of this obser­vation lies in the fact that it marries the histopathologic evidence of Patrick and Lake [7] with a biochemical explanation and defines cystinosis as a disease of diminished efflux of cystine from the lysosome.

It had been shown in 1976 [9] that β-­mercaptoethylamine, or cysteamine had the ability to quickly reduce extensive cystine concentrations of cystinotic skin fibroblasts in culture. Subsequent work has demonstrated that cysteamine is specifically transported into the lysosome, [10] reacts with cystine to form cysteine and cysteine-cysteamine mixed disulfide, [11] and that the mixed disulfide stru­cturally resembles lysine and is transported by the intact lysine carrier at a significant rate out of the lysosome. [12] Thus, cysteamine has emerged as a therapeutic modality, which slows the progress of cystinosis by diminishing the rate of lysosomal cystine storage. However, the fundamental relation­ship of cystine storage to cellular toxicity continues to elude investigators. It should be noted that, despite the progress of cystine storage in virtually all tissues, the kidney is the clinical target organ.


Since recognition by Garrod in 1908 as a hereditary or inborn error of metabolism, [2] cystinuria has intrigued clinicians and membrane biologists. As one of the most common monogenetic disorders of mankind, with an estimated incidence of 1:7000, [13] this disorder has the potential to create significant renal disease in an affected indivi­dual. Cystine is the least soluble of the naturally occurring amino acids, with a solubility of 300 mg/L in urine at physiologic pH. It is now clear that this relative insolubility, coupled with its hyperexcretion account for the only known complication of the disorder, nephrolithiasis. Although the chemical nature of cystine was elucidated a century ago, analytical methods for amino acid quantitation in biological fluids were not developed for another 50 years. Almost immediately thereafter, increased arginine, lysine [14] and ornithine [15] were described in association with cystine in the urine of cystinuric patients, while plasma amino acid concentrations were reported by Dent and Rose to be normal. [16] Based upon their own and the earlier observations, Dent and Rose [16] proposed the concept that a defective renal tubular membrane transport system, normally shared by cystine and the dibasic amino acids, formed the fundamental patho­genetic abnormality in cystinuria. Their hypothesis not only provided the basis for our current understanding of cystinuria, but also it broadened our view of inborn errors to include an entire family of additional membrane transport disorders.

Early observations by Brand [17] suggested that the defect was not exclusively confined to the renal tubular epithelium, since admini­stration of an oral cystine load did not enhance urinary cystine excretion. Subsequently, direct in vitro evidence was provided by Segal and coworkers [18],[19] for an intestinal transport defect in some cystinuric indivi­duals. In a later report from the same laboratory, Rosenberg, et al [4] defined three clinical subtypes by analysis of renal and intestinal amino acid handling, two of which had been proposed earlier by Harris, et al [20] based upon urinary amino acid patterns alone. Thus, the hypothesis of Dent and Rose that cystinuria was a disorder of membrane transport was broadened to include the intestinal epithelium as well. Several other such membrane transport disorders are now known to involve the transporting epithelium of both organs.

It is possible to view genetic expression in heterozygotes for cystinuric subtypes from a clinical perspective as completely recessive (Type I), incompletely recessive (Type III) and dominant (Type II). [21] The straight for­ward implication of this view is that carriers for Type I disease will remain unaffected, those for Type III may, under certain circum­stances, become symptomatic, and carriers for Type II will be affected. A corollary of this is that these individuals will typically excrete <300 mg/L, =300 mg/L and >300 mg /L of cystine, respectively. Moreover, these three types of heterozygotic expression are translated into a complex clinical mix of compound heterozygotes, so that it is quite difficult to determine the specific genotype on biochemical grounds alone. Yet, despite the present extensive level of understanding of the molecular defect, it is still the individual phenotypic expression dictating treatment and prognosis. The essence of the molecular defect lies in an abnormality of the high-affinity transport system for cystine and dibasic amino acids, leading to increased cystine concentration in the luminal fluid with the threat of saturation and precipi­tation. In fact, recurrent stone formation is the sole clinical manifestation of the abnormal gene, deriving from a combination of native insolubility of cystine and its excess in urine due to uptake abnormalities.

   Prognosis and Long-term Consequences Top


As a member of the group of lysosomal storage disorders, cystinosis shares many of the grimmer prognostic aspects of these diseases. These include an inexorable increase in cellular stored material, cellular and organ dysfunction and frequently, death in middle to late childhood. In the specific case of cystinosis, the initial organ manifesting dysfunction is typically the kidney. Signs of involvement include hyposthenuria and urinary losses of amino acids, glucose, protein, sodium, phosphate and bicarbonate, all findings of the renal Fanconi syndrome, with an age of onset in the first 6-8 months. Systemic consequences of these losses include unexplained episodes of fever and dehydration, chronic metabolic acidosis, rachitic bone changes, weakness and failure to thrive. While all but the calcium-related problems are fairly easily treatable, no curative remedy exists. Complicating matters further is the fact that the rachitic changes derive from loss of renal ability to convert 25-OH-vitamin D to the active α-1, 25­ diOH form, due to tubular injury by cystine storage. Thus, adequate treatment requires the use of an active analogue, such as dihy­drotachysterol (DHT) in order to restore normal bone metabolism.

As mentioned earlier, the use of cystea­mine has significantly moderated the natural clinical course of cystinosis. Continuing cystine storage will predictably lead to glome­rulosclerosis and chronic renal failure by the age of 9-10 years. By contrast, patients started on cysteamine therapy prior to 2 years of age can be assumed to maintain adequate renal function beyond age 25 years. [22] Equally important is the fact that children diagnosed and treated with cystea­mine in the first 2 years of life manifest the same increase in renal function as seen in normal children, thus increasing renal reserve capacity prior to the onset of glomerulos­clerosis. [22] Consequently, while the need for renal allograft remains in patients with cystinosis, the time of renal death has been very significantly prolonged since the inception of cysteamine treatment.

Initially overlooked in the earliest clinical descriptions of cystinosis, it is now clear that cystine storage is present at birth in many extrarenal organs [23] and continues slowly, but unabated throughout life. [24],[25] In addition to 100-fold increased cystine content of skin fibroblasts, the presence of cystine crystals in cornea [26] and rectal mucosa have long been recognized as diagnostic. [27 However, the functional ramifications of systemic cystine storage are only recently becoming apparent as the combination of early cystea­mine therapy and subsequent renal allograft prolong the lives of affected individuals into the third and fourth decades. First reported in 1970 by Chan, et al [28] clinical hypothyroi­dism is now a well-established clinical feature of the disease. More recently, myopathy has come to be recognized as a long-term result of continued, post-transplant cystine storage. [29],[30] Perhaps most distressing of all are the long- term implications of cystinosis for central nervous system dysfunction, first noted by Ehrich, et al in 1979. [31] Additional reports [32],[33] have confirmed this disturbing finding, and a functional assessment documented reduced intellectual performance in several affected children. [34] These, and many other such disturbing reports have prompted debate concerning post-transplant continuation of cysteamine treatment. In this context, it should be noted that while allografts accumulate cystine over time, the storage appears to be confined to migratory reticulo­endothelial cells of the genetically-affected host and function is not impaired in any way.


Given that urinary tract stone formation is the sole known consequence of cystinuria, the long-range consequences of the disease are confined to the kidney. Unlike cystinosis, there is no intracellular storage and the essential determinants of the pathophy­siology are those of the physicochemical properties of increased urinary cystine concen­tration, deriving from the genetic membrane transport defect. Also, unlike cystinosis, there are no diagnostic clues other than family history, since stone formation proceeds slowly and silently. Consequently, although hyperexcretion of cystine begins at birth, the typical age of onset is at initial presen­tation with urolithiasis, often in the third to fourth decade of life.

Repeated episodes of obstructive uropathy frequently complicated by infection may eventually result in the need for nephrectomy, and are significantly associated with develop­ment of chronic renal failure. [35] At least one group has reported recurrence of stone formation within 3 months of surgical removal or lithotripsy in a majority of their cystinu­ric patients. [36] Cystine stones appear to be more resistant to shock wave treatment than simple calcium oxalate calculi, making litho­tripsy relatively ineffective as a therapeutic approach in cystinuric patients. [36],[37]

Most authors advocate urinary alkalinization with potassium citrate, [38] modest reduction of dietary sodium and maintenance of a daily urinary volume of 3 liters [39] to prevent stone recurrence in adult cystinuric patients. However, because the fractional excretion of cystine in patients is fixed at supraphysio­logic concentrations, urinary dilution must be maintained 24 hours a day. Children and adolescents are highly unlikely to comply with a requirement to wake several times each night to drink and void, since many adults are noncompliant. For this reason, many patients will require treatment with a thiol compound, either D-penicillamine or a-mercaptopropionylglycine. [40] Each of these two compounds cleaves the disulfide bond of cystine and forms a soluble mixed­disulfide. Stone dissolution has been repo­rted [41] and chronic therapy will maintain urinary free cystine concentration below the level of maximal solubility even with normal daily urinary volume.

Two groups [39],[42] have reported relatively good long-term therapeutic results in cysti­nuric adults for up to 32 years, using the standard medical approach outlined above. Nonetheless, there was a significant recurrence rate of stone formation, especially in those who were unable to maintain >3L urine volume per day. [39] It is, therefore, to be expected that therapeutic results in children over time would be no better, and perhaps, worse than in adults. In fact, one study in children [43] reported a stone recurrence rate of 0.64 per patient year, a rate 2-3 times as high as that in the adult studies cited. Clearly, while cystinuria appears to be treatable, the therapeutic modalities need considerable refi­nement to uniformly prevent eventual chronic renal failure in all affected individuals.

   Summary Top

Frequently confused with each other because of the similarities of terminology, cystinosis and cystinuria have completely disparate underlying pathophysiologic mecha­nisms to account for their clinical manifest­ations. Cystinosis is a lysosomal storage disease of cystine in which all organs store as much as 100-fold normal cystine content. Cystine storage can be slowed by treatment with cysteamine and the time to renal death greatly prolonged. However, even after renal transplantation, the storage continues in other organs resulting in long-term impair­ment. By contrast, cystinuria is a prototypic membrane transport disorder, in which the abnormal gene is clinically expressed in renal tubular epithelium as increased urinary loss of cystine. Due to its essential insolubility at normal urine pH, the enhanced cystine concentration carries the significant risk of precipitation and stone formation. The consequent obstruction and infection are the factors, which affect the long-term outcome in cystinuria, despite the best medical treatment.

   References Top

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13.Levy HL: Genetic screening, in Harris H, Hirschorn K (eds.). Advances in Human Genetics 1973; vol. 4, pg. 1.  Back to cited text no. 13    
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19.Fox M, Their S, Rosenberg LE, et al. Evidence against a single renal transport defect in cystinuria. N Engl J Med 1964; 270:556-61.  Back to cited text no. 19    
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38.Fjellstedt E, Denneberg T, Jeppsson JO, Tiselius HG. A comparison of the effects of potassium citrate and sodium bicarbonate in the alkalinization of urine in homozygous cystinuria. Urol Res 2001; 29:295-302.  Back to cited text no. 38    
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40.Joly D, Rieu P, Mejean A, et al. Treatment of cystinuria. Pediatr Nephrol 1999; 13:945-50.  Back to cited text no. 40    
41.McDonald JE, Henneman PH. Stone dissolution in vivo and control of cystinuria with penicillamine. N Engl J Med 1965; 273:578-83.  Back to cited text no. 41    
42.Akakura K, Egoshi K, Ueda T, et al. The long-term outcome of cystinuria in Japan. Urol Int 1998; 61:86-9.  Back to cited text no. 42    
43.Tekin A, Tekgul S, Atsu N, Sahin A, Bakkaloglu M. Cystine calculi in children: The results of a metabolic evaluation and response to medical therapy. J Urol 2001; 165:2328-30.  Back to cited text no. 43    

Correspondence Address:
Karl S Roth
Department of Pediatrics, Creighton University, Omaha, NE
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