BACKGROUND:Idiopathic calcium oxalate stone formers (ICSFs) are a heterogeneous group. Randall's plaque (RP) and ductal plugs are two common papillary features observed in ICSFs. These papillary phenotypes, implicated in early stone formation, may be susceptible to different risk factors and have differing long-term health outcomes such as stone events and kidney function. We investigate these outcomes using clinical data from a well-characterized cohort of ICSFs undergoing endoscopic stone removal. METHODS:ICSFs undergoing stone removal procedures were consented for the study between August 2005 and May 2023. Papillae were imaged endoscopically per standard protocol. Two 24-hour urine tests were collected postoperatively while patients were off stone prevention medications. Chart review was performed for comorbidities, serum laboratories, and medication usage related to stone formation. RESULTS:We identify three distinct phenotypes. Of 106 ICSFs, 37 had high plugging without plaque, 44 had high plaque without plugging, and 25 had low plaque and low plugging. High plugging ICSFs had lower estimated glomerular filtration rate (eGFR), increased history of prior urinary tract infection (UTI), and more prior stone events than ICSFs with high plaque or neither feature. Multivariable regression revealed plugging as a significant predictor of eGFR when correcting for age, gender, prior UTIs, and prior stone events. CONCLUSIONS:Plugging appears to be an important predictor for eGFR and multiple stone events. Prior UTIs appear to have a significant effect on plugging. RP did not appear to influence stone events or kidney function.

Rational & Objective: Diabetes and uric acid kidney stones are strongly associated. Patients with calcium kidney stones also have higher risk of developing diabetes compared with nonkidney stone patients yet this has not been further investigated. We aimed to characterize insulin resistance in calcium kidney stone patients. Study Design: Observational. Setting & Population: This study was performed in the University of Chicago Clinical Research Center. Kidney stone patients (N = 42) were selected for having idiopathic hypercalciuria and calcium stones with no other medical conditions, and controls (N = 27) were healthy. Exposures: All participants presented to the Clinical Research Center in a fasting state and at least 2 timed fasting blood and urine collections were collected before a fixed breakfast. Six additional timed blood and urine collections were performed after breakfast. Outcomes: We compared fasting and fed indices of insulin resistance between the groups. Analytic Approach: We used t tests and multivariable linear regression models. A sensitivity analysis removing all patients who had ever been on a thiazide diuretic was also performed. Results: In separate multivariable linear models, kidney stone patients had higher fasting serum insulin levels (24 (3-46 pmol/L), P = 0.03) and higher homeostatic model of insulin resistance (HOMA-IR) (1.0 (0.2-1.8), P = 0.02). In separate multivariable linear models, kidney stone patients had higher fed serum glucose levels (10 (2-18 mg/dL), P = 0.01). Results were similar in a sensitivity analysis removing all patients who had ever been on a thiazide diuretic. There were no differences in urine composition based on HOMA-IR levels. Limitations: Single institution. Small sample size limited subanalyses by different calcium stone types. Conclusions: Calcium kidney stone patients without diabetes or other medical conditions demonstrated signs of insulin resistance compared with healthy matched controls. Plain-Language Summary: Diabetes is strongly associated with kidney stones, particularly uric acid kidney stones. However, patients who form calcium kidney stones may also have an increased risk of developing diabetes, but this has not been further explored. We collected markers of insulin resistance in otherwise healthy patients with calcium kidney stones and healthy control volunteers to evaluate for early signs of insulin resistance in patients with calcium kidney stones. Compared to healthy control participants, we found that patients with calcium kidney stones are more likely to have insulin resistance. Follow-up research is needed to determine the mechanisms contributing to insulin resistance in these patients. Earlier screening for insulin resistance may be beneficial for patients with calcium kidney stones.

Sugar increases urine calcium and magnesium as well as kidney stone and bone disease risk. Our study provided new insights into the underlying mechanism as we gave healthy subjects an oral glucose load and used newer tools such as fractional excretion of lithium, serum parathyroid hormone, and microvesicular abundance of tubular transport proteins to characterize the mechanism and identify the thick ascending limb with possible calcium-sensing receptor mediation as a likely contributor to this mechanism.

We examined how physicians made therapeutic choices to decrease stone risk in patients with bowel disease without colon resection, many of whom have enteric hyperoxaluria (EH), at a single clinic. We analyzed clinic records and 24-h urine collections before and after the first clinic visit, among 100 stone formers with bowel disease. We used multivariate linear regression and t tests to compare effects of fluid intake, alkali supplementation, and oxalate-focused interventions on urine characteristics. Patients advised to increase fluid intake had lower initial urine volumes (L/day; 1.3 ± 0.5 vs. 1.7 ± 0.7) and increased volume more than those not so advised (0.7 ± 0.6 vs. 0.3 ± 0.6 p = 0.03; intervention vs. non-intervention). Calcium oxalate supersaturation (CaOx SS) fell (95% CI −4.3 to −0.8). Alkali supplementation increased urine pH (0.34 ± 0.53 vs. 0.22 ± 0.55, p = 0.26) and urine citrate (mg/d; 83 ± 256 vs. 98 ± 166, p = 0.74). Patients advised to reduce oxalate (mg/day) absorption had higher urine oxalate at baseline (88 ± 44 vs. 50 ± 26) which was unchanged on follow-up (88 (baseline) vs. 91 (follow-up), p = 0.90). Neither alkali (95% CI −1.4 to 2.1) nor oxalate-focused advice (95% CI −1.2 to 2.3) lowered CaOx SS. Physicians chose treatments based on baseline urine characteristics. Advice to increase fluid intake increased urine volume and decreased CaOx SS. Alkali and oxalate interventions were ineffective.

Introduction: Lowering kidney stone risk and urine calcium oxalate supersaturation is a primary clinical focus for kidney stone prevention and can be achieved with multiple strategies. Common strategies include advice to increase fluid intake, restrict dietary sodium, or prescribing a thiazide-type diuretic. We investigated how physicians make these decisions in real-world practice and evaluate their efficacy based on 24-h urine collections. Methods: We reviewed medical charts for 203 kidney stone formers with idiopathic calcium stones from University of Chicago Kidney Stone Clinic between 2005 and 2020. Patients had three 24-h urines before an initial pre-treatment clinic visit and one follow-up 24-h urine. We analyzed changes in urine composition based on treatment advice using t tests and ANOVA. Results: Patients who received advice to increase fluid intake had lower urine volume at baseline (1.5 vs. 2.5 L/day, p < 0.001) and larger increase in urine volume at follow-up (0.6 vs. 0.1 L/day, p < 0.001) compared to those who did not receive the advice. Patients who were advised to restrict dietary sodium had a higher urine sodium at baseline (208 vs. 139 mEq/day, p < 0.001), a larger reduction in urine sodium (−28 vs. 13 mEq/day, p = 0.002), and larger reduction in urine calcium (−74 vs. −28 mg/day, p = 0.005) compared with those not advised to restrict dietary sodium. Patients started on a thiazide had a higher baseline urine calcium (281 vs. 213 mg/day) and larger reduction in urine calcium (−83 vs. −9 mg/day, p < 0.001) compared with patients not started on a thiazide. In combination, thiazide prescriptions with dietary sodium restriction reduced urine calcium by 99 mg/day and reduced calcium oxalate supersaturation from 8.0 to 5.5 and calcium phosphate supersaturation from 1.4 to 1.0. Conclusion: Providers use 24-h urine data to guide treatment strategy decisions. These strategies achieved the intended effects on urine composition and lowered kidney stone risk.

You have accessJournal of UrologyStone Disease: Basic Research & Pathophysiology (MP07)1 Sep 2021MP07-15 CALCIUM OXALATE STONE FORMERS WHO MAKE EVEN ONE STONE ON RANDALL'S PLAQUE HAVE SMALLER STONE BURDENS AND DISTINCTIVE PAPILLARY MINERAL PATHOLOGY James Williams, Haider Al-Awadi, Manognya Muthenini, Sharon Bledsoe, Tarek El-Achkar, Andrew Evan, Fredric Coe, Elaine Worcester, and James Lingeman James WilliamsJames Williams More articles by this author , Haider Al-AwadiHaider Al-Awadi More articles by this author , Manognya MutheniniManognya Muthenini More articles by this author , Sharon BledsoeSharon Bledsoe More articles by this author , Tarek El-AchkarTarek El-Achkar More articles by this author , Andrew EvanAndrew Evan More articles by this author , Fredric CoeFredric Coe More articles by this author , Elaine WorcesterElaine Worcester More articles by this author , and James LingemanJames Lingeman More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001980.15AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The purpose of this study was to compare idiopathic calcium oxalate stone formers with (RP) and without (Non-RP) positive evidence for formation of stones on Randall’s (interstitial) plaque. METHODS: Patients undergoing stone removal by percutaneous (PNL) or ureteroscopic (URS) endoscopy were consented for study. Included patients had stone analysis of >50% calcium oxalate, with no brushite, medullary sponge, bariatric surgery, primary hyperoxaluria or hyperparathyroidism. all stone material was imaged by micro CT and stones growing on Randall’s plaque were identified by adherent regions of apatite that showed characteristics of calcified tissue (including lumens of vessels/tubules in 76% of the cases). Endoscopic papillary appearance was graded and measured on endoscopic video by an investigator blinded to the patient classification. RESULTS: 32 RP patients had on average 5±6 stones on Randall’s plaque, with none in the 42 Non-RP patients. The RP group was younger (48±17 v 56±14, p=0.04), had more stones (8±8 v 5±4 stones/kidney, p=0.02), less total stone removed (80±120 v 480±1200 cubic mm/kidney), and smaller stones (160±230 v 560±1200 cubic mm per stone, p=0.01) than did Non-RP patients, and RP were more likely to have undergone URS. RP had on average 240% more Randall's plaque area (5.2±4.3 v 1.5±1.7 as percent of papilla area, p <0.0001) and 77% less ductal plugging area (0.17±0.38 v 0.73±0.77, p <0.0001). In semi-quantitative scores, RP had more plaque and pitting, less plugging/dilated ducts, and less loss of papillary contour (figure 1). 24-hour urine values did not differ between RP and Non-RP on any measure. CONCLUSIONS: Calcium oxalate stone formers who showed positive evidence of having even a single stone on plaque had small stone burdens and were more likely to have undergone URS. Their renal papillae showed much more plaque and much less ductal plugging than the Non-RP group. These data support RP as a distinct phenotype among calcium oxalate stone formers. Source of Funding: NIH P01 DK056788; NIH R01 DK124776 © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e145-e145 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information James Williams More articles by this author Haider Al-Awadi More articles by this author Manognya Muthenini More articles by this author Sharon Bledsoe More articles by this author Tarek El-Achkar More articles by this author Andrew Evan More articles by this author Fredric Coe More articles by this author Elaine Worcester More articles by this author James Lingeman More articles by this author Expand All Advertisement Loading ...

Patients with brushite kidney stones have more severe renal papillary pathology than idiopathic calcium oxalate (CaOx) stone formers (SFs).1Evan A.P. Lingeman J.E. Coe F.L. et al.Crystal-associated nephropathy in patients with brushite nephrolithiasis.Kidney Int. 2005; 67: 576-591Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar We have shown that papillary tissue from brushite but not CaOx SFs demonstrates abundant neutrophil activation including neutrophil extracellular trap formation, a neutrophil response to bacteria and other perceived pathogens.2Makki M.S. Winfree S. Lingeman J.E. et al.A precision medicine approach uncovers a unique signature of neutrophils in patients with brushite kidney stones.Kidney Int Rep. 2020; 5: 663-677Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar This neutrophil infiltration may explain the increased scarring and inflammation observed in the papillae of brushite SFs. Brushite stones have an increased risk of recurrence,3Singh P. Enders F.T. Vaughan L.E. et al.Stone composition among first-time symptomatic kidney stone formers in the community.Mayo Clin Proc. 2015; 90: 1356-1365Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar,S1 are frequently large and bilateral,4Krambeck A.E. Handa S.E. Evan A.P. Lingeman J.E. Profile of the brushite stone former.J Urol. 2010; 184: 1367-1371Crossref PubMed Scopus (46) Google Scholar,S2 and require more stone removal procedures compared with CaOx stones.5Parks J.H. Worcester E.M. Coe F.L. Evan A.P. Lingeman J.E. Clinical implications of abundant calcium phosphate in routinely analyzed kidney stones.Kidney Int. 2004; 66: 777-785Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar Their prevalence is increasing, including among pediatric SFs.6Wood K.D. Stanasel I.S. Koslov D.S. Mufarrij P.W. McLorie G.A. Assimos D.G. Changing stone composition profile of children with nephrolithiasis.Urology. 2013; 82: 210-213Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar,S3 It would be useful to know whether a signal of the papillary inflammatory response in kidneys of brushite SFs could be detected in urine. Neutrophil proteins in urine, such as leukocyte esterase (LEU), are routinely measured by a urine dipstick. We investigated whether this signal of neutrophil elevation in the kidney could be detected in the urine of brushite SFs when not associated with infection. We studied 812 24-hour urine samples collected from 215 SFs (Supplementary Table S1, Supplementary Methods). Nitrite in urine may signal the presence of Gram-negative bacteria and infection. The stone type was not associated with positive urine nitrite when tested by the Pearson chi-square analysis (Supplementary Table S2). We performed a Kruskal-Wallis test for LEU by stone type. The results were H(3) = 83.8, P < 0.000001, indicating that stone type populations have different distributions of LEU. The rank sums were 83,734, 107,123, 68,601, and 70,619 for apatite, brushite, CaOx, and uric acid SFs, respectively. The differences between groups are highly significant. We performed analysis of variance of LEU in urine using 4 different models to look at the effects of covariates on LEU measurements (Table 1). In model 1, adjusted for sex and age, LEU differed significantly by stone type and sex. Brushite SFs had significantly higher urinary LEU than other SFs. Females had higher LEU than males (0.57 ± 0.04 vs. 0.28 ± 0.03, P < 0.00001), but the cross product between stone type and sex was not significant.Table 1Analysis of variance of urine leukocyte esterase by stone typeModelStone typeP valuesR2ApatiteBrushiteCaOxUAStone typeSexStone∗sex10.44 ± 0.05aP < 0.05 versus CaOx.0.77 ± 0.05bP < 0.001 versus other stone types.0.23 ± 0.050.25 ± 0.06<0.000001<0.0000010.510.13420.46 ± 0.05aP < 0.05 versus CaOx.,cP < 0.001 versus UA.0.77 ± 0.05bP < 0.001 versus other stone types.0.29 ± 0.050.17 ± 0.06<0.000001<0.0000010.180.25930.47 ± 0.05aP < 0.05 versus CaOx.,cP < 0.001 versus UA.0.76 ± 0.05bP < 0.001 versus other stone types.0.28 ± 0.050.18 ± 0.06<0.000001<0.000010.300.26940.45 ± 0.05cP < 0.001 versus UA.0.72 ± 0.05bP < 0.001 versus other stone types.0.32 ± 0.050.17 ± 0.06<0.000001<0.000010.540.256CaOx, calcium oxalate; UA, uric acid.Values are mean leukocyte esterase ± SEM. Model 1 adjusted for sex and age. Model 2 adjusted for sex, age, nitrite, blood, and protein. Model 3 adjusted for sex, age, nitrite, blood, protein, and urine ammonium. Model 4 adjusted for sex, age, nitrite, blood, protein, ammonium, and 24-hour urine volume.a P < 0.05 versus CaOx.b P < 0.001 versus other stone types.c P < 0.001 versus UA. Open table in a new tab CaOx, calcium oxalate; UA, uric acid. Values are mean leukocyte esterase ± SEM. Model 1 adjusted for sex and age. Model 2 adjusted for sex, age, nitrite, blood, and protein. Model 3 adjusted for sex, age, nitrite, blood, protein, and urine ammonium. Model 4 adjusted for sex, age, nitrite, blood, protein, ammonium, and 24-hour urine volume. In model 2 (Table 1), we adjusted model 1 further for other dipstick measurements that could be associated with possible infection such as blood, protein, or nitrite. Brushite and uric acid SFs had significantly more blood in their urine than apatite or CaOx SFs (Supplementary Table S3). Uric acid SFs had elevated urine protein compared with all other groups (Supplementary Table S3). The analysis of variance results were essentially the same as for model 1, except apatite SFs had more LEU than both uric acid and CaOx SFs. Blood, protein, nitrite, and age were all significant in this model at P < 0.05. Model 3 (Table 1) added adjustment for urine ammonium. High urine ammonium can indicate infection by urea-splitting bacteria. Urine ammonium was not higher in brushite SFs than in other SFs (35.3 ± 1.2, 32.0 ± 1.2, 33.4 ± 1.3, and 34.8 ± 1.6 mmol/l for brushite, apatite, CaOx, and uric acid SFs, respectively; P = not significant for all comparisons). Blood, protein, nitrite, age, and ammonium were all significant in this model at P < 0.05, but the addition of ammonium only slightly increased the R2 to a final value of 0.269. Urea-splitting bacteria are unlikely to be the cause of the increased LEU in the urine of brushite SFs. Model 4 (Table 1) further adjusted for the 24-hour urine volume. The results were essentially the same as the previous models. The increased LEU concentration in the urine of brushite SFs cannot be explained by the differences in the urine volume (Supplementary Table S1). Procedures to remove stones can injure the kidney and may lead to the infiltration of neutrophils. Brushite SFs had significantly more procedures than other SFs (Supplementary Table S4). To evaluate the contribution of stone removal procedures to urinary LEU, we performed analysis of variance of the mean LEU adjusted for sex, age, LEU, blood, protein, nitrite, ammonium, and urine volume as well as the total number of each of 5 procedures. LEU was significantly different by stone type and sex (P < 0.05 for each), but the cross product between stone type and sex was not significant (P = 0.80). Brushite SFs had higher urinary LEU than CaOx SFs, whereas all other comparisons between stone types were insignificant (Figure 1). Other significant contributors to the model at P < 0.05 were blood, nitrite, ammonium, and the number of cystoscopies. The R2 for the model was 0.402. Urine LEU was higher in brushite SFs compared with CaOx SFs. Nitrite and ammonium were not different between stone types, making infection by Gram-negative or urea-splitting bacteria unlikely as the cause of increased LEU. Adjusting the analysis of variance models for ammonium, nitrite, and other possible indicators of infection, such as blood and protein as well as the number of stone removal procedures, did not abolish this increase. We have found that increased neutrophil infiltration and neutrophil extracellular trap formation in the renal papillae of brushite SFs differentiate them from CaOx SFs.2Makki M.S. Winfree S. Lingeman J.E. et al.A precision medicine approach uncovers a unique signature of neutrophils in patients with brushite kidney stones.Kidney Int Rep. 2020; 5: 663-677Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Brushite SFs also had increased neutrophil markers in stone matrix compared with CaOx SFs. Our work here showing elevated urine LEU in brushite versus CaOx SFs echoes these findings. Others have used dipstick LEU to detect neutrophil infiltration and predict infection in other disease conditions such as cirrhosis (ascites fluid)7Oey R.C. Kuiper J.J. van Buuren H.R. de Man R.A. Reagent strips are efficient to rule out spontaneous bacterial peritonitis in cirrhotics.Neth J Med. 2016; 74: 257-261PubMed Google Scholar and joint infection (synovial fluid).8Li X. Li R. Ni M. et al.Leukocyte esterase strip test: a rapid and reliable method for the diagnosis of infections in arthroplasty.Orthopedics. 2018; 41: e189-e193Crossref PubMed Scopus (8) Google Scholar High fecal neutrophil levels have been detected in inflammatory bowel disease, and LEU activity in stool has been investigated as a promising biomarker for monitoring inflammatory bowel disease status.9Dumoulin E.N. Van B.S. De V.M. Himpe J. Speeckaert M.M. Delanghe J.R. Faecal leukocyte esterase activity is an alternative biomarker in inflammatory bowel disease.Clin Chem Lab Med. 2015; 53: 2003-2008Crossref PubMed Scopus (10) Google Scholar Similarly, our results show that urine dipstick LEU may be a biomarker of inflammatory activity of neutrophils in the kidney rather than infection per se. The differences in urine LEU between stone types are striking and reflect what is known about renal histopathology in the various stone types. CaOx SFs produce interstitial apatite particles that form Randall’s plaques but do not damage epithelial cells or cause interstitial inflammation or fibrosis.S4 Uric acid SFs form plaque and have crystal deposits in the inner medullary collecting ducts and the ducts of Bellini but with generally absent or mild interstitial fibrosis.S5 In contrast, brushite SFs have severe collecting duct injury and interstitial fibrosis along with prominent cortical fibrosis and tubule atrophy.S6 Hydroxyapatite SFs have a somewhat intermediate phenotype with numerous intratubular crystal deposits that can lead to some papillary damage, but tubular atrophy and interstitial fibrosis are uncommon.S6 The amount of papillary damage in each of these stone types is mirrored by the amount of urinary LEU, reinforcing the idea that urine LEU is a marker of inflammatory conditions in the kidney. This study has some limitations. It is a retrospective study, so the cause of elevated LEU in the urine of brushite SFs cannot be determined, only the association. It is impossible to rule out the presence of infection in all cases, although we have tried to adjust for infection with measurements of nitrite and ammonium. Infection by organisms that are Gram positive but not urea splitting would not be detected by these assays. Likewise, it is impossible to rule out the contribution of blood in the urine as a source of LEU, although we adjusted for it statistically. In conclusion, we have demonstrated the presence in urine of a brushite-specific molecular signature of neutrophil activation that aligns with the pathogenesis of brushite stone formation in the kidney. Our results suggest that urine dipstick LEU is informative in SFs aside from predicting infection and may serve as a biomarker of renal histopathology. All the authors declared no competing interests. This work was supported by grant PO1 DK56788 from the National Institute of Diabetes and Digestive and Kidney Diseases . Download .pdf (.48 MB) Help with pdf files Supplementary File (PDF) Supplementary Methods. Table S1. Patients. Table S2. Urine nitrite. Table S3. Urine blood and protein. Table S4. Stone removal procedures per patient. Supplementary References.

Describe correlations between 3 day food records completed outside of a research setting with biological measurements of intake and understand possible limitations.

In stone formers (SFs) with idiopathic hypercalciuria, urine pH governs the mineral phase of stones. Calcium phosphate (CaP) SFs have higher urine pH than calcium oxalate (CaOx) SFs. Normal women have higher urine pH than men on fixed diets, accompanied by greater absorption of food alkali. Female CaP and male CaOx SFs have similar urine pH as same sex normal individuals, but male CaP and female CaOx SFs may have abnormal acid-base handling. We studied 25 normal individuals (13 men and 12 women), 17 CaOx SFs (11 men and 6 women), and 15 CaP SFs (8 men and 7 women) on fixed diets. Urine and blood samples were collected under fasting and fed conditions. Female CaOx SFs had lower urine pH and lower alkali absorption, fed, compared with normal women; their urine NH 4 was higher and urine citrate excretion lower than in normal women, consistent with their higher net acid excretion. Male CaOx SFs had higher urine citrate excretion and higher serum ultrafilterable citrate levels than normal men. Both male and female CaP SFs had higher urine pH fasting than same sex normal individuals, but only men were higher in the fed period, and there were no differences from normal in gut alkali absorption. CaP SFs of both sexes had higher urine NH 4 and lower urine citrate than same sex normal individuals. The lower urine pH of female CaOx SFs seems related to decreased gut alkali absorption, while the higher pH of CaP SFs, accompanied by higher urine NH 4 and lower urine citrate, suggests a proximal tubule disorder.

Objectives: To describe the papillary pathology found in uric acid (UA) stone formers, and to investigate the mineral form of tissue deposits. Materials and Methods: We studied eight UA stone formers treated with percutaneous nephrolithotomy. Papillae were imaged intraoperatively using digital endoscopy, and cortical and papillary biopsies were taken. Biopsies were analyzed by light microscopy, micro-CT, and microinfrared spectroscopy. Results: As expected, urine pH was generally low. UA supersaturation exceeded one in all but one case, compatible with the stone material. By intraoperative imaging, the renal papillae displayed a heterogeneous mixture of plaque and plugging, ranging from normal to severe. All patients had mineral in ducts of Bellini and inner medullary collecting ducts, mainly apatite with lesser amounts of urate and/or calcium oxalate in some specimens. Papillary and cortical interstitial tissue injury was modest despite the tubule plugging. No instance was found of a stone growing attached to either plaque or plugs. Conclusions: UA stone formers resemble those with ileostomy in having rather low urine pH while forming tubule plugs that contain crystals that can only form at pH values above those of their bulk urine. This discrepancy between tissue mineral deposits and stone type suggests that local tubular pH exceeds that of the bulk urine, perhaps because of localized tubule injury. The manner in which UA stones form and the discordance between tubule crystals and stone type remain open research questions.

One of the main functions of the kidney is to excrete an acid load derived from both dietary and endogenous sources, thus maintaining the pH of other fluids in the body. Urine pH is also of particular interest in stone formers, since it determines the presence of either calcium phosphate or uric acid content in stones. Others have noted in epidemiological studies a rise in incidence of low pH-dependent uric acid stones with age, coinciding with a decrease in the incidence of high pH-dependent phosphate stones. Taken together, these trends are suggestive of a longitudinal decline in urine pH in stone-forming patients, and, if true, this could explain the observed trends in stone incidence. We studied 7,891 stone formers, all of whom collected a 24-h urine sample and matching serum. Multivariate modeling revealed that urine pH did indeed fall with age and particularly between the ages of 20 and 50 yr old in both men and women. We sought to explain this trend through the inclusion of traditionally understood determinants of urine pH such as urinary buffers, estimates of glomerular filtration, and dietary acid load, but these, taken together, accounted for but a small fraction of the pH fall. Gastrointestinal anion absorption was the strongest predictor of urine pH in all age groups, as we have previously reported in middle-aged normal men and women. However, we found that, despite a decreasing urine pH, gastrointestinal anion absorption increased monotonically with age. In fact, after adjustment for gastrointestinal anion absorption, urine pH declined more markedly, suggesting that bicarbonate-producing anion absorption is regulated in a manner that offsets the decline of urine pH.