Calcium Oxalate Kidney Stone Disease Research Articles

Primary hyperoxaluria type 1: pathophysiology and genetics.

ABSTRACTPrimary hyperoxaluria type 1 (PH1) is a rare genetic form of calcium oxalate kidney stone disease. It is caused by a deficiency in the liver-specific enzyme, alanine:glyoxylate aminotransferase (AGT), a pyridoxal-5′-phosphate (PLP)-dependent enzyme involved in the metabolism of glyoxylate. The excessive endogenous synthesis of oxalate that ensues leads to hyperoxaluria, and the crystallization of the poorly soluble calcium salt of oxalate is responsible for a severe kidney stone disease, which can progress to end-stage renal disease, systemic deposition of oxalate and death. Knowledge about metabolic precursors of glyoxylate and oxalate, molecular pathology of AGT and analytical methods for diagnosis and clinical assessment have allowed a better understanding of the mechanisms underlying PH1 and opened the door to new therapeutic strategies.

Hydroxyproline stimulates inflammation and reprograms macrophage signaling in a rat kidney stone model

Meals rich in oxalate are associated with calcium oxalate (CaOx) kidney stone disease. Hydroxy-L-proline (HLP) is an oxalate precursor found in milk and collagen-containing foods. HLP has been shown to induce CaOx crystal formation in rodents. The purpose of this study was to evaluate the effect of HLP induced oxalate levels on inflammation and renal leukocytes during crystal formation. Male Sprague-Dawley rats (6–8 weeks old) were fed a control diet containing no oxalate for 3 days before being randomized to continue the control diet or 5% HLP for up to 28 days. Blood, 24 h urine, and kidneys were collected on Days 0, 7, 14, or 28. Urinary oxalate levels, crystal deposition, and renal macrophage markers were evaluated using ion chromatography-mass spectrometry, immunohistochemistry, and qRT-PCR. Renal leukocytes were assessed using flow cytometry and RNA-sequencing. HLP feeding increased urinary oxalate levels and renal crystal formation in animals within 7 days. HLP also increased renal macrophage populations on Days 14 and 28. Transcriptome analysis revealed that renal macrophages from animals fed HLP for 7 days were involved in inflammatory response and disease, stress response to LPS, oxidative stress, and immune cell trafficking. Renal macrophages isolated on Day 14 were involved in cell-mediated immunological pathways, ion homeostasis, and inflammatory response. Collectively, these findings suggest that HLP-mediated oxalate levels induce markers of inflammation, leukocyte populations, and reprograms signaling pathways in macrophages in a time-dependent manner. Additional studies investigating the significance of oxalate on renal macrophages could aid in our understanding of kidney stone formation.

Forty Years of Oxalobacter formigenes, a Gutsy Oxalate-Degrading Specialist.

Oxalobacter formigenes, a unique anaerobic bacterium that relies solely on oxalate for growth, is a key oxalate-degrading bacterium in the mammalian intestinal tract. Degradation of oxalate in the gut by O. formigenes plays a critical role in preventing renal toxicity in animals that feed on oxalate-rich plants. The role of O. formigenes in reducing the risk of calcium oxalate kidney stone disease and oxalate nephropathy in humans is less clear, in part due to difficulties in culturing this organism and the lack of studies which have utilized diets in which the oxalate content is controlled. Herein, we review the literature on the 40th anniversary of the discovery of O. formigenes, with a focus on its biology, its role in gut oxalate metabolism and calcium oxalate kidney stone disease, and potential areas of future research. Results from ongoing clinical trials utilizing O. formigenes in healthy volunteers and in patients with primary hyperoxaluria type 1 (PH1), a rare but severe form of calcium oxalate kidney stone disease, are also discussed. Information has been consolidated on O. formigenes strains and best practices to culture this bacterium, which should serve as a good resource for researchers.

The Relationship between Major Dietary Patterns in Patients with and without Calcium Oxalate Kidney Stone: A Case-Control Study

Background: It was suggested that dietary patterns might play a role in the pathogenesis of nephrolithiasis. The aim of this study was to determine the relationship between dietary patterns and the occurrence of calcium oxalate kidney stone disease.
 Methods: A case-control study was conducted on 634 male and female participants aged 18-65 in Tehran using a convenient sampling method. The participants were investigated in the case (n = 317) and control (n = 317) groups. Demographic and anthropometric information, medical history, physical activity, and dietary intake were collected by interview. A validated 147-item food frequency questionnaire was administered to assess the dietary patterns. Factor analysis was also applied with principal component approach (PCA) to determine the major dietary patterns.
 Results: The findings showed two major dietary patterns using 41 food groups. Significant differences were observed in nutritional factors and physical activity between the case and the control groups. After adjusting the covariates, the risk of calcium oxalate kidney stone was significantly higher for those in the highest tertile of unhealthy dietary pattern compared to the lowest ones (OR, 3.83; 95%CI, 2.22-6.61). Additionally, no relationship was found between the healthy dietary pattern and the risk of calcium oxalate kidney stone in any of the four logistic regression models (P for trend > 0.05) (OR,0.95; 95%CI, 0.58-1.55).
 Conclusion: We found that the unhealthy dietary pattern was strongly associated with increased risk for calcium oxalate kidney stones.

Perturbations of the Gut Microbiome and Metabolome in Children with Calcium Oxalate Kidney Stone Disease.

The relationship between the composition and function of gut microbial communities and early-onset calcium oxalate kidney stone disease is unknown. We conducted a case-control study of 88 individuals aged 4-18 years, which included 44 individuals with kidney stones containing ≥50% calcium oxalate and 44 controls matched for age, sex, and race. Shotgun metagenomic sequencing and untargeted metabolomics were performed on stool samples. Participants who were kidney stone formers had a significantly less diverse gut microbiome compared with controls. Among bacterial taxa with a prevalence >0.1%, 31 taxa were less abundant among individuals with nephrolithiasis. These included seven taxa that produce butyrate and three taxa that degrade oxalate. The lower abundance of these bacteria was reflected in decreased abundance of the gene encoding butyryl-coA dehydrogenase (P=0.02). The relative abundance of these bacteria was correlated with the levels of 18 fecal metabolites, and levels of these metabolites differed in individuals with kidney stones compared with controls. The oxalate-degrading bacterial taxa identified as decreased in those who were kidney stone formers were components of a larger abundance correlation network that included Eggerthella lenta and several Lactobacillus species. The microbial (α) diversity was associated with age of stone onset, first decreasing and then increasing with age. For the individuals who were stone formers, we found the lowest α diversity among individuals who first formed stones at age 9-14 years, whereas controls displayed no age-related differences in diversity. Loss of gut bacteria, particularly loss of those that produce butyrate and degrade oxalate, associates with perturbations of the metabolome that may be upstream determinants of early-onset calcium oxalate kidney stone disease.

Reduction in urinary oxalate excretion in mouse models of Primary Hyperoxaluria by RNA interference inhibition of liver lactate dehydrogenase activity

The Primary Hyperoxaluria's (PH) are rare autosomal recessive disorders characterized by elevated oxalate production. PH patients suffer recurrent calcium oxalate kidney stone disease, and in severe cases end stage renal disease. Recent evidence has shown that RNA interference may be a suitable approach to reduce oxalate production in PH patients by knocking down key enzymes involved in hepatic oxalate synthesis. In the current study, wild type mice and mouse models of PH1 (AGT KO) and PH2 (GR KO) were treated with siRNA that targets hepatic LDHA. Although siRNA treatment substantially reduced urinary oxalate excretion [75%] in AGT KO animals, there was a relatively modest reduction [32%] in GR KO animals. Plasma and liver pyruvate levels significantly increased with siRNA treatment and liver organic acid analysis indicated significant changes in a number of glycolytic and TCA cycle metabolites, consistent with the known role of LDHA in metabolism. However, siRNA dosing data suggest that it may be possible to identify a dose that limits changes in liver organic acid levels, while maintaining a desired effect of reducing glyoxylate to oxalate synthesis. These results suggest that RNAi mediated reduction of hepatic LDHA may be an effective strategy to reduce oxalate synthesis in PH, and further analysis of its metabolic effects should be explored. Additional studies should also clarify in GR KO animals whether there are alternate enzymatic pathways in the liver to create oxalate and whether tissues other than liver contribute significantly to oxalate production.

Oxalate induces mitochondrial dysfunction and disrupts redox homeostasis in a human monocyte derived cell line

Monocytes/macrophages are thought to be recruited to the renal interstitium during calcium oxalate (CaOx) kidney stone disease for crystal clearance. Mitochondria play an important role in monocyte function during the immune response. We recently determined that monocytes in patients with CaOx kidney stones have decreased mitochondrial function compared to healthy subjects. The objective of this study was to determine whether oxalate, a major constituent found in CaOx kidney stones, alters cell viability, mitochondrial function, and redox homeostasis in THP-1 cells, a human derived monocyte cell line. THP-1 cells were treated with varying concentrations of CaOx crystals (insoluble form) or sodium oxalate (NaOx; soluble form) for 24h. In addition, the effect of calcium phosphate (CaP) and cystine crystals was tested. CaOx crystals decreased cell viability and induced mitochondrial dysfunction and redox imbalance in THP-1 cells compared to control cells. However, NaOx only caused mitochondrial damage and redox imbalance in THP-1 cells. In contrast, both CaP and cystine crystals did not affect THP-1 cells. Separate experiments showed that elevated oxalate also induced mitochondrial dysfunction in primary monocytes from healthy subjects. These findings suggest that oxalate may play an important role in monocyte mitochondrial dysfunction in CaOx kidney stone disease.

Dietary oxalate induces monocyte mitochondrial dysfunction and crystalluria in healthy subjects: A role of spinach in kidney stone disease?

Dietary oxalate contributes significantly to urinary oxalate excretion and is linked to calcium oxalate kidney stone formation. Oxalate is a common component found in kidney stones and in plants such as spinach. We have previously shown that patients with calcium oxalate kidney stone disease have decreased mitochondrial function and increased IL‐6 levels compared to healthy subjects. The purpose of this study was to investigate whether a dietary oxalate load has any effect on monocyte mitochondrial function and urinary oxalate levels in healthy subjects. Nine healthy subjects between the ages of 21 and 31 with an average BMI of 24.6 ±1.2 were included in the study. Participants consumed a low oxalate diet for 3 days prior to drinking a high dietary oxalate load (spinach smoothie). Blood and urine was collected from participants prior to consuming a high oxalate spinach load (pre‐smoothie) and 5 hours following smoothie consumption (post‐smoothie). Monocyte mitochondrial function was measured using Seahorse XF96 technology. Urinary oxalate levels (both crystalline and soluble) were determined using ion chromatography‐mass spectrometry. The high dietary oxalate load caused a significant decrease in monocyte mitochondrial function in healthy subjects. These responses were similar to levels previously found in patients with calcium oxalate kidney stone disease. In addition, both crystalline and soluble urinary oxalate levels were significantly increased in post‐smoothie samples compared to pre‐smoothie samples. These findings suggest that a high dietary oxalate could affect monocyte mitochondrial function in patients. Future studies will investigate potential mechanisms responsible for these findings.Support or Funding InformationThis work was supported by NIH K01DK106284 and the UAB Department of Urology.

The role of intestinal oxalate transport in hyperoxaluria and the formation of kidney stones in animals and man.

The intestine exerts a considerable influence over urinary oxalate in two ways, through the absorption of dietary oxalate and by serving as an adaptive extra-renal pathway for elimination of this waste metabolite. Knowledge of the mechanisms responsible for oxalate absorption and secretion by the intestine therefore have significant implications for understanding the etiology of hyperoxaluria, as well as offering potential targets for future treatment strategies for calcium oxalate kidney stone disease. In this review, we present the recent developments and advances in this area over the past 10years, and put to the test some of the new ideas that have emerged during this time, using human and mouse models. A key focus for our discussion are the membrane-bound anion exchangers, belonging to the SLC26 gene family, some of which have been shown to participate in transcellular oxalate absorption and secretion. This has offered the opportunity to not only examine the roles of these specific transporters, revealing their importance to oxalate homeostasis, but to also probe the relative contributions made by the active transcellular and passive paracellular components of oxalate transport across the intestine. We also discuss some of the various physiological stimuli and signaling pathways which have been suggested to participate in the adaptation and regulation of intestinal oxalate transport. Finally, we offer an update on research into Oxalobacter formigenes, alongside recent investigations of other oxalate-degrading gut bacteria, in both laboratory animals and humans.

Response of germ-free mice to colonization with O. formigenes and altered Schaedler flora.

Despite evidence suggesting a lack of O. formigenes colonization is a risk factor for calcium oxalate stone formation, little is known about O. formigenes biology. This study is the first to utilize germ-free mice to examine the response to mono-colonization with O. formigenes and the impact of a defined bacterial cocktail, altered Schaedler flora, on O. formigenes colonization. This study demonstrates that germ-free mice on their regular diet remain mono-colonized with O. formigenes, and suggests that further studies with O. formigenes gnotobiotic mouse models could improve our understanding of O. formigenes biology and host/O. formigenes and microbe/O. formigenes interactions.

Proteome Dynamics of the Specialist Oxalate Degrader Oxalobacter formigenes.

Oxalobacter formigenes is a unique intestinal organism that relies on oxalate degradation to meet most of its energy and carbon needs. A lack of colonization is a risk factor for calcium oxalate kidney stone disease. The release of the genome sequence of O. formigenes has provided an opportunity to increase our understanding of the biology of O. formigenes. This study used mass spectrometry based shotgun proteomics to examine changes in protein levels associated with the transition of growth from log to stationary phase. Of the 1867 unique protein coding genes in the genome of O. formigenes strain OxCC13, 1822 proteins were detected, which is at the lower end of the range of 1500–7500 proteins found in free-living bacteria. From the protein datasets presented here it is clear that O. formigenes contains a repertoire of metabolic pathways expected of an intestinal microbe that permit it to survive and adapt to new environments. Although further experimental testing is needed to confirm the physiological and regulatory processes that mediate adaptation with nutrient shifts, the O. formigenes protein datasets presented here can be used as a reference for studying proteome dynamics under different conditions and have significant potential for hypothesis development.

Oxalate-degrading microorganisms or oxalate-degrading enzymes: which is the future therapy for enzymatic dissolution of calcium-oxalate uroliths in recurrent stone disease?

Renal urolithiasis is a pathological condition common to a multitude of genetic, physiological and nutritional disorders, ranging from general hyperoxaluria to obesity. The concept of quickly dissolving renal uroliths via chemolysis, especially calcium-oxalate kidney stones, has long been a clinical goal, but yet to be achieved. Over the past 25 years, there has been a serious effort to examine the prospects of using plant and microbial oxalate-degrading enzymes known to catabolize oxalic acid and oxalate salts. While evidence is emerging that bacterial probiotics can reduce recurrent calcium-oxalate kidney stone disease by lowering systemic hyperoxaluria, the possible use of free oxalate-degrading enzyme therapy remains a challenge with several hurdles to overcome before reaching clinical practice.

Astaxanthin modulates osteopontin and transforming growth factor β1 expression levels in a rat model of nephrolithiasis: a comparison with citrate administration

To evaluate the effect of astaxanthin on renal angiotensin-I converting enzyme (ACE) levels, osteopontin (OPN) and transforming growth factor β1 (TGF-β1) expressions and the extent of crystal deposition in experimentally induced calcium oxalate kidney stone disease in a male Wistar rat model. To compare the efficacy of astaxanthin treatment with a currently used treatment strategy (citrate administration) for kidney stones. The expression of OPN was assessed by immunohistochemistry. One step reverse transcriptase polymerase chain reaction followed by densitometry was used to assess renal OPN and TGF-β1 levels. Renal ACE levels were quantified by an enzyme-linked immunosorbent assay method. Crystal deposition in kidney was analysed by scanning electron microscopic (SEM)-energy-dispersive X-ray (EDX). The renal ACE levels and the expression of OPN and TGF-β1 were upregulated in the nephrolithiasis-induced rats. Astaxanthin treatment reduced renal ACE levels and the expression OPN and TGF-β1. SEM-EDX analysis showed that crystal deposition was reduced in the astaxanthin-treated nephrolithiatic group. Astaxanthin treatment was more effective than citrate administration in the regulation of renal ACE levels, OPN and TGF-β1 expressions. Astaxanthin administration reduced renal calcium oxalate crystal deposition possibly by modulating the renal renin-angiotensin system (RAS), which reduced the expression of OPN and TGF-β1 levels. Astaxanthin administration was more effective than citrate treatment in reducing crystal deposition and down-regulating the expression of OPN and TGF-β1.

Multiple mechanisms of action of pyridoxine in primary hyperoxaluria type 1

Primary hyperoxaluria type 1 (PH1) is a rare hereditary calcium oxalate kidney stone disease caused by a deficiency of the liver-specific pyridoxal-phosphate-dependent peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). About one third of patients are responsive to pharmacological doses of pyridoxine (vitamin B6), but its mechanism of action is unknown. Using stably transformed Chinese Hamster Ovary (CHO) cells expressing various normal and mutant forms of AGT, we have shown that pyridoxine increases the net expression, catalytic activity and peroxisomal import of the most common mistargeted mutant form of AGT (i.e. Gly170Arg on the background of the polymorphic minor allele). These multiple effects explain for the first time the action of pyridoxine in the most common group of responsive patients. Partial effects of pyridoxine were also observed for two other common AGT mutants on the minor allele (i.e. Phe152Ile and Ile244Thr) but not for the minor allele mutant AGT containing a Gly41Arg replacement. These findings demonstrate that pyridoxine, which is metabolised to pyridoxal phosphate, the essential cofactor of AGT, achieves its effects both as a prosthetic group (increasing enzyme catalytic activity) and a chemical chaperone (increasing peroxisome targeting and net expression). This new understanding should aid the development of pharmacological treatments that attempt to enhance efficacy of pyridoxine in PH1, as well as encouraging a re-evaluation of the extent of pyridoxine responsiveness in PH1, as more patients than previously thought might benefit from such treatment.

Cellular adaptive response of distal renal tubular cells to high-oxalate environment highlights surface alpha-enolase as the enhancer of calcium oxalate monohydrate crystal adhesion

Hyperoxaluria is one of etiologic factors of calcium oxalate kidney stone disease. However, response of renal tubular cells to high-oxalate environment remained largely unknown. We applied a gel-based proteomics approach to characterize changes in cellular proteome of MDCK cells induced by 10mM sodium oxalate. A total of 14 proteins were detected as differentially expressed proteins. The oxalate-induced up-regulation of alpha-enolase in whole cell lysate was confirmed by 2-D Western blot analysis. Interaction network analysis revealed that cellular adaptive response under high-oxalate condition involved stress response, energy production, metabolism and transcriptional regulation. Down-regulation of RhoA, which was predicted to be associated with the identified proteins, was confirmed by immunoblotting. In addition, the up-regulation of alpha-enolase on apical surface of renal tubular epithelial cells was also confirmed by immunoblotting of the isolated apical membranes and immunofluorescence study. Interestingly, blockage of alpha-enolase expressed on the cell surface by antibody neutralization significantly reduced the number of calcium oxalate monohydrate (COM) crystals adhered on the cells. These results strongly suggest that surface alpha-enolase plays an important role as the enhancer of COM crystal binding. The increase of alpha-enolase expressed on the cell surface may aggravate kidney stone formation in patients with hyperoxaluria.

Four of the Most Common Mutations in Primary Hyperoxaluria Type 1 Unmask the Cryptic Mitochondrial Targeting Sequence of Alanine:glyoxylate Aminotransferase Encoded by the Polymorphic Minor Allele

The gene encoding the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT, EC. 2.6.1.44) exists as two common polymorphic variants termed the "major" and "minor" alleles. The P11L amino acid replacement encoded by the minor allele creates a hidden N-terminal mitochondrial targeting sequence, the unmasking of which occurs in the hereditary calcium oxalate kidney stone disease primary hyperoxaluria type 1 (PH1). This unmasking is due to the additional presence of a common disease-specific G170R mutation, which is encoded by about one third of PH1 alleles. The P11L and G170R replacements interact synergistically to reroute AGT to the mitochondria where it cannot fulfill its metabolic role (i.e. glyoxylate detoxification) effectively. In the present study, we have reinvestigated the consequences of the interaction between P11L and G170R in stably transformed CHO cells and have studied for the first time whether a similar synergism exists between P11L and three other mutations that segregate with the minor allele (i.e. I244T, F152I, and G41R). Our investigations show that the latter three mutants are all able to unmask the cryptic P11L-generated mitochondrial targeting sequence and, as a result, all are mistargeted to the mitochondria. However, whereas the G170R, I244T, and F152I mutants are able to form dimers and are catalytically active, the G41R mutant aggregates and is inactive. These studies open up the possibility that all PH1 mutations, which segregate with the minor allele, might also lead to the peroxisome-to-mitochondrion mistargeting of AGT, a suggestion that has important implications for the development of treatment strategies for PH1.

Gene expression and its role on urolithiasis

Kidney stone disease is a common condition, affecting up to 10% of the population in Japan as well as in the industrial world. Calcium oxalate is major stone composition, consists of crystal and stone matrix, and arises from a combination of environmental and genetic factors. To date, considerable progress has been made identifying the metabolic risk factors predisposing to this complex disease. The familial association of calcium oxalate stone has been corroborated by numerous studies. The specific genetic and epigenetic factors have remained less clear. However genetic variations have indicated using single nucleotide polymorphism (SNP) , and recent technological advances by way of commercially available SNP array or chips, which capture common human variation across the entire genome, have been revolutionizing the study and identifying a new gene as a risk locus in idiopathic calcium oxalate kidney stone disease.

Metabolism of Fructose to Oxalate and Glycolate

Much attention has been recently directed at fructose consumption because of its association with obesity and subsequent development of chronic diseases. It was recently reported that an increased fructose intake increases the risk of forming kidney stones. It was postulated that fructose consumption may increase urinary oxalate, a risk factor for calcium oxalate kidney stone disease. However, conflicting results have been obtained in human studies examining the relationship between fructose metabolism and oxalate synthesis. To test whether fructose intake influences urinary excretions impacting kidney stone risk, healthy subjects consumed diets controlled in their contents of fructose, oxalate, calcium, and other nutrients. Subjects consumed diets containing 4, 13, and 21% of calories as fructose in a randomized order. No changes in the excretions of oxalate, calcium, and uric acid were observed. In vitro investigations with cultured liver cells incubated with (13)C-labeled sugars indicated that neither fructose nor glucose was converted to oxalate by these cells. Fructose metabolism accounted for 12.4 ± 1.6% of the glycolate detected in the culture medium and glucose 6.4 ± 0.9%. Our results suggest that mechanisms for stone risk associated with fructose intake may lie in factors other than those affecting the major stone risk parameters in urine.

Experimental Induction of Calcium Oxalate Nephrolithiasis in Mice

The availability of various transgenic and knockout mice provides an excellent opportunity to better understand the pathophysiology of calcium oxalate stone disease. However, attempts to produce calcium oxalate nephrolithiasis in mice have not been successful. We hypothesized that calcium oxalate nephrolithiasis in mice requires increasing urine calcium and oxalate excretion, and experimentally induced hyperoxaluria alone is not sufficient. To provide evidence we induced hyperoxaluria by administering hyperoxaluria inducing agents in normocalciuric and hypercalciuric mice, and investigating various aspects of nephrolithiasis. We administered ethylene glycol, glyoxylate or hydroxyl proline via diet in male and female normocalciuric B6 mice, and in hypercalciuric sodium phosphate co-transporter type 2 a -/- mice for 4 weeks. We collected 24-hour urine samples on days 0, 3, 7, 14, 21 and 28, and analyzed them for pH, creatinine, lactate dehydrogenase calcium and oxalate. Kidneys were examined using light microscopy. Urine was examined for crystals using light and scanning electron microscopy. Hypercalciuric mice on hydroxyl proline did not tolerate treatment and were sacrificed before 28 days. All mice on ethylene glycol, glyoxylate or hydroxyl proline became hyperoxaluric and showed calcium oxalate crystalluria. No female, normocalciuric or hypercalciuric mice showed renal calcium oxalate crystal deposits. Calcium oxalate nephrolithiasis developed in all mice on glyoxylate and in some on ethylene glycol. In all mice the kidneys showed epithelial injury. Male mice particularly on glyoxylate had more renal injury and inflammatory cell migration into the interstitium around the crystal deposits. Results confirm that hyperoxaluria induction alone is not sufficient to create calcium oxalate nephrolithiasis in mice. Hypercalciuria is also required. Kidneys in male mice are more prone to injury than those in female mice and are susceptible to calcium oxalate crystal deposition. Perhaps epithelial injury promotes crystal retention. Thus, calcium oxalate nephrolithiasis in mice is gender dependent, and requires hypercalciuria and hyperoxaluria.

Diabetic Kidney Stone Formers Excrete More Oxalate and Have Lower Urine pH Than Nondiabetic Stone Formers

The epidemiological relationship between nephrolithiasis and type 2 diabetes mellitus is well-known. Patients with diabetes mellitus are at increased risk for nephrolithiasis and those with nephrolithiasis are at risk for diabetes mellitus. We examined 24-hour urine composition in stone formers with and without diabetes mellitus. We retrospectively reviewed a database of 462 stone forming patients to examine the relationship between hypertension and 24-hour urine composition. Multivariate linear regression models were adjusted for age, race, gender, body mass index, hypertension, relevant medications and 24-hour urine constituents. On univariate analysis diabetic patients had significantly greater urine volume than nondiabetic patients (2.5 vs 2.1 l daily, p = 0.004). Those with diabetes mellitus also excreted less daily potassium (61.1 vs 68.8 mEq, p = 0.04), phosphate (0.84 vs 1.0 gm, p = 0.002) and creatinine (1405.5 vs 1562.8 mg, p = 0.03), and had significantly lower daily urine pH (5.78 vs 6.09, p <0.001) and CaP supersaturation (0.49 vs 1.20, p <0.001) than nondiabetic patients. On multivariate analysis compared to patients without diabetes mellitus those with type II diabetes mellitus had significantly lower urine pH (-0.34, 95% CI -0.48 to -0.21) and significantly greater urine oxalate (6.43 mg daily, 95% CI 1.26 to 11.60) and volume (0.38 l daily, 95% CI 0.13 to 0.64). Results show that of stone formers patients with type II diabetes mellitus excrete significantly greater urinary oxalate and significantly lower urine pH than those without diabetes mellitus. These findings are important for treating nephrolithiasis since they may influence dietary counseling, medical management and stone prevention.