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End Point Considerations for Clinical Trials in Enteric Hyperoxaluria

Langman, Craig B; Assimos, Dean; Blank, Melanie; Calle, Juan; Grauer, Andreas; Kausz, Annamaria; Milliner, Dawn; Nazzal, Lama; Smith, Kimberly; Tasian, Greg; Thompson, Aliza; Wood, Kyle D; Worcester, Elaine; Yang, Sixun; Malley, Meaghan A; Knauf, Felix; Lieske, John C
Enteric hyperoxaluria is a medical condition characterized by elevated urinary oxalate excretion due to increased gastrointestinal oxalate absorption. Causative features include fat malabsorption and/or increased intestinal permeability to oxalate. Enteric hyperoxaluria has long been known to cause nephrolithiasis and nephrocalcinosis, and, more recently, an association with CKD and kidney failure has been shown. Currently, there are no US Food and Drug Administration-approved therapies for enteric hyperoxaluria, and it is unclear what end points should be used to evaluate the efficacy of new drugs and biologics for this condition. This study represents work of a multidisciplinary group convened by the Kidney Health Initiative to review the evidence supporting potential end points for clinical trials in enteric hyperoxaluria. A potential clinical outcome is symptomatic kidney stone events. Potential surrogate end points include ( 1 ) an irreversible loss of kidney function as a surrogate for progression to kidney failure, ( 2 ) asymptomatic kidney stone growth/new stone formation observed on imaging as a surrogate for symptomatic kidney stone events, ( 3 ) urinary oxalate and urinary calcium oxalate supersaturation as surrogates for the development of symptomatic kidney stone events, and ( 4) plasma oxalate as a surrogate for the development of the clinical manifestations of systemic oxalosis. Unfortunately, because of gaps in the data, this Kidney Health Initiative workgroup was unable to provide definitive recommendations. Work is underway to obtain robust information that can be used to inform trial design and medical product development in this space.
PMID: 37342976
ISSN: 1555-905x
CID: 5542752

Correction to: Effect of a high-citrate beverage on urine chemistry in patients with calcium kidney stones

Goldfarb, David S; Modersitzki, Frank; Asplin, John R; Nazzal, Lama
PMID: 37584782
ISSN: 2194-7236
CID: 5619172

Effect of a high-citrate beverage on urine chemistry in patients with calcium kidney stones

Goldfarb, David S; Modersitzki, Frank; Asplin, John R; Nazzal, Lama
A well-accepted strategy to prevent kidney stones is to increase urine volume by increasing oral intake of fluids, especially water, to lower supersaturation of the relevant, relatively insoluble salts, and thereby lower the risk of precipitation. Randomized controlled trials have shown that this strategy works. It is inexpensive, safe, and intuitively attractive to patients. However, although any beverage can increase urine volume, and citrus juices can increase urine citrate content and pH, no beverage other than water has been clearly shown by randomized controlled trial to prevent kidney stones. We designed an innovative, palatable, low-calorie, high alkali citrate beverage to prevent kidney stones, called Moonstone. One packet of Moonstone powder, mixed in 500 ml of water, contains 24.5 meq of alkali citrate. We administered one packet twice a day to ten calcium stone formers. Moonstone resulted in an increase in mean 24-h urine citrate and urine pH, and a decrease in supersaturation of calcium oxalate in calcium stone formers compared to an equal volume of water. These changes, comparable to those seen in a prior study of a similar amount of (potassium-magnesium) citrate, will likely be associated with a clinically meaningful reduction in kidney stone burden in patients with calcium stones. The effect to increase urine pH would also be expected to benefit patients with uric acid and cystine stones, groups that we hope to study in a subsequent study. The study preparation was well tolerated and was selected as a preferred preventative strategy by about half the participants. Moonstone is an alternative, over-the-counter therapy for kidney stone prevention.
PMID: 37479949
ISSN: 2194-7236
CID: 5536262

Oxalate homeostasis

Ermer, Theresa; Nazzal, Lama; Tio, Maria Clarissa; Waikar, Sushrut; Aronson, Peter S; Knauf, Felix
Oxalate homeostasis is maintained through a delicate balance between endogenous sources, exogenous supply and excretion from the body. Novel studies have shed light on the essential roles of metabolic pathways, the microbiome, epithelial oxalate transporters, and adequate oxalate excretion to maintain oxalate homeostasis. In patients with primary or secondary hyperoxaluria, nephrolithiasis, acute or chronic oxalate nephropathy, or chronic kidney disease irrespective of aetiology, one or more of these elements are disrupted. The consequent impairment in oxalate homeostasis can trigger localized and systemic inflammation, progressive kidney disease and cardiovascular complications, including sudden cardiac death. Although kidney replacement therapy is the standard method for controlling elevated plasma oxalate concentrations in patients with kidney failure requiring dialysis, more research is needed to define effective elimination strategies at earlier stages of kidney disease. Beyond well-known interventions (such as dietary modifications), novel therapeutics (such as small interfering RNA gene silencers, recombinant oxalate-degrading enzymes and oxalate-degrading bacterial strains) hold promise to improve the outlook of patients with oxalate-related diseases. In addition, experimental evidence suggests that anti-inflammatory medications might represent another approach to mitigating or resolving oxalate-induced conditions.
PMID: 36329260
ISSN: 1759-507x
CID: 5387512

The Microbiome and Uremic Solutes

Zaidan, Nadim; Nazzal, Lama
Uremic retention solutes, especially the protein-bound compounds, are toxic metabolites, difficult to eliminate with progressive renal functional decline. They are of particular interest because these uremic solutes are responsible for the pathogenesis of cardiovascular and chronic kidney diseases. Evidence suggests that the relation between uremic toxins, the microbiome, and its host is altered in patients with chronic kidney disease, with the colon's motility, epithelial integrity, and absorptive properties also playing an important role. Studies found an alteration of the microbiota composition with differences in species proportion, diversity, and function. Since uremic toxins precursors are generated by the microbiota, multiple therapeutic options are currently being explored to address dysbiosis. While an oral adsorbent can decrease the transport of bacterial metabolites from the intestinal lumen to the blood, dietary measures, supplements (prebiotics, probiotics, and synbiotics), and antibiotics aim to target directly the gut microbiota composition. Innovative approaches, such as the modulation of bacterial enzymes, open new perspectives to decrease the plasma level of uremic toxins.
PMID: 35448854
ISSN: 2072-6651
CID: 5202142

Effect of antibiotic treatment on Oxalobacter formigenes colonization of the gut microbiome and urinary oxalate excretion

Nazzal, Lama; Francois, Fritz; Henderson, Nora; Liu, Menghan; Li, Huilin; Koh, Hyunwook; Wang, Chan; Gao, Zhan; Perez, Guillermo Perez; Asplin, John R; Goldfarb, David S; Blaser, Martin J
The incidence of kidney stones is increasing in the US population. Oxalate, a major factor for stone formation, is degraded by gut bacteria reducing its intestinal absorption. Intestinal O. formigenes colonization has been associated with a lower risk for recurrent kidney stones in humans. In the current study, we used a clinical trial of the eradication of Helicobacter pylori to assess the effects of an antibiotic course on O. formigenes colonization, urine electrolytes, and the composition of the intestinal microbiome. Of 69 healthy adult subjects recruited, 19 received antibiotics for H. pylori eradication, while 46 were followed as controls. Serial fecal samples were examined for O. formigenes presence and microbiota characteristics. Urine, collected serially fasting and following a standard meal, was tested for oxalate and electrolyte concentrations. O. formigenes prevalence was 50%. Colonization was significantly and persistently suppressed in antibiotic-exposed subjects but remained stable in controls. Urinary pH increased after antibiotics, but urinary oxalate did not differ between the control and treatment groups. In subjects not on antibiotics, the O. formigenes-positive samples had higher alpha-diversity and significantly differed in Beta-diversity from the O. formigenes-negative samples. Specific taxa varied in abundance in relation to urinary oxalate levels. These studies identified significant antibiotic effects on O. formigenes colonization and urinary electrolytes and showed that overall microbiome structure differed in subjects according to O. formigenes presence. Identifying a consortium of bacterial taxa associated with urinary oxalate may provide clues for the primary prevention of kidney stones in healthy adults.
PMID: 34385560
ISSN: 2045-2322
CID: 5004452

Effect of Vancomycin on the Gut Microbiome and Plasma Concentrations of Gut-Derived Uremic Solutes

Nazzal, Lama; Soiefer, Leland; Chang, Michelle; Tamizuddin, Farah; Schatoff, Daria; Cofer, Lucas; Aguero-Rosenfeld, Maria E; Matalon, Albert; Meijers, Bjorn; Holzman, Robert; Lowenstein, Jerome
Introduction/UNASSIGNED:Declining renal function results in the accumulation of solutes normally excreted by healthy kidneys. Data suggest that some of the protein-bound solutes mediate accelerated cardiovascular disease. Many of the poorly dialyzable protein-bound uremic retention solutes are products of gut bacterial metabolism. Methods/UNASSIGNED:We performed a blinded-randomized controlled trial comparing the changes in plasma concentrations of a panel of protein-bound solutes and microbiome structure in response to the once-weekly oral administration of 250 mg of vancomycin or placebo over a period of 12 weeks in a cohort of stable patients with end-stage kidney disease. We also examined the pattern of recovery of the solutes and gut microbiome over 12 weeks of placebo administration following vancomycin. Results/UNASSIGNED:. We demonstrated microbiome recovery after stopping vancomycin. However, recovery in the solutes was highly variable between subjects. Conclusions/UNASSIGNED:We demonstrated that microbiome suppression using vancomycin resulted in changes in multiple gut-derived uremic solutes. Future studies are needed to address whether reduction in those uremic solutes results in improvement of cardiovascular outcomes in ESKD patients.
PMID: 34386661
ISSN: 2468-0249
CID: 4966092

40 Years of Oxalobacter formigenes, a Gutsy Oxalate-Degrading Specialist

Daniel, Steven L; Moradi, Luke; Paiste, Henry; Wood, Kyle D; Assimos, Dean G; Holmes, Ross P; Nazzal, Lama; Hatch, Marguerite; Knight, John
PMID: 34190610
ISSN: 1098-5336
CID: 4926602

Microbial genetic and transcriptional contributions to oxalate degradation by the gut microbiota in health and disease

Liu, Menghan; Devlin, Joseph C; Hu, Jiyuan; Volkova, Angelina; Battaglia, Thomas W; Ho, Melody; Asplin, John R; Byrd, Allyson; Loke, P'ng; Li, Huilin; Ruggles, Kelly V; Tsirigos, Aristotelis; Blaser, Martin J; Nazzal, Lama
Over-accumulation of oxalate in humans may lead to nephrolithiasis and nephrocalcinosis. Humans lack endogenous oxalate degradation pathways (ODP), but intestinal microbes can degrade oxalate using multiple ODPs and protect against its absorption. The exact oxalate-degrading taxa in the human microbiota and their ODP have not been described. We leverage multi-omics data (>3000 samples from >1000 subjects) to show that the human microbiota primarily uses the type II ODP, rather than type I. Further, among the diverse ODP-encoding microbes, an oxalate autotroph, Oxalobacter formigenes, dominates this function transcriptionally. Patients with Inflammatory Bowel Disease (IBD) frequently suffer from disrupted oxalate homeostasis and calcium oxalate nephrolithiasis. We show that the enteric oxalate level is elevated in IBD patients, with highest levels in Crohn's disease patients with both ileal and colonic involvement consistent with known nephrolithiasis risk. We show that the microbiota ODP expression is reduced in IBD patients, which may contribute to the disrupted oxalate homeostasis. The specific changes in ODP expression by several important taxa suggest that they play distinct roles in IBD-induced nephrolithiasis risk. Lastly, we colonize mice that are maintained in the gnotobiotic facility with O. formigenes, using either a laboratory isolate or an isolate we cultured from human stools, and observed a significant reduction in host fecal and urine oxalate levels, supporting our in silico prediction of the importance of the microbiome, particularly O. formigenes in host oxalate homeostasis.
PMID: 33769280
ISSN: 2050-084x
CID: 4823012

Oxalate Nephropathy in an Oxalobacter formigenes-Negative Subject [Case Report]

Nazzal, Lama; Ho, Melody; Wu, Ming; Charytan, David M
PMID: 32405600
ISSN: 2468-0249
CID: 4431442