Urolithiasis in patients with inflam­matory bowel diseases

Overview

Inflammatory bowel diseases are typically accompanied by diarrhoea and malabsorption, both of which are predispos­ing factors for the formation of renal calculi. In patients who have not undergone bowel surgery the prevalence of urolithiasis has ranged from 1.5% to 5%, but after surgery stone prevalence can increase to up to 16%. Enteric hyperoxaluria is a frequent complication of inflammatory bowel diseases, ileal resection and Roux-En-Y gastric bypass and is a recognised cause of nephrolithiasis and nephrocalcinosis. The excess of oxalate is primarily excreted by the kidneys. Increased urinary excretion of oxalate results in urinary calcium oxalate supersaturation, leading to crystal aggregation, urolithiasis, and/ or nephrocalcinosis. Prevention of oxalate lithiasis includes high fluid intake, prescription of oral citrate and magnesium, calcium supplement, nutritionally balanced low-oxalate low-fat diet and also biological manipulation of intestinal flora (Oxalobacter formigenes, Bifidobacterium lactis, etc.). New therapeutic approaches to patients with inflammatory bowel diseases have completely changed the natural history of these diseases. Whether this has changed the prevalence and risk factors for urinary calculi in patients with inflammatory bowel diseases is still unknown.

Key words:
inflammatory bowel diseases –  urolithiasis –  hyperoxaluria –  intestinal flora –  prevention

Introduction

Inflam­matory bowel diseases (IBD) are chronic diseases compris­ing Crohn’sdisease (CD) and ulcerative colitis (UC) result­ing from a disregulated im­mune response in genetical­ly susceptible individuals [1].

IBD are typical­ly accompanied by diar­rhoea and malabsorption, both of which are predispos­ing factors for the formation of renal calculi, e. g. a great­-er than expected number of patients with asymp­tomatic and symp­tomatic urolithiasis were noticed in IBD clinical practice. Patients with IBD are thought to develop nephrolithiasis more often than the general population [2,3]. Among those patients who have not had bowel surgery the prevalence of urolithiasis has ranged from 1.5% to 5% [4– 10], which is very similar to the usual values for stone prevalence rates in the United States (3% to 5%) [11]. However, given bowel surgery, rates are approximately two- to three-fold higher giv­ing a stone prevalence of 3.7% to 16% for surgeries combined [4,7].

To date, few data are available about urolithiasis in IBD and previous stud­ies have reported a wide variation in the incidence of urolithiasis. New therapeutic approaches to patients with IBD have emerged recently and these have completely changed the natural history of these diseases. These ap­-proaches are aimed not only at lower­ing the rates of surgery but also at bet­ter prognoses, fewer hospitalisations, and improved quality of life [5– 8]. Whether this has changed the prevalence and risk factors for urinary calculi in patients with CD is still unknown. Determin­ing clinical risk factors for the development of urinary stones in patients with CD might uncover new strategies for treatment and prevention.

Malabsorption, and malabsorption secondary to bowel resection are factors as­sociated with IBD that predispose these patients to urinary calculi formation [12– 14]. As a result, they often present with multiple stones and are at risk of stone recur­rence if the underly­ing causes are not adequately addres­sed.

UC is the most com­mon form of IBD worldwide. Despite advances in medical therapy, approximately 30% of patients with UC eventual­ly require colectomy [15,16]. Restorative proctocolectomy with ileal pouch-anal anastomosis has become a standard of care in UC patients fol­low­ing colectomy. While restorative proctocolectomy with ileal pouch-anal anastomosis improves a pa­tient’s health-related quality of life, a number of metabolic complications can occur, includ­ing bone loss anaemia and vitamin D deficiency [17– 19]. Patients with IBD are known to have a high frequency of nephrolithiasis. The reported frequency of nephrolithiasis ranges from 0.2% to 11.0% in non-colectomy UC patients and from 8.4% to 40.0% in UC patients with total colectomy and ileo­stomy [20– 23]. Similarly, the report­-ed frequency of nephrolithiasis ranges from 4.0% to 5.5% in patients with CD without bowel resection surgery and from 15.0% to 30.5% in CD patients after small bowel surgery [22,23].

Various fluid and electrolyte changes in these patients increase the risk of nephrolithiasis. Low urine volume, pH, and urine citrate and magnesium levels along with high urine oxalate are speculated to be the main mechanisms for urinary supersaturation and nephrolithiasis in IBD patients. It is anticipated that pouch patients (with a prior history of IBD) after undergo­ing bowel-anatomy-alter­ing surgery may have a further increase in risk of nephrolithiasis.

Enteric hyperoxaluria in IBD

Hyperoxaluria is general­ly a rare metabolic disorder characterised by calcium oxalate deposition in dif­ferent tis­sues. It is caused either by an inherited dis­ease of oxalate metabolism (PH – primary hyperoxaluria) [24] or by an acquired disturbance (SH –secondary hyperoxaluria) [25]. Oxalate can bind with various cations, such as sodium, potas­sium, magnesium, and calcium. Even though sodium oxalate, potas­sium oxalate, and magnesium oxalate are water soluble, calcium oxalate (CaOx) is almost insoluble [26]. The excess oxalate is primarily excreted by the kidneys. Increased urinary excretion of oxalate results in urinary CaOx supersaturation, lead­ing to crystal aggregation, urolithiasis, and/ or nephrocalcinosis. CaOx crystals are typical­ly deposited within the renal interstitium and renal tubule cel­ls. When the glomerular filtration rate fal­ls below 30– 40 mL/ min per 1.73 sqm, plasma oxalate levels increase due to reduced urinary oxalate excretion. Oxalate nephropathy should be considered in the dif­ferential dia­gnosis of acute renal failure, especial­ly when previous renal impairment and fat mal­absorption are present. Oxalosis represents the histological manifestation of crystal­line deposits of CaOx in various tis­sues and organs. This phenomenon typical­ly occurs when plasma oxalate exceeds 30 µmol/ L, which represents its plasma supersaturation threshold, result­ing in deposition into several tis­sues, includ­ing the retina, myocardium, ves­sel wal­ls, skin, bone, and the central nervous system. Deposition of these crystals in the kidneys may cause either acute kidney injury, or may lead to the formation of dif­fuse renal calcifications (nephrocalcinosis) and stones (nephrolithiasis) in the long term. Patients present­ing with renal calculi require screen­ing for hyperoxaluria. In order to minimise renal damage, patients suf­fer­ing from SH should be promptly identified and appropriately treated. Enteric hyperoxaluria is a frequent complication of IBD, ileal resection and RYGB and is a recognised cause of nephrolithiasis and nephrocalcinosis. Less wel­l-known is that it also contributes to chronic kidney dis­ease and end-stage kidney disease. The urinary solubility product of CaOx, a determinant of the tendency of urine to yield crystals, is 10× more af­fected by a rise of urinary oxalate concentration than an equimolar rise in urinary calcium concentration [27]. The prevalence of hyperoxaluria has been estimated at 5– 24% of all patients with gastrointestinal diseases as­sociated with malabsorption [28,29]. Hyperoxaluria is becom­ing more com­mon, secondary to an increase in IBD [30] and bariatric surgery. The as­sociated prevalence of chronic kidney disease and end-stage kidney disease is less clear but may be more consequential than recognised.

IBD and urinary tract infection

Infection is also a com­mon complication of IBD, and compound­ing factors such as im­munosuppres­sion [31] and malnutrition [32,33] put these patients at risk for severe clinical sequelae. Not surprisingly, a recent population-based study found a four-fold increase in mortality among IBD patients requir­ing hospitalisation for infection [34]. Interestingly, urinary tract infections (UTIs) were the most frequently reported infection among these patients. IBD is also as­sociated with unusual genito-urinary complications, such that both infection and urolithiasis are com­monly seen in patients with IBD. Furthermore, IBD patients with infected calculi have much higher odds of develop­ing significant clinical sequelae, includ­ing higher rates of end-organ failure, sepsis, and hospital admis­sion. It was also found that IBD patients with upper tract urinary calculi had significantly higher odds of either acute cystitis or pyelonephritis than the general stone population.

Furthermore, an IBD dia­gnosis was an independent predictor for sepsis with almost two-fold higher odds of urosepsis than those of the non-IBD stone population. Given that previous literature review­ing infections in IBD patients has demonstrated that patients treated with infliximab, prednisone, and im­munomodulators such as azathioprine and 6-mercaptopurine are at increased risk of opportunistic and serious infections [31,32,35], as well as evidence that bacterial translocation as well as structural abnormalities, such as enterovesical fistulas, may cause UTIs more frequently in IBD patients [36].

Another important find­ing is the high rate of renal failure among IBD patients. This find­ing is likely multifactorial in nature, includ­ing underly­ing intrinsic renal disease, acute obstruction, prerenal azotemia, and exposure to nephrotoxic therapies. Potential nephrologic and urologic complications of IBD outside of stone dis­ease include noncalculus obstruction secondary to retroperitoneal fibrosis or ureteral stricture, parenchymal disease from nephrocalcinosis, distal renal tubular acidosis, and interstitial nephritis, as well as nephrotoxicity from certain medical treatments [37]. In a matched cohort study by Primas et al. [38], recur­rent urolithiasis and the number of interventions due to kidney stones were significant risk factors for renal insuf­ficiency in IBD patients. The previously mentioned genito-urinary and renal complications of IBD along with chronic dehydration likely render these patients less able to physiological­ly mitigate an acute kidney injury as­sociated with obstruction and/ or infection from urinary calculi. Unfortunately, urolithiasis is often asymp­tomatic and may go undetected until pas­sage or obstruction occurs [39]. In the case of IBD patients, even when stone symp­toms are present, they may be overshadowed by concur­rent bowel symp­toms, increas­ing the chance of mis­sed detection. These patients may also be unaware that their IBD puts them at risk of nephrolithiasis [40]. In a prospective study of newly dia­gnosed IBD patients, Cury et al. [39] found 38% had asymp­tomatic stone formation and 10% had hydronephrosis on screen­ing ultrasound. Given this high rate of neph­rolithiasis in the general IBD population and the findings that there is significant morbidity as­sociated with infected urolithiasis in this group, ef­forts at early identification are merited. These patients may form a select group who urologists should consider for elective stone treatment, even if asymp­tomatic. IBD had concomitant hydronephrosis and multiple urinary calculi population.

Gastroenterologists should consider urine microscopy or ultrasound to identify urolithiasis in their IBD patients. Similar screen­ing guidelines for osteoporosis in IBD patients were published in 2003 and resulted in significant im-provements in the detection of osteopenia and osteoporosis in these patients, whereas the level of care given by gastroenterologists in treat­ing these conditions has improved [41]. Screen­ing for urolithiasis in IBD patients may lead to early surgical intervention for asymp­tomatic stone patients as well as pre-emptive dietary and medical management of stone disease, where pos­sible. Stone prevention protocols tailored to IBD patients, incorporat­ing periodic 24-hour urine metabolic stud­ies, could also reduce the frequency of serious infections, renal damage, and hospitalisation. Future research in this area, such as noninvasive low-cost screening, could result in significant quality improvement and cost savings.

Despite higher rates of UTI, sepsis, and end-organ failure among IBD patients, there was no recorded dif­ference for in-hospital mortality between the two groups of stone-formers. This find­ing suggests that although patients with IBD are likely to progress to systemic and serious infection more frequently and rapidly than a typical stone patient, the management of this condition, namely decompres­sion of the obstructed urinary tract, is extremely ef­fective [42– 45].

Interestingly, a previous population-based study investigat­ing infection-related hospitalisations among IBD patients showed that infection itself was as­sociated with significant mortality (OR, 4.4 fold) but that infections such as pneumonia and Clostridium dif­ficile colitis were much stronger predictors of mortality than UTI among IBD patients [34]. Another study look­ing at all infected urolithiasis demonstrat­ed that mortality rates have remained stable over time [46].

IBD, extraintestinal manifestation and renal insuf­ficiency

Apart from the intestinal manifestation, there is also a wide range of extra­intestinal manifestations, includ­ing renal insuf­ficiency (RI) which may some­times gain greater importance than the underly­ing disease due to their severity and pos­sible life-threaten­ing consequences [47– 49]. They can be divided into reactive manifestations (often as­sociated with inflam­matory disease activity) and genuine extraintestinal complications (due to metabolic or anatomical abnormalities caused directly by IBD) [48]. Although some extraintestinal manifestations are more com­mon in CD, they can be found in both entities and add significantly to the burden of the disease [49]. The prevalence of extraintestinal manifestations in IBD varies from 6% to  46% [50– 52]. Often joints (arthropathies), skin (erythema nodosum and pyoderma gangrenosum)or eyes are involved, however parenchymatous organs may be af­fected as wel­l. These manifestations are not frequently encountered and therefore rarely reported; the best known is primary scleros­ing cholangitis (mostly linked to UC), a chronic inflam­matory condition of the intra- and extrahepatic bile ducts lead­ing to fibrosis and death [50– 52]. Other involvement of parenchymatous organs such as kidney or lung receives little mention in the literature. The literature provides little data on renal involvement; so far there are no data available focus­ing solely on the prevalence of renal insuf­ficiency in IBD.

The first task is to determine the prevalence of RI in IBD and to look for a pos­sible dif­ference between CD and UC. The second one is to investigate if renal impairment might be a complication of the underly­ing disease or just a side-ef­fect of drugs –  at least some of them, mainly cyclosporine, are known to have a nephrotoxic potential –  used to treat the disease.

In the study of Primas et al. [38] 2% of the patients with CD developed RI, but none of the patients with UC. A longer duration of CD was as­sociated with a higher frequency of RI in our patients. A longer duration of CD may lead to accumulative damage of the bowel, thus more complications result­ing in a greater need for surgeries.

The risk of develop­ing urolithiasis in IBD is 10– 100× greater than the risk for general hospital patients [53]. The reasons for that may be volume depletion (lead­ing primarily to uric acid stones) and hyperoxaluria in CD. Small bowel resection leads to both –  volume depletion and hyperoxaluria –  therefore promot­ing stone formation and the development of RI. Support­ing that, there was a cor­relation between the length of resected small bowel and the number of interventions due to urolithiasis. Although it would have been interesting, there is suprisingly only limited data on the nature of the stones found in the patients, as the stones are not routinely analysed.

Other causes of renal impairment included amyloidosis, glomerulonephritis, tubulointerstitial nephritis, and nephrolithiasis [54– 58]. There are many case reports on amyloidosis, but a review of the literature shows the over­all prevalence in IBD to be below 1% [54,55]. Glomerulonephritis has recently emerged as an extraintestinal manifestation and seems to be very rare with about 40 reports in the literature; it appears to be linked to disease activity as renal function improves after remis­sion of IBD [53,56,57]. Tubulointerstitial nephritis seems to be a com­mon clinical feature among IBD patients, manifest­ing with proteinuria. Lukas et al. [59] in IBD patients on long-term therapy of mesalazin (similar to acetylosalicylic acid) confirmed potential nephrotoxic ef­fect (prevalence 1 : 500 treated patients) and recom­mended routinly performed control of blood urea, creatinine and urine every six months. As with glomerulonephritis there seems to be a cor­relation with disease activity [53,58]. The emergence of new drugs and the use of more potent drugs earlier in the course of IBD might prevent ir­reversible damage to the small bowel, therefore reduc­ing the need for surgery. Thus, long-term the prevalence of RI in IBD will hopeful­ly be reduced. In the meantime, it is important to pay attention to older patients with resections in the small bowel and/ or urolithiasis and to closely monitor them for signs of RI.

Treatment of urolithiasis in patients with IBD

Patients with a short bowel who develop hyperoxaluria are typical­ly managed by restrict­ing dietary fat and oxalate and by provid­ing an oral calcium supplement, but one must be care­ful with calcium therapy and monitor it. Exces­sive calcium can actual­ly increase the CaOx supersaturation in the urine and thus increase the risk of stone formation. Patients with refractory hyperoxaluria may benefit from cholestyramine, which limits bile salt injury to the colon. Bile salts can make the colon more permeable to oxalate and thus facilitate oxalate absorption from the colon.

Rationale for prescrib­ing oral citrate and magnesium to patients with hyperoxaluria, hypocitraturia, and hypomagnesiuria for the prevention of oxalate nephrolithiasis

Hypocitraturia is an important risk factor for CaOx nephrolithiasis [60]. Kato et al. [61] administered potas­sium-sodium citrate and magnesium oxide to 14 patients with recur­rent CaOx stones. After administration of both sup­plements to the patients with stones, the citrate, magnesium, and potas­sium levels in 24-hour urine samples increased by 62.1%, 63.3%, and 25.3%, respectively, and oxalate decreased by 66.5%. These authors concluded that the combination of potas­sium-sodium citrate and magnesium oxide is more ef­fective than either supplement alone in inhibit­ing the crystal­lization of CaOx stones by improv­ing the urinary parameters of patients with hypocitraturia and/ or hypomagnesiuria. However, in a double-blind, randomized, placebo-control­led trial, there was no significant dif­ference between recur­rence rates with 650 or 1,300 mg magnesium oxide daily and the placebo. Another trial reported 391 mg (21 mEq) magnesium daily as a mixed salt, magnesium potas­sium citrate, reduced calcium stone recur­rence by 90%, similar to potas­sium citrate, but with better gastrointestinal tolerance [62]. Neither magnesium potas­sium citrate nor potas­sium-sodium citrate was available in the British National Formulary, therefore potas­sium citrate mixture was prescribed to this patient.

Importance of nutritional­lybalanced diet in prevention of urolithiasis

Siener et al. [63] demonstrated that a nutritional­ly balanced diet significantly reduced stone-form­ing potential in men and women with CaOx stone disease, although no change occur­red in urinary oxalate and magnesium excretion. This patient was prescribed potas­sium citrate and was advised to adhere to a nutritional­ly balanced diet avoiding: 1. oxalate-rich food, 2. low fluid intake, and 3. in­creased intake of protein and alcohol. Fol­low­ing the nutritional intervention with the patient, 24-hour urine oxalate excretion decreased from 0.618 to 0.385 m­mol/ day; 24-hour urine citrate increased from 0.58 to 1.0 m­mol/ day.

Biological manipulation of intestinal flora in treatment of hyperoxaluria and oxalate nephrolithiasis

Oxalate is present in many foods and beverages. Bacterial enzymes are required for the intestinal degradation of oxalate in humans [64]. Intestinal oxalate-degrad­ing bacteria are cap­able of degrad­ing oxalate to CO₂ and formate, the latter be­ing absorbed or further metabolized. O. formigenes, an obligate anaerobic microbe normal­ly found in the intestinal tract, contains two enzymes –  formyl CoA transferase and oxalyl-coenzyme A decarbo­x­ylase –  that al­low it to utilise oxalate as an energy source, in the process convert­ing oxalate to formate and CO₂, as well as a specific oxalate/ formate antiporter (Ox1T). The oxalate- -degrad­ing enzyme oxalyl-coenzyme Adecarboxylase is also found in Bifidobacterium lactis. Lack of O. formigenes can result in higher absorption of oxalate, lead­ing to an increased risk of CaOx kidney stone formation [65].

Duncan et al. [66] administered O. formigenes by mouth to human volunteers and found a reduction in the amount of oxalate excreted dur­ing the six hours im­mediately fol­low­ing ingestion of an oxalate load (from 3.0 ± 0.6 to 1.9 ± 0.1 mg/ h). In the same tests, the ingestion of O. formigenes also decreased the urinary oxalate/ creatinine ratio from 45.2 ± 9.9 to 27.0 ± 4. 2 mg/ g. Hoppe et al. [67] found the oral application of O. formigenes succes­sful in patients with PH. In one patient with constant intestinal colonization with O. formigenes, urinary oxalate excretion returned to a normal level over time. Other bacteria with pos­sible oxalate-degrad­ing potency are lactic acid bacteria, as well as Enterococcus faecalis and Eubacterium lentum. Although no strain of Lactobacil­lus acidophilus, L. plantarum, L. brevis, S. thermophilus, or B. infantis expres­sed the Ox1T gene, the urinary excretion of oxalate, which is a major risk factor for renal stone formation and growth in patients with CaOx urolithiasis, can be reduced with treatment us­ing a high concentration of freeze-dried lactic acid bacteria [68]. Administration of lactic acid bacteria mixture to patients with chronic fat malabsorption, CaOx stones, and hyperoxaluria, resulted in a de­-crease in mean urinary oxalate excretion by 19% after one month [69]. Such bio­logical manipulation of the endogenous digestive microflora can be a novel approach for the prevention of urinary stone formation. Therapeutic administration of O. formigenes may ultimately provide the best practical approach for the prevention or al­leviation of hyperoxaluria together with potas­sium citrate supplementation.

Ef­fect of antibio­tic therapy on intestinal colonization with O. formigenes

O. formigenes is as­sumed to be antibio­tic-sensitive and repeated antibio­tic therapies could eradicate it.

Mittal et al. [70] observed a direct as­sociation between antibio­tic consumption and absence of O. formigenes in stool samples. However, frequent use of antibio­tics may adversely af­fect intestinal colonization of O. formigenes. In children with cystic fibrosis, prolong­-ed and widespread use of antibio­tics induced a permanent decolonization of the intestine by O. formigenes. Only 1 of the 43 children with cystic fibrosis who were tested for O. formigenes had normal numbers of O. formigenes in stool samples; this patient with normal colonization by O. formigenes had not been treated with antibio­tics [71]. Seven patients who were colonized with O. formigenes had normal urinary oxalate levels, but 19 (53%) of 36 patients who were not colonized with O. formigenes were hyperoxaluric. Absence of O. formigenes from the intestinal tract of children with cystic fibrosis appeared to lead to increased absorption of oxalate, thereby increas­ing the risk of hyperoxaluria. Such antibio­tic induced decolonization of the gut may occur in spinal cord injury patients as wel­l. Troxel et al. [72,73] recom­mended the use of antibio­tics such as penicil­lin or trimethoprim-sulfamethoxazole instead of quinolones (e. g., ciprofloxacin for urine infection) in CaOx stone-formers, since quinolones reduced the level of O. formigenes in the gut, whereas penicil­lin or trimethoprim-sulfamethoxazole did not have any ef­fect on the O. formigenes level in the gut.

In future, oral administration of O. for-migenes or lactic acid bacteria may prove to be a promis­ing new therapeutic tool in patients with PH and SH. Lactic acid bacteria are cur­rently clas­sified as nonpathogenic bacteria, which are permitted in food by the U.S. Food and Drug Administration. How­ever, caution may be required when probio­tic preparations are used in im­munocompromised patients [74,75].

Dietary treatment of hyperoxaluria

Dietary oxalate, its precursors and management [76]

• In human experiments, the intestinal absorption of oxalate is greater on a diet high in oxalate (600 mg) compared to that on a diet poor in oxalate (63 mg), although there is an adaptation with lower rate of absorption if the diet with a high content of oxalate continues for over six weeks.
• A diet rich in oxalate causes a significant increase in urinary oxalate levels.
• A diet low in oxalate is ef­fective in reduc­ing urinary excretion of oxalate and urinary saturation for CaOx with respect to a basal free choice diet.
• In patients with idiopathic calculi an intake of ascorbic acid > 1 g/ day is more frequent than in controls. An intake of ascorbic acid may lead to an increase in serum and urinary levels of oxalate by increas­ing the intestinal absorption and endogenous synthesis. In total parenteral nutrition, an increase of ascorbic acid infusion from 100 to 200 mg induces an increase of oxaluria of about 0.10 m­mol/ day.
• The increase of oxaluria after oral ingestion of large amounts of ascorbic acid is not easily predictable and has not been confirmed unanimously but it was suggested that patients at risk of kidney stones should not exceed an intake of 500 mg/ day.

Dietary calcium and magnesium

• Epidemiological studies have shown that the excretion of oxalate is inversely related to a dietary intake of magnesium.
• The rate of intestinal absorption of oxalate, evaluated with [¹³C₂]oxalate in healthy volunteers on a diet contain­ing 800 mg of calcium, ranges from between 2.2% and 18.5%. The intraindividual variation is wide (3.4 ± 1.7%).
• The intestinal absorption of radioac­tive [¹³C₂]oxalate in a diet contain­ing 1,200 mg of calcium (diet + supplements of calcium citrate and calcium carbonate) is 2%, but it increases to 17% at 200 mg of dietary calcium. The increase is linear with a decrease of dietary calcium, but there is no further reduction of intestinal absorption of oxalate when dietary calcium increases > 1,200 mg.
• In healthy subjects and calcium renal stone-formers, a low-calcium diet causes a significant decrease in the levels of urinary calcium but increases urinary excretion of oxalate and the risk of renal stone formation.
• In idiopathic renal calcium stone-formers with hypercalciuria, a low-calcium diet increases urinary oxalate excretion more than in normocalciuric. On low-calcium diet urinary oxalate excretion is related to the degree of intestinal absorption of calcium.
• In renal stone-formers with idiopathic hypercalciuria, a high-calcium diet (900– 1,070 mg/ day) decreases the excretion of oxalate, the oxalate/ creatinine ratio and the lithogenic risk in comparison with a normal-calcium diet (700 mg/ day).
• In CaOx renal stone patients with hyperoxaluria, the addition of sup­plements of calcium citrate to the low-oxalate diet did not result in a great­er decrease of urinary excretion of oxalate than diet alone, although the supersaturation for CaOx decreases more.

Vegetarian

• Vegetarians have higher urinary oxalate levels than controls on a free-choice mixed mediter­ranean diet with significantly higher calcium/ oxalate ratio result­ing from a higher intake of oxalate and increased fractional intestinal absorption of oxalate.
• In vegetarians the risk of CaOx crystal­lization is not decreased (in­crease in urinary pH, citrate and magnesium excretion and decline in calcium excretion, but increase in urinary oxalate by 30%).

Fruit and vegetables

• In patients with hyperoxaluria (> 40 mg), a diet rich in fruits, vegetables, whole grains and low-fat dairy products and low in total fat and saturated fat, cholesterol, refined carbohydrates and sweets and meat, which is recom­mended for patients with hypertension (DASH –  dietary approaches to stop hypertension) results in a slight increase in urinary excretion of oxalate compared with a diet low in oxalates, but decreases the supersaturation with respect to CaOx due to the concomitant increase in the excretion of magnesium and citrate and increase of urinary pH.
• In normal healthy subjects the abolition of fruits and vegetables induces a slight increase of CaOx and calcium phosphate saturation as it reduces excretion of citrate, magnesium, potas­sium and also oxalate, while increas­ing urinary excretion of calcium and am­monium.

In hypocitraturic calcium renal stone-formers, add­ing fruits and vegetables increases excretion of magnesium and citrate, urinary pH and urinary volume, without chang­ing the excretion of oxalate and calcium. The result is a significant reduction of lithogenic risk for calcium salts and for uric acid.

Protein

• A moderate intake of glycine (4.5 g daily) or protein (50 g daily, 50% animal protein) has no ef­fect on serum or urinary oxalate.
• A diet very rich in meat (700 g of meat or fish daily, 2.26 g of protein/ kg daily) increases urinary oxalate in approximately one third of patients with calcium nephrolithiasis, with an average increase of 73 µmol/ 24 hours whereas no change is observed in normal subjects. Patients with mild hyper­oxaluria have a more substantial in­crease of urinary oxalate (+ 100 µmol). The mechanism of sensitivity is not clear, but does not involve a deficit in vitamin B₆.
• The ef­fect of a reduction in dietary protein on urinary excretion of oxalate is controversial. Chang­ing calcium stone-formers from a high to a low animal protein intake causes no variation in urolithiasis. In renal stone-formers with idiopathic hypercalciuria, a moderate restriction of protein intake causes a reduction of urinary calcium, urate and oxalate and improves the profile of lithogenic patients. A diet with a reduced intake of protein (< 93 g) and salt (50 m­mol) results in a significant reduction of urinary oxalate excretion and CaOx product.

In patients with idiopathic CaOx nephrolithiasis and mild hyperoxaluria (> 40 mg/ day), a diet low in protein and salt with normalised calcium intake for the duration of three months proved to be more ef­fective in reduc­ing oxaluria in comparison with a diet low in oxalate administered to a historical control group of hyperoxaluric patients.

Wheat bran

• In hypercalciuric renal stone-formers, the addition of 30 g of dietary fibre as unproces­sed wheat bran to a low-calcium and low-oxalate diet results in a 23.5% decrease of urinary calcium with respect to the 5.6% decrease obtained with the diet alone whereas the addition of fibre results in a 3.9% decrease in urinary oxalate comparedto the 21.4% on diet alone.

Pyridoxine

• The administration of pyridoxine in oral doses of 250– 500 mg daily to both normo- or hyperoxaluric calcium renal stone-formers decreases urinary oxalate excretion.

Probio­tics (lactobacil­li)

• The administration of lactobacil­li has proved to be ef­fective in reduc­ing the levels of urinary excretion of oxalate in renal calcium stone patients with idiopathic hyperoxaluria and calcium (> 40 mg/ day), in healthy subjects consum­ing a high oxalate diet and in renal stone formers without hyper­oxaluria on a diet rich in oxalate.

General measures

• Hyperoxaluric patients show higher lipid intake and lower glucidic and calcium intake.

Dietary counsel­l­ing accord­ing to the Recom­mended Dietary Al­lowance results in a reduction of intake of total protein, animal protein, fat, and carbohydrates, and it is as­sociated with a reduction in the excretion of oxalate. The ef­fect of general dietary mea­sures (balanced diet, specific diet) on urinary oxalate has not always proven ef­fective in reduc­ing urinary oxalate. The dietary approach is particularly recom­mended after extracorporeal shock wave lithotripsy.

Example of medical treatment towards prevention of recur­rent kidney stone

This patient had a short bowel and hyperoxaluria; a sample of stool tested negative for O. formigenes.

He was therefore advised to avoid oxalate-rich food as well as fatty food, and adhere to a nutritional­ly balanced diet, which included recom­mended levels of calcium and bio­ yogurt contain­ing Lactobacil­lus acidophilus, Streptococ­-cus thermophilus, and bifidobacterium. He was also prescribed potas­sium citrate mixture 10 mL, 3× daily, well diluted with water, by mouth. The composition of this oral solution was potas­sium citrate, 3 g; citric acid monohydrate, 500 mg; syrup, 2.5 mL; quil­laia tincture, 0.1 mL; lemon spirit, 0.05 mL; double-strength chloroform water, 3 mL; water to 10 mL. This mixture contained about 28 m­mol K+/ 10 mL. Two months later, 24-hour urinary oxalate decreased from 0.618 to 0.411 m­mol/ day; 24-hour urine citrate increased from 0.58 to 1.10 m­mol/ day. Six months later, an oxalate absorption test was performed.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE „uniform requirements“ for biomedical papers.

Submitted: 20. 11. 2015

Accepted: 27. 11. 2015

Prof. MU Dr. Vladimír Teplan, DrSc

IBD Clinical and Research Centre, ISCARE Lighthouse

Jankovcova 1569/ 2c

170 04 Praha 7

vladimir.teplan@seznam.cz