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The association of nephrolithiasis with cystic fibrosis
The Official Journal of the
National Kidney Foundation
AJKD
VOL 42, NO 1, JULY 2003
American Journal of Kidney Diseases
REVIEW
The Association of Nephrolithiasis With Cystic Fibrosis Eric M. Gibney, MD, and David S. Goldfarb, MD ● Background: There is a growing body of evidence regarding the association between cystic fibrosis (CF) and nephrolithiasis and the role that Oxalobacter formigenes may have in that association. Methods: We performed a MEDLINE search of “cystic fibrosis and nephrolithiasis” and “Oxalobacter formigenes.” Epidemiological and experimental evidence and possible mechanisms explaining the association were critically reviewed. Results: Of patients with CF, 3.0% to 6.3% are affected with nephrolithiasis, a percentage greater than that of age-matched controls without CF, in whom the rate is 1% to 2%. Studies have suggested possible mechanisms for the association, including hyperuricosuria, hyperoxaluria, primary defects in calcium handling caused by mutation of the CF transmembrane regulator (CFTR), hypocitraturia, and lack of colonization with O formigenes, an enteric oxalate-degrading bacterium. The absence of colonization could be related to frequent courses of antibiotics. Conclusion: Although the incidence of stones in patients with CF may be increased compared with controls without CF, many possible mechanisms are implicated. The relative contributions of these mechanisms remain uncertain. Future directions may include specific identification of lithogenic risks and therapy aimed at stone prevention in this population. Am J Kidney Dis 42:1-11. This is a US government work. There are no restrictions on its use. INDEX WORDS: Calcium oxalate; cystic fibrosis transmembrane conductance regulator (CFTR); hyperoxaluria; nephrolithiasis; oxalates; Oxalobacter formigenes (O formigenes); oxaluria; urinary calculi; urolithiasis.
A
S PATIENTS WITH cystic fibrosis (CF) live longer because of improved supportive care, nutrition, and organ transplantation, they are increasingly susceptible to conditions that usually affect adults, including nephrolithiasis. There is a growing body of evidence showing an association between CF and nephrolithiasis.1 The role of Oxalobacter formigenes, a recently characterized enteric oxalate-degrading organism, is an area of increasing interest. Specifically, its presence or absence may be a determinant of intestinal oxalate absorption and thereby may affect oxaluria and the formation of calcium oxalate stones in patients with and without CF.2 Although O formigenes may have a role in the relationship, several possible mechanisms were believed to contribute to the association of stone formation with CF before this new organism was implicated. Furthermore, although epidemiological and experimental data have argued for an
association between nephrolithiasis and CF, supporting studies contained limitations in design and size. Therefore, we sought to critically review available evidence for an association between CF and nephrolithiasis and explore possible mechanisms that could explain the association, including the role of O formigenes.
From the University of Colorado Health Sciences Center, Denver, CO; Department of Veterans Affairs Medical Center; St Vincents Hospital; and New York University School of Medicine, New York, NY. Received December 9, 2002; accepted in revised form February 27, 2003. Supported in part by VSL Pharmaceuticals, Inc (D.S.G.). Address reprint requests to David S. Goldfarb, MD, Nephrology Section/111G, New York DVAMC, 423 E 23 St, New York, NY 10010. E-mail: [email protected] This is a US government work. There are no restrictions on its use. 0272-6386/03/4201-0001$0.00/0 doi:10.1016/S0272-6386(03)00403-7
American Journal of Kidney Diseases, Vol 42, No 1 (July), 2003: pp 1-11
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EPIDEMIOLOGY
A group of relatively small epidemiological studies have been conducted to assess the relationship between CF and nephrolithiasis. (When these same studies reported on specific urinary risk factors for stone disease, findings are described in later sections specifically summarizing individual risk factors). Large CF registries, such as the Cystic Fibrosis Foundation’s patient registry, have not systematically collected prospective data on the incidence or prevalence of stone disease; therefore, only these small studies are available. In 1993, a brief report by Strandvik and Hjelte3 noted stone disease in 5 of 140 patients with CF (3.6%); affected patients had an average age of 29 years. Four of the 5 patients had calcium oxalate stones. Their brief report contained limited information on how data were gathered, length of follow-up, and patient characteristics and lacked controls, but it provided the first assessment in the literature of the incidence of stone disease in patients with CF. Three years later, Matthews et al4 reported on the findings of a larger study. Two hundred one patients with CF aged at least 15 years (average age, 25.9 years) were interviewed by telephone about a history of nephrolithiasis. Only episodes that could be documented through chart review were included. Their study found 11 of 201 interviewed patients (5.5%) with documented nephrolithiasis. Seven patients had recurrent (2 or more) episodes. Mean age at the first episode was 27 years, with a range of 19 to 33 years. Four patients reported a history of stones that could not be confirmed by chart review, which may have led to underestimation of the prevalence of stone disease. Stone analysis was not included, but each of 9 urograms performed showed radiopaque stones, consistent with the presence of calcium-containing stones. Although they mentioned rates of nephrolithiasis in previous epidemiological studies of healthy adults, their study lacked a control population. Chidekel and Dolan5 also reported on the incidence of stones in 140 patients with CF seen during 6 years. Eight patients with an average age of 23 years had nephrolithiasis (5.7%), with seven stones composed of calcium oxalate. An additional 4.2% of patients had calcium oxalate crystalluria, but had not formed stones. All stones
were documented by ultrasound, radiography, or intravenous pyelogram, and crystalluria, by microscopic examination of urine. Mean age of stone formers was 23 years, and all had pancreatic insufficiency on clinical grounds. In 1998, Hoppe et al6 reported on a group of patients with CF. Four of 64 patients (6.3%) had nephrolithiasis, and 4 patients (6.3%) had nephrocalcinosis, but the method of patient selection was not described. All stone formers were older than 15 years, and the average age of the entire group was 15.9 years. Neither of these studies contained contemporary or historic controls without CF. Most recently, 496 patients at a CF care center were screened for a history of nephrolithiasis.7 Average age was 25 years. Thirteen patients (3%; average age, 27 years) had a history of nephrolithiasis; all stones were radiopaque on plain radiography and the nine stones analyzed contained calcium oxalate as the dominant component. The study compared metabolic stone risk factors between 13 stone formers with CF and 86 patients with CF without stones. Again, this study lacked controls without CF, but provided more evidence on the baseline rate of nephrolithiasis in populations with CF. Another recent study of metabolic risks for stone formation in patients with CF found a history of stones in 10 of 190 patients (5.3%) surveyed at their center.8 Stone formers had an average age of 13.5 years, and non–stone formers were aged 14.3 years. Their study contained control patients for assessment of metabolic risks, but not for the background prevalence rate of stone formation. Other limitations stem from the use of referral centers; it is possible to miss both less-affected children who avoid specialized care centers and extremely ill children who have died or spent little time in outpatient settings. Also, asymptomatic stones are not well represented in reviews of medical records. However, these 2 recent studies confirm the approximate prevalence rates of previous smaller studies. Although these 6 studies had limitations, a few conclusions can be made. They all reported similar rates of nephrolithiasis, with a range of 3.0% to 6.3%. When we combine all patients in these 6 studies, mean prevalence rate was 4.1% (51 of 1,231 patients). Mean age of the patients studied was between 13.5 and 27 years, which means
CYSTIC FIBROSIS AND KIDNEY STONES
that nephrolithiasis in patients with CF appears to be a disease of adolescence and early adulthood. Three of the studies had little information about how patients were selected for study. Furthermore, none of the studies contained a control group of healthy or comparatively sick patients without CF, which necessitated a comparison with historic controls. As Matthews et al4 observed, this can be a difficult task because prevalence rates usually are obtained from middleaged populations in large epidemiological databases. Population-based studies have estimated lifetime prevalence rates of stone formation in North America between 3.5% and 13.7%.9-11 Prevalence rates vary according to age, sex, and region, with the greatest rates in older patients, men, and in the southeast. However, age-specific prevalence rates are much lower in studies of individuals aged 20 to 29 years (1%) and 30 to 39 years (2.1%).12 These age-based prevalence rates were obtained from adults enrolled in a large California health plan and suggest that if the prevalence of nephrolithiasis in patients with CF is 3.0% to 6.3%, there is an increased risk for nephrolithiasis in the disorder. However, the true rate of nephrolithiasis in patients with CF is difficult to determine from these studies, which lack controls, differ in design, and are taken from different regions. MECHANISMS FOR THE ASSOCIATION
Perhaps because stone formation has multifactorial causes, several possible explanations for the association of CF with increased prevalence rates of nephrolithiasis have been offered. Some of these mechanisms have been explored experimentally and are reviewed here, with a focus on conclusions and study limitations. Hyperuricosuria Although uric acid stones have not been found in increased frequency in patients with CF, hyperuricosuria can be a factor in the nucleation of calcium oxalate and formation of calcium oxalate stones.13 Although definitions of this abnormality vary in the studies we reviewed, hyperuricosuria was one of the first urinary abnormalities reported in patients with CF.14 In 1976, Stapleton et al14 reported on dysuria, uric acid crystalluria, and hyperuricosuria in 1 child and hyperuricosuria in 2 other children with CF. Hyperuricosuria
3
was defined as urinary uric acid excretion greater than 600 mg/1.73 m2/d (3.6 mmol/1.73 m2/d) or greater than 17.7 mg/kg/d (0.1 mmol/kg/d). Hyperuricosuria was attributed to high-dose purinerich pancreatic extracts, leading to increased purine ingestion and subsequent elevated urinary uric acid excretion. In all 3 cases, the hyperuricosuria responded to a reduction in dose of pancreatic extract. The investigators then screened 32 patients, 15 of whom were taking higher than prescribed doses of pancreatic enzymes. Fourteen of these 15 children had hyperuricosuria. In 1977, this same group noted a direct relationship between pancreatic enzyme dose and uric acid excretion. Hyperuricosuria in these patients responded to a reduction in dose of extract.15 Similarly, a study of 16 Israeli patients with CF found hyperuricosuria and hyperuricemia, which correlated with dose of pancreatic extract.16 The study was strengthened by comparison with 65 healthy Israeli children. More recently, Hoppe et al6 documented hyperuricosuria with uric acid greater than 1,000 mg/1.73 m2/d (6 mmol/1.73 m2/d) in 16 of 63 studied patients in a study that lacked controls. Follow-up studies to assess the mechanism for hyperuricosuria have been less conclusive. One study found that levels of uric acid excretion far exceeded levels attributable to intake from pancreatic extract, leading to the hypothesis that hyperuricosuria was derived from increased endogenous urate production in patients with CF.17 Wiersbitzsky et al18 studied serum and urinary uric acid levels before and 8 hours after a standard meal with pancreatic enzyme supplementation. No change in uricemia or urinary uric acid excretion was observed. Purine contamination of pancreatic extracts may vary among preparations. Also, purine ingestion by patients with CF probably has been reduced in recent years by decreasing the dose of pancreatic enzymes because of advances in drug formulation. Specifically, microencapsulation, enteric coating, and coadministration of acid-blocking therapies have been used to limit acid destruction of enzymes in the stomach.19 Another mechanism involving uric acid and stone formation could involve the effects of diarrheal illnesses and excessive stool fluid losses caused by malabsorption, both of which occur in
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CF. Although acute diarrheal states are associated with decreases in uric acid excretion and hyperuricemia rather than hyperuricosuria, decreasing urine pH can lead to increased uric acid supersaturation, even with diminished uricosuria. With more chronic states of increased bowel losses, hyperuricemia would lead to increased filtered loads of uric acid, reestablishing uric acid balance and normal urinary uric acid content. Such mechanisms might be invoked if an increased incidence of uric acid stones was observed in patients with CF, but this has not been shown. As we state next, correlations of stone formation with stool losses or effectiveness of pancreatic enzyme replacement are lacking. Although hyperuricosuria is an established risk factor for calcium oxalate stone formation, increased uric acid supersaturation mediated by decreased urinary pH in the absence of hyperuricosuria has not been definitively shown to promote calcium oxalate stones. Together, this group of studies suggests that hyperuricosuria affects many patients with CF and may be associated with greater doses of pancreatic extract or increased endogenous production of uric acid. The relative contributions of these mechanisms to increases in urinary uric acid excretion remain unclear, and the importance of hyperuricosuria or uric acid supersaturation to the increased incidence of stone disease is uncertain. Hyperoxaluria Hyperoxaluria and calcium oxalate nephrolithiasis are known complications of other malabsorptive states, including inflammatory bowel disease and ileal resection. With malabsorption, calcium binds to fatty acids in the intestinal lumen rather than to oxalate, facilitating increased absorption of the free oxalate.20 Malabsorbed bile salts create greater colonic oxalate permeability, which also facilitates oxalate absorption.21 There also is evidence of alterations in oxalate homeostasis in CF. Before a relationship between nephrolithiasis and CF had been established, Bohles and Michalk22 studied factors affecting urinary lithogenicity in 43 patients with CF, 21 healthy controls, and 5 calcium oxalate stone formers. They reported elevations in urinary oxalate excretion (factored for urinary creatinine level) in patients
GIBNEY AND GOLDFARB
with CF compared with controls, but expressed results as a mean for the group and did not report the number of affected individuals. In the previously mentioned study by Hoppe et al,6 urinary oxalate excretion in patients with CF was measured. Twenty-five of 63 patients had hyperoxaluria, defined as oxalate levels of 45 mg/1.73 m2/d (0.5 mmol/1.73 m2/d). Oxalate excretion tended to be greater in males and older patients. Relative urinary calcium oxalate saturation was elevated in 26 of 63 patients. Of all lithogenic factors studied, secondary hyperoxaluria was the most common disorder. Study conclusions are limited by the lack of an age-matched control population. Perez-Brayfield et al7 measured urinary oxalate in 13 patients with CF with nephrolithiasis (mean age, 27 years) compared with 86 patients with CF without stones and found no difference between the 2 groups, but did not compare urinary oxalate excretion with that of matched healthy populations. Mean oxalate excretions were 45.5 and 42.5 mg/d, with their upper limit of normal cited as 30 mg/d. Both groups had increased urinary calcium oxalate supersaturation. Bohles et al8 found elevated urinary oxalate excretion in patients with CF with and without stones compared with control patients; normal values were not defined. Stone formers had an average age of 13.5 years at the time of their first episode. The investigators’ use of clinic patients with “constitutional short stature” in the control group limits conclusions about metabolic risks compared with healthy controls. It is entirely possible that heterogeneous disorders affecting stature would affect urinary excretion of oxalate, calcium, citrate, and uric acid because of variations in bone and muscle mass, diet, and prescribed drug, vitamin, and dietary therapy. Recently, oxalate, calcium, and glycolate excretion were studied in 26 patients with CF and no evidence of stone disease. Glycolate was measured as a marker for precursors of oxalate in an attempt to decipher whether hyperoxaluria had metabolic causes.23 Little is known about glycolate ingestion and excretion in healthy people or patients with CF with malabsorption; thus, the reliability of this assumption is unproven. Normal values used for oxalate excretion were 31.5 mg/24 h (0.35 mmol/24 h) in patients younger than 13 years, 43.2 mg/24 h
CYSTIC FIBROSIS AND KIDNEY STONES
(0.48 mmol/24 h) in males older than 13 years, and 46.8 mg/24 h (0.52 mmol/24 h) in females older than 13 years; excretion was not factored for body size or urinary creatinine excretion. Urinary oxalate levels were elevated in 14 of 26 patients, and oxalate level correlated positively with urinary glycolate level, suggesting, if the investigators’ assumptions are correct, that some component of hyperoxaluria is of metabolic origin. Hyperoxaluria therefore is an important and relatively frequent metabolic abnormality in patients with CF and a major risk factor for stone formation. It is likely that increased enteric oxalate absorption associated with fat malabsorption is a major factor contributing to hyperoxaluria in patients with CF. It is unfortunate that only one of the studies we reviewed described the bowel status of stone-forming patients. In this study, there was a slightly greater incidence of steatorrhea in stone formers with CF compared with non–stone formers with CF, and the amount of stool fat did not correlate with urinary oxalate excretion.22 Little attention has been given in most of the studies to whether patients had pancreatic insufficiency (as in 85% of patients with CF) and, if present, to possible associations of effectiveness of therapy, presence of steatorrhea, or stool volume with stone formation. In the age groups in which stones are seen, diarrhea and malabsorption still occur, even in patients treated with adequate doses of pancreatic enzymes. Estimates of the prevalence of continued fat malabsorption are as high as 20% of patients administered enzyme supplementation, in part because of failure of patients to adhere to treatment regimens.24 The relative contribution of increased endogenous production is less clear. Whether all these factors causing hyperoxaluria interact with or are important variables independent of O formigenes colonization, discussed later, remains to be learned. Calcium Excretion and Microscopic Nephrocalcinosis Because of the increased incidence of calciumcontaining stones in patients with CF, the study of renal calcium handling in CF has generated much interest. In all the studies reviewed, the definition of hypercalciuria used was calcium
5
greater than 4 mg/kg/d (0.1 mmol/kg/d). Bohles and Michalk22 found that calcium excretion factored by urinary creatinine excretion was decreased in urine of patients with CF compared with controls and calcium oxalate stone formers. They postulated that relative hypocalciuria seemed to be protective in the setting of multiple lithogenic factors. Calcium oxalate supersaturation was not measured or calculated in their study. Bentur et al25 found normal urinary calcium excretion in 30 of 34 non–stone-forming patients with CF. The 4 patients with hypercalciuria had possible secondary causes, such as glucocorticoid administration and immobilization. The investigators concluded that no primary renal defect in calcium handling existed. Hoppe et al6 examined 24-hour urine collections in 63 patients with CF and found increased urinary calcium levels in 13 patients. The investigators did not specify whether urinary calcium excretion distinguished stone formers and patients with nephrocalcinosis from unaffected patients. The majority of patients showed normal or low urinary calcium excretion, and mean values of the cohort were not reported. In that study, urinary calcium oxalate supersaturation was elevated in 26 of 63 patients, most often as the result of an increase in urinary oxalate excretion (19 patients). Urinary saturation of brushite, one crystalline form of calcium phosphate, also was elevated in 19 patients. Turner et al23 studied calcium and oxalate excretion in 26 children with CF. The majority (15 of 24 children) showed relative hypocalciuria (calcium ⬍ 4 mg/kg/d [⬍0.1 mmol/kg/d]), which again was postulated to have a protective effect on nephrolithiasis. Finally, Bohles et al8 recently found hypercalciuria in stone-forming patients with CF compared with non–stoneforming patients with CF and in all patients with CF compared with controls. However, the aforementioned use of control patients with “constitutional short stature” limits the investigators’ ability to conclude that patients with CF have hypercalciuria compared with healthy children and is not easily explained in conflict with Bohle’s own and other historic data. Although multiple mechanisms for altered calcium homeostasis are possible, some studies of patients with CF have shown decreased bone density, decreased gastrointestinal absorption of
6
calcium (not entirely corrected by pancreatic enzyme replacement), and lower serum 25hydroxy-vitamin D levels. Some patients also have greater parathyroid hormone (PTH) levels at baseline and after meals high in calcium content.26 These abnormalities potentially could be explained by vitamin D deficiency.27,28 Despite the relative lack of hypercalciuria, nephrocalcinosis has been described in patients with CF. Microscopic nephrocalcinosis is associated with multiple metabolic disorders, such as idiopathic hypercalciuria, renal tubular acidosis, disorders of vitamin D metabolism, and genetic disorders of chloride channels. Microscopic nephrocalcinosis also is associated with increased rates of nephrolithiasis in patients without CF.29-31 Microscopic nephrocalcinosis was described first in CF in autopsy specimens of 35 of 38 patients.32 The affected children included 6 patients younger than 1 year, which supported a hypothesis that nephrocalcinosis was the result of a primary renal defect and not a manifestation of chronic illness and organ dysfunction. This series later was criticized for a lack of similarly ill autopsy controls. Measurements of urinary calcium excretion in 14 patients and 15 controls found individual patients with CF with increased calcium excretion, but mean levels in patients with CF were no different from those of controls. After these observations, another group showed sparse nephrocalcinosis at autopsy in just 5 of 14 patients with CF and also found nephrocalcinosis in 6 of 12 control patients with chronic diseases and similar preterminal events.25 Combined with their own data on urinary calcium excretion, they concluded that evidence of a primary renal defect in patients with CF was lacking. Similarly, immunoreactive calmodulin studied in a small group of patients with CF did not differ from controls or correlate with nephrocalcinosis.33 Recently, a case report of nephrocalcinosis in patients with CF after lung transplantation was described, but no definite mechanism was elucidated.34 In summary, there is scant evidence of altered calcium homeostasis in patients with CF, and alterations in homeostasis likely are neutral or even protective with regard to urinary calcium excretion and nephrolithiasis. Although infrequent, hypercalciuria may occur in some individuals and contribute to the overall risk for stones
GIBNEY AND GOLDFARB
when other factors also are present. Although there may be an increased frequency of microscopic nephrocalcinosis in patients with CF, small studies with control populations do not confirm the association, and larger more definitive series with adequate controls are not available. At present, there is insufficient evidence to accept a primary defect in renal calcium handling leading to hypercalciuria as an explanation for stones in patients with CF. Chloride Channels and Nephrolithiasis Mutations in the CF transmembrane conductance regulator (CFTR) are the cause of CF, leading to a host of downstream clinical manifestations.35 CFTR is expressed in the kidney, although the function of normal CFTR in renal physiology has not been established. It is of interest that mutations in voltage-gated chloride channels (CLCs) expressed in the kidney have been associated with nephrolithiasis.36 We speculate that abnormal function of CFTR also could contribute to stone formation and therefore briefly review the association of chloride channel mutations with stone disease. The CLC family of chloride channels consists of 12 channels described to date. Nine CLCs have been identified in mammals, named CLC 1-7, CLC-Ka, and CLC-Kb. Mutations in genes that code for these channels have been associated with a variety of mammalian diseases. CLCN-5 mutations (coding for the CLC-5 channel) are responsible for Dent’s disease, an X-linked recessive renal disease characterized by hypercalciuria, stone formation, nephrocalcinosis, low-molecular-weight proteinuria, and renal insufficiency.37 Other features of proximal tubular dysfunction are common. Idiopathic hypercalciuria without low-molecular-weight proteinuria also has been associated with mutations in CLC-5. Currently, it is thought that chloride channel defects in CLC-5 cause defects in endosomal acidification and an inability to reabsorb lowmolecular-weight proteins, including PTH, in the proximal tubule. Hypercalciuria and stone formation may follow because of increased luminal PTH-mediated stimulation of renal vitamin D 1-hydroxylation, leading to increased intestinal calcium absorption and absorptive hypercalciuria.38 Another disorder associated with defects in
CYSTIC FIBROSIS AND KIDNEY STONES
renal chloride transporters and variably with nephrocalcinosis is Bartter’s syndrome. Neonatal Bartter’s syndrome, characterized by hypercalciuria and nephrocalcinosis, results from mutations in the gene encoding the Na-K-2Cl cotransporter (NKCC2) or the gene encoding the outwardly rectifying potassium channel (ROMK), a regulator of NKCC2. Classic Bartter’s syndrome results from mutations in the gene encoding the basolateral chloride channel (CLCNKB), also a regulator of NKCC2, but in these cases, hypercalciuria may be present without nephrocalcinosis.30 In brief, given the associations of such disorders of chloride transporters as Dent’s disease and Bartter’s syndrome with nephrocalcinosis, it is tempting to consider that a dysfunctional CFTR, the chloride channel mutated in CF, may lead to this phenotypic manifestation. However, both Dent’s disease and Bartter’s syndrome are associated with hypercalciuria, a disorder seen only variably and infrequently in patients with CF. The pathophysiological sequence leading chloride channel mutations to cause hypercalciuria is still under investigation; how a mutated CFTR would affect calcium flux in the kidney remains unknown. The finding of microscopic nephrocalcinosis in infants with CF probably is evidence of some uncharacterized abnormality in renal electrolyte handling.32 Although these autopsy studies had important limitations, confirmation of these findings would suggest that mutations in CFTR lead to a primary defect in renal electrolyte handling and a risk for nephrolithiasis. Other specific evidence implicating abnormal CFTR in nephrolithiasis is not available. Hypocitraturia Citrate is an important urinary inhibitor of calcium stone formation, and hypocitraturia is a risk factor for the formation of calcium-containing stones. Citrate binds calcium to form a soluble complex and inhibits crystal growth and agglomeration. Hypocitrituria (citrate ⬍ 230 mg/1.73 m2/d [⬍1.2 mmol/1.73 m2/d]) was present in 14 of 63 patients with CF in 1 study, but was linked with hyperoxaluria in only 2 patients and elevated urinary calcium oxalate supersaturation in only 1 patient.6 In another group of 43 patients, 21 controls, and 5 calcium oxalate stone formers, citrate excretion was decreased in pa-
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tients with CF, but was expressed as a group mean.22 A more recent study found hypocitraturia to be the only statistically significant difference between 13 stone-forming patients with CF and 86 patients with CF without stones. The investigators thus concluded that patients with CF should be screened and treated for hypocitraturia.7 Finally, a study of 10 patients with CF with stones, 86 patients with CF without stones, and 30 controls found hypocitraturia (citrate ⬍ 280 mg/d [⬍1.5 mmol/d]) and decreased urinary citrate-calcium ratios in stone formers with CF.8 Thus, recent evidence has implicated hypocitraturia as an important lithogenic risk in patients with CF. Citrate reabsorption by the proximal tubule is stimulated in states of increased dietary acid loads or metabolic acidosis, leading to hypocitraturia, an important risk factor for stones. Stool losses of bicarbonate result in metabolic acidosis, which in turn stimulates renal tubular reabsorption of citrate. This is another possible mechanism by which intestinal salt and water losses could contribute to calcium oxalate stones in patients with CF. Depletion of total-body potassium stores, with or without hypokalemia, also leads to intracellular acidification and stimulation of citrate reabsorption. Potassium depletion can contribute to hypocitraturia in states of chronic diarrhea or diuretic use. Hypocitraturia in some patients with CF also could be the result of increased dietary acid represented by protein ingestion in the form of pancreatic enzymes. Hypomagnesemia, an electrolyte disorder frequently seen in patients with malabsorption, also has been shown to contribute to hypocitraturia in patients without CF.39 Diminished urinary magnesium concentrations in stone formers with CF compared with non–stone formers with CF was reported in 1 study,22 but not another.7 Changes in urinary citrate excretion in response to magnesium supplementation have not been reported. Any link between altered renal CFTR activity and tubular citrate reabsorption has yet to be postulated. Also at this time, no data are available on the effect of limiting enzyme ingestion on urinary citrate excretion or the effect of treating patients with CF with citrate on rates of nephrolithiasis.
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Low Urine Volume Low urine volume, as the result of sweat or stool losses, is a possible contributor to stone formation in patients with CF, and one that surprisingly has been little commented on in the studies we reviewed. Low urine volume is an important cause of stones in patients without CF because it is a major determinant of supersaturations of calcium salts and uric acid. One report noted no difference in urine volume between stone formers with CF and non–stone formers with CF.22 Low urine volume could result from excessive losses of sodium-rich sweat, a hallmark of the disease. There is evidence that as patients with CF exercise, their sweat volume and sweat sodium losses are greater than those of agematched peers.40 With greater sweat sodium concentrations, the increase in serum osmolality that normally accompanies hypotonic fluid losses is of a lesser magnitude. Thirst therefore is stimulated less and less oral fluid is taken ad lib.41 The unstated implication from these data is that patients with CF would have lower urine volumes and higher urine concentrations of calcium salts and uric acid, with greater supersaturations, as well. Chronic manifestations of these phenomena, if any, and their impact on stone formation have not been studied. Excessive stool sodium and fluid losses could lead to chronic depletion of extracellular fluid volume and chronically diminished urine volume. The result again would be an increase in urinary supersaturation of calcium salts and uric acid. As we reviewed, diarrhea also has the potential to contribute to hypocitraturia, a risk factor for calcium stones, and low urine pH, a risk for uric acid stones. It may be that multiple metabolic abnormalities are important in the increased prevalence of stones associated with CF. It might be true, for instance, that hyperoxaluria is an important risk factor, but important only if other factors, such as low urine volume, hypocitraturia, or hyperuricosuria, also are present. Other Possible Factors in Stone Formation A variety of other factors have received slight attention as risk factors for stones in patients with CF. Antibiotic administration with consequent tubular dysfunction has been theorized34
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and examined8 as a possible cause of microscopic nephrocalcinosis and stone formation. Bohles and Michalk22 found a significant negative correlation between total use of co-trimoxazole and ceftazidime and tubular phosphate reabsorption. However, they did not find this relationship in non–stone formers with CF or for other antibiotics, such as aminoglycosides. Low urinary phosphate concentration, a possible lithogenic risk, also has been found in some patients with CF.22 Although zinc excretion appears to be elevated in calcium stone formers and patients with CF have abnormalities in zinc metabolism, data on urinary zinc excretion in patients with CF currently are unavailable.42,43 Proteins that function as inhibitors or promoters of crystallization or crystal growth and agglomeration, such as osteopontin, Tamm-Horsfall protein, calgranulin, and others, also may be important factors in clinical disease, but studies of inhibitors and promoters specifically in CF are not available. O FORMIGENES
Background Recent studies have implicated the absence of the organism O formigenes, an oxalate-degrading bacteria, in the colons of patients with CF as a cause of stone disease. The organism was identified by Allison et al44-46 in the early 1980s and shown to be a gram-negative obligate anaerobe that resides in the intestines of sheep, pigs, and humans. It possesses an oxalate-formate exchanger that allows it to take up oxalate, its only substrate for the production of adenosine triphosphate. The organism then uses 2 enzymes, a formyl-coenzyme A (CoA) transferase and an oxalyl-CoA decarboxylase, to metabolize oxalate. The latter enzyme is coded for by the gene oxc, the basis for reliable detection of the organism in fresh or frozen stool samples using polymerase chain reaction (PCR).47,48 A number of findings have supported the possible role of O formigenes in intestinal oxalate handling. Humans undergoing jejunoileal bypass surgery have little or no colonization with the organism and far less intestinal oxalate degradation compared with control patients. This led to the hypothesis that the absence of the organism might be a contributor to the increased intestinal oxalate absorption and resultant hyperoxaluria
CYSTIC FIBROSIS AND KIDNEY STONES
that occurs in patients after this surgical procedure.44 Laboratory rats lacking the bacterium in their colons can be colonized with O formigenes if fed a high-oxalate diet before inoculation. Colonization is associated with less urinary oxalate excretion and increased oxalate degradation in the gastrointestinal tract.49-51 Humans also have been successfully colonized after long periods of negative O formigenes PCR test results.52 Addition of the organism to a test meal containing a fixed load of sodium oxalate also reduces postprandial urinary oxalate excretion in people.52 O formigenes in CF and Nephrolithiasis In a study of urinary oxalate excretion in patients with CF, 71% of 21 control patients were colonized with the bacterium compared with only 16% of 43 patients with CF.2 The 7 patients with CF colonized by O formigenes had normal urinary oxalate excretion (⬍45 mg/d [⬍0.5 mmol/d]), whereas 53% of 36 patients not colonized had hyperoxaluria. This supported the hypothesis that the presence of the organism protected against hyperoxaluria. Interestingly, the only patient with CF with normal quantitative PCR levels for O formigenes had never been administered a course of antibiotics. One potential explanation for lower rates of colonization in patients with CF is the multiple courses of antibiotics that patients with CF usually undergo as a result of recurrent pulmonary infections. The association of hyperoxaluria with the absence of O formigenes has not yet been shown prospectively. An alternative speculative interpretation of the data relies on the work by Freel et al53 showing that intestinal oxalate secretion occurs through chloride channels that may be identical to CFTR. If this is true, one could postulate diminished oxalate secretion from blood to the intestinal lumen in patients with CF. A lack of luminal oxalate to serve as substrate for O formigenes could lead to loss of colonization with this oxalate-dependent organism. Whether CFTR is a conductor of oxalate and O formigenes colonization is dependent on secreted, rather than ingested, oxalate remain unknown. Because none of the studies examining the associations of hyperoxaluria and the presence or absence of the organism have controlled dietary oxalate content, there is further reason to remain uncertain
9
about whether the association is causative. Although extremely suggestive, these studies to date have fallen short of proving that the organism’s absence is causative of calcium oxalate nephrolithiasis in patients with CF. There is a need for long-term prospective data showing that O formigenes colonization protects against future stone development. If colonization can be induced by administration of the organism and maintained without increasing dietary oxalate ingestion, the therapy could be an important one for hyperoxaluria. Long-term reduction in urinary oxalate excretion would be expected to lead to reduced rates of stone recurrence. Another option, administration of the oxalatedegrading enzymes by mouth, also could be useful. Other bacteria, including a species of enterococcus with oxalate-degrading properties, have been identified, but not yet shown to have epidemiological significance,54 whether in stone formers without CF or patients with CF. Lactic acid bacteria, lacking the gene for the oxalate transporter seen in O formigenes, have reduced urinary oxalate excretion in stone formers without CF with hyperoxaluria through an unknown mechanism.55 The specific importance of O formigenes in patients with CF as a protective agent or future therapeutic modality remains uncertain. The possibility that intestinal organisms normally affect the absorption and secretion of various solutes in health and disease remains an intriguing possibility. CONCLUSION
Although the available epidemiological evidence on nephrolithiasis and CF is not without flaws, there now appears to be a clearly increased risk for calcium oxalate nephrolithiasis in patients with CF compared with historic controls of healthy age-matched populations. This increased risk appears to be greater in older patients with CF. As the life expectancy of people affected by CF continues to increase, the population at risk for stones will increase in size. Currently, approximately 37% of people with CF are older than 18 years.56 Hyperoxaluria, hyperuricosuria, and hypocitraturia are the most commonly found metabolic risks and provide opportunities to modify stone recurrence rates in affected patients. Low urine
10
GIBNEY AND GOLDFARB
volume likely is of importance in some patients. Although lack of colonization with O formigenes is associated with calcium oxalate stone formation, it is not clear whether this is causative or simply an association. If more or longer courses of antibiotics reduce colonization and lead to hyperoxaluria, changes in the use of antibiotics may affect rates of stone formation. Other factors, such as renal calcium handling and microscopic nephrocalcinosis caused by chloride channel defects or abnormal inhibitors, also may have a role. It is likely that future efforts will involve studies on screening and treatment for known metabolic risks in both affected and unaffected patients. The intentional administration of nonpathogenic oxalate-degrading bacteria has been studied in patients with hyperoxaluria and may be an area of future study in patients with CF. REFERENCES 1. Gutknecht DR: Kidney stones and cystic fibrosis. Am J Med 111:83, 2001 (letter) 2. Sidhu H, Hoppe B, Hesse A, et al: Absence of Oxalobacter formigenes in cystic fibrosis patients: A risk factor for hyperoxaluria. Lancet 352:1026-1029, 1998 3. Strandvik B, Hjelte L: Nephrolithiasis in cystic fibrosis. Acta Paediatr 82:306-307, 1993 4. Matthews LA, Doershuk CF, Stern RC, Resnick MI: Urolithiasis and cystic fibrosis. J Urol 155:1563-1564, 1996 5. Chidekel AS, Dolan TF: Cystic fibrosis and calcium oxalate nephrolithiasis. Yale J Biol Med 69:317-321, 1997 6. Hoppe B, Hesse A, Bromme S, Rietschel E, Michalk D: Urinary excretion substances in patients with cystic fibrosis: Risk of urolithiasis? Pediatr Nephrol 12:275-279, 1998 7. Perez-Brayfield MR, Caplan D, Gatti JM, Smith EA, Kirsch AJ: Metabolic risk factors for stone formation in patients with cystic fibrosis. J Urol 167:480-484, 2002 8. Bohles H, Gebhardt B, Beeg T, Sewell AC, Solem E, Posselt G: Antibiotic treatment-induced tubular dysfunction as a risk factor for renal stone formation in cystic fibrosis. J Pediatr 140:103-109, 2002 9. Soucie JM, Thun MJ, Coates RJ, McClellan W, Austin H: Demographic and geographic variability of kidney stones in the United States. Kidney Int 46:893-899, 1994 10. Curhan GC, Rimm EB, Willett WC, Stampfer MJ: Regional variation in nephrolithiasis incidence and prevalence among United States men. J Urol 151:838-841, 1994 11. Johnson CM, Wilson DM, O’Fallon WM, Malek RS, Kurland LT: Renal stone epidemiology: A 25-year study in Rochester, Minnesota. Kidney Int 16:624-631, 1979 12. Hiatt RA, Dales LG, Friedman GD, Hunkeler EM: Frequency of urolithiasis in a prepaid medical care program. Am J Epidemiol 115:255-265, 1982 13. Ryall RL, Grover PK, Marshall VR: Urate and calcium stones—Picking up a drop of mercury with one’s fingers? Am J Kidney Dis 17:426-430, 1991
14. Stapleton FB, Kennedy J, Nousia-Arvanitakis S, Linshaw MA: Hyperuricosuria due to high-dose pancreatic extract therapy in cystic fibrosis. N Engl J Med 295:246248, 1976 15. Nouisa-Arvanitakis S, Stapleton FB, Linshaw MA, Kennedy J: Therapeutic approach to pancreatic extractinduced hyperuricosuria in cystic fibrosis. J Pediatr 90:302305, 1977 16. Sack J, Blau H, Goldfarb D, Ben Zaray S, Katznelson D: Hyperuricosuria in cystic fibrosis patients treated with pancreatic enzyme supplements. A study of 16 patients in Israel. Isr J Med Sci 16:417-419, 1980 17. Niessen KH, Wolf A: Studies on the cause of hyperuricosuria in cystic fibrosis patients. J Pediatr Gastroenterol Nutr 1:349-354, 1982 18. Wiersbitzky S, Ballke EH, Wolf E, Paul W: Uric acid serum concentrations in CF-children after pancreatic enzyme supplementation. Padiatr Grenzgeb 28:171-173, 1989 19. Kraisinger M, Hochhaus G, Stecenko A, Bowser E, Hendeles L: Clinical pharmacology of pancreatic enzymes in patients with cystic fibrosis and in vitro performance of microencapsulated formulations. J Clin Pharmacol 34:158166, 1994 20. Dharmsathaphorn K, Freeman DH, Binder HJ, Dobbins JW: Increased risk of nephrolithiasis in patients with steatorrhea. Dig Dis Sci 27:401-405, 1982 21. Dobbins JW, Binder HJ: Importance of the colon in enteric hyperoxaluria. N Engl J Med 296:298-301, 1977 22. Bohles H, Michalk D: Is there a risk for kidney stone formation in cystic fibrosis? Helv Paediatr Acta 37:267-272, 1982 23. Turner MA, Goldwater D, David TJ: Oxalate and calcium excretion in cystic fibrosis. Arch Dis Child 83:244247, 2000 24. Davidson AGF: Gastrointestinal and pancreatic disease in cystic fibrosis, in Hodson ME, Geddes DM (eds): Cystic Fibrosis (ed 2). New York, NY, Arnold, 2000, pp 261-288 25. Bentur L, Kerem E, Couper R, et al: Renal calcium handling in cystic fibrosis: Lack of evidence for a primary renal defect. J Pediatr 116:556-560, 1990 26. Aris RM, Lester GE, Dingman S, Ontjes DA: Altered calcium homeostasis in adults with cystic fibrosis. Osteoporos Int 10:102-108, 1999 27. Lark RK, Lester GE, Ontjes DA, et al: Diminished and erratic absorption of ergocalciferol in adult cystic fibrosis patients. Am J Clin Nutr 73:602-606, 2001 28. Feranchak AP, Sontag MK, Wagener JS, Hammond KB, Accurso FJ, Sokol RJ: Prospective, long-term study of fat-soluble vitamin status in children with cystic fibrosis identified by newborn screen. J Pediatr 135:601-610, 1999 29. Moxey-Mims MM, Stapleton FB: Hypercalciuria and nephrocalcinosis in children. Curr Opin Pediatr 5:186-190, 1993 30. Shaer AJ: Inherited primary renal tubular hypokalemic alkalosis: A review of Gitelman and Bartter syndromes. Am J Med Sci 322:316-332, 2001 31. Ronnefarth G, Misselwitz J: Nephrocalcinosis in children: A retrospective survey. Members of the Arbeitsgemeinschaft fur padiatrische Nephrologie. Pediatr Nephrol 14:10161021, 2000
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32. Katz SM, Krueger LJ, Falkner B: Microscopic nephrocalcinosis in cystic fibrosis. N Engl J Med 319:263-266, 1988 33. Couper R, Bentur L, Kilbourn JP, Wolf P: Immunoreactive calmodulin in cystic fibrosis kidneys. Aust N Z J Med 23:484-488, 1993 34. Schindler R, Radke C, Paul K, Frei U: Renal problems after lung transplantation of cystic fibrosis patients. Nephrol Dial Transplant 16:1324-1328, 2001 35. Foskett JK: ClC and CFTR chloride channel gating. Annu Rev Physiol 60:689-717, 1998 36. Thakker RV: Pathogenesis of Dent’s disease and related syndromes of X-linked nephrolithiasis. Kidney Int 57:787-793, 2000 37. Scheinman SJ, Cox JP, Lloyd SE, et al: Isolated hypercalciuria with mutation in CLCN5: Relevance to idiopathic hypercalciuria. Kidney Int 57:232-239, 2000 38. George AL Jr, Bianchi L, Link EM, Vanoye CG: From stones to bones: The biology of ClC chloride channels. Curr Biol 11:R620-R628, 2001 39. Reungjui S, Prasongwatana V, Premgamone A, Tosukhowong P, Jirakulsomchok S, Sriboonlue P: Magnesium status of patients with renal stones and its effect on urinary citrate excretion. BJU Int 90:635-639, 2002 40. Bar-Or O, Blimkie CJ, Hay JA, MacDougall JD, Ward DS, Wilson WM: Voluntary dehydration and heat intolerance in cystic fibrosis. Lancet 339:696-699, 1992 41. Kriemler S, Wilk B, Schurer W, Wilson WM, Bar-Or O: Preventing dehydration in children with cystic fibrosis who exercise in the heat. Med Sci Sports Exerc 31:774-779, 1999 42. Trinchieri A, Mandressi A, Luongo P, Rovera F, Longo G: Urinary excretion of citrate, glycosaminoglycans, magnesium and zinc in relation to age and sex in normal subjects and in patients who form calcium stones. Scand J Urol Nephrol 26:379-386, 1992 43. Krebs NF, Westcott JE, Arnold TD, et al: Abnormalities in zinc homeostasis in young infants with cystic fibrosis. Pediatr Res 48:256-261, 2000 44. Allison MJ, Cook HM, Milne DB, Gallagher S, Clayman RV: Oxalate degradation by gastrointestinal bacteria from humans. J Nutr 116:455-460, 1986 45. Allison MJ, Cook HM: Oxalate degradation by mi-
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crobes of the large bowel of herbivores: The effect of dietary oxalate. Science 212:675-676, 1981 46. Allison MJ, Dawson KA, Mayberry WR, Foss JG: Oxalobacter formigenes gen nov, sp nov: Oxalate-degrading anaerobes that inhabit the gastrointestinal tract. Arch Microbiol 141:1-7, 1985 47. Kwak C, Jeong BC, Lee JH, Kim HK, Kim EC, Kim HH: Molecular identification of Oxalobacter formigenes with the polymerase chain reaction in fresh or frozen fecal samples. BJU Int 88:627-632, 2001 48. Sidhu H, Holmes RP, Allison MJ, Peck AB: Direct quantification of the enteric bacterium Oxalobacter formigenes in human fecal samples by quantitative competitivetemplate PCR. J Clin Microbiol 37:1503-1509, 1999 49. Daniel SL, Hartman PA, Allison MJ: Intestinal colonization of laboratory rats with Oxalobacter formigenes. Appl Environ Microbiol 53:2767-2770, 1987 50. Sidhu H, Allison MJ, Chow JM, Clark A, Peck AB: Rapid reversal of hyperoxaluria in a rat model after probiotic administration of Oxalobacter formigenes. J Urol 166:14871491, 2001 51. Sidhu H, Schmidt ME, Cornelius JG, et al: Direct correlation between hyperoxaluria/oxalate stone disease and the absence of the gastrointestinal tract-dwelling bacterium Oxalobacter formigenes: Possible prevention by gut recolonization or enzyme replacement therapy. J Am Soc Nephrol 10:S334-S340, 1999 (suppl 14) 52. Duncan SH, Richardson AJ, Kaul P, Holmes RP, Allison MJ, Stewart CS: Oxalobacter formigenes and its potential role in human health. Appl Environ Microbiol 68:3841-3847, 2002 53. Freel RW, Hatch M, Vaziri ND: Conductive pathways for chloride and oxalate in rabbit ileal brush-border membrane vesicles. Am J Physiol 275:C748-C757, 1998 54. Hokama S, Honma Y, Toma C, Ogawa Y: Oxalatedegrading Enterococcus faecalis. Microbiol Immunol 44:235240, 2000 55. Campieri C, Campieri M, Bertuzzi V, et al: Reduction of oxaluria after an oral course of lactic acid bacteria at high concentration. Kidney Int 60:1097-1105, 2001 56. Cystic Fibrosis Foundation: Patient Registry 2001, in Annual Report. Bethesda, MD, Cystic Fibrosis Foundation, 2002
National Kidney Foundation
AJKD
VOL 42, NO 1, JULY 2003
American Journal of Kidney Diseases
REVIEW
The Association of Nephrolithiasis With Cystic Fibrosis Eric M. Gibney, MD, and David S. Goldfarb, MD ● Background: There is a growing body of evidence regarding the association between cystic fibrosis (CF) and nephrolithiasis and the role that Oxalobacter formigenes may have in that association. Methods: We performed a MEDLINE search of “cystic fibrosis and nephrolithiasis” and “Oxalobacter formigenes.” Epidemiological and experimental evidence and possible mechanisms explaining the association were critically reviewed. Results: Of patients with CF, 3.0% to 6.3% are affected with nephrolithiasis, a percentage greater than that of age-matched controls without CF, in whom the rate is 1% to 2%. Studies have suggested possible mechanisms for the association, including hyperuricosuria, hyperoxaluria, primary defects in calcium handling caused by mutation of the CF transmembrane regulator (CFTR), hypocitraturia, and lack of colonization with O formigenes, an enteric oxalate-degrading bacterium. The absence of colonization could be related to frequent courses of antibiotics. Conclusion: Although the incidence of stones in patients with CF may be increased compared with controls without CF, many possible mechanisms are implicated. The relative contributions of these mechanisms remain uncertain. Future directions may include specific identification of lithogenic risks and therapy aimed at stone prevention in this population. Am J Kidney Dis 42:1-11. This is a US government work. There are no restrictions on its use. INDEX WORDS: Calcium oxalate; cystic fibrosis transmembrane conductance regulator (CFTR); hyperoxaluria; nephrolithiasis; oxalates; Oxalobacter formigenes (O formigenes); oxaluria; urinary calculi; urolithiasis.
A
S PATIENTS WITH cystic fibrosis (CF) live longer because of improved supportive care, nutrition, and organ transplantation, they are increasingly susceptible to conditions that usually affect adults, including nephrolithiasis. There is a growing body of evidence showing an association between CF and nephrolithiasis.1 The role of Oxalobacter formigenes, a recently characterized enteric oxalate-degrading organism, is an area of increasing interest. Specifically, its presence or absence may be a determinant of intestinal oxalate absorption and thereby may affect oxaluria and the formation of calcium oxalate stones in patients with and without CF.2 Although O formigenes may have a role in the relationship, several possible mechanisms were believed to contribute to the association of stone formation with CF before this new organism was implicated. Furthermore, although epidemiological and experimental data have argued for an
association between nephrolithiasis and CF, supporting studies contained limitations in design and size. Therefore, we sought to critically review available evidence for an association between CF and nephrolithiasis and explore possible mechanisms that could explain the association, including the role of O formigenes.
From the University of Colorado Health Sciences Center, Denver, CO; Department of Veterans Affairs Medical Center; St Vincents Hospital; and New York University School of Medicine, New York, NY. Received December 9, 2002; accepted in revised form February 27, 2003. Supported in part by VSL Pharmaceuticals, Inc (D.S.G.). Address reprint requests to David S. Goldfarb, MD, Nephrology Section/111G, New York DVAMC, 423 E 23 St, New York, NY 10010. E-mail: [email protected] This is a US government work. There are no restrictions on its use. 0272-6386/03/4201-0001$0.00/0 doi:10.1016/S0272-6386(03)00403-7
American Journal of Kidney Diseases, Vol 42, No 1 (July), 2003: pp 1-11
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EPIDEMIOLOGY
A group of relatively small epidemiological studies have been conducted to assess the relationship between CF and nephrolithiasis. (When these same studies reported on specific urinary risk factors for stone disease, findings are described in later sections specifically summarizing individual risk factors). Large CF registries, such as the Cystic Fibrosis Foundation’s patient registry, have not systematically collected prospective data on the incidence or prevalence of stone disease; therefore, only these small studies are available. In 1993, a brief report by Strandvik and Hjelte3 noted stone disease in 5 of 140 patients with CF (3.6%); affected patients had an average age of 29 years. Four of the 5 patients had calcium oxalate stones. Their brief report contained limited information on how data were gathered, length of follow-up, and patient characteristics and lacked controls, but it provided the first assessment in the literature of the incidence of stone disease in patients with CF. Three years later, Matthews et al4 reported on the findings of a larger study. Two hundred one patients with CF aged at least 15 years (average age, 25.9 years) were interviewed by telephone about a history of nephrolithiasis. Only episodes that could be documented through chart review were included. Their study found 11 of 201 interviewed patients (5.5%) with documented nephrolithiasis. Seven patients had recurrent (2 or more) episodes. Mean age at the first episode was 27 years, with a range of 19 to 33 years. Four patients reported a history of stones that could not be confirmed by chart review, which may have led to underestimation of the prevalence of stone disease. Stone analysis was not included, but each of 9 urograms performed showed radiopaque stones, consistent with the presence of calcium-containing stones. Although they mentioned rates of nephrolithiasis in previous epidemiological studies of healthy adults, their study lacked a control population. Chidekel and Dolan5 also reported on the incidence of stones in 140 patients with CF seen during 6 years. Eight patients with an average age of 23 years had nephrolithiasis (5.7%), with seven stones composed of calcium oxalate. An additional 4.2% of patients had calcium oxalate crystalluria, but had not formed stones. All stones
were documented by ultrasound, radiography, or intravenous pyelogram, and crystalluria, by microscopic examination of urine. Mean age of stone formers was 23 years, and all had pancreatic insufficiency on clinical grounds. In 1998, Hoppe et al6 reported on a group of patients with CF. Four of 64 patients (6.3%) had nephrolithiasis, and 4 patients (6.3%) had nephrocalcinosis, but the method of patient selection was not described. All stone formers were older than 15 years, and the average age of the entire group was 15.9 years. Neither of these studies contained contemporary or historic controls without CF. Most recently, 496 patients at a CF care center were screened for a history of nephrolithiasis.7 Average age was 25 years. Thirteen patients (3%; average age, 27 years) had a history of nephrolithiasis; all stones were radiopaque on plain radiography and the nine stones analyzed contained calcium oxalate as the dominant component. The study compared metabolic stone risk factors between 13 stone formers with CF and 86 patients with CF without stones. Again, this study lacked controls without CF, but provided more evidence on the baseline rate of nephrolithiasis in populations with CF. Another recent study of metabolic risks for stone formation in patients with CF found a history of stones in 10 of 190 patients (5.3%) surveyed at their center.8 Stone formers had an average age of 13.5 years, and non–stone formers were aged 14.3 years. Their study contained control patients for assessment of metabolic risks, but not for the background prevalence rate of stone formation. Other limitations stem from the use of referral centers; it is possible to miss both less-affected children who avoid specialized care centers and extremely ill children who have died or spent little time in outpatient settings. Also, asymptomatic stones are not well represented in reviews of medical records. However, these 2 recent studies confirm the approximate prevalence rates of previous smaller studies. Although these 6 studies had limitations, a few conclusions can be made. They all reported similar rates of nephrolithiasis, with a range of 3.0% to 6.3%. When we combine all patients in these 6 studies, mean prevalence rate was 4.1% (51 of 1,231 patients). Mean age of the patients studied was between 13.5 and 27 years, which means
CYSTIC FIBROSIS AND KIDNEY STONES
that nephrolithiasis in patients with CF appears to be a disease of adolescence and early adulthood. Three of the studies had little information about how patients were selected for study. Furthermore, none of the studies contained a control group of healthy or comparatively sick patients without CF, which necessitated a comparison with historic controls. As Matthews et al4 observed, this can be a difficult task because prevalence rates usually are obtained from middleaged populations in large epidemiological databases. Population-based studies have estimated lifetime prevalence rates of stone formation in North America between 3.5% and 13.7%.9-11 Prevalence rates vary according to age, sex, and region, with the greatest rates in older patients, men, and in the southeast. However, age-specific prevalence rates are much lower in studies of individuals aged 20 to 29 years (1%) and 30 to 39 years (2.1%).12 These age-based prevalence rates were obtained from adults enrolled in a large California health plan and suggest that if the prevalence of nephrolithiasis in patients with CF is 3.0% to 6.3%, there is an increased risk for nephrolithiasis in the disorder. However, the true rate of nephrolithiasis in patients with CF is difficult to determine from these studies, which lack controls, differ in design, and are taken from different regions. MECHANISMS FOR THE ASSOCIATION
Perhaps because stone formation has multifactorial causes, several possible explanations for the association of CF with increased prevalence rates of nephrolithiasis have been offered. Some of these mechanisms have been explored experimentally and are reviewed here, with a focus on conclusions and study limitations. Hyperuricosuria Although uric acid stones have not been found in increased frequency in patients with CF, hyperuricosuria can be a factor in the nucleation of calcium oxalate and formation of calcium oxalate stones.13 Although definitions of this abnormality vary in the studies we reviewed, hyperuricosuria was one of the first urinary abnormalities reported in patients with CF.14 In 1976, Stapleton et al14 reported on dysuria, uric acid crystalluria, and hyperuricosuria in 1 child and hyperuricosuria in 2 other children with CF. Hyperuricosuria
3
was defined as urinary uric acid excretion greater than 600 mg/1.73 m2/d (3.6 mmol/1.73 m2/d) or greater than 17.7 mg/kg/d (0.1 mmol/kg/d). Hyperuricosuria was attributed to high-dose purinerich pancreatic extracts, leading to increased purine ingestion and subsequent elevated urinary uric acid excretion. In all 3 cases, the hyperuricosuria responded to a reduction in dose of pancreatic extract. The investigators then screened 32 patients, 15 of whom were taking higher than prescribed doses of pancreatic enzymes. Fourteen of these 15 children had hyperuricosuria. In 1977, this same group noted a direct relationship between pancreatic enzyme dose and uric acid excretion. Hyperuricosuria in these patients responded to a reduction in dose of extract.15 Similarly, a study of 16 Israeli patients with CF found hyperuricosuria and hyperuricemia, which correlated with dose of pancreatic extract.16 The study was strengthened by comparison with 65 healthy Israeli children. More recently, Hoppe et al6 documented hyperuricosuria with uric acid greater than 1,000 mg/1.73 m2/d (6 mmol/1.73 m2/d) in 16 of 63 studied patients in a study that lacked controls. Follow-up studies to assess the mechanism for hyperuricosuria have been less conclusive. One study found that levels of uric acid excretion far exceeded levels attributable to intake from pancreatic extract, leading to the hypothesis that hyperuricosuria was derived from increased endogenous urate production in patients with CF.17 Wiersbitzsky et al18 studied serum and urinary uric acid levels before and 8 hours after a standard meal with pancreatic enzyme supplementation. No change in uricemia or urinary uric acid excretion was observed. Purine contamination of pancreatic extracts may vary among preparations. Also, purine ingestion by patients with CF probably has been reduced in recent years by decreasing the dose of pancreatic enzymes because of advances in drug formulation. Specifically, microencapsulation, enteric coating, and coadministration of acid-blocking therapies have been used to limit acid destruction of enzymes in the stomach.19 Another mechanism involving uric acid and stone formation could involve the effects of diarrheal illnesses and excessive stool fluid losses caused by malabsorption, both of which occur in
4
CF. Although acute diarrheal states are associated with decreases in uric acid excretion and hyperuricemia rather than hyperuricosuria, decreasing urine pH can lead to increased uric acid supersaturation, even with diminished uricosuria. With more chronic states of increased bowel losses, hyperuricemia would lead to increased filtered loads of uric acid, reestablishing uric acid balance and normal urinary uric acid content. Such mechanisms might be invoked if an increased incidence of uric acid stones was observed in patients with CF, but this has not been shown. As we state next, correlations of stone formation with stool losses or effectiveness of pancreatic enzyme replacement are lacking. Although hyperuricosuria is an established risk factor for calcium oxalate stone formation, increased uric acid supersaturation mediated by decreased urinary pH in the absence of hyperuricosuria has not been definitively shown to promote calcium oxalate stones. Together, this group of studies suggests that hyperuricosuria affects many patients with CF and may be associated with greater doses of pancreatic extract or increased endogenous production of uric acid. The relative contributions of these mechanisms to increases in urinary uric acid excretion remain unclear, and the importance of hyperuricosuria or uric acid supersaturation to the increased incidence of stone disease is uncertain. Hyperoxaluria Hyperoxaluria and calcium oxalate nephrolithiasis are known complications of other malabsorptive states, including inflammatory bowel disease and ileal resection. With malabsorption, calcium binds to fatty acids in the intestinal lumen rather than to oxalate, facilitating increased absorption of the free oxalate.20 Malabsorbed bile salts create greater colonic oxalate permeability, which also facilitates oxalate absorption.21 There also is evidence of alterations in oxalate homeostasis in CF. Before a relationship between nephrolithiasis and CF had been established, Bohles and Michalk22 studied factors affecting urinary lithogenicity in 43 patients with CF, 21 healthy controls, and 5 calcium oxalate stone formers. They reported elevations in urinary oxalate excretion (factored for urinary creatinine level) in patients
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with CF compared with controls, but expressed results as a mean for the group and did not report the number of affected individuals. In the previously mentioned study by Hoppe et al,6 urinary oxalate excretion in patients with CF was measured. Twenty-five of 63 patients had hyperoxaluria, defined as oxalate levels of 45 mg/1.73 m2/d (0.5 mmol/1.73 m2/d). Oxalate excretion tended to be greater in males and older patients. Relative urinary calcium oxalate saturation was elevated in 26 of 63 patients. Of all lithogenic factors studied, secondary hyperoxaluria was the most common disorder. Study conclusions are limited by the lack of an age-matched control population. Perez-Brayfield et al7 measured urinary oxalate in 13 patients with CF with nephrolithiasis (mean age, 27 years) compared with 86 patients with CF without stones and found no difference between the 2 groups, but did not compare urinary oxalate excretion with that of matched healthy populations. Mean oxalate excretions were 45.5 and 42.5 mg/d, with their upper limit of normal cited as 30 mg/d. Both groups had increased urinary calcium oxalate supersaturation. Bohles et al8 found elevated urinary oxalate excretion in patients with CF with and without stones compared with control patients; normal values were not defined. Stone formers had an average age of 13.5 years at the time of their first episode. The investigators’ use of clinic patients with “constitutional short stature” in the control group limits conclusions about metabolic risks compared with healthy controls. It is entirely possible that heterogeneous disorders affecting stature would affect urinary excretion of oxalate, calcium, citrate, and uric acid because of variations in bone and muscle mass, diet, and prescribed drug, vitamin, and dietary therapy. Recently, oxalate, calcium, and glycolate excretion were studied in 26 patients with CF and no evidence of stone disease. Glycolate was measured as a marker for precursors of oxalate in an attempt to decipher whether hyperoxaluria had metabolic causes.23 Little is known about glycolate ingestion and excretion in healthy people or patients with CF with malabsorption; thus, the reliability of this assumption is unproven. Normal values used for oxalate excretion were 31.5 mg/24 h (0.35 mmol/24 h) in patients younger than 13 years, 43.2 mg/24 h
CYSTIC FIBROSIS AND KIDNEY STONES
(0.48 mmol/24 h) in males older than 13 years, and 46.8 mg/24 h (0.52 mmol/24 h) in females older than 13 years; excretion was not factored for body size or urinary creatinine excretion. Urinary oxalate levels were elevated in 14 of 26 patients, and oxalate level correlated positively with urinary glycolate level, suggesting, if the investigators’ assumptions are correct, that some component of hyperoxaluria is of metabolic origin. Hyperoxaluria therefore is an important and relatively frequent metabolic abnormality in patients with CF and a major risk factor for stone formation. It is likely that increased enteric oxalate absorption associated with fat malabsorption is a major factor contributing to hyperoxaluria in patients with CF. It is unfortunate that only one of the studies we reviewed described the bowel status of stone-forming patients. In this study, there was a slightly greater incidence of steatorrhea in stone formers with CF compared with non–stone formers with CF, and the amount of stool fat did not correlate with urinary oxalate excretion.22 Little attention has been given in most of the studies to whether patients had pancreatic insufficiency (as in 85% of patients with CF) and, if present, to possible associations of effectiveness of therapy, presence of steatorrhea, or stool volume with stone formation. In the age groups in which stones are seen, diarrhea and malabsorption still occur, even in patients treated with adequate doses of pancreatic enzymes. Estimates of the prevalence of continued fat malabsorption are as high as 20% of patients administered enzyme supplementation, in part because of failure of patients to adhere to treatment regimens.24 The relative contribution of increased endogenous production is less clear. Whether all these factors causing hyperoxaluria interact with or are important variables independent of O formigenes colonization, discussed later, remains to be learned. Calcium Excretion and Microscopic Nephrocalcinosis Because of the increased incidence of calciumcontaining stones in patients with CF, the study of renal calcium handling in CF has generated much interest. In all the studies reviewed, the definition of hypercalciuria used was calcium
5
greater than 4 mg/kg/d (0.1 mmol/kg/d). Bohles and Michalk22 found that calcium excretion factored by urinary creatinine excretion was decreased in urine of patients with CF compared with controls and calcium oxalate stone formers. They postulated that relative hypocalciuria seemed to be protective in the setting of multiple lithogenic factors. Calcium oxalate supersaturation was not measured or calculated in their study. Bentur et al25 found normal urinary calcium excretion in 30 of 34 non–stone-forming patients with CF. The 4 patients with hypercalciuria had possible secondary causes, such as glucocorticoid administration and immobilization. The investigators concluded that no primary renal defect in calcium handling existed. Hoppe et al6 examined 24-hour urine collections in 63 patients with CF and found increased urinary calcium levels in 13 patients. The investigators did not specify whether urinary calcium excretion distinguished stone formers and patients with nephrocalcinosis from unaffected patients. The majority of patients showed normal or low urinary calcium excretion, and mean values of the cohort were not reported. In that study, urinary calcium oxalate supersaturation was elevated in 26 of 63 patients, most often as the result of an increase in urinary oxalate excretion (19 patients). Urinary saturation of brushite, one crystalline form of calcium phosphate, also was elevated in 19 patients. Turner et al23 studied calcium and oxalate excretion in 26 children with CF. The majority (15 of 24 children) showed relative hypocalciuria (calcium ⬍ 4 mg/kg/d [⬍0.1 mmol/kg/d]), which again was postulated to have a protective effect on nephrolithiasis. Finally, Bohles et al8 recently found hypercalciuria in stone-forming patients with CF compared with non–stoneforming patients with CF and in all patients with CF compared with controls. However, the aforementioned use of control patients with “constitutional short stature” limits the investigators’ ability to conclude that patients with CF have hypercalciuria compared with healthy children and is not easily explained in conflict with Bohle’s own and other historic data. Although multiple mechanisms for altered calcium homeostasis are possible, some studies of patients with CF have shown decreased bone density, decreased gastrointestinal absorption of
6
calcium (not entirely corrected by pancreatic enzyme replacement), and lower serum 25hydroxy-vitamin D levels. Some patients also have greater parathyroid hormone (PTH) levels at baseline and after meals high in calcium content.26 These abnormalities potentially could be explained by vitamin D deficiency.27,28 Despite the relative lack of hypercalciuria, nephrocalcinosis has been described in patients with CF. Microscopic nephrocalcinosis is associated with multiple metabolic disorders, such as idiopathic hypercalciuria, renal tubular acidosis, disorders of vitamin D metabolism, and genetic disorders of chloride channels. Microscopic nephrocalcinosis also is associated with increased rates of nephrolithiasis in patients without CF.29-31 Microscopic nephrocalcinosis was described first in CF in autopsy specimens of 35 of 38 patients.32 The affected children included 6 patients younger than 1 year, which supported a hypothesis that nephrocalcinosis was the result of a primary renal defect and not a manifestation of chronic illness and organ dysfunction. This series later was criticized for a lack of similarly ill autopsy controls. Measurements of urinary calcium excretion in 14 patients and 15 controls found individual patients with CF with increased calcium excretion, but mean levels in patients with CF were no different from those of controls. After these observations, another group showed sparse nephrocalcinosis at autopsy in just 5 of 14 patients with CF and also found nephrocalcinosis in 6 of 12 control patients with chronic diseases and similar preterminal events.25 Combined with their own data on urinary calcium excretion, they concluded that evidence of a primary renal defect in patients with CF was lacking. Similarly, immunoreactive calmodulin studied in a small group of patients with CF did not differ from controls or correlate with nephrocalcinosis.33 Recently, a case report of nephrocalcinosis in patients with CF after lung transplantation was described, but no definite mechanism was elucidated.34 In summary, there is scant evidence of altered calcium homeostasis in patients with CF, and alterations in homeostasis likely are neutral or even protective with regard to urinary calcium excretion and nephrolithiasis. Although infrequent, hypercalciuria may occur in some individuals and contribute to the overall risk for stones
GIBNEY AND GOLDFARB
when other factors also are present. Although there may be an increased frequency of microscopic nephrocalcinosis in patients with CF, small studies with control populations do not confirm the association, and larger more definitive series with adequate controls are not available. At present, there is insufficient evidence to accept a primary defect in renal calcium handling leading to hypercalciuria as an explanation for stones in patients with CF. Chloride Channels and Nephrolithiasis Mutations in the CF transmembrane conductance regulator (CFTR) are the cause of CF, leading to a host of downstream clinical manifestations.35 CFTR is expressed in the kidney, although the function of normal CFTR in renal physiology has not been established. It is of interest that mutations in voltage-gated chloride channels (CLCs) expressed in the kidney have been associated with nephrolithiasis.36 We speculate that abnormal function of CFTR also could contribute to stone formation and therefore briefly review the association of chloride channel mutations with stone disease. The CLC family of chloride channels consists of 12 channels described to date. Nine CLCs have been identified in mammals, named CLC 1-7, CLC-Ka, and CLC-Kb. Mutations in genes that code for these channels have been associated with a variety of mammalian diseases. CLCN-5 mutations (coding for the CLC-5 channel) are responsible for Dent’s disease, an X-linked recessive renal disease characterized by hypercalciuria, stone formation, nephrocalcinosis, low-molecular-weight proteinuria, and renal insufficiency.37 Other features of proximal tubular dysfunction are common. Idiopathic hypercalciuria without low-molecular-weight proteinuria also has been associated with mutations in CLC-5. Currently, it is thought that chloride channel defects in CLC-5 cause defects in endosomal acidification and an inability to reabsorb lowmolecular-weight proteins, including PTH, in the proximal tubule. Hypercalciuria and stone formation may follow because of increased luminal PTH-mediated stimulation of renal vitamin D 1-hydroxylation, leading to increased intestinal calcium absorption and absorptive hypercalciuria.38 Another disorder associated with defects in
CYSTIC FIBROSIS AND KIDNEY STONES
renal chloride transporters and variably with nephrocalcinosis is Bartter’s syndrome. Neonatal Bartter’s syndrome, characterized by hypercalciuria and nephrocalcinosis, results from mutations in the gene encoding the Na-K-2Cl cotransporter (NKCC2) or the gene encoding the outwardly rectifying potassium channel (ROMK), a regulator of NKCC2. Classic Bartter’s syndrome results from mutations in the gene encoding the basolateral chloride channel (CLCNKB), also a regulator of NKCC2, but in these cases, hypercalciuria may be present without nephrocalcinosis.30 In brief, given the associations of such disorders of chloride transporters as Dent’s disease and Bartter’s syndrome with nephrocalcinosis, it is tempting to consider that a dysfunctional CFTR, the chloride channel mutated in CF, may lead to this phenotypic manifestation. However, both Dent’s disease and Bartter’s syndrome are associated with hypercalciuria, a disorder seen only variably and infrequently in patients with CF. The pathophysiological sequence leading chloride channel mutations to cause hypercalciuria is still under investigation; how a mutated CFTR would affect calcium flux in the kidney remains unknown. The finding of microscopic nephrocalcinosis in infants with CF probably is evidence of some uncharacterized abnormality in renal electrolyte handling.32 Although these autopsy studies had important limitations, confirmation of these findings would suggest that mutations in CFTR lead to a primary defect in renal electrolyte handling and a risk for nephrolithiasis. Other specific evidence implicating abnormal CFTR in nephrolithiasis is not available. Hypocitraturia Citrate is an important urinary inhibitor of calcium stone formation, and hypocitraturia is a risk factor for the formation of calcium-containing stones. Citrate binds calcium to form a soluble complex and inhibits crystal growth and agglomeration. Hypocitrituria (citrate ⬍ 230 mg/1.73 m2/d [⬍1.2 mmol/1.73 m2/d]) was present in 14 of 63 patients with CF in 1 study, but was linked with hyperoxaluria in only 2 patients and elevated urinary calcium oxalate supersaturation in only 1 patient.6 In another group of 43 patients, 21 controls, and 5 calcium oxalate stone formers, citrate excretion was decreased in pa-
7
tients with CF, but was expressed as a group mean.22 A more recent study found hypocitraturia to be the only statistically significant difference between 13 stone-forming patients with CF and 86 patients with CF without stones. The investigators thus concluded that patients with CF should be screened and treated for hypocitraturia.7 Finally, a study of 10 patients with CF with stones, 86 patients with CF without stones, and 30 controls found hypocitraturia (citrate ⬍ 280 mg/d [⬍1.5 mmol/d]) and decreased urinary citrate-calcium ratios in stone formers with CF.8 Thus, recent evidence has implicated hypocitraturia as an important lithogenic risk in patients with CF. Citrate reabsorption by the proximal tubule is stimulated in states of increased dietary acid loads or metabolic acidosis, leading to hypocitraturia, an important risk factor for stones. Stool losses of bicarbonate result in metabolic acidosis, which in turn stimulates renal tubular reabsorption of citrate. This is another possible mechanism by which intestinal salt and water losses could contribute to calcium oxalate stones in patients with CF. Depletion of total-body potassium stores, with or without hypokalemia, also leads to intracellular acidification and stimulation of citrate reabsorption. Potassium depletion can contribute to hypocitraturia in states of chronic diarrhea or diuretic use. Hypocitraturia in some patients with CF also could be the result of increased dietary acid represented by protein ingestion in the form of pancreatic enzymes. Hypomagnesemia, an electrolyte disorder frequently seen in patients with malabsorption, also has been shown to contribute to hypocitraturia in patients without CF.39 Diminished urinary magnesium concentrations in stone formers with CF compared with non–stone formers with CF was reported in 1 study,22 but not another.7 Changes in urinary citrate excretion in response to magnesium supplementation have not been reported. Any link between altered renal CFTR activity and tubular citrate reabsorption has yet to be postulated. Also at this time, no data are available on the effect of limiting enzyme ingestion on urinary citrate excretion or the effect of treating patients with CF with citrate on rates of nephrolithiasis.
8
Low Urine Volume Low urine volume, as the result of sweat or stool losses, is a possible contributor to stone formation in patients with CF, and one that surprisingly has been little commented on in the studies we reviewed. Low urine volume is an important cause of stones in patients without CF because it is a major determinant of supersaturations of calcium salts and uric acid. One report noted no difference in urine volume between stone formers with CF and non–stone formers with CF.22 Low urine volume could result from excessive losses of sodium-rich sweat, a hallmark of the disease. There is evidence that as patients with CF exercise, their sweat volume and sweat sodium losses are greater than those of agematched peers.40 With greater sweat sodium concentrations, the increase in serum osmolality that normally accompanies hypotonic fluid losses is of a lesser magnitude. Thirst therefore is stimulated less and less oral fluid is taken ad lib.41 The unstated implication from these data is that patients with CF would have lower urine volumes and higher urine concentrations of calcium salts and uric acid, with greater supersaturations, as well. Chronic manifestations of these phenomena, if any, and their impact on stone formation have not been studied. Excessive stool sodium and fluid losses could lead to chronic depletion of extracellular fluid volume and chronically diminished urine volume. The result again would be an increase in urinary supersaturation of calcium salts and uric acid. As we reviewed, diarrhea also has the potential to contribute to hypocitraturia, a risk factor for calcium stones, and low urine pH, a risk for uric acid stones. It may be that multiple metabolic abnormalities are important in the increased prevalence of stones associated with CF. It might be true, for instance, that hyperoxaluria is an important risk factor, but important only if other factors, such as low urine volume, hypocitraturia, or hyperuricosuria, also are present. Other Possible Factors in Stone Formation A variety of other factors have received slight attention as risk factors for stones in patients with CF. Antibiotic administration with consequent tubular dysfunction has been theorized34
GIBNEY AND GOLDFARB
and examined8 as a possible cause of microscopic nephrocalcinosis and stone formation. Bohles and Michalk22 found a significant negative correlation between total use of co-trimoxazole and ceftazidime and tubular phosphate reabsorption. However, they did not find this relationship in non–stone formers with CF or for other antibiotics, such as aminoglycosides. Low urinary phosphate concentration, a possible lithogenic risk, also has been found in some patients with CF.22 Although zinc excretion appears to be elevated in calcium stone formers and patients with CF have abnormalities in zinc metabolism, data on urinary zinc excretion in patients with CF currently are unavailable.42,43 Proteins that function as inhibitors or promoters of crystallization or crystal growth and agglomeration, such as osteopontin, Tamm-Horsfall protein, calgranulin, and others, also may be important factors in clinical disease, but studies of inhibitors and promoters specifically in CF are not available. O FORMIGENES
Background Recent studies have implicated the absence of the organism O formigenes, an oxalate-degrading bacteria, in the colons of patients with CF as a cause of stone disease. The organism was identified by Allison et al44-46 in the early 1980s and shown to be a gram-negative obligate anaerobe that resides in the intestines of sheep, pigs, and humans. It possesses an oxalate-formate exchanger that allows it to take up oxalate, its only substrate for the production of adenosine triphosphate. The organism then uses 2 enzymes, a formyl-coenzyme A (CoA) transferase and an oxalyl-CoA decarboxylase, to metabolize oxalate. The latter enzyme is coded for by the gene oxc, the basis for reliable detection of the organism in fresh or frozen stool samples using polymerase chain reaction (PCR).47,48 A number of findings have supported the possible role of O formigenes in intestinal oxalate handling. Humans undergoing jejunoileal bypass surgery have little or no colonization with the organism and far less intestinal oxalate degradation compared with control patients. This led to the hypothesis that the absence of the organism might be a contributor to the increased intestinal oxalate absorption and resultant hyperoxaluria
CYSTIC FIBROSIS AND KIDNEY STONES
that occurs in patients after this surgical procedure.44 Laboratory rats lacking the bacterium in their colons can be colonized with O formigenes if fed a high-oxalate diet before inoculation. Colonization is associated with less urinary oxalate excretion and increased oxalate degradation in the gastrointestinal tract.49-51 Humans also have been successfully colonized after long periods of negative O formigenes PCR test results.52 Addition of the organism to a test meal containing a fixed load of sodium oxalate also reduces postprandial urinary oxalate excretion in people.52 O formigenes in CF and Nephrolithiasis In a study of urinary oxalate excretion in patients with CF, 71% of 21 control patients were colonized with the bacterium compared with only 16% of 43 patients with CF.2 The 7 patients with CF colonized by O formigenes had normal urinary oxalate excretion (⬍45 mg/d [⬍0.5 mmol/d]), whereas 53% of 36 patients not colonized had hyperoxaluria. This supported the hypothesis that the presence of the organism protected against hyperoxaluria. Interestingly, the only patient with CF with normal quantitative PCR levels for O formigenes had never been administered a course of antibiotics. One potential explanation for lower rates of colonization in patients with CF is the multiple courses of antibiotics that patients with CF usually undergo as a result of recurrent pulmonary infections. The association of hyperoxaluria with the absence of O formigenes has not yet been shown prospectively. An alternative speculative interpretation of the data relies on the work by Freel et al53 showing that intestinal oxalate secretion occurs through chloride channels that may be identical to CFTR. If this is true, one could postulate diminished oxalate secretion from blood to the intestinal lumen in patients with CF. A lack of luminal oxalate to serve as substrate for O formigenes could lead to loss of colonization with this oxalate-dependent organism. Whether CFTR is a conductor of oxalate and O formigenes colonization is dependent on secreted, rather than ingested, oxalate remain unknown. Because none of the studies examining the associations of hyperoxaluria and the presence or absence of the organism have controlled dietary oxalate content, there is further reason to remain uncertain
9
about whether the association is causative. Although extremely suggestive, these studies to date have fallen short of proving that the organism’s absence is causative of calcium oxalate nephrolithiasis in patients with CF. There is a need for long-term prospective data showing that O formigenes colonization protects against future stone development. If colonization can be induced by administration of the organism and maintained without increasing dietary oxalate ingestion, the therapy could be an important one for hyperoxaluria. Long-term reduction in urinary oxalate excretion would be expected to lead to reduced rates of stone recurrence. Another option, administration of the oxalatedegrading enzymes by mouth, also could be useful. Other bacteria, including a species of enterococcus with oxalate-degrading properties, have been identified, but not yet shown to have epidemiological significance,54 whether in stone formers without CF or patients with CF. Lactic acid bacteria, lacking the gene for the oxalate transporter seen in O formigenes, have reduced urinary oxalate excretion in stone formers without CF with hyperoxaluria through an unknown mechanism.55 The specific importance of O formigenes in patients with CF as a protective agent or future therapeutic modality remains uncertain. The possibility that intestinal organisms normally affect the absorption and secretion of various solutes in health and disease remains an intriguing possibility. CONCLUSION
Although the available epidemiological evidence on nephrolithiasis and CF is not without flaws, there now appears to be a clearly increased risk for calcium oxalate nephrolithiasis in patients with CF compared with historic controls of healthy age-matched populations. This increased risk appears to be greater in older patients with CF. As the life expectancy of people affected by CF continues to increase, the population at risk for stones will increase in size. Currently, approximately 37% of people with CF are older than 18 years.56 Hyperoxaluria, hyperuricosuria, and hypocitraturia are the most commonly found metabolic risks and provide opportunities to modify stone recurrence rates in affected patients. Low urine
10
GIBNEY AND GOLDFARB
volume likely is of importance in some patients. Although lack of colonization with O formigenes is associated with calcium oxalate stone formation, it is not clear whether this is causative or simply an association. If more or longer courses of antibiotics reduce colonization and lead to hyperoxaluria, changes in the use of antibiotics may affect rates of stone formation. Other factors, such as renal calcium handling and microscopic nephrocalcinosis caused by chloride channel defects or abnormal inhibitors, also may have a role. It is likely that future efforts will involve studies on screening and treatment for known metabolic risks in both affected and unaffected patients. The intentional administration of nonpathogenic oxalate-degrading bacteria has been studied in patients with hyperoxaluria and may be an area of future study in patients with CF. REFERENCES 1. Gutknecht DR: Kidney stones and cystic fibrosis. Am J Med 111:83, 2001 (letter) 2. Sidhu H, Hoppe B, Hesse A, et al: Absence of Oxalobacter formigenes in cystic fibrosis patients: A risk factor for hyperoxaluria. Lancet 352:1026-1029, 1998 3. Strandvik B, Hjelte L: Nephrolithiasis in cystic fibrosis. Acta Paediatr 82:306-307, 1993 4. Matthews LA, Doershuk CF, Stern RC, Resnick MI: Urolithiasis and cystic fibrosis. J Urol 155:1563-1564, 1996 5. Chidekel AS, Dolan TF: Cystic fibrosis and calcium oxalate nephrolithiasis. Yale J Biol Med 69:317-321, 1997 6. Hoppe B, Hesse A, Bromme S, Rietschel E, Michalk D: Urinary excretion substances in patients with cystic fibrosis: Risk of urolithiasis? Pediatr Nephrol 12:275-279, 1998 7. Perez-Brayfield MR, Caplan D, Gatti JM, Smith EA, Kirsch AJ: Metabolic risk factors for stone formation in patients with cystic fibrosis. J Urol 167:480-484, 2002 8. Bohles H, Gebhardt B, Beeg T, Sewell AC, Solem E, Posselt G: Antibiotic treatment-induced tubular dysfunction as a risk factor for renal stone formation in cystic fibrosis. J Pediatr 140:103-109, 2002 9. Soucie JM, Thun MJ, Coates RJ, McClellan W, Austin H: Demographic and geographic variability of kidney stones in the United States. Kidney Int 46:893-899, 1994 10. Curhan GC, Rimm EB, Willett WC, Stampfer MJ: Regional variation in nephrolithiasis incidence and prevalence among United States men. J Urol 151:838-841, 1994 11. Johnson CM, Wilson DM, O’Fallon WM, Malek RS, Kurland LT: Renal stone epidemiology: A 25-year study in Rochester, Minnesota. Kidney Int 16:624-631, 1979 12. Hiatt RA, Dales LG, Friedman GD, Hunkeler EM: Frequency of urolithiasis in a prepaid medical care program. Am J Epidemiol 115:255-265, 1982 13. Ryall RL, Grover PK, Marshall VR: Urate and calcium stones—Picking up a drop of mercury with one’s fingers? Am J Kidney Dis 17:426-430, 1991
14. Stapleton FB, Kennedy J, Nousia-Arvanitakis S, Linshaw MA: Hyperuricosuria due to high-dose pancreatic extract therapy in cystic fibrosis. N Engl J Med 295:246248, 1976 15. Nouisa-Arvanitakis S, Stapleton FB, Linshaw MA, Kennedy J: Therapeutic approach to pancreatic extractinduced hyperuricosuria in cystic fibrosis. J Pediatr 90:302305, 1977 16. Sack J, Blau H, Goldfarb D, Ben Zaray S, Katznelson D: Hyperuricosuria in cystic fibrosis patients treated with pancreatic enzyme supplements. A study of 16 patients in Israel. Isr J Med Sci 16:417-419, 1980 17. Niessen KH, Wolf A: Studies on the cause of hyperuricosuria in cystic fibrosis patients. J Pediatr Gastroenterol Nutr 1:349-354, 1982 18. Wiersbitzky S, Ballke EH, Wolf E, Paul W: Uric acid serum concentrations in CF-children after pancreatic enzyme supplementation. Padiatr Grenzgeb 28:171-173, 1989 19. Kraisinger M, Hochhaus G, Stecenko A, Bowser E, Hendeles L: Clinical pharmacology of pancreatic enzymes in patients with cystic fibrosis and in vitro performance of microencapsulated formulations. J Clin Pharmacol 34:158166, 1994 20. Dharmsathaphorn K, Freeman DH, Binder HJ, Dobbins JW: Increased risk of nephrolithiasis in patients with steatorrhea. Dig Dis Sci 27:401-405, 1982 21. Dobbins JW, Binder HJ: Importance of the colon in enteric hyperoxaluria. N Engl J Med 296:298-301, 1977 22. Bohles H, Michalk D: Is there a risk for kidney stone formation in cystic fibrosis? Helv Paediatr Acta 37:267-272, 1982 23. Turner MA, Goldwater D, David TJ: Oxalate and calcium excretion in cystic fibrosis. Arch Dis Child 83:244247, 2000 24. Davidson AGF: Gastrointestinal and pancreatic disease in cystic fibrosis, in Hodson ME, Geddes DM (eds): Cystic Fibrosis (ed 2). New York, NY, Arnold, 2000, pp 261-288 25. Bentur L, Kerem E, Couper R, et al: Renal calcium handling in cystic fibrosis: Lack of evidence for a primary renal defect. J Pediatr 116:556-560, 1990 26. Aris RM, Lester GE, Dingman S, Ontjes DA: Altered calcium homeostasis in adults with cystic fibrosis. Osteoporos Int 10:102-108, 1999 27. Lark RK, Lester GE, Ontjes DA, et al: Diminished and erratic absorption of ergocalciferol in adult cystic fibrosis patients. Am J Clin Nutr 73:602-606, 2001 28. Feranchak AP, Sontag MK, Wagener JS, Hammond KB, Accurso FJ, Sokol RJ: Prospective, long-term study of fat-soluble vitamin status in children with cystic fibrosis identified by newborn screen. J Pediatr 135:601-610, 1999 29. Moxey-Mims MM, Stapleton FB: Hypercalciuria and nephrocalcinosis in children. Curr Opin Pediatr 5:186-190, 1993 30. Shaer AJ: Inherited primary renal tubular hypokalemic alkalosis: A review of Gitelman and Bartter syndromes. Am J Med Sci 322:316-332, 2001 31. Ronnefarth G, Misselwitz J: Nephrocalcinosis in children: A retrospective survey. Members of the Arbeitsgemeinschaft fur padiatrische Nephrologie. Pediatr Nephrol 14:10161021, 2000
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32. Katz SM, Krueger LJ, Falkner B: Microscopic nephrocalcinosis in cystic fibrosis. N Engl J Med 319:263-266, 1988 33. Couper R, Bentur L, Kilbourn JP, Wolf P: Immunoreactive calmodulin in cystic fibrosis kidneys. Aust N Z J Med 23:484-488, 1993 34. Schindler R, Radke C, Paul K, Frei U: Renal problems after lung transplantation of cystic fibrosis patients. Nephrol Dial Transplant 16:1324-1328, 2001 35. Foskett JK: ClC and CFTR chloride channel gating. Annu Rev Physiol 60:689-717, 1998 36. Thakker RV: Pathogenesis of Dent’s disease and related syndromes of X-linked nephrolithiasis. Kidney Int 57:787-793, 2000 37. Scheinman SJ, Cox JP, Lloyd SE, et al: Isolated hypercalciuria with mutation in CLCN5: Relevance to idiopathic hypercalciuria. Kidney Int 57:232-239, 2000 38. George AL Jr, Bianchi L, Link EM, Vanoye CG: From stones to bones: The biology of ClC chloride channels. Curr Biol 11:R620-R628, 2001 39. Reungjui S, Prasongwatana V, Premgamone A, Tosukhowong P, Jirakulsomchok S, Sriboonlue P: Magnesium status of patients with renal stones and its effect on urinary citrate excretion. BJU Int 90:635-639, 2002 40. Bar-Or O, Blimkie CJ, Hay JA, MacDougall JD, Ward DS, Wilson WM: Voluntary dehydration and heat intolerance in cystic fibrosis. Lancet 339:696-699, 1992 41. Kriemler S, Wilk B, Schurer W, Wilson WM, Bar-Or O: Preventing dehydration in children with cystic fibrosis who exercise in the heat. Med Sci Sports Exerc 31:774-779, 1999 42. Trinchieri A, Mandressi A, Luongo P, Rovera F, Longo G: Urinary excretion of citrate, glycosaminoglycans, magnesium and zinc in relation to age and sex in normal subjects and in patients who form calcium stones. Scand J Urol Nephrol 26:379-386, 1992 43. Krebs NF, Westcott JE, Arnold TD, et al: Abnormalities in zinc homeostasis in young infants with cystic fibrosis. Pediatr Res 48:256-261, 2000 44. Allison MJ, Cook HM, Milne DB, Gallagher S, Clayman RV: Oxalate degradation by gastrointestinal bacteria from humans. J Nutr 116:455-460, 1986 45. Allison MJ, Cook HM: Oxalate degradation by mi-
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crobes of the large bowel of herbivores: The effect of dietary oxalate. Science 212:675-676, 1981 46. Allison MJ, Dawson KA, Mayberry WR, Foss JG: Oxalobacter formigenes gen nov, sp nov: Oxalate-degrading anaerobes that inhabit the gastrointestinal tract. Arch Microbiol 141:1-7, 1985 47. Kwak C, Jeong BC, Lee JH, Kim HK, Kim EC, Kim HH: Molecular identification of Oxalobacter formigenes with the polymerase chain reaction in fresh or frozen fecal samples. BJU Int 88:627-632, 2001 48. Sidhu H, Holmes RP, Allison MJ, Peck AB: Direct quantification of the enteric bacterium Oxalobacter formigenes in human fecal samples by quantitative competitivetemplate PCR. J Clin Microbiol 37:1503-1509, 1999 49. Daniel SL, Hartman PA, Allison MJ: Intestinal colonization of laboratory rats with Oxalobacter formigenes. Appl Environ Microbiol 53:2767-2770, 1987 50. Sidhu H, Allison MJ, Chow JM, Clark A, Peck AB: Rapid reversal of hyperoxaluria in a rat model after probiotic administration of Oxalobacter formigenes. J Urol 166:14871491, 2001 51. Sidhu H, Schmidt ME, Cornelius JG, et al: Direct correlation between hyperoxaluria/oxalate stone disease and the absence of the gastrointestinal tract-dwelling bacterium Oxalobacter formigenes: Possible prevention by gut recolonization or enzyme replacement therapy. J Am Soc Nephrol 10:S334-S340, 1999 (suppl 14) 52. Duncan SH, Richardson AJ, Kaul P, Holmes RP, Allison MJ, Stewart CS: Oxalobacter formigenes and its potential role in human health. Appl Environ Microbiol 68:3841-3847, 2002 53. Freel RW, Hatch M, Vaziri ND: Conductive pathways for chloride and oxalate in rabbit ileal brush-border membrane vesicles. Am J Physiol 275:C748-C757, 1998 54. Hokama S, Honma Y, Toma C, Ogawa Y: Oxalatedegrading Enterococcus faecalis. Microbiol Immunol 44:235240, 2000 55. Campieri C, Campieri M, Bertuzzi V, et al: Reduction of oxaluria after an oral course of lactic acid bacteria at high concentration. Kidney Int 60:1097-1105, 2001 56. Cystic Fibrosis Foundation: Patient Registry 2001, in Annual Report. Bethesda, MD, Cystic Fibrosis Foundation, 2002