Publications by authors named "Dawn S Milliner"

63 Publications

Clinical characterization of primary hyperoxaluria type 3 in comparison to types 1 and 2: a retrospective cohort study.

Nephrol Dial Transplant 2021 Feb 5. Epub 2021 Feb 5.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.

Background: Primary hyperoxaluria type 3 (PH3) is caused by mutations in the HOGA1 gene. PH3 patients often present with recurrent urinary stone disease (USD) in first decade of life, but prior reports suggested PH3 may have a milder phenotype in adults. The current study characterized clinical manifestations of PH3 across the decades of life in comparison to PH1 and PH2.

Methods: Clinical information was obtained from the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry (PH1 n = 384; PH2 n = 51; PH3 n = 62).

Results: PH3 patients presented with symptoms at a median 2.7 yrs old compared to PH1 (4.9 yrs) and PH2 (5.7 yrs) (p = 0.14). Nephrocalcinosis was present at diagnosis in 4 (7%) PH3 patients while 55 (89%) had stones. Median urine oxalate excretion was lowest in PH3 patients compared to PH1 and PH2 (1.1 vs 1.6 and 1.5 mmol/day/1.73m2, respectively, p < 0.001) while urine calcium was highest in PH3 (112 vs 51 and 98 mg/day/1.73m2 in PH1 and PH2, respectively, p < 0.001). Stone events per decade of life were similar across the age span and the 3 PH types. At 40 years of age, 97% of PH3 patients had not progressed to ESKD compared to 36% PH1 and 66% PH2 patients.

Conclusions: Patients with all forms of PH experience lifelong stone events often beginning in childhood. Kidney failure is common in PH1 but rare in PH3. Longer term follow up of larger cohorts will be important for a more complete understanding of the PH3 phenotype.
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http://dx.doi.org/10.1093/ndt/gfab027DOI Listing
February 2021

Plasma oxalate and eGFR are correlated in primary hyperoxaluria patients with maintained kidney function-data from three placebo-controlled studies.

Pediatr Nephrol 2021 Jan 30. Epub 2021 Jan 30.

OxThera Intellectual Property AB, Stockholm, Sweden.

Background: In patients with primary hyperoxaluria (PH), endogenous oxalate overproduction increases urinary oxalate excretion, leading to compromised kidney function and often kidney failure. Highly elevated plasma oxalate (Pox) is associated with systemic oxalate deposition in patients with PH and severe chronic kidney disease (CKD). The relationship between Pox and estimated glomerular filtration rate (eGFR) in patients with preserved kidney function, however, is not well established. Our analysis aimed to investigate a potential correlation between these parameters in PH patients from three randomized, placebo-controlled trials (studies OC3-DB-01, OC3-DB-02, and OC5-DB-01).

Methods: Baseline data from patients with a PH diagnosis (type 1, 2, or 3) and eGFR > 40 mL/min/1.73 m were analyzed for a correlation between eGFR and Pox using Spearman's rank and Pearson's correlation coefficients. Data were analyzed by individual study and additionally were pooled for Studies OC3-DB-02 and OC5-DB-01 in which the same Pox assay was used.

Results: A total of 106 patients were analyzed. A statistically significant inverse Spearman's correlation between eGFR and Pox was observed across all analyses; correlation coefficients were - 0.44 in study OC3-DB-01, - 0.55 in study OC3-DB-02, - 0.51 in study OC5-DB-01, and - 0.49 in the pooled studies (p < 0.0064).

Conclusions: Baseline evaluations showed a moderate and statistically significant inverse correlation between eGFR and Pox in patients with PH already at early stages of CKD (stages 1-3b), demonstrating that a correlation is present before substantial loss in kidney function occurs.
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http://dx.doi.org/10.1007/s00467-020-04894-9DOI Listing
January 2021

Specific populations of urinary extracellular vesicles and proteins differentiate type 1 primary hyperoxaluria patients without and with nephrocalcinosis or kidney stones.

Orphanet J Rare Dis 2020 11 11;15(1):319. Epub 2020 Nov 11.

Division of Nephrology and Hypertension, College of Medicine and Science, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.

Background: Primary hyperoxaluria type 1 (PH1) is associated with nephrocalcinosis (NC) and calcium oxalate (CaOx) kidney stones (KS). Populations of urinary extracellular vesicles (EVs) can reflect kidney pathology. The aim of this study was to determine whether urinary EVs carrying specific biomarkers and proteins differ among PH1 patients with NC, KS or with neither disease process.

Methods: Mayo Clinic Rare Kidney Stone Consortium bio-banked cell-free urine from male and female PH1 patients without (n = 10) and with NC (n = 6) or KS (n = 9) and an eGFR > 40 mL/min/1.73 m were studied. Urinary EVs were quantified by digital flow cytometer and results expressed as EVs/ mg creatinine. Expressions of urinary proteins were measured by customized antibody array and results expressed as relative intensity. Data were analyzed by ANCOVA adjusting for sex, and biomarkers differences were considered statistically significant among groups at a false discovery rate threshold of Q < 0.20.

Results: Total EVs and EVs from different types of glomerular and renal tubular cells (11/13 markers) were significantly (Q < 0.20) altered among PH1 patients without NC and KS, patients with NC or patients with KS alone. Three cellular adhesion/inflammatory (ICAM-1, MCP-1, and tissue factor) markers carrying EVs were statistically (Q < 0.20) different between PH1 patients groups. Three renal injury (β2-microglobulin, laminin α5, and NGAL) marker-positive urinary EVs out of 5 marker assayed were statistically (Q < 0.20) different among PH1 patients without and with NC or KS. The number of immune/inflammatory cell-derived (8 different cell markers positive) EVs were statistically (Q < 0.20) different between PH1 patients groups. EV generation markers (ANO4 and HIP1) and renal calcium/phosphate regulation or calcifying matrixvesicles markers (klotho, PiT1/2) were also statistically (Q < 0.20) different between PH1 patients groups. Only 13 (CD14, CD40, CFVII, CRP, E-cadherin, EGFR, endoglin, fetuin A, MCP-1, neprilysin, OPN, OPGN, and PDGFRβ) out of 40 proteins were significantly (Q < 0.20) different between PH1 patients without and with NC or KS.

Conclusions: These results imply activation of distinct renal tubular and interstitial cell populations and processes associated with KS and NC, and suggest specific populations of urinary EVs and proteins are potential biomarkers to assess the pathogenic mechanisms between KS versus NC among PH1 patients.
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http://dx.doi.org/10.1186/s13023-020-01607-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659070PMC
November 2020

Recovery From Dialysis in Patients With Primary Hyperoxaluria Type 1 Treated With Pyridoxine: A Report of 3 Cases.

Am J Kidney Dis 2020 Sep 4. Epub 2020 Sep 4.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN.

Primary hyperoxaluria type 1 (PH1) is a genetic disorder characterized by overproduction of oxalate and eventual kidney failure. Kidney failure is usually irreversible in PH1. However, in patients with PH1 homozygous for the G170R mutation (in which the glycine at amino acid 170 is replaced by an arginine), pyridoxine is an enzyme cofactor and decreases urinary oxalate excretion by reducing hepatic oxalate production. We report recovery from dialysis in 3 patients with PH1 homozygous for the G170R mutation in response to pharmacologic-dose pyridoxine treatment. Median age at initiation or resumption of pyridoxine treatment was 37 (range, 20-53) years, and median daily pyridoxine dose was 8.8 (range, 6.8-14.0) mg per kilogram of body weight. Duration of hemodialysis before recovery of kidney function was 10 (range, 5-19) months. Plasma oxalate concentration improved after recovery of kidney function. At a median of 3 (range, 2-46) months following discontinuation of hemodialysis, estimated glomerular filtration rate was 34 (range, 23-52) mL/min/1.73m, plasma oxalate concentration was 8.8 (range, 4.6-11.3) μmol/L, and urinary oxalate excretion was 0.93 (range, 0.47-1.03) mmol/d. Kidney function was maintained during a median of 3.2 (range, 1.3-3.8) years of follow-up. These observations suggest that kidney failure may be reversible in a subset of patients with PH1 homozygous for the G170R mutation treated with pharmacologic-dose pyridoxine.
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http://dx.doi.org/10.1053/j.ajkd.2020.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930154PMC
September 2020

Plasma Oxalate as a Predictor of Kidney Function Decline in a Primary Hyperoxaluria Cohort.

Int J Mol Sci 2020 May 20;21(10). Epub 2020 May 20.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.

This retrospective analysis investigated plasma oxalate (POx) as a potential predictor of end-stage kidney disease (ESKD) among primary hyperoxaluria (PH) patients. PH patients with type 1, 2, and 3, age 2 or older, were identified in the Rare Kidney Stone Consortium (RKSC) PH Registry. Since POx increased with falling estimated glomerular filtration rate (eGFR), patients were stratified by chronic kidney disease (CKD) subgroups (stages 1, 2, 3a, and 3b). POx values were categorized into quartiles for analysis. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for risk of ESKD were estimated using the Cox proportional hazards model with a time-dependent covariate. There were 118 patients in the CKD1 group (nine ESKD events during follow-up), 135 in the CKD 2 (29 events), 72 in CKD3a (34 events), and 45 patients in CKD 3b (31 events). During follow-up, POx Q4 was a significant predictor of ESKD compared to Q1 across CKD2 (HR 14.2, 95% CI 1.8-115), 3a (HR 13.7, 95% CI 3.0-62), and 3b stages (HR 5.2, 95% CI 1.1-25), < 0.05 for all. Within each POx quartile, the ESKD rate was higher in Q4 compared to Q1-Q3. In conclusion, among patients with PH, higher POx concentration was a risk factor for ESKD, particularly in advanced CKD stages.
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http://dx.doi.org/10.3390/ijms21103608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279271PMC
May 2020

End Points for Clinical Trials in Primary Hyperoxaluria.

Clin J Am Soc Nephrol 2020 07 12;15(7):1056-1065. Epub 2020 Mar 12.

Division of Nephrology, Mayo Clinic, Rochester, Minnesota.

Patients with primary hyperoxaluria experience kidney stones from a young age and can develop progressive oxalate nephropathy. Progression to kidney failure often develops over a number of years, and is associated with systemic oxalosis, intensive dialysis, and often combined kidney and liver transplantation. There are no therapies approved by the Food and Drug Association. Thus, the Kidney Health Initiative, in partnership with the Oxalosis and Hyperoxaluria Foundation, initiated a project to identify end points for clinical trials. A workgroup of physicians, scientists, patients with primary hyperoxaluria, industry, and United States regulators critically examined the published literature for clinical outcomes and potential surrogate end points that could be used to evaluate new treatments. Kidney stones, change in eGFR, urine oxalate, and plasma oxalate were the strongest candidate end points. Kidney stones affect how patients with primary hyperoxaluria feel and function, but standards for measurement and monitoring are lacking. Primary hyperoxaluria registry data suggest that eGFR decline in most patients is gradual, but can be unpredictable. Epidemiologic data show a strong relationship between urine oxalate and long-term kidney function loss. Urine oxalate is reasonably likely to predict clinical benefit, due to its causal role in stone formation and kidney damage in CKD stages 1-3a, and plasma oxalate is likely associated with risk of systemic oxalosis in CKD 3b-5. Change in slope of eGFR could be considered the equivalent of a clinically meaningful end point in support of traditional approval. A substantial change in urine oxalate as a surrogate end point could support traditional approval in patients with primary hyperoxaluria type 1 and CKD stages 1-3a. A substantial change in markedly elevated plasma oxalate could support accelerated approval in patients with primary hyperoxaluria and CKD stages 3b-5. Primary hyperoxaluria type 1 accounts for the preponderance of available data, thus heavily influences the conclusions. Addressing gaps in data will further facilitate testing of promising new treatments, accelerating improved outcomes for patients with primary hyperoxaluria.
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http://dx.doi.org/10.2215/CJN.13821119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341772PMC
July 2020

Clinical features of genetically confirmed patients with primary hyperoxaluria identified by clinical indication versus familial screening.

Kidney Int 2020 04 13;97(4):786-792. Epub 2019 Dec 13.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

Primary hyperoxaluria is a rare monogenic disorder characterized by excessive hepatic production of oxalate leading to recurrent nephrolithiasis, nephrocalcinosis, and progressive kidney damage. Most patients with primary hyperoxaluria are diagnosed after clinical suspicion based on symptoms. Since some patients are detected by family screening following detection of an affected family member, we compared the clinical phenotype of these two groups. Patients with primary hyperoxaluria types 1, 2, and 3 enrolled in the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry were retrospectively analyzed following capture of clinical and laboratory results in the Registry. Among 495 patients with primary hyperoxaluria, 47 were detected by family screening. After excluding 150 patients with end stage kidney disease at diagnosis, 300 clinical suspicion and 45 family screening individuals remained. Compared to patients with clinical suspicion, those identified by family screening had significantly fewer stones at diagnosis (mean 1.2 vs. 3.6), although initial symptoms occurred at a similar age (median age 6.1 vs. 7.6 years). Urinary oxalate did not differ between these groups. The estimated glomerular filtration rate at diagnosis and its decline over time were similar for the two groups. Altogether, five of 45 in family screening and 67 of 300 of clinical suspicion individuals developed end stage kidney disease at last follow-up. Thus, patients with primary hyperoxaluria identified through family screening have significant disease despite no outward clinical suspicion at diagnosis. Since promising novel treatments are emerging, genetic screening of family members is warranted because they are at significant risk for disease progression.
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http://dx.doi.org/10.1016/j.kint.2019.11.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175669PMC
April 2020

Kidney Transplant Outcomes in Patients With Adenine Phosphoribosyltransferase Deficiency.

Transplantation 2020 10;104(10):2120-2128

Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.

Background: Adenine phosphoribosyltransferase (APRT) deficiency is a rare, hereditary cause of kidney stones and chronic kidney disease (CKD) which is characterized by 2,8-dihydroxyadenine renal parenchymal crystal deposition. The aim of this study was to examine outcomes of kidney transplantation in APRT deficiency patients.

Methods: Included were 13 patients in the APRT Deficiency Registry of the Rare Kidney Stone Consortium, 2 from Westmead Hospital in Sydney, Australia, and 2 from Necker Hospital in Paris, France. The CKD-EPI and CKiD equations were used to calculate glomerular filtration rate estimates. Allograft survival was analyzed employing the Kaplan-Meier method. The Wilcoxon-Mann-Whitney test was used to compare alllograft outcomes according to xanthine oxidoreductase (XOR) inhibitor treatment status at transplantation.

Results: Seventeen patients (9 females) received 22 kidney transplants. Age at first transplantation was 47.2 (14.9-67.0) years. Ten patients received XOR inhibitor therapy pretransplant (11 allografts), while 8 patients did not receive such treatment before transplantation (11 allografts). Two-year allograft survival was 91% and 55% in the 2 groups, respectively (P = 0.16). The median (range) estimated glomerular filtration rate at 2 years posttransplant was 61.3 (24.0-90.0) mL/min/1.73 m when XOR inhibitor therapy was initiated before transplantation, and 16.2 (10.0-39.0) mL/min/1.73 m (P = 0.009) when such treatment was not administered pretransplant.

Conclusions: Kidney allograft outcomes are good in APRT deficiency patients beginning XOR inhibitor therapy pretransplant. Delay in such treatment is a major cause of premature graft loss in these patients. Increased awareness among clinicians is imperative, promoting early diagnosis of APRT deficiency and pharmacotherapy initiation before kidney transplantation.
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http://dx.doi.org/10.1097/TP.0000000000003088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316615PMC
October 2020

Correction to: Recent advances in the identification and management of inherited hyperoxalurias.

Urolithiasis 2020 Feb;48(1):93

Mayo Clinic, Rochester, MN, USA.

The original version of this article unfortunately contained a mistake. On page 84, the dose for oral potassium citrate is incorrectly written as "0.1 mg/kg/day divided BID-QID for children, 30-60 mg per day divided BID-QID for adults".
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http://dx.doi.org/10.1007/s00240-019-01166-6DOI Listing
February 2020

Oxalosis Associated With High-Dose Vitamin C Ingestion in a Peritoneal Dialysis Patient.

Am J Kidney Dis 2019 09 22;74(3):417-420. Epub 2019 Mar 22.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN; The Rare Kidney Stone Consortium, Mayo Clinic, Rochester, MN; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN. Electronic address:

We report a case of systemic oxalosis involving the eyes and joints due to long-term use of high-dose vitamin C in a patient receiving maintenance peritoneal dialysis (PD). This 76-year-old woman with autosomal dominant polycystic kidney disease underwent living unrelated kidney transplantation 10 years earlier. The transplant failed 6 months before presentation, and she initiated hemodialysis therapy before transitioning to PD therapy 4 months later. During the month before presentation, the patient noted worsening arthralgias and decreased vision. Ophthalmologic examination revealed proliferative retinopathy and calcium oxalate crystals. Plasma oxalate level was markedly elevated at 187 (reference range, <1.7) μmol/L, and urine oxalate-creatinine ratio was high (0.18mg/mg). The patient reported taking up to 4g of vitamin C per day for several years. Workup for causes of primary and secondary hyperoxaluria was otherwise negative. Vitamin C use was discontinued, and the patient transitioned to daily hemodialysis for 2 weeks. Plasma oxalate level before the dialysis session decreased but remained higher (30-53μmol/L) than typical for dialysis patients. Upon discharge, the patient remained on thrice-weekly hemodialysis therapy with stabilized vision and improved joint symptoms. This case highlights the risk of high-dose vitamin C use in patients with advanced chronic kidney disease, especially when maintained on PD therapy.
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http://dx.doi.org/10.1053/j.ajkd.2019.01.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708738PMC
September 2019

Prevalence of low molecular weight proteinuria and Dent disease 1 CLCN5 mutations in proteinuric cohorts.

Pediatr Nephrol 2020 04 10;35(4):633-640. Epub 2019 Mar 10.

Rare Kidney Stone Consortium, Rochester, USA.

Background: Dent disease type 1 (DD1) is a rare X-linked disorder caused mainly by CLCN5 mutations. Patients may present with nephrotic-range proteinuria leading to erroneous diagnosis of focal segmental glomerulosclerosis (FSGS) and unnecessary immunosuppressive treatments.

Methods: The following cohorts were screened for CLCN5 mutations: Chronic Kidney Disease in Children (CKiD; n = 112); Multicenter FSGS-Clinical Trial (FSGS-CT) (n = 96), and Novel Therapies for Resistant FSGS Trial (FONT) (n = 30). Urinary α-microglobulin (αM), albumin (A), total protein (TP), and creatinine (Cr) were assessed from CKiD subjects (n = 104); DD1 patients (n = 14); and DD1 carriers (DC; n = 8). TP/Cr, αM/Cr, αM/TP, and A/TP from the CKiD cohort were compared with DD1 and DC.

Results: No CLCN5 mutations were detected. TP/Cr was lower in DC and CKiD with tubulointerstitial disease than in DD1 and CKiD with glomerular disease (p < 0.002). αM/Cr was higher in DD1 than in CKiD and DC (p < 0.001). A/TP was lower in DD1, DC, and CKiD with tubulointerstitial disease and higher in CKiD with glomerular disease (p < 0.001). Thresholds for A/TP of ≤ 0.21 and αM/Cr of ≥ 120 mg/g (> 13.6 mg/mmol) creatinine were good screens for Dent disease.

Conclusions: CLCN5 mutations were not seen in screened CKiD/FSGS cohorts. In our study, a cutoff of TP/Cr > 600 mg/g (> 68 mg/mmol) and A/TP of < 0.3 had a high sensitivity and specificity to distinguish DD1 from both CKiD glomerular and tubulointerstitial cohorts. αM/Cr ≥ 120 mg/g (> 13.6 mg/mmol) had the highest sensitivity and specificity when differentiating DD1 and studied CKiD populations.
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http://dx.doi.org/10.1007/s00467-019-04210-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736764PMC
April 2020

Recent advances in the identification and management of inherited hyperoxalurias.

Urolithiasis 2019 Feb 10;47(1):79-89. Epub 2018 Dec 10.

Mayo Clinic, Rochester, MN, USA.

Primary hyperoxaluria (PH) is caused by genetic mutations resulting in oxalate overproduction leading to nephrolithiasis, nephrocalcinosis, extrarenal manifestations, chronic kidney disease, and end-stage renal disease. Advances in genetic testing techniques have improved our ability to efficiently and effectively obtain a definitive diagnosis of PH as well as easily screen at-risk family members. Similarly, advances in technologies related to intervening at the genetic and molecular level promise to change the way we treat patients with PH. In this review, we provide an update regarding the identification of underlying molecular and biochemical causes of inherited hyperoxalurias, clinical manifestations, and treatment strategies.
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http://dx.doi.org/10.1007/s00240-018-1093-3DOI Listing
February 2019

Hydroxyproline Metabolism and Oxalate Synthesis in Primary Hyperoxaluria.

J Am Soc Nephrol 2018 06 27;29(6):1615-1623. Epub 2018 Mar 27.

Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama;

Endogenous oxalate synthesis contributes to calcium oxalate stone disease and is markedly increased in the inherited primary hyperoxaluria (PH) disorders. The incomplete knowledge regarding oxalate synthesis complicates discovery of new treatments. Hydroxyproline (Hyp) metabolism results in the formation of oxalate and glycolate. However, the relative contribution of Hyp metabolism to endogenous oxalate and glycolate synthesis is not known. To define this contribution, we performed primed, continuous, intravenous infusions of the stable isotope [N,C]-Hyp in nine healthy subjects and 19 individuals with PH and quantified the levels of urinary C-oxalate and C-glycolate formed using ion chromatography coupled to mass detection. The total urinary oxalate-to-creatinine ratio during the infusion was 73.1, 70.8, 47.0, and 10.6 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3 and controls, respectively. Hyp metabolism accounted for 12.8, 32.9, and 14.8 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3, respectively, compared with 1.6 mg oxalate/g creatinine in controls. The contribution of Hyp to urinary oxalate was 15% in controls and 18%, 47%, and 33% in subjects with PH1, PH2, and PH3, respectively. The contribution of Hyp to urinary glycolate was 57% in controls, 30% in subjects with PH1, and <13% in subjects with PH2 or PH3. Hyp metabolism differs among PH types and is a major source of oxalate synthesis in individuals with PH2 and PH3. In patients with PH1, who have the highest urinary excretion of oxalate, the major sources of oxalate remain to be identified.
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http://dx.doi.org/10.1681/ASN.2017040390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054332PMC
June 2018

Invited response to recurrence of oxalate nephropathy after isolated kidney transplantation for primary hyperoxaluria type 2.

Am J Transplant 2018 02 15;18(2):527. Epub 2017 Dec 15.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.

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http://dx.doi.org/10.1111/ajt.14596DOI Listing
February 2018

Plasma oxalate in relation to eGFR in patients with primary hyperoxaluria, enteric hyperoxaluria and urinary stone disease.

Clin Biochem 2017 Dec 29;50(18):1014-1019. Epub 2017 Jul 29.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States. Electronic address:

Background: Since plasma oxalate (POx) concentrations increase at lower glomerular filtration rate (GFR) levels, even among those without enteric (EH) or primary hyperoxaluria (PH), the appropriate thresholds for considering a disorder of oxalate metabolism are poorly defined. The current study was completed to establish relationships between POx, GFR, and urine oxalate excretion (UOx) among patients with PH, EH, and routine urinary stone disease (USD).

Methods: The most recent POx measurement on all Mayo Clinic patients between 2005 and 2015 were electronically pulled from the Lab Information System together with the closest serum creatinine within 14days and 24h urine study within 60days. After exclusion of patients not in steady state at the time of blood draw, 270 patients were available for study. Records were reviewed for clinical diagnoses to categorize patients as PH, EH, or USD. Waste plasma for Pox was also obtained from controls without USD undergoing clinical GFR testing.

Results: In all 3 groups POx increased as eGFR fell. For any given eGFR, POx was highest in the PH group and lowest in the USD and control groups (p<0.0001). POx was also influenced by UOx excretion (reflecting total body oxalate burden, absorption from diet and endogenous production). Generalized estimating equations of POx vs eGFR revealed higher average POx levels in PH compared to EH,USD or control, and for EH compared to USD or control. GEE prediction models were created that use POx, UOx, age, and serum creatinine to estimate the probability of a PH diagnosis.

Conclusions: New models were developed to help interpret POx when considering PH in clinical practice even when it was not previously suspected and/or eGFR is reduced.
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http://dx.doi.org/10.1016/j.clinbiochem.2017.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705406PMC
December 2017

Knowledge as a Service at the Point of Care.

AMIA Annu Symp Proc 2016 10;2016:1139-1148. Epub 2017 Feb 10.

Office of Information and Knowledge Management, Mayo Clinic, Rochester, MN.

An electronic health record (EHR) can assist the delivery of high-quality patient care, in part by providing the capability for a broad range of clinical decision support, including contextual references (e.g., Infobuttons), alerts and reminders, order sets, and dashboards. All of these decision support tools are based on clinical knowledge; unfortunately, the mechanisms for managing rules, order sets, Infobuttons, and dashboards are often unrelated, making it difficult to coordinate the application of clinical knowledge to various components of the clinical workflow. Additional complexity is encountered when updating enterprise-wide knowledge bases and delivering the content through multiple modalities to different consumers. We present the experience of Mayo Clinic as a case study to examine the requirements and implementation challenges related to knowledge management across a large, multi-site medical center. The lessons learned through the development of our knowledge management and delivery platform will help inform the future development of interoperable knowledge resources.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333226PMC
August 2017

Knowledge management in the era of digital medicine: A programmatic approach to optimize patient care in an academic medical center.

Learn Health Syst 2017 Apr 13;1(2):e10022. Epub 2017 Feb 13.

Mayo Clinic College of Medicine Mayo Clinic Rochester Minnesota.

Introduction: The pace of medical discovery is accelerating to the point where caregivers can no longer keep up with the latest diagnosis or treatment recommendations. At the same time, sophisticated and complex electronic medical records and clinical systems are generating increasing volumes of patient data, making it difficult to find the important information required for patient care. To address these challenges, Mayo Clinic established a knowledge management program to curate, store, and disseminate clinical knowledge.

Methods: The authors describe AskMayoExpert, a point-of-care knowledge delivery system, and discuss the process by which the clinical knowledge is captured, vetted by clinicians, annotated, and stored in a knowledge content management system. The content generated for AskMayoExpert is considered to be core clinical content and serves as the basis for knowledge diffusion to clinicians through order sets and clinical decision support rules, as well as to patients and consumers through patient education materials and internet content. The authors evaluate alternative approaches for better integration of knowledge into the clinical workflow through development of computer-interpretable care process models.

Results: Each of the modeling approaches evaluated has shown promise. However, because each of them addresses the problem from a different perspective, there have been challenges in coming to a common model. Given the current state of guideline modeling and the need for a near-term solution, Mayo Clinic will likely focus on breaking down care process models into components and on standardization of those components, deferring, for now, the orchestration.

Conclusion: A point-of-care knowledge resource developed to support an individualized approach to patient care has grown into a formal knowledge management program. Translation of the textual knowledge into machine executable knowledge will allow integration of the knowledge with specific patient data and truly serve as a colleague and mentor for the physicians taking care of the patient.
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http://dx.doi.org/10.1002/lrh2.10022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508510PMC
April 2017

Effect of a Novel Clinical Decision Support Tool on the Efficiency and Accuracy of Treatment Recommendations for Cholesterol Management.

Appl Clin Inform 2017 Feb 8;8(1):124-136. Epub 2017 Feb 8.

Rajeev Chaudhry, MBBS,MPH, Associate Professor of Medicine, Division of Primary Care Internal Medicine, Knowledge and Delivery Center, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, TEL: (507) 255-3956,

Background: The 2013 American College of Cardiology / American Heart Association Guidelines for the Treatment of Blood Cholesterol emphasize treatment based on cardiovascular risk. But finding time in a primary care visit to manually calculate cardiovascular risk and prescribe treatment based on risk is challenging. We developed an informatics-based clinical decision support tool, MayoExpertAdvisor, to deliver automated cardiovascular risk scores and guideline-based treatment recommendations based on patient-specific data in the electronic heath record.

Objective: To assess the impact of our clinical decision support tool on the efficiency and accuracy of clinician calculation of cardiovascular risk and its effect on the delivery of guideline-consistent treatment recommendations.

Methods: Clinicians were asked to review the EHR records of selected patients. We evaluated the amount of time and the number of clicks and keystrokes needed to calculate cardiovascular risk and provide a treatment recommendation with and without our clinical decision support tool. We also compared the treatment recommendation arrived at by clinicians with and without the use of our tool to those recommended by the guidelines.

Results: Clinicians saved 3 minutes and 38 seconds in completing both tasks with MayoExpertAdvisor, used 94 fewer clicks and 23 fewer key strokes, and improved accuracy from the baseline of 60.61% to 100% for both the risk score calculation and guideline-consistent treatment recommendation.

Conclusion: Informatics solution can greatly improve the efficiency and accuracy of individualized treatment recommendations and have the potential to increase guideline compliance.
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http://dx.doi.org/10.4338/ACI-2016-07-RA-0114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373758PMC
February 2017

Silent Tyrosinemia Type I Without Elevated Tyrosine or Succinylacetone Associated with Liver Cirrhosis and Hepatocellular Carcinoma.

Hum Mutat 2016 10 8;37(10):1097-105. Epub 2016 Aug 8.

Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.

Tyrosinemia type I (TYRSN1, TYR I) is caused by fumarylacetoacetate hydrolase (FAH) deficiency and affects approximately one in 100,000 individuals worldwide. Pathogenic variants in FAH cause TYRSN1, which induces cirrhosis and can progress to hepatocellular carcinoma (HCC). TYRSN1 is characterized by the production of a pathognomonic metabolite, succinylacetone (SUAC) and is included in the Recommended Uniform Screening Panel for newborns. Treatment intervention is effective if initiated within the first month of life. Here, we describe a family with three affected children who developed HCC secondary to idiopathic hepatosplenomegaly and cirrhosis during infancy. Whole exome sequencing revealed a novel homozygous missense variant in FAH (Chr15(GRCh38):g.80162305A>G; NM_000137.2:c.424A > G; NP_000128.1:p.R142G). This novel variant involves the catalytic pocket of the enzyme, but does not result in increased SUAC or tyrosine, making the diagnosis of TYRSN1 problematic. Testing this novel variant using a rapid, in vivo somatic mouse model showed that this variant could not rescue FAH deficiency. In this case of atypical TYRSN1, we show how reliance on SUAC as a primary diagnostic test can be misleading in some patients with this disease. Augmentation of current screening for TYRSN1 with targeted sequencing of FAH is warranted in cases suggestive of the disorder.
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http://dx.doi.org/10.1002/humu.23047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5108417PMC
October 2016

Assessment of Urine Proteomics in Type 1 Primary Hyperoxaluria.

Am J Nephrol 2016 3;43(4):293-303. Epub 2016 May 3.

Feinberg School of Medicine, Northwestern University, Department of Pediatrics, Chicago, Ill., USA.

Background: Primary hyperoxaluria type 1 (PH1) and idiopathic hypercalciuria (IHC) are stone-forming diseases that may result in the formation of calcium (Ca) oxalate (Ox) stones, nephrocalcinosis, and progressive chronic kidney disease (CKD). Poorer clinical outcome in PH1 is segregated by the highest urine (Ur)-Ox (UrOx), while IHC outcomes are not predictable by UrCa. We hypothesized that differences would be found in selected Ur-protein (PRO) patterns in PH1 and IHC, compared to healthy intra-familial sibling controls (C) of PH1 patients. We also hypothesized that the PRO patterns associated with higher UrOx levels would reflect injury, inflammation, biomineralization, and abnormal tissue repair processes in PH1.

Methods: Twenty four-hour Ur samples were obtained from 3 cohorts: PH1 (n = 47); IHC (n = 35) and C (n = 13) and were analyzed using targeted platform-based multi-analyte profile immunoassays and for UrOx and UrCa by biochemical measurements.

Results: Known stone matrix constituents, osteopontin, calbindin, and vitronectin were lowest in PH1 (C > IHC > PH1; p < 0.05). Ur-interleukin-10; chromogranin A; epidermal growth factor (EGF); insulin-like growth factor-1 (IGF-1), and macrophage inflammatory PRO-1α (MIP-1α) were higher in PH1 > C (p = 0.03 to p < 0.05). Fetuin A; IGF-1, MIP-1α, and vascular cell adhesion molecule-1 were highest in PH1 > IHC (p < 0.001 to p = 0.005).

Conclusion: PH1 Ur-PROs reflected overt inflammation, chemotaxis, oxidative stress, growth factors (including EGF), and pro-angiogenic and calcification regulation/inhibition compared to the C and IHC cohorts. Many of the up- and downregulated PH1-PROs found in this study are also found in CKD, acute kidney injury, stone formers, and/or stone matrices. Further data analyses may provide evidence for PH1 unique PROs or demonstrate a poorer clinical outcome.
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http://dx.doi.org/10.1159/000445448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904731PMC
January 2018

siRNA Therapeutics for Primary Hyperoxaluria: A Beginning.

Authors:
Dawn S Milliner

Mol Ther 2016 Apr;24(4):666-7

Division of Nephrology, Departments of Pediatrics and Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.

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http://dx.doi.org/10.1038/mt.2016.50DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886951PMC
April 2016

Predictors of Incident ESRD among Patients with Primary Hyperoxaluria Presenting Prior to Kidney Failure.

Clin J Am Soc Nephrol 2016 Jan 10;11(1):119-26. Epub 2015 Dec 10.

Division of Nephrology and Hypertension, Division of Pediatric Nephrology, Mayo Clinic, Rochester, Minnesota

Background And Objectives: Overproduction of oxalate in patients with primary hyperoxaluria (PH) leads to calcium oxalate deposition in the kidney and ESRD in a substantial number of cases. However, the key determinants for renal outcome remain unclear. Thus, we performed a retrospective analysis to identify predictors for renal outcome among patients with PH participating in the Rare Kidney Stone Consortium (RKSC) PH Registry.

Design, Setting, Participants, & Measurements: We characterized clinical and laboratory features of patients enrolled in the RKSC PH Registry. We assessed correlation between urinary measures and eGFR at diagnosis by Spearman rank correlation and estimated renal survival using the Kaplan-Meier method. We determined factors associated with renal survival by Cox proportional hazard models.

Results: Of 409 patients enrolled in the RKSC Registry as of March 2014, we excluded 112 patients who had ESRD at PH diagnosis from analysis. Among the remaining 297 patients, 65% had PH type 1, 12% had type 2, 13% had type 3, and 11% had unclassified PH. Median (25th, 75th percentile) age at PH diagnosis was 8.1 (4.0, 18.2) years with an eGFR of 73.0 (56.4, 97.5) ml/min per 1.73 m(2) and urinary oxalate excretion rate of 1.64 (1.11, 2.44) mmol/1.73 m(2) per 24 hours. During a median follow-up of 3.9 (1.0, 12.8) years, 59 (20%) patients developed ESRD. Urinary oxalate excretion at diagnosis stratified by quartile was strongly associated with incident ESRD (hazard ratio [HR], 3.4; 95% confidence interval [95% CI], 1.4 to 7.9). During follow-up there was a significant association between urinary oxalate quartile (Q) and incident ESRD (Q4 versus Q1: HR, 3.3; 95% CI, 1.2 to 9.3). This association remained even when adjusted for sex, age, and baseline eGFR (HR, 4.2; 95% CI, 1.6 to 10.8).

Conclusions: Among patients with PH, higher urinary oxalate excretion is predictive of poor renal outcome.
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http://dx.doi.org/10.2215/CJN.02810315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702224PMC
January 2016

Surgical management of stone disease in patients with primary hyperoxaluria.

Urology 2015 Mar;85(3):522-6

Department of Urology, Mayo Clinic, Rochester, MN.. Electronic address:

Objective: To present our experience with surgical management of nephrolithiasis in patients with primary hyperoxaluria (PH).

Methods: A retrospective chart review from 1994 to 2012 was performed to identify patients with diagnosis of PH.

Results: A total of 14 patients with PH were identified with a median follow-up of 18.6 years (range, 0.9-51 years). Median ages at initial symptom and subsequent diagnosis were 6.7 years (range, 1.1-35.5 years) and 0.42 years (range, 0-33.25 years), respectively. Patients underwent a total of 54 procedures at our institution, including ureteroscopy (27 [50%]), percutaneous nephrolithotomy (15 [28%]), shock wave lithotripsy (8 [15%]), and combined procedures (4 [7%]). Overall nonintraparenchymal stone-free rate after the first, second, and third procedures were 59%, 76%, and 78%, respectively. On average, 1.6 procedures (range, 1-4) were required to rid patients of symptomatic stones, which subsequently afforded them a mean of 3.62 years (range, 0.25-21.5 years) without the need for additional intervention. There were 6 Clavien grade ≥III complications in 4 patients, including immediate postoperative end-stage renal disease in 3 patients.

Conclusion: Despite optimal medical and surgical management, patients experience recurrent acute stone events requiring multiple urologic interventions. Significant complications such as end-stage renal disease can occur secondary to surgical intervention.
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http://dx.doi.org/10.1016/j.urology.2014.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559267PMC
March 2015

Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria.

J Am Soc Nephrol 2015 Oct 2;26(10):2559-70. Epub 2015 Feb 2.

Division of Nephrology and Hypertension, Department of Biochemistry and Molecular Biology, and

Primary hyperoxaluria (PH) is a rare autosomal recessive disease characterized by oxalate accumulation in the kidneys and other organs. Three loci have been identified: AGXT (PH1), GRHPR (PH2), and HOGA1 (PH3). Here, we compared genotype to phenotype in 355 patients in the Rare Kidney Stone Consortium PH registry and calculated prevalence using publicly available whole-exome data. PH1 (68.4% of families) was the most severe PH type, whereas PH3 (11.0% of families) showed the slowest decline in renal function but the earliest symptoms. A group of patients with disease progression similar to that of PH3, but for whom no mutation was detected (11.3% of families), suggested further genetic heterogeneity. We confirmed that the AGXT p.G170R mistargeting allele resulted in a milder PH1 phenotype; however, other potential AGXT mistargeting alleles caused more severe (fully penetrant) disease. We identified the first PH3 patient with ESRD; a homozygote for two linked, novel missense mutations. Population analysis suggested that PH is an order of magnitude more common than determined from clinical cohorts (prevalence, approximately 1:58,000; carrier frequency, approximately 1:70). We estimated PH to be approximately three times less prevalent among African Americans than among European Americans because of a limited number of common European origin alleles. PH3 was predicted to be as prevalent as PH1 and twice as common as PH2, indicating that PH3 (and PH2) cases are underdiagnosed and/or incompletely penetrant. These results highlight a role for molecular analyses in PH diagnostics and prognostics and suggest that wider analysis of the idiopathic stone-forming population may be beneficial.
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http://dx.doi.org/10.1681/ASN.2014070698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587693PMC
October 2015

Progressive polyradiculoneuropathy due to intraneural oxalate deposition in type 1 primary hyperoxaluria.

Muscle Nerve 2015 Mar 16;51(3):449-54. Epub 2015 Jan 16.

Peripheral Neuropathy Laboratory, Department of Neurology, Mayo Clinic and Mayo Foundation, 200 First Street SW, Rochester, Minnesota, 55905, USA.

Introduction: A 24-year-old man with primary hyperoxaluria type 1 (PH1) presented with a rapidly progressive axonal and demyelinating sensorimotor polyradiculoneuropathy shortly after the onset of end-stage renal disease. His plasma oxalate level was markedly elevated at 107 µmol/L (normal<1.8 µmol/L).

Methods: A sural nerve biopsy was performed. Teased fiber and paraffin and epoxy sections were done and morphometric procedures were performed on this sample and on an archived sample from a 22-year-old man as an age- and gender-matched control. Embedded teased fiber electron microscopy was also performed.

Results: The biopsy revealed secondary demyelination and axonal degeneration. Under polarized light, multiple bright hexagonal, rectangular, and starburst inclusions, typical of calcium oxalate monohydrate crystals, were seen.

Conclusions: The proposed mechanisms of nerve damage include disruption of axonal transport due to crystal deposition, toxic effect of oxalate, or nerve ischemia related to vessel occlusion from oxalate crystal deposition.
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http://dx.doi.org/10.1002/mus.24495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4577279PMC
March 2015

Kidney stones are common after bariatric surgery.

Kidney Int 2015 Apr 29;87(4):839-45. Epub 2014 Oct 29.

Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA.

Obesity, a risk factor for kidney stones and chronic kidney disease (CKD), is effectively treated with bariatric surgery. However, it is unclear whether surgery alters stone or CKD risk. To determine this we studied 762 Olmsted County, Minnesota residents who underwent bariatric surgery and matched them with equally obese control individuals who did not undergo surgery. The majority of bariatric patients underwent standard Roux-en-Y gastric bypass (RYGB; 78%), with the remainder having more malabsorptive procedures (very long limb RYGB or biliopancreatic diversion/duodenal switch; 14%) or restrictive procedures (laparoscopic banding or sleeve gastrectomy; 7%). The mean age was 45 years with 80% being female. The mean preoperative body mass index (BMI) was 46.7 kg/m(2) for both cohorts. Rates of kidney stones were similar between surgery patients and controls at baseline, but new stone formation significantly increased in surgery patients (11.0%) compared with controls (4.3%) during 6.0 years of follow-up. After malabsorptive and standard surgery, the comorbidity-adjusted hazard ratio of incident stones was significantly increased to 4.15 and 2.13, respectively, but was not significantly changed for restrictive surgery. The risk of CKD significantly increased after the malabsorptive procedures (adjusted hazard ratio of 1.96). Thus, while RYGB and malabsorptive procedures are more effective for weight loss, both are associated with increased risk of stones, while malabsorptive procedures also increase CKD risk.
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http://dx.doi.org/10.1038/ki.2014.352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382441PMC
April 2015