Data directly demonstrating the relationship between urinary oxalate (UOx) excretion and stone ev... more Data directly demonstrating the relationship between urinary oxalate (UOx) excretion and stone events in those with enteric hyperoxaluria (EH) are limited. Therefore, we assessed the relationship between UOx excretion and risk of kidney stone events in a retrospective population-based EH cohort. In all, 297 patients from Olmsted County, Minnesota were identified with EH based upon having a 24-h UOx ≥40 mg/24 h preceded by a diagnosis or procedure associated with malabsorption. Diagnostic codes and urologic procedures consistent with kidney stones during follow-up after baseline UOx were considered a new stone event. Logistic regression and accelerated failure time modeling were performed as a function of UOx excretion to predict the probability of new stone event and the annual rate of stone events, respectively, with adjustment for urine calcium and citrate. Mean ± standard deviation age was 51.4 ± 11.4 years and 68% were female. Median (interquartile range) UOx was 55.4 (46.6–73.0...
Mayo Clinic Proceedings: Innovations, Quality & Outcomes, 2019
Objectives: The urinary excretion of organic and inorganic substances and their concentrations ha... more Objectives: The urinary excretion of organic and inorganic substances and their concentrations have attracted extensive attention for their role in the pathogenesis of urinary stone disease. The urinary excretion of specific factors associates with sex and age and seems to have a hereditary component, but the precise genomic determinants remain ill-defined. Methods: Genome-wide association studies previously conducted in 3 cohorts (Genetic Epidemiology
American Journal of Physiology-Renal Physiology, 2019
Randall’s plaque (RP; subepithelial calcification) appears to be an important precursor of kidney... more Randall’s plaque (RP; subepithelial calcification) appears to be an important precursor of kidney stone disease. However, RP cannot be noninvasively detected. The present study investigated candidate biomarkers associated with extracellular vesicles (EVs) in the urine of calcium stone formers (CSFs) with low (<5% papillary surface area) and high (≥5% papillary surface area) percentages of RP and a group of nonstone formers. RPs were quantitated via videotaping and image processing in consecutive CSFs undergoing percutaneous surgery for stone removal. Urinary EVs derived from cells of different nephron segments of CSFs ( n = 64) and nonstone formers ( n = 40) were quantified in biobanked cell-free urine by standardized and validated digital flow cytometer using fluorophore-conjugated antibodies. Overall, the number of EVs carrying surface monocyte chemoattractant protein (MCP)-1 and neutrophil gelatinase-associated lipocalin (NGAL) were significantly lower in CSFs compared with no...
Hereditary mutations in Tamm-Horsfall protein (THP/uromodulin) gene cause autosomal dominant kidn... more Hereditary mutations in Tamm-Horsfall protein (THP/uromodulin) gene cause autosomal dominant kidney diseases characterized by juvenile-onset hyperuricemia, gout and progressive kidney failure, although the disease pathogenesis remains unclear. Here we show that targeted expression in transgenic mice of a mutation within the domain of 8 cysteines of THP in kidneys' thick ascending limb (TAL) caused unfolded protein response in younger (1-month old) mice and apoptosis in older (12-month old) mice. While the young mice had urine concentration defects and polyuria, such defects progressively reversed in the older mice to marked oliguria, highly concentrated urine, fibrotic kidneys and reduced creatinine clearance. Both the young and the old transgenic mice had significantly higher serum uric acid and its catabolic product, allantoin, than age-matched wild-type mice. This THP mutation apparently caused primary defects in TAL by compromising the luminal translocation and reabsorptive ...
Urinary citrate (Ucit) protects against urinary stone formation. Acid base status and diet influe... more Urinary citrate (Ucit) protects against urinary stone formation. Acid base status and diet influence Ucit. However, the effect of demographics, diet, and glucose metabolism on Ucit excretion, urinary pH (U-pH) and net gastrointestinal alkali absorption (NAA) are not known. Twenty-four hour urine samples, blood glucose, creatinine, and cystatin C were obtained from non-Hispanic white sibships in Rochester, MN (n = 446; 64.5 ± 9 years; 58% female). Diet was assessed by a food frequency questionnaire. The impact of blood glucose, demographics and dietary elements on Ucit excretion, U-pH, and NAA were evaluated in bivariate and multivariable models and interaction models that included age, sex, and weight. NAA significantly associated with Ucit and U-pH In multivariate models Ucit increased with age, weight, eGFRCys, and blood glucose, but decreased with loop diuretic and thiazide use. U-pH decreased with serum creatinine, blood glucose, and dietary protein but increased with dietary po...
Clinical journal of the American Society of Nephrology : CJASN, Jan 7, 2017
Prior work has suggested a higher risk of hypertension in kidney stone formers but lacked disease... more Prior work has suggested a higher risk of hypertension in kidney stone formers but lacked disease validation and adjustment for potential confounders. Certain types of stone formers may also be at higher risk of hypertension. In our study, incident symptomatic stone formers in Olmsted County from 2000 to 2011 were manually validated by chart review and age and sex matched to Olmsted County controls. We followed up patients through November 20, 2015. Hypertension was also validated by manual chart review, and the risk of hypertension in stone formers compared with controls was assessed both univariately and after adjusting for comorbidities. The risk of hypertension among different subtypes of stone formers was also evaluated. Among 3023 coded stone formers from 2000 to 2011, a total of 1515 were validated and matched to 1515 controls (mean age was 45 years old, and 56% were men). After excluding those with baseline hypertension (20% of stone formers and 18% of controls), 154 stone f...
Recently published guidelines on the medical management of renal stone disease did not address re... more Recently published guidelines on the medical management of renal stone disease did not address relevant topics in the field of idiopathic calcium nephrolithiasis, which are important also for clinical research. A steering committee identified 27 questions, which were proposed to a faculty of 44 experts in nephrolithiasis and allied fields. A systematic review of the literature was conducted and 5216 potentially relevant articles were selected; from these, 407 articles were deemed to provide useful scientific information. The Faculty, divided into working groups, analysed the relevant literature. Preliminary statements developed by each group were exhaustively discussed in plenary sessions and approved. Statements were developed to inform clinicians on the identification of secondary forms of calcium nephrolithiasis and systemic complications; on the definition of idiopathic calcium nephrolithiasis; on the use of urinary tests of crystallization and of surgical observations during st...
Demographics influence kidney stone risk and the type of stone that is more likely to form. Commo... more Demographics influence kidney stone risk and the type of stone that is more likely to form. Common kidney stone risk factors include having a low urine volume and a high urine concentration. The goal of the current study was to evaluate the effect of demographics on urinary concentration and osmole excretion. Twenty-four-hour urine samples were collected from non-Hispanic white sibships in Rochester, MN. Height, weight, blood pressure, serum creatinine, and cystatin C were measured. Diet was assessed using the Viocare food frequency questionnaire. Effects of demographics and dietary elements on urine osmolality and volume were evaluated in bivariate and multivariable models, as well as models that included dietary interactions with age, sex, and weight. Samples were available from 709 individuals (mean age 66 ± 9 years, 59 % female). Across the age spectrum, males had higher urine osmolality (~140 mOsm/kg, p < 0.0001) and total osmole excretion (~270 mOsm, p < 0.0001) compared...
Background: Allografts with minimal fi brosis and without infl ammation on protocol (surveillance... more Background: Allografts with minimal fi brosis and without infl ammation on protocol (surveillance) biopsies have a good prognosis. This study evaluated the ability of a panel of specifi c urinary proteins that refl ect different pathophysiologic processes to identify allografts with favorable histology, in order to reduce the need for surveillance biopsies. Methods: Urine samples of 391 KTx patients were biobanked beween 2005 and 2009 at the time of allograft biopsy. Patients with urine total protein (tP) to creatinine (Cr) ratio greater than 1 g/g were excluded (n=14). Urinary alpha1microglobulin (alpha1m), retinol binding protein (RBP), neutrophil gelatinase-associated lipocalin (NGAL), Immunoglobulin (Ig) G, IgM, albumin (A), and tP, were measured and normalized to Cr concentration. Acute tubulointerstitial, chronic tubulointerstitial, and acute and chronic glomerular damages were graded using combined tubular + interstitial (t+i), chronic tubular + chronic interstitial (ct+ci), ...
Elevated serum 1,25-dihydroxyvitamin D (1,25(OH)2D) concentrations have been reported among cohor... more Elevated serum 1,25-dihydroxyvitamin D (1,25(OH)2D) concentrations have been reported among cohorts of recurrent calcium (Ca) kidney stone-formers and implicated in the pathogenesis of hypercalciuria. Variations in Ca and vitamin D metabolism, and excretion of urinary solutes among first-time male and female Ca stone-formers in the community, however, have not been defined. In a 4-year community-based study we measured serum Ca, phosphorus (P), 25-hydroxyvitamin D (25(OH)D), 1,25(OH)2D, 24,25-dihydroxyvitamin D (24,25(OH)2D), parathyroid hormone (PTH), and fibroblast growth factor-23 (FGF-23) concentrations in first-time Ca stone-formers and age- and gender frequency-matched controls. Serum Ca and 1,25(OH)2D were increased in Ca stone-formers compared to controls (P = 0.01 and P = 0.001). Stone-formers had a lower serum 24,25(OH)2D/25(OH)D ratio compared to controls (P = 0.008). Serum PTH and FGF-23 concentrations were similar in the groups. Urine Ca excretion was similar in the two...
The objective of this systematic review and meta-analysis were to evaluate the effectiveness of h... more The objective of this systematic review and meta-analysis were to evaluate the effectiveness of high fluid intake for the prevention of incident and recurrent kidney stones, as well as its adherence and safety. A literature search was performed encompassing 1980 through July 2014. Studies that reported relative risks, odds ratios, or hazard ratios comparing the risk of kidney stone events in patients with high vs inadequate fluid intake were included. Pooled risk ratios (RRs) and 95 % confidence intervals (CIs) were calculated using a random-effect, generic inverse variance method. Nine studies [2 randomized controlled trials (RCTs) with 269 patients; 7 observational studies with 273,685 individuals] were included in the meta-analysis. Pooled RRs of kidney stones in individuals with high-fluid intake were 0.40 (95 % CI 0.20-0.79) and 0.49 (0.34-0.71) in RCTs and observational studies, respectively. High fluid intake was significantly associated with reduced risk of recurrent kidney ...
Saudi Journal of Kidney Diseases and Transplantation, 2015
Background: Patients with primary hyperoxaluria (PH) often develop kidney stones and chronic kidn... more Background: Patients with primary hyperoxaluria (PH) often develop kidney stones and chronic kidney disease. Noninvasive urine markers reflective of active kidney injury could be useful to gauge the effectiveness of ongoing treatments. Methods: A panel of biomarkers that reflect different nephron sites and potential mechanisms of injury (clusterin, neutrophil gelatinase-associated lipocalin (NGAL), 8-isoprostane (8IP), monocyte-chemoattractant protein 1(MCP-1), liver-type fatty acid binding protein (L-FABP), heart-type fatty acid binding protein (H-FABP), and osteopontin (OPN)) were measured in 114 urine specimens from 30 PH patients over multiple visits. Generalized estimating equations were used to assess associations between biomarkers and 24 h urine excretions, calculated proximal tubular oxalate concentration (PTOx), and eGFR. Results: Mean (±SD) age at first visit was 19.5 ± 16.6 years with an estimated glomerular filtration rate (eGFR) of 68.4 ± 21.0 ml/min/1.73m 2. After adjustment for age, sex, and eGFR, a higher urine MCP-1 concentration and MCP-1/ creatinine ratio was positively associated with CaOx supersaturation (SS). Higher urine NGAL and NGAL/creatinine as well as OPN and OPN/creatinine were associated with higher eGFR. 8IP was negatively associated with PTOx and urinary Ox, but positively associated with CaOx SS. Conclusion: In PH patients greater urine MCP-1 and 8IP excretion might reflect ongoing collecting tubule crystallization, while greater NGAL and OPN excretion may reflect preservation of kidney mass and function. CaOx crystals, rather than oxalate ion may mediate oxidative stress in hyperoxaluric conditions. Further studies are warranted to determine whether urine MCP-1 excretion predicts long term outcome or is altered in response to treatment.
Current opinion in nephrology and hypertension, 2014
Nephrolithiasis is a common systemic disease associated with both acute kidney injury (AKI) and c... more Nephrolithiasis is a common systemic disease associated with both acute kidney injury (AKI) and chronic kidney disease (CKD). The purpose of this review is to discuss recent publications regarding nephrolithiasis-associated kidney damage, with an emphasis on AKI. Nephrolithiasis is not a common cause of adult AKI (1-2% of cases), although it may be a more important factor in young children (up to 30%). The primary mechanism of nephrolithiasis-associated AKI is obstructive nephropathy, and factors on presentation with obstructive uropathy predict the likelihood of long-term renal recovery. Crystalline nephropathy is another potential pathway in certain circumstances that is often associated with a worse outcome. Recent studies have elucidated additional pathways whereby calcium oxalate crystals can cause acute injury, implicating innate immunity and intracellular inflammasome pathways. Several large cohort studies have demonstrated an independent association of nephrolithiasis with C...
Background: The lifetime incidence of kidney stones is about two times greater in men compared to... more Background: The lifetime incidence of kidney stones is about two times greater in men compared to women. Extracellular vesicles (EVs) shed from activated cells are present in the urine and may reflect or even mediate renal physiology and/or pathology. This study was designed to standardize methodology to characterize urinary EVs by digital flow cytometry and to identify possible sex differences in EVs in persons with and without their first symptomatic kidney stones. Methods: Twenty-four-hour urine collections were obtained from persons presenting with their first kidney stone episode (n = 50 women, 60 men; age 19-76 years) and sex-and age-matched controls from the general population (n = 24 women, 36 men). Results: Standardization: Size of EV was variable within all groups. EV positivity was verified with two fluorophores for surface phosphatidylserine and/or using two different protein markers specific for renal-specific cells. The number of phosphatidylserine-and exosome marker-positive EVs did not correlate with urine osmolality and were similar in fresh vs. frozen and between two sequential urine collections from the same individual. Sex differences: Urine from women controls contained greater (P < 0.05) numbers of EVs positive for phosphatidylserine, exosomes, inflammatory factors and adhesion molecules, and cell-specific markers from different segments of the nephron, renal pelvis, and bladder compared to control men. In contrast, urine from women with kidney stones contained significantly (P < 0.05) lower numbers of EVs derived from podocytes, parietal cells, proximal convoluted tubule, thin and thick loop of Henle, distal tubule, collecting duct, renal pelvis, and bladder compared to control women and contained similar quantities of these types of EVs in men with and without kidney stones. There were also no sex differences in EVs positive for cell adhesion (E-cadherin and inter-cellular adhesion molecule-1 [ICAM-1]) molecules. Conclusions: Unlike women who do not have kidney stones, EVs in urine from women with nephrolithiasis are similar to men with and without kidney stones. Thus, EVs may mediate or reflect aspects of kidney stone pathogenesis and perhaps provide clues regarding sex differences in kidney stone incidence rates.
Clinical journal of the American Society of Nephrology : CJASN, Jan 5, 2014
Kidney stones are heterogeneous but often grouped together. The potential effects of patient demo... more Kidney stones are heterogeneous but often grouped together. The potential effects of patient demographics and calendar month (season) on stone composition are not widely appreciated. The first stone submitted by patients for analysis to the Mayo Clinic Metals Laboratory during 2010 was studied (n=43,545). Stones were classified in the following order: any struvite, any cystine, any uric acid, any brushite, majority (≥50%) calcium oxalate, or majority (≥50%) hydroxyapatite. Calcium oxalate (67%) was the most common followed by hydroxyapatite (16%), uric acid (8%), struvite (3%), brushite (0.9%), and cystine (0.35%). Men accounted for more stone submissions (58%) than women. However, women submitted more stones than men between the ages of 10-19 (63%) and 20-29 (62%) years. Women submitted the majority of hydroxyapatite (65%) and struvite (65%) stones, whereas men submitted the majority of calcium oxalate (64%) and uric acid (72%) stones (P<0.001). Although calcium oxalate stones w...
Clinical Journal of the American Society of Nephrology, 2014
Background Overgrowth of calcium oxalate on Randall's plaque is a mechanism of stone formation am... more Background Overgrowth of calcium oxalate on Randall's plaque is a mechanism of stone formation among idiopathic calcium oxalate stone-formers (ICSFs). It is less clear how stones form when there is little or no plaque. Design, setting, participants, & measurements Participants were a consecutive cohort of ICSFs who underwent percutaneous nephroscopic papillary mapping in the kidney or kidneys containing symptomatic stones and a papillary tip biopsy from a representative calyx during a stone removal procedure between 2009 and 2013. The distribution of Randall's plaque coverage was analyzed and used to divide ICSFs into those with a high ($5%; mean, 10.5%; n=10) versus low (,5%; mean, 1.5%; n=32) amount of plaque coverage per papilla. Demographic and laboratory features were compared between these two groups. Results Low-plaque stone formers tended to be obese (50% versus 10%; P=0.03) and have a history of urinary tract infection (34% versus 0%; P=0.04). They were less likely to have multiple prior stone events (22% versus 80%; P=0.002) and had a lower mean 24-hour urine calcium excretion (187686 mg versus 291699 mg; P,0.01). Morphologically, stones from patients with low amounts of plaque lacked a calcium phosphate core by microcomputed tomography. Papillary biopsies from low plaque stone-formers revealed less interstitial and basement membrane punctate crystallization. Conclusions These findings suggest that other pathways independent of Randall's plaque may contribute to stone pathogenesis among a subgroup of ICSFs who harbor low amounts of plaque.
Background: Urinary sulfate (SO 4 22) and thiosulfate (S 2 O 3 22) can potentially bind with calc... more Background: Urinary sulfate (SO 4 22) and thiosulfate (S 2 O 3 22) can potentially bind with calcium and decrease kidney stone risk. We modeled the effects of these species on the concentration of ionized calcium (iCa) and on supersaturation (SS) of calcium oxalate (CaOx) and calcium phosphate (CaP), and measured their in vitro effects on iCa and the upper limit of stability (ULM) of these salts. Methods: Urine data from 4 different types of stone patients were obtained from the Mayo Nephrology Clinic (Model 1). A second data set was obtained from healthy controls and hypercalciuric stone formers in the literature who had been treated with sodium thiosulfate (STS) (Model 2). The Joint Expert Speciation System (JESS) was used to calculate iCa and SS. In Model 1, these parameters were calculated as a function of sulfate and thiosulfate concentrations. In Model 2, data from pre-and post STS urines were analyzed. ULM and iCa were determined in human urine as a function of sulfate and thiosulfate concentrations. Results: Calculated iCa and SS values for all calcium salts decreased with increasing sulfate concentration. Thiosulfate had no effect on these parameters. In Model 2, calculated iCa and CaOx SS increased after STS treatment, but CaP SS decreased, perhaps due to a decrease in pH after STS treatment. In confirmatory in vitro experiments supplemental sulfate, but not thiosulfate, significantly increased the calcium needed to achieve the ULM of CaP and tended to increase the oxalate needed to reach the ULM of CaOx. Sulfate also significantly decreased iCa in human urine, while thiosulfate had no effect. Conclusion: Increasing urinary sulfate could theoretically reduce CaOx and CaP stone risk. Although STS may reduce CaP stone risk by decreasing urinary pH, it might also paradoxically increase iCa and CaOx SS. As such, STS may not be a viable treatment option for stone disease.
Surgical intervention has become an accepted therapeutic alternative for the patient with medical... more Surgical intervention has become an accepted therapeutic alternative for the patient with medically complicated obesity. Multiple investigators have reported significant and sustained weight loss after bariatric surgery that is associated with improvement of many weight related medical co-morbidities, and statistically-significant decreased overall mortality for surgically-treated as compared to medically-treated subjects. Although the Roux-en-Y Gastric bypass (RYGB) is considered an acceptably safe treatment, an increasing number of patients are being recognized with nephrolithiasis after this, the most common bariatric surgery currently performed. The main risk factor appears to be hyperoxaluria, although low urine volume and citrate concentrations may contribute. The incidence of these urinary risk factors amongst the total post-RYGB population is unknown, but may be more than previously suspected based upon small pilot studies. The etiology of the hyperoxaluria is unknown, but may be related to subtle and seemingly sub clinical fat malabsorption. Clearly, further study is needed, especially to define better treatment options than the standard advice for a low fat, low oxalate diet, and use of calcium as an oxalate binder.
Use of a probioitic to decrease enteric hyperoxaluria. Background. Patients with inflammatory bow... more Use of a probioitic to decrease enteric hyperoxaluria. Background. Patients with inflammatory bowel disease have a 10-to 100-fold increased risk of nephrolithiasis, with enteric hyperoxaluria being the major risk factor for these and other patients with fat malabsorptive states. Endogenous components of the intestinal microflora can potentially limit dietary oxalate absorption. Methods. Ten patients were studied with chronic fat malabsorption, calcium oxalate stones, and hyperoxaluria thought to be caused by jejunoileal bypass (1) and Roux-en-Y gastric bypass surgery for obesity (4), dumping syndrome secondary to gastrectomy (2), celiac sprue (1), chronic pancreatitis (1), and ulcerative colitis in remission (1). For 3 months, patients received increasing doses of a lactic acid bacteria mixture (Oxadrop , VSL Pharmaceuticals), followed by a washout month. Twenty-four-hour urine collections were performed at baseline and after each month. Results. Mean urinary oxalate excretion fell by 19% after 1 month (1 dose per day, P < 0.05), and oxalate excretion remained reduced by 24% during the second month (2 doses per day, P < 0.05). During the third month on 3 doses per day oxalate excretion increased slightly, so that the mean was close to the baseline established off treatment. Urinary oxalate again fell 20% from baseline during the washout period. Calcium oxalate supersaturation was reduced while on Oxadrop , largely due to the decrease in oxalate excretion, although mean changes did not reach statistical significance. Conclusion. Manipulation of gastrointestinal (GI) flora can influence urinary oxalate excretion to reduce urinary supersaturation levels. These changes could have a salutary effect on stone formation rates. Further studies will be needed to establish the optimal dosing regimen. Patients with inflammatory bowel disease have a risk of nephrolithiasis that is 10 to 100 times that of the normal population, ranging from 1% to 25% [1]. Enteric
Data directly demonstrating the relationship between urinary oxalate (UOx) excretion and stone ev... more Data directly demonstrating the relationship between urinary oxalate (UOx) excretion and stone events in those with enteric hyperoxaluria (EH) are limited. Therefore, we assessed the relationship between UOx excretion and risk of kidney stone events in a retrospective population-based EH cohort. In all, 297 patients from Olmsted County, Minnesota were identified with EH based upon having a 24-h UOx ≥40 mg/24 h preceded by a diagnosis or procedure associated with malabsorption. Diagnostic codes and urologic procedures consistent with kidney stones during follow-up after baseline UOx were considered a new stone event. Logistic regression and accelerated failure time modeling were performed as a function of UOx excretion to predict the probability of new stone event and the annual rate of stone events, respectively, with adjustment for urine calcium and citrate. Mean ± standard deviation age was 51.4 ± 11.4 years and 68% were female. Median (interquartile range) UOx was 55.4 (46.6–73.0...
Mayo Clinic Proceedings: Innovations, Quality & Outcomes, 2019
Objectives: The urinary excretion of organic and inorganic substances and their concentrations ha... more Objectives: The urinary excretion of organic and inorganic substances and their concentrations have attracted extensive attention for their role in the pathogenesis of urinary stone disease. The urinary excretion of specific factors associates with sex and age and seems to have a hereditary component, but the precise genomic determinants remain ill-defined. Methods: Genome-wide association studies previously conducted in 3 cohorts (Genetic Epidemiology
American Journal of Physiology-Renal Physiology, 2019
Randall’s plaque (RP; subepithelial calcification) appears to be an important precursor of kidney... more Randall’s plaque (RP; subepithelial calcification) appears to be an important precursor of kidney stone disease. However, RP cannot be noninvasively detected. The present study investigated candidate biomarkers associated with extracellular vesicles (EVs) in the urine of calcium stone formers (CSFs) with low (<5% papillary surface area) and high (≥5% papillary surface area) percentages of RP and a group of nonstone formers. RPs were quantitated via videotaping and image processing in consecutive CSFs undergoing percutaneous surgery for stone removal. Urinary EVs derived from cells of different nephron segments of CSFs ( n = 64) and nonstone formers ( n = 40) were quantified in biobanked cell-free urine by standardized and validated digital flow cytometer using fluorophore-conjugated antibodies. Overall, the number of EVs carrying surface monocyte chemoattractant protein (MCP)-1 and neutrophil gelatinase-associated lipocalin (NGAL) were significantly lower in CSFs compared with no...
Hereditary mutations in Tamm-Horsfall protein (THP/uromodulin) gene cause autosomal dominant kidn... more Hereditary mutations in Tamm-Horsfall protein (THP/uromodulin) gene cause autosomal dominant kidney diseases characterized by juvenile-onset hyperuricemia, gout and progressive kidney failure, although the disease pathogenesis remains unclear. Here we show that targeted expression in transgenic mice of a mutation within the domain of 8 cysteines of THP in kidneys' thick ascending limb (TAL) caused unfolded protein response in younger (1-month old) mice and apoptosis in older (12-month old) mice. While the young mice had urine concentration defects and polyuria, such defects progressively reversed in the older mice to marked oliguria, highly concentrated urine, fibrotic kidneys and reduced creatinine clearance. Both the young and the old transgenic mice had significantly higher serum uric acid and its catabolic product, allantoin, than age-matched wild-type mice. This THP mutation apparently caused primary defects in TAL by compromising the luminal translocation and reabsorptive ...
Urinary citrate (Ucit) protects against urinary stone formation. Acid base status and diet influe... more Urinary citrate (Ucit) protects against urinary stone formation. Acid base status and diet influence Ucit. However, the effect of demographics, diet, and glucose metabolism on Ucit excretion, urinary pH (U-pH) and net gastrointestinal alkali absorption (NAA) are not known. Twenty-four hour urine samples, blood glucose, creatinine, and cystatin C were obtained from non-Hispanic white sibships in Rochester, MN (n = 446; 64.5 ± 9 years; 58% female). Diet was assessed by a food frequency questionnaire. The impact of blood glucose, demographics and dietary elements on Ucit excretion, U-pH, and NAA were evaluated in bivariate and multivariable models and interaction models that included age, sex, and weight. NAA significantly associated with Ucit and U-pH In multivariate models Ucit increased with age, weight, eGFRCys, and blood glucose, but decreased with loop diuretic and thiazide use. U-pH decreased with serum creatinine, blood glucose, and dietary protein but increased with dietary po...
Clinical journal of the American Society of Nephrology : CJASN, Jan 7, 2017
Prior work has suggested a higher risk of hypertension in kidney stone formers but lacked disease... more Prior work has suggested a higher risk of hypertension in kidney stone formers but lacked disease validation and adjustment for potential confounders. Certain types of stone formers may also be at higher risk of hypertension. In our study, incident symptomatic stone formers in Olmsted County from 2000 to 2011 were manually validated by chart review and age and sex matched to Olmsted County controls. We followed up patients through November 20, 2015. Hypertension was also validated by manual chart review, and the risk of hypertension in stone formers compared with controls was assessed both univariately and after adjusting for comorbidities. The risk of hypertension among different subtypes of stone formers was also evaluated. Among 3023 coded stone formers from 2000 to 2011, a total of 1515 were validated and matched to 1515 controls (mean age was 45 years old, and 56% were men). After excluding those with baseline hypertension (20% of stone formers and 18% of controls), 154 stone f...
Recently published guidelines on the medical management of renal stone disease did not address re... more Recently published guidelines on the medical management of renal stone disease did not address relevant topics in the field of idiopathic calcium nephrolithiasis, which are important also for clinical research. A steering committee identified 27 questions, which were proposed to a faculty of 44 experts in nephrolithiasis and allied fields. A systematic review of the literature was conducted and 5216 potentially relevant articles were selected; from these, 407 articles were deemed to provide useful scientific information. The Faculty, divided into working groups, analysed the relevant literature. Preliminary statements developed by each group were exhaustively discussed in plenary sessions and approved. Statements were developed to inform clinicians on the identification of secondary forms of calcium nephrolithiasis and systemic complications; on the definition of idiopathic calcium nephrolithiasis; on the use of urinary tests of crystallization and of surgical observations during st...
Demographics influence kidney stone risk and the type of stone that is more likely to form. Commo... more Demographics influence kidney stone risk and the type of stone that is more likely to form. Common kidney stone risk factors include having a low urine volume and a high urine concentration. The goal of the current study was to evaluate the effect of demographics on urinary concentration and osmole excretion. Twenty-four-hour urine samples were collected from non-Hispanic white sibships in Rochester, MN. Height, weight, blood pressure, serum creatinine, and cystatin C were measured. Diet was assessed using the Viocare food frequency questionnaire. Effects of demographics and dietary elements on urine osmolality and volume were evaluated in bivariate and multivariable models, as well as models that included dietary interactions with age, sex, and weight. Samples were available from 709 individuals (mean age 66 ± 9 years, 59 % female). Across the age spectrum, males had higher urine osmolality (~140 mOsm/kg, p < 0.0001) and total osmole excretion (~270 mOsm, p < 0.0001) compared...
Background: Allografts with minimal fi brosis and without infl ammation on protocol (surveillance... more Background: Allografts with minimal fi brosis and without infl ammation on protocol (surveillance) biopsies have a good prognosis. This study evaluated the ability of a panel of specifi c urinary proteins that refl ect different pathophysiologic processes to identify allografts with favorable histology, in order to reduce the need for surveillance biopsies. Methods: Urine samples of 391 KTx patients were biobanked beween 2005 and 2009 at the time of allograft biopsy. Patients with urine total protein (tP) to creatinine (Cr) ratio greater than 1 g/g were excluded (n=14). Urinary alpha1microglobulin (alpha1m), retinol binding protein (RBP), neutrophil gelatinase-associated lipocalin (NGAL), Immunoglobulin (Ig) G, IgM, albumin (A), and tP, were measured and normalized to Cr concentration. Acute tubulointerstitial, chronic tubulointerstitial, and acute and chronic glomerular damages were graded using combined tubular + interstitial (t+i), chronic tubular + chronic interstitial (ct+ci), ...
Elevated serum 1,25-dihydroxyvitamin D (1,25(OH)2D) concentrations have been reported among cohor... more Elevated serum 1,25-dihydroxyvitamin D (1,25(OH)2D) concentrations have been reported among cohorts of recurrent calcium (Ca) kidney stone-formers and implicated in the pathogenesis of hypercalciuria. Variations in Ca and vitamin D metabolism, and excretion of urinary solutes among first-time male and female Ca stone-formers in the community, however, have not been defined. In a 4-year community-based study we measured serum Ca, phosphorus (P), 25-hydroxyvitamin D (25(OH)D), 1,25(OH)2D, 24,25-dihydroxyvitamin D (24,25(OH)2D), parathyroid hormone (PTH), and fibroblast growth factor-23 (FGF-23) concentrations in first-time Ca stone-formers and age- and gender frequency-matched controls. Serum Ca and 1,25(OH)2D were increased in Ca stone-formers compared to controls (P = 0.01 and P = 0.001). Stone-formers had a lower serum 24,25(OH)2D/25(OH)D ratio compared to controls (P = 0.008). Serum PTH and FGF-23 concentrations were similar in the groups. Urine Ca excretion was similar in the two...
The objective of this systematic review and meta-analysis were to evaluate the effectiveness of h... more The objective of this systematic review and meta-analysis were to evaluate the effectiveness of high fluid intake for the prevention of incident and recurrent kidney stones, as well as its adherence and safety. A literature search was performed encompassing 1980 through July 2014. Studies that reported relative risks, odds ratios, or hazard ratios comparing the risk of kidney stone events in patients with high vs inadequate fluid intake were included. Pooled risk ratios (RRs) and 95 % confidence intervals (CIs) were calculated using a random-effect, generic inverse variance method. Nine studies [2 randomized controlled trials (RCTs) with 269 patients; 7 observational studies with 273,685 individuals] were included in the meta-analysis. Pooled RRs of kidney stones in individuals with high-fluid intake were 0.40 (95 % CI 0.20-0.79) and 0.49 (0.34-0.71) in RCTs and observational studies, respectively. High fluid intake was significantly associated with reduced risk of recurrent kidney ...
Saudi Journal of Kidney Diseases and Transplantation, 2015
Background: Patients with primary hyperoxaluria (PH) often develop kidney stones and chronic kidn... more Background: Patients with primary hyperoxaluria (PH) often develop kidney stones and chronic kidney disease. Noninvasive urine markers reflective of active kidney injury could be useful to gauge the effectiveness of ongoing treatments. Methods: A panel of biomarkers that reflect different nephron sites and potential mechanisms of injury (clusterin, neutrophil gelatinase-associated lipocalin (NGAL), 8-isoprostane (8IP), monocyte-chemoattractant protein 1(MCP-1), liver-type fatty acid binding protein (L-FABP), heart-type fatty acid binding protein (H-FABP), and osteopontin (OPN)) were measured in 114 urine specimens from 30 PH patients over multiple visits. Generalized estimating equations were used to assess associations between biomarkers and 24 h urine excretions, calculated proximal tubular oxalate concentration (PTOx), and eGFR. Results: Mean (±SD) age at first visit was 19.5 ± 16.6 years with an estimated glomerular filtration rate (eGFR) of 68.4 ± 21.0 ml/min/1.73m 2. After adjustment for age, sex, and eGFR, a higher urine MCP-1 concentration and MCP-1/ creatinine ratio was positively associated with CaOx supersaturation (SS). Higher urine NGAL and NGAL/creatinine as well as OPN and OPN/creatinine were associated with higher eGFR. 8IP was negatively associated with PTOx and urinary Ox, but positively associated with CaOx SS. Conclusion: In PH patients greater urine MCP-1 and 8IP excretion might reflect ongoing collecting tubule crystallization, while greater NGAL and OPN excretion may reflect preservation of kidney mass and function. CaOx crystals, rather than oxalate ion may mediate oxidative stress in hyperoxaluric conditions. Further studies are warranted to determine whether urine MCP-1 excretion predicts long term outcome or is altered in response to treatment.
Current opinion in nephrology and hypertension, 2014
Nephrolithiasis is a common systemic disease associated with both acute kidney injury (AKI) and c... more Nephrolithiasis is a common systemic disease associated with both acute kidney injury (AKI) and chronic kidney disease (CKD). The purpose of this review is to discuss recent publications regarding nephrolithiasis-associated kidney damage, with an emphasis on AKI. Nephrolithiasis is not a common cause of adult AKI (1-2% of cases), although it may be a more important factor in young children (up to 30%). The primary mechanism of nephrolithiasis-associated AKI is obstructive nephropathy, and factors on presentation with obstructive uropathy predict the likelihood of long-term renal recovery. Crystalline nephropathy is another potential pathway in certain circumstances that is often associated with a worse outcome. Recent studies have elucidated additional pathways whereby calcium oxalate crystals can cause acute injury, implicating innate immunity and intracellular inflammasome pathways. Several large cohort studies have demonstrated an independent association of nephrolithiasis with C...
Background: The lifetime incidence of kidney stones is about two times greater in men compared to... more Background: The lifetime incidence of kidney stones is about two times greater in men compared to women. Extracellular vesicles (EVs) shed from activated cells are present in the urine and may reflect or even mediate renal physiology and/or pathology. This study was designed to standardize methodology to characterize urinary EVs by digital flow cytometry and to identify possible sex differences in EVs in persons with and without their first symptomatic kidney stones. Methods: Twenty-four-hour urine collections were obtained from persons presenting with their first kidney stone episode (n = 50 women, 60 men; age 19-76 years) and sex-and age-matched controls from the general population (n = 24 women, 36 men). Results: Standardization: Size of EV was variable within all groups. EV positivity was verified with two fluorophores for surface phosphatidylserine and/or using two different protein markers specific for renal-specific cells. The number of phosphatidylserine-and exosome marker-positive EVs did not correlate with urine osmolality and were similar in fresh vs. frozen and between two sequential urine collections from the same individual. Sex differences: Urine from women controls contained greater (P < 0.05) numbers of EVs positive for phosphatidylserine, exosomes, inflammatory factors and adhesion molecules, and cell-specific markers from different segments of the nephron, renal pelvis, and bladder compared to control men. In contrast, urine from women with kidney stones contained significantly (P < 0.05) lower numbers of EVs derived from podocytes, parietal cells, proximal convoluted tubule, thin and thick loop of Henle, distal tubule, collecting duct, renal pelvis, and bladder compared to control women and contained similar quantities of these types of EVs in men with and without kidney stones. There were also no sex differences in EVs positive for cell adhesion (E-cadherin and inter-cellular adhesion molecule-1 [ICAM-1]) molecules. Conclusions: Unlike women who do not have kidney stones, EVs in urine from women with nephrolithiasis are similar to men with and without kidney stones. Thus, EVs may mediate or reflect aspects of kidney stone pathogenesis and perhaps provide clues regarding sex differences in kidney stone incidence rates.
Clinical journal of the American Society of Nephrology : CJASN, Jan 5, 2014
Kidney stones are heterogeneous but often grouped together. The potential effects of patient demo... more Kidney stones are heterogeneous but often grouped together. The potential effects of patient demographics and calendar month (season) on stone composition are not widely appreciated. The first stone submitted by patients for analysis to the Mayo Clinic Metals Laboratory during 2010 was studied (n=43,545). Stones were classified in the following order: any struvite, any cystine, any uric acid, any brushite, majority (≥50%) calcium oxalate, or majority (≥50%) hydroxyapatite. Calcium oxalate (67%) was the most common followed by hydroxyapatite (16%), uric acid (8%), struvite (3%), brushite (0.9%), and cystine (0.35%). Men accounted for more stone submissions (58%) than women. However, women submitted more stones than men between the ages of 10-19 (63%) and 20-29 (62%) years. Women submitted the majority of hydroxyapatite (65%) and struvite (65%) stones, whereas men submitted the majority of calcium oxalate (64%) and uric acid (72%) stones (P<0.001). Although calcium oxalate stones w...
Clinical Journal of the American Society of Nephrology, 2014
Background Overgrowth of calcium oxalate on Randall's plaque is a mechanism of stone formation am... more Background Overgrowth of calcium oxalate on Randall's plaque is a mechanism of stone formation among idiopathic calcium oxalate stone-formers (ICSFs). It is less clear how stones form when there is little or no plaque. Design, setting, participants, & measurements Participants were a consecutive cohort of ICSFs who underwent percutaneous nephroscopic papillary mapping in the kidney or kidneys containing symptomatic stones and a papillary tip biopsy from a representative calyx during a stone removal procedure between 2009 and 2013. The distribution of Randall's plaque coverage was analyzed and used to divide ICSFs into those with a high ($5%; mean, 10.5%; n=10) versus low (,5%; mean, 1.5%; n=32) amount of plaque coverage per papilla. Demographic and laboratory features were compared between these two groups. Results Low-plaque stone formers tended to be obese (50% versus 10%; P=0.03) and have a history of urinary tract infection (34% versus 0%; P=0.04). They were less likely to have multiple prior stone events (22% versus 80%; P=0.002) and had a lower mean 24-hour urine calcium excretion (187686 mg versus 291699 mg; P,0.01). Morphologically, stones from patients with low amounts of plaque lacked a calcium phosphate core by microcomputed tomography. Papillary biopsies from low plaque stone-formers revealed less interstitial and basement membrane punctate crystallization. Conclusions These findings suggest that other pathways independent of Randall's plaque may contribute to stone pathogenesis among a subgroup of ICSFs who harbor low amounts of plaque.
Background: Urinary sulfate (SO 4 22) and thiosulfate (S 2 O 3 22) can potentially bind with calc... more Background: Urinary sulfate (SO 4 22) and thiosulfate (S 2 O 3 22) can potentially bind with calcium and decrease kidney stone risk. We modeled the effects of these species on the concentration of ionized calcium (iCa) and on supersaturation (SS) of calcium oxalate (CaOx) and calcium phosphate (CaP), and measured their in vitro effects on iCa and the upper limit of stability (ULM) of these salts. Methods: Urine data from 4 different types of stone patients were obtained from the Mayo Nephrology Clinic (Model 1). A second data set was obtained from healthy controls and hypercalciuric stone formers in the literature who had been treated with sodium thiosulfate (STS) (Model 2). The Joint Expert Speciation System (JESS) was used to calculate iCa and SS. In Model 1, these parameters were calculated as a function of sulfate and thiosulfate concentrations. In Model 2, data from pre-and post STS urines were analyzed. ULM and iCa were determined in human urine as a function of sulfate and thiosulfate concentrations. Results: Calculated iCa and SS values for all calcium salts decreased with increasing sulfate concentration. Thiosulfate had no effect on these parameters. In Model 2, calculated iCa and CaOx SS increased after STS treatment, but CaP SS decreased, perhaps due to a decrease in pH after STS treatment. In confirmatory in vitro experiments supplemental sulfate, but not thiosulfate, significantly increased the calcium needed to achieve the ULM of CaP and tended to increase the oxalate needed to reach the ULM of CaOx. Sulfate also significantly decreased iCa in human urine, while thiosulfate had no effect. Conclusion: Increasing urinary sulfate could theoretically reduce CaOx and CaP stone risk. Although STS may reduce CaP stone risk by decreasing urinary pH, it might also paradoxically increase iCa and CaOx SS. As such, STS may not be a viable treatment option for stone disease.
Surgical intervention has become an accepted therapeutic alternative for the patient with medical... more Surgical intervention has become an accepted therapeutic alternative for the patient with medically complicated obesity. Multiple investigators have reported significant and sustained weight loss after bariatric surgery that is associated with improvement of many weight related medical co-morbidities, and statistically-significant decreased overall mortality for surgically-treated as compared to medically-treated subjects. Although the Roux-en-Y Gastric bypass (RYGB) is considered an acceptably safe treatment, an increasing number of patients are being recognized with nephrolithiasis after this, the most common bariatric surgery currently performed. The main risk factor appears to be hyperoxaluria, although low urine volume and citrate concentrations may contribute. The incidence of these urinary risk factors amongst the total post-RYGB population is unknown, but may be more than previously suspected based upon small pilot studies. The etiology of the hyperoxaluria is unknown, but may be related to subtle and seemingly sub clinical fat malabsorption. Clearly, further study is needed, especially to define better treatment options than the standard advice for a low fat, low oxalate diet, and use of calcium as an oxalate binder.
Use of a probioitic to decrease enteric hyperoxaluria. Background. Patients with inflammatory bow... more Use of a probioitic to decrease enteric hyperoxaluria. Background. Patients with inflammatory bowel disease have a 10-to 100-fold increased risk of nephrolithiasis, with enteric hyperoxaluria being the major risk factor for these and other patients with fat malabsorptive states. Endogenous components of the intestinal microflora can potentially limit dietary oxalate absorption. Methods. Ten patients were studied with chronic fat malabsorption, calcium oxalate stones, and hyperoxaluria thought to be caused by jejunoileal bypass (1) and Roux-en-Y gastric bypass surgery for obesity (4), dumping syndrome secondary to gastrectomy (2), celiac sprue (1), chronic pancreatitis (1), and ulcerative colitis in remission (1). For 3 months, patients received increasing doses of a lactic acid bacteria mixture (Oxadrop , VSL Pharmaceuticals), followed by a washout month. Twenty-four-hour urine collections were performed at baseline and after each month. Results. Mean urinary oxalate excretion fell by 19% after 1 month (1 dose per day, P < 0.05), and oxalate excretion remained reduced by 24% during the second month (2 doses per day, P < 0.05). During the third month on 3 doses per day oxalate excretion increased slightly, so that the mean was close to the baseline established off treatment. Urinary oxalate again fell 20% from baseline during the washout period. Calcium oxalate supersaturation was reduced while on Oxadrop , largely due to the decrease in oxalate excretion, although mean changes did not reach statistical significance. Conclusion. Manipulation of gastrointestinal (GI) flora can influence urinary oxalate excretion to reduce urinary supersaturation levels. These changes could have a salutary effect on stone formation rates. Further studies will be needed to establish the optimal dosing regimen. Patients with inflammatory bowel disease have a risk of nephrolithiasis that is 10 to 100 times that of the normal population, ranging from 1% to 25% [1]. Enteric
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