Contribution of thick ascending limb and distal convoluted tubule to glucose-induced hypercalciuria in healthy controls.

Carbohydrates increase kidney stone risk and increase urine calcium and magnesium. We hypothesize that the effects of glucose as an allosteric modulator of calcium-sensing receptors may mediate this effect. Six healthy subjects were on a low-sodium diet before consuming 100 g of glucose beverage. Timed fasting (3) and postglucose (6) urine and blood samples were collected every 30 min. Urine composition and serum markers were measured and microvesicular abundance of tubular transport proteins (NHE3, NKCC2, NCC, and TRPV5) were quantified. Postglucose, serum glucose, and insulin rose rapidly with a parallel increase in calcium and magnesium excretion and no change in fractional excretion of sodium. Both serum parathyroid hormone (PTH) and urine TRPV5 fell in the postglucose periods. The rise in the calcium and magnesium excretion likely occurred primarily in the thick ascending limb where they are both under control of the calcium-sensing receptor. The fall in PTH and TRPV5 support the role of glucose as an allosteric modulator of calcium-sensing receptor.NEW & NOTEWORTHY 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.

Metabolomic profiles and pathogenesis of nephrolithiasis.

PURPOSE OF REVIEW: Kidney stone disease is caused by supersaturation of urine with certain metabolites and minerals. The urine composition of stone formers has been measured to prevent stone recurrence, specifically calcium, uric acid, oxalate, ammonia, citrate. However, these minerals and metabolites have proven to be unreliable in predicting stone recurrence. Metabolomics using high throughput technologies in well defined patient cohorts can identify metabolites that may provide insight into the pathogenesis of stones as well as offer possibilities in therapeutics. RECENT FINDINGS: Techniques including 1H-NMR, and liquid chromatography paired with tandem mass spectroscopy have identified multiple possible metabolites involved in stone formation. Compared to formers of calcium oxalate stones, healthy controls had higher levels of hippuric acid as well as metabolites involved in caffeine metabolism. Both the gut and urine microbiome may contribute to the altered metabolome of stone formers. SUMMARY: Although metabolomics has offered several potential metabolites that may be protective against or promote stone formation, the mechanisms behind these metabolomic profiles and their clinical significance requires further investigation.

Clinical Effectiveness of Calcium Oxalate Stone Treatments.

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.

Sex Differences of Kidney Stone Urine Risk Factors after Roux-en-Y Gastric Bypass.

INTRODUCTION: Roux-en-Y gastric bypass (RYGB) is a bariatric surgical procedure that is associated with higher risk of kidney stones after surgery. We examined urine composition in 18 men and women before and after RYGB to examine differences in kidney stone risk. METHODS: Three 24-h urine collections were performed before and 1 year after RYGB. We analyzed mean urinary values for pre- and post-RYGB collections and compared men and women. RESULTS: Seven men and eleven women completed pre- and post-RYGB urine collections. Pre-RYGB, men had higher calcium oxalate supersaturation (CaOx SS) (7.0 vs. 5.0, p = 0.04) compared with women. Post-RYGB, women had higher urine CaOx SS (13.1 vs. 4.6, p = 0.002), calcium phosphate supersaturation (1.04 vs. 0.59, p = 0.05), and lower urine volumes (1.7 vs. 2.7L, p < 0.001) compared with men. DISCUSSION/CONCLUSION: There are important differences in urine composition by sex that may contribute to higher kidney stone risk in women after RYGB compared with men.

Evidence for disordered acid-base handling in calcium stone-forming patients.

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 NH4 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 NH4 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 NH4 and lower urine citrate, suggests a proximal tubule disorder.

Mechanisms for falling urine pH with age in stone formers.

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.

Randall's plaque in stone formers originates in ascending thin limbs.

Randall's plaque, an attachment site over which calcium oxalate stones form, begins in the basement membranes of thin limbs of the loop of Henle. The mechanism of its formation is unknown. Possibly, enhanced delivery of calcium out of the proximal tubule, found in many stone formers, increases reabsorption of calcium from the thick ascending limb into the interstitium around descending vasa recta, which convey that calcium into the deep medulla, and raises supersaturations near thin limbs ("vas washdown"). According to this hypothesis, plaque should form preferentially on ascending thin limbs, which do not reabsorb water. We stained serial sections of papillary biopsies from stone-forming patients for aquaporin 1 (which is found in the descending thin limb) and the kidney-specific chloride channel ClC-Ka (which is found in the ascending thin limb). Plaque (which is detected using Yasue stain) colocalized with ClC-Ka, but not with aquaporin 1 (χ2 = 464, P < 0.001). We conclude that plaque forms preferentially in the basement membranes of ascending thin limbs, fulfilling a critical prediction of the vas washdown theory of plaque pathogenesis. The clinical implication is that treatments such as a low-sodium diet or thiazide diuretics that raise proximal tubule calcium reabsorption may reduce formation of plaque as well as calcium kidney stones.

Mechanism for higher urine pH in normal women compared with men.

Regulation of acid-base metabolism maintains the pH of body fluids within a tight range. Urine pH (UpH) is also regulated under normal conditions. Median pH of 24-h urines is ~6, but others have noted that UpH in women is higher than men, which has been attributed to differences in diet. If true, it would help to explain the fact that calcium phosphate stones, which form at higher urine pH, are much more common in women than in men. We studied 14 normal subjects (7 men and 7 women) fed identical meals in a Clinical Research Center. Urine and blood samples were collected during fasting and after meals. UpH of women (6.74 ± 0.11) exceeded that of men (6.07 ± 0.17) fed, but not fasting, and UpH rose significantly with meals in women but not men. Serum and urine total CO2 rose with meals in women but not men, and in women net acid excretion fell to zero during the fed period. In a general linear model adjusted for age, sex, and weight, net gastrointestinal anion uptake was the main predictor of UpH and was significantly higher in women (3.9 ± 0.6) than men (1.8 ± 0.7) in the fed period. Urine citrate, an anion absorbed by the gastrointestinal tract, was higher in women than men in the fed state, and fractional excretion of citrate was higher in women than men. The higher fed UpH in women is related to a greater absorption of food anions and raises 24-h UpH.

Papillary Ductal Plugging is a Mechanism for Early Stone Retention in Brushite Stone Disease.

PURPOSE: Mechanisms of early stone retention in the kidney are under studied and poorly understood. To date attachment via Randall's plaque is the only widely accepted theory in this regard, which is best described in idiopathic calcium oxalate stone formers. Brushite stone formers are known to have distinct papillary morphology relative to calcium oxalate stone formers. As such we sought to determine whether stone attachment mechanisms in such patients may be similarly unique. MATERIALS AND METHODS: Patients undergoing percutaneous and or ureteroscopic procedures for stone removal consented to endoscopic renal papillary examination and individual stone collection. Each removed stone was processed using micro computerized tomography to assess the 3-dimensional microstructure and the minerals contained, and search for common structural features indicative of novel mechanisms of early growth and attachment to renal tissue. RESULTS: A total of 25 intact brushite stones were removed from 8 patients and analyzed. Video confirmed attachment of 13 of the 25 stones with the remainder believed to have been accidently dislodged during the procedure. Microscopic examination by light and computerized tomography failed to show evidence of Randall's plaque associated with any stone containing brushite. Conversely each brushite stone demonstrated microstructural evidence of having grown attached to a ductal plug formed of apatite. CONCLUSIONS: Three-dimensional analysis of small brushite stones suggests overgrowth on ductal apatite plugs as a mechanism of early stone growth and retention. Such findings represent what is to our knowledge the initial supporting evidence for a novel mechanism of stone formation which has previously been hypothesized but never verified.

Evidence for a role of PDZ domain-containing proteins to mediate hypophosphatemia in calcium stone formers.

Background: Hypophosphatemia (HYP) is common among calcium stone formers (SFs) and in rare cases is associated with mutations in sodium-phosphate cotransporters or in Na+/H+ exchanger regulatory factor 1 (NHERF1), but the majority of cases are unexplained. We hypothesized that reduced sodium-phosphate cotransporter activity mediated via NHERF1 or a similar PDZ domain-containing protein, causes HYP. If so, other transport activities controlled by NHERF1, such as NHE3 and URAT1, might be reduced in HYP. Methods: To test this idea, we analyzed two large but separate sets of 24-h urine samples and paired serums of 2700 SFs from the University of Chicago and 11 073 SFs from Litholink, a national laboratory. Patients were divided into quintiles based on serum phosphate. Results: Males were more common in the lowest phosphate tiles in both datasets. Phosphate excretion did not vary across the quintiles, excluding diet as a cause of HYP. Tubule maximum (Tm) phosphate per unit glomerular filtration rate decreased and fractional excretion increased with decreasing phosphate quintiles, indicating reduced tubule phosphate reabsorption was responsible for HYP. Urine pH and serum chloride increased with decreasing serum phosphate, suggesting a coordinate change in NHE3 activity. Serum uric acid and Tm uric acid decreased significantly with decreasing serum phosphate, while uric acid excretion did not vary. Conclusion. HYP in SFs results from decreased tubule phosphate reabsorption and, being associated with related changes in other proximal tubule transporters, may arise from alterations in or signaling to PDZ-containing proteins.

Label-free proteomic methodology for the analysis of human kidney stone matrix composition.

BACKGROUND: Kidney stone matrix protein composition is an important yet poorly understood aspect of nephrolithiasis. We hypothesized that this proteome is considerably more complex than previous reports have indicated and that comprehensive proteomic profiling of the kidney stone matrix may demonstrate relevant constitutive differences between stones. We have analyzed the matrices of two unique human calcium oxalate stones (CaOx-Ia and CaOx-Id) using a simple but effective chaotropic reducing solution for extraction/solubilization combined with label-free quantitative mass spectrometry to generate a comprehensive profile of their proteomes, including physicochemical and bioinformatic analysis.`. RESULTS: We identified and quantified 1,059 unique protein database entries in the two human kidney stone samples, revealing a more complex proteome than previously reported. Protein composition reflects a common range of proteins related to immune response, inflammation, injury, and tissue repair, along with a more diverse set of proteins unique to each stone. CONCLUSION: The use of a simple chaotropic reducing solution and moderate sonication for extraction and solubilization of kidney stone powders combined with label-free quantitative mass spectrometry has yielded the most comprehensive list to date of the proteins that constitute the human kidney stone proteome.

Mechanism by which shock wave lithotripsy can promote formation of human calcium phosphate stones.

Human stone calcium phosphate (CaP) content correlates with higher urine CaP supersaturation (SS) and urine pH as well as with the number of shock wave lithotripsy (SWL) treatments. SWL does damage medullary collecting ducts and vasa recta, sites for urine pH regulation. We tested the hypothesis that SWL raises urine pH and therefore Cap SS, resulting in CaP nucleation and tubular plugging. The left kidney (T) of nine farm pigs was treated with SWL, and metabolic studies were performed using bilateral ureteral catheters for up to 70 days post-SWL. Some animals were given an NH4Cl load to sort out effects on urine pH of CD injury vs. increased HCO3 (-) delivery. Histopathological studies were performed at the end of the functional studies. The mean pH of the T kidneys exceeded that of the control (C) kidneys by 0.18 units in 14 experiments on 9 pigs. Increased HCO3 (-) delivery to CD is at least partly responsible for the pH difference because NH4Cl acidosis abolished it. The T kidneys excreted more Na, K, HCO3 (-), water, Ca, Mg, and Cl than C kidneys. A single nephron site that could produce losses of all of these is the thick ascending limb. Extensive injury was noted in medullary thick ascending limbs and collecting ducts. Linear bands showing nephron loss and fibrosis were found in the cortex and extended into the medulla. Thus SWL produces tubule cell injury easily observed histopathologically that leads to functional disturbances across a wide range of electrolyte metabolism including higher than control urine pH.

Do kidney stone formers have a kidney disease?

Nephrolithiasis is a highly prevalent disorder affecting approximately one in eleven people and is associated with multiple complications including hypertension, cardiovascular disease, and chronic kidney disease. Significant epidemiologic associations with chronic kidney disease and ESRD have been noted and are reviewed herein, but debate persists in the literature as to whether kidney stone formation is a pathogenic process contributing to kidney disease. Corroborating evidence supporting the presence of kidney disease in stone formers includes the variability of renal function by stone type, the positive association of stone size with renal dysfunction, the presence of markers of renal injury in the urine of even asymptomatic stone formers, and direct evidence of renal tissue injury on histopathology. Proposed pathogenic mechanisms include recurrent obstruction and comorbid conditions such as recurrent urinary tract infections and structural abnormalities. Recent work evaluating the renal histopathology of different groups of stone formers adds further granularity, suggesting variability in mechanisms of renal injury by stone type and confirming the pathogenic effects of crystal formation. Genetic abnormalities leading to stone formation including cystinuria and primary hyperoxaluria, among others, contribute to the burden of disease in the stone-forming population.

Nephrocalcinosis in Calcium Stone Formers Who Do Not have Systemic Disease.

PURPOSE: Nephrocalcinosis is commonly present in primary hyperparathyroidism, distal renal tubular acidosis and medullary sponge kidney disease. To our knowledge it has not been studied in patients with calcium phosphate stones who do not have systemic disease. MATERIALS AND METHODS: We studied patients undergoing percutaneous nephrolithotomy who had calcium phosphate or calcium oxalate stones and did not have hyperparathyroidism, distal renal tubular acidosis or medullary sponge kidney disease. On postoperative day 1 all patients underwent noncontrast computerized tomography. If there were no residual calcifications, the patient was categorized as not having nephrocalcinosis. If there were residual calcifications, the patient underwent secondary percutaneous nephrolithotomy. If the calcifications were found to be stones, the patient was categorized as not having nephrocalcinosis. If the calcifications were not stones, the patient was categorized as having nephrocalcinosis. Patients were grouped based on the type of stones that formed, including hydroxyapatite, brushite and idiopathic calcium oxalate. The extent of nephrocalcinosis was quantified as 0--absent nephrocalcinosis to 3--extensive nephrocalcinosis. Patients with residual calcifications on postoperative day 1 noncontrast computerized tomography who did not undergo secondary percutaneous nephrolithotomy were excluded from analysis. The presence or absence of nephrocalcinosis was correlated with metabolic studies. RESULTS: A total of 67 patients were studied, including 14 with hydroxyapatite, 19 with brushite and 34 with idiopathic calcium oxalate calculi. Nephrocalcinosis was present in 10 of 14 (71.4%), 11 of 19 (57.9%) and 6 of 34 patients (17.6%) in the hydroxyapatite, brushite and idiopathic calcium oxalate groups, respectively (chi-square p = 0.01). The mean extent of nephrocalcinosis per group was 1.98, 1.32 and 0.18 for hydroxyapatite, brushite and idiopathic calcium oxalate, respectively (p ≤0.001). The presence of nephrocalcinosis positively correlated with urine calcium excretion (mean ± SD 287.39 ± 112.49 vs 223.68 ± 100.67 mg per day, p = 0.03). CONCLUSIONS: Patients without systemic disease who form hydroxyapatite and brushite stones commonly have coexistent nephrocalcinosis. Nephrocalcinosis can occur in calcium oxalate stone formers but the quantity and frequency of nephrocalcinosis in this group are dramatically less.

Sex differences in proximal and distal nephron function contribute to the mechanism of idiopathic hypercalcuria in calcium stone formers.

Idiopathic hypercalciuria (IH) is a common familial trait among patients with calcium nephrolithiasis. Previously, we have demonstrated that hypercalciuria is primarily due to reduced renal proximal and distal tubule calcium reabsorption. Here, using measurements of the clearances of sodium, calcium, and endogenous lithium taken from the General Clinical Research Center, we test the hypothesis that patterns of segmental nephron tubule calcium reabsorption differ between the sexes in IH and normal subjects. When the sexes are compared, we reconfirm the reduced proximal and distal calcium reabsorption. In IH women, distal nephron calcium reabsorption is decreased compared to normal women. In IH men, proximal tubule calcium reabsorption falls significantly, with a more modest reduction in distal calcium reabsorption compared to normal men. Additionally, we demonstrate that male IH patients have lower systolic blood pressures than normal males. We conclude that women and men differ in the way they produce the hypercalciuria of IH, with females reducing distal reabsorption and males primarily reducing proximal tubule function.

Clinical decision support improves physician guideline adherence for laboratory monitoring of chronic kidney disease: a matched cohort study.

BACKGROUND: Guidelines exist for chronic kidney disease (CKD) but are not well implemented in clinical practice. We evaluated the impact of a guideline-based clinical decision support system (CDSS) on laboratory monitoring and achievement of laboratory targets in stage 3-4 CKD patients. METHODS: We performed a matched cohort study of 12,353 stage 3-4 CKD patients whose physicians opted to receive an automated guideline-based CDSS with CKD-related lab results, and 42,996 matched controls whose physicians did not receive the CDSS. Physicians were from US community-based physician practices utilizing a large, commercial laboratory (LabCorp®). We compared the percentage of laboratory tests obtained within guideline-recommended intervals and the percentage of results within guideline target ranges between CDSS and non-CDSS patients. Laboratory tests analyzed included estimated glomerular filtration rate, plasma parathyroid hormone, serum calcium, phosphorus, 25-hydroxy vitamin D (25-D), total carbon dioxide, transferrin saturation (TSAT), LDL cholesterol (LDL-C), blood hemoglobin, and urine protein measurements. RESULTS: Physicians who used the CDSS ordered all CKD-relevant testing more in accord with guidelines than those who did not use the system. Odds ratios favoring CDSS ranged from 1.29 (TSAT) to 1.88 (serum phosphorus) [CI, 1.20 to 2.01], p < 0.001 for all tests. The CDSS impact was greater for primary care physicians versus nephrologists. CDSS physicians met guideline targets for LDL-C and 25-D more often, but hemoglobin targets less often, than non-CDSS physicians. Use of CDSS did not impact guideline target achievement for the remaining tests. CONCLUSIONS: Use of an automated laboratory-based CDSS may improve physician adherence to guidelines with respect to timely monitoring of CKD.

Role of proximal tubule in the hypocalciuric response to thiazide of patients with idiopathic hypercalciuria.

The most common metabolic abnormality found in calcium (Ca) kidney stone formers is idiopathic hypercalciuria (IH). Using endogenous lithium (Li) clearance, we previously showed that in IH, there is decreased proximal tubule sodium absorption, and increased delivery of Ca into the distal nephron. Distal Ca reabsorption may facilitate the formation of Randall's plaque (RP) by washdown of excess Ca through the vasa recta toward the papillary tip. Elevated Ca excretion leads to increased urinary supersaturation (SS) with respect to calcium oxalate (CaOx) and calcium phosphate (CaP), providing the driving force for stone growth on RP. Thiazide (TZ) diuretics reduce Ca excretion and prevent stone recurrence, but the mechanism in humans is unknown. We studied the effect of chronic TZ administration on renal mineral handling in four male IH patients using a fixed three meal day in the General Clinical Research Center. Each subject was studied twice: once before treatment and once after 4-7 mo of daily chlorthalidone treatment. As expected, urine Ca fell with TZ, along with fraction of filtered Ca excreted. Fraction of filtered Li excreted also fell sharply with TZ, as did distal delivery of Ca. Unexpectedly, TZ lowered urine pH. Together with reduced urine Ca, this led to a marked fall in CaP SS, but not CaOx SS. Since CaOx stone formation begins with an initial CaP overlay on RP, by lowering urine pH and decreasing distal nephron Ca delivery, TZ might diminish stone risk both by reducing CaP SS, as well as slowing progression of RP.

Evidence for increased renal tubule and parathyroid gland sensitivity to serum calcium in human idiopathic hypercalciuria.

Patients with idiopathic hypercalciuria (IH) have decreased renal calcium reabsorption, most marked in the postprandial state, but the mechanisms are unknown. We compared 29 subjects with IH and 17 normal subjects (N) each fed meals providing identical amounts of calcium. Urine and blood samples were collected fasting and after meals. Levels of three candidate signalers, serum calcium (SCa), insulin (I), and plasma parathyroid hormone (PTH), did not differ between IH and N either fasting or fed, but all changed with feeding, and the change in SCa was greater in IH than in N. Regression analysis of fractional excretion of calcium (FECa) was significant for PTH and SCa in IH but not N. With the use of multivariable analysis, Sca entered the model while PTH and I did not. To avoid internal correlation we decomposed FECa into its independent terms: adjusted urine calcium (UCa) and UFCa molarity. Analyses using adjusted Uca and unadjusted Uca parallel those using FECa, showing a dominant effect of SCa with no effect of PTH or I. The effect of SCa may be mediated via vitamin D receptor-stimulated increased abundance of basolateral Ca receptor, which is supported by the fact PTH levels also seem more responsive to serum Ca in IH than in N. Although our data support an effect of SCa on FECa and UCa, which is more marked in IH than in N, it can account for only a modest fraction of the meal effect, perhaps 10-20%, suggesting additional mediators are also responsible for the exaggerated postprandial hypercalciuria seen in IH.

A test of the hypothesis that oxalate secretion produces proximal tubule crystallization in primary hyperoxaluria type I.

The sequence of events by which primary hyperoxaluria type 1 (PH1) causes renal failure is unclear. We hypothesize that proximal tubule (PT) is vulnerable because oxalate secretion raises calcium oxalate (CaOx) supersaturation (SS) there, leading to crystal formation and cellular injury. We studied cortical and papillary biopsies from two PH1 patients with preserved renal function, and seven native kidneys removed from four patients at the time of transplant, after short-term (2) or longer term (2) dialysis. In these patients, and another five PH1 patients without renal failure, we calculated oxalate secretion, and estimated PT CaOx SS. Plasma oxalate was elevated in all PH1 patients and inverse to creatinine clearance. Renal secretion of oxalate was present in all PH1 but rare in controls. PT CaOx SS was >1 in all nonpyridoxine-responsive PH1 before transplant and most marked in patients who developed end stage renal disease (ESRD). PT from PH1 with preserved renal function had birefringent crystals, confirming the presence of CaOx SS, but had no evidence of cortical inflammation or scarring by histopathology or hyaluronan staining. PH1 with short ESRD showed CaOx deposition and hyaluronan staining particularly at the corticomedullary junction in distal PT while cortical collecting ducts were spared. Longer ESRD showed widespread cortical CaOx, and in both groups papillary tissue had marked intratubular CaOx deposits and fibrosis. CaOx SS in PT causes CaOx crystal formation, and CaOx deposition in distal PT appears to be associated with ESRD. Minimizing PT CaOx SS may be important for preserving renal function in PH1.