Natural history of urine and plasma oxalate in children with primary hyperoxaluria type 1.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is a rare, severe genetic disease causing increased hepatic oxalate production resulting in urinary stone disease, nephrocalcinosis, and often progressive chronic kidney disease. Little is known about the natural history of urine and plasma oxalate values over time in children with PH1. METHODS: For this retrospective observational study, we analyzed data from genetically confirmed PH1 patients enrolled in the Rare Kidney Stone Consortium PH Registry between 2003 and 2018 who had at least 2 measurements before age 18 years of urine oxalate-to-creatinine ratio (Uox:cr), 24-h urine oxalate excretion normalized to body surface area (24-h Uox), or plasma oxalate concentration (Pox). We compared values among 3 groups: homozygous G170R, heterozygous G170R, and non-G170R AGXT variants both before and after initiating pyridoxine (B6). RESULTS: Of 403 patients with PH1 in the registry, 83 met the inclusion criteria. Uox:cr decreased rapidly over the first 5 years of life. Both before and after B6 initiation, patients with non-G170R had the highest Uox:cr, 24-h Uox, and Pox. Patients with heterozygous G170R had similar Uox:cr to homozygous G170R prior to B6. Patients with homozygous G170R had the lowest 24-h Uox and Uox:cr after B6. Urinary oxalate excretion and Pox tend to decrease over time during childhood. eGFR over time was not different among groups. CONCLUSIONS: Children with PH1 under 5 years old have relatively higher urinary oxalate excretion which may put them at greater risk for nephrocalcinosis and kidney failure than older PH1 patients. Those with homozygous G170R variants may have milder disease. A higher resolution version of the Graphical abstract is available as Supplementary information.

Clinical characterization of primary hyperoxaluria type 3 in comparison with types 1 and 2.

BACKGROUND: Primary hyperoxaluria (PH) type 3 (PH3) is caused by mutations in the hydroxy-oxo-glutarate aldolase 1 gene. PH3 patients often present with recurrent urinary stone disease in the first decade of life, but prior reports suggested PH3 may have a milder phenotype in adults. This study characterized clinical manifestations of PH3 across the decades of life in comparison with PH1 and PH2. METHODS: Clinical information was obtained from the Rare Kidney Stone Consortium PH Registry (PH1, n = 384; PH2, n = 51; PH3, n = 62). RESULTS: PH3 patients presented with symptoms at a median of 2.7 years old compared with PH1 (4.9 years) and PH2 (5.7 years) (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 with PH1 and PH2 (1.1 versus 1.6 and 1.5 mmol/day/1.73 m2, respectively, P < 0.001) while urine calcium was highest in PH3 (112 versus 51 and 98 mg/day/1.73 m2 in PH1 and PH2, respectively, P < 0.001). Stone events per decade of life were similar across the age span and the three PH types. At 40 years of age, 97% of PH3 patients had not progressed to end-stage kidney disease compared with 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.

Comprehensive Genetic Analysis Reveals Complexity of Monogenic Urinary Stone Disease.

INTRODUCTION: Because of phenotypic overlap between monogenic urinary stone diseases (USD), gene-specific analyses can result in missed diagnoses. We used targeted next generation sequencing (tNGS), including known and candidate monogenic USD genes, to analyze suspected primary hyperoxaluria (PH) or Dent disease (DD) patients genetically unresolved (negative; N) after Sanger analysis of the known genes. Cohorts consisted of 285 PH (PHN) and 59 DD (DDN) families. METHODS: Variants were assessed using disease-specific and population databases plus variant assessment tools and categorized using the American College of Medical Genetics (ACMG) guidelines. Prior Sanger analysis identified 47 novel PH or DD gene pathogenic variants. RESULTS: Screening by tNGS revealed pathogenic variants in 14 known monogenic USD genes, accounting for 45 families (13.1%), 27 biallelic and 18 monoallelic, including 1 family with a copy number variant (CNV). Recurrent genes included the following: SLC34A3 (n = 13), CLDN16 (n = 8), CYP24A1 (n = 4), SLC34A1 (n = 3), SLC4A1 (n = 3), APRT (n = 2), CLDN19 (n = 2), HNF4A1 (n = 2), and KCNJ1 (n = 2), whereas ATP6V1B1, CASR, and SLC12A1 and missed CNVs in the PH genes AGXT and GRHPR accounted for 1 pedigree each. Of the 48 defined pathogenic variants, 27.1% were truncating and 39.6% were novel. Most patients were diagnosed before 18 years of age (76.1%), and 70.3% of biallelic patients were homozygous, mainly from consanguineous families. CONCLUSION: Overall, in patients suspected of DD or PH, 23.9% and 7.3% of cases, respectively, were caused by pathogenic variants in other genes. This study shows the value of a tNGS screening approach to increase the diagnosis of monogenic USD, which can optimize therapies and facilitate enrollment in clinical trials.

Natural History of Clinical, Laboratory, and Echocardiographic Parameters of a Primary Hyperoxaluria Cohort on Long Term Hemodialysis.

Background: Primary hyperoxaluria type 1 (PH1) is a rare monogenic disorder characterized by excessive hepatic production of oxalate leading to recurrent nephrolithiasis, nephrocalcinosis, and progressive kidney damage, often requiring renal replacement therapy (RRT). Though systemic oxalate deposition is well-known, the natural history of PH1 during RRT has not been systematically described. In this study, we describe the clinical, laboratory, and echocardiographic features of a cohort of PH1 patients on RRT. Methods: Patients with PH1 enrolled in the Rare Kidney Stone Consortium PH Registry who progressed to require RRT, had ≥2 plasma oxalate (pOx) measurements 3-36 months after start of RRT, and at least one pair of pOx measurements between 6 and 18 months apart were retrospectively analyzed. Clinical, echocardiographic, and laboratory results were obtained from the Registry. Results: The 17 PH1 patients in our cohort had a mean total HD hours/week of 17.4 (SD 7.9; range 7.5-36) and a range of age of RRT start of 0.2-75.9 years. The average change in plasma oxalate (pOx) over time on RRT was -0.74 [-2.9, 1.4] µmol/L/month with the mean pOx never declining below 50 µmol/L. Over time on RRT, oxalosis progressively developed in multiple organ systems. Echocardiography performed on 13 subjects showed worsening of left ventricular global longitudinal strain correlated with pOx (p < 0.05). Conclusions: Even when a cohort of PH1 patients were treated with intensified RRT, their predialysis pOx remained above target and they developed increasing evidence of oxalosis. Echocardiographic data suggest that cardiac dysfunction could be related to elevated pOx and may worsen over time.

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

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/1.73m2, 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.

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

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.

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

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.

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

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.

Primary hyperoxaluria type III gene HOGA1 (formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis.

BACKGROUND AND OBJECTIVES: Primary hyperoxaluria types I and II (PHI and PHII) are rare monogenic causes of hyperoxaluria and calcium oxalate urolithiasis. Recently, we described type III, due to mutations in HOGA1 (formerly DHDPSL), hypothesized to cause a gain of mitochondrial 4-hydroxy-2-oxoglutarate aldolase activity, resulting in excess oxalate. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: To further explore the pathophysiology of HOGA1, we screened additional non-PHI-PHII patients and performed reverse transcription PCR analysis. Postulating that HOGA1 may influence urine oxalate, we also screened 100 idiopathic calcium oxalate stone formers. RESULTS: Of 28 unrelated hyperoxaluric patients with marked hyperoxaluria not due to PHI, PHII, or any identifiable secondary cause, we identified 10 (36%) with two HOGA1 mutations (four novel, including a nonsense variant). Reverse transcription PCR of the stop codon and two common mutations showed stable expression. From the new and our previously described PHIII cohort, 25 patients were identified for study. Urine oxalate was lower and urine calcium and uric acid were higher when compared with PHI and PHII. After 7.2 years median follow-up, mean eGFR was 116 ml/min per 1.73 m(2). HOGA1 heterozygosity was found in two patients with mild hyperoxaluria and in three of 100 idiopathic calcium oxalate stone formers. No HOGA1 variants were detected in 166 controls. CONCLUSIONS: These findings, in the context of autosomal recessive inheritance for PHIII, support a loss-of-function mechanism for HOGA1, with potential for a dominant-negative effect. Detection of HOGA1 variants in idiopathic calcium oxalate urolithiasis also suggests HOGA1 may be a predisposing factor for this condition.

Relation of bowel habits to fecal incontinence in women.

BACKGROUND: Though most women with fecal incontinence (FI) have anorectal dysfunctions, a majority have intermittent symptoms. Variations in bowel habits and daily routine may partly explain this. AIM: To compare bowel habits and daily routine between controls and FI, and between continent and incontinent stools among women with FI. METHOD: Using a mailed questionnaire, we identified 507 women with FI among 5,300 women in Olmsted County, MN. Bowel habits were compared among 127 randomly selected controls and 154 women with self-reported FI, who did ("active" FI, N = 106) or did not ("inactive" FI, N = 48) have an incontinent episode during a 2-wk bowel diary period. RESULTS: Independent risk factors for FI were: rectal urgency (odds ratio [OR] for inactive FI vs controls 5.6, 95% confidence interval [CI] 2.3-13.3; and OR for active FI vs inactive FI 2.0, 95% CI 0.9-4.3) and a sense of incomplete evacuation (OR for inactive FI vs controls 3.5, 95% CI 1.4-8.8; and OR for active FI vs inactive FI 2.2, 95% CI 1.1-4.9). Similar results were found for stool frequency and form. Among incontinent women, incontinent stools (versus continent stools) were less formed, more likely to occur at work, and to be preceded by rectal urgency. CONCLUSIONS: Bowel patterns, rectal urgency, and daily routine influence the occurrence of FI. Stool characteristics explained 46% of the likelihood for incontinence episodes, emphasizing that anorectal sensorimotor dysfunctions must also contribute to FI in women.

Insights into normal and disordered bowel habits from bowel diaries.

BACKGROUND: While symptom questionnaires provide a snapshot of bowel habits, they may not reflect day-to-day variations or the relationship between bowel symptoms and stool form. AIM: To assess bowel habits by daily diaries in women with and without functional bowel disorders. METHOD: From a community-based survey among Olmsted County, MN, women, 278 randomly selected subjects were interviewed by a gastroenterologist, who completed a bowel symptom questionnaire. Subjects also maintained bowel diaries for 2 wk. RESULTS: Among 278 subjects, questionnaires revealed diarrhea (26%), constipation (21%), or neither (53%). Asymptomatic subjects reported bowel symptoms (e.g., urgency) infrequently (i.e., <25% of the time) and generally for hard or loose stools. Urgency for soft, formed stools (i.e., Bristol form = 4) was more prevalent in subjects with diarrhea (31%) and constipation (27%) than in normals (16%). Stool form, straining to begin (odds ratio [OR] 4.1, 95% confidence interval [CI] 1.7-10.2) and end (OR 4.7, 95% CI 1.6-15.2) defecation increased the odds for constipation. Straining to end defecation (OR 3.7, 95% CI 1.2-12.0), increased stool frequency (OR 1.9, 95% CI 1.02-3.7), incomplete evacuation (OR 2.2, 95% CI 1.04-4.6), and rectal urgency (OR 3.1, 95% CI 1.4-6.6) increased the odds for diarrhea. In contrast, variations in stool frequency and form were not useful for discriminating between health and disease. CONCLUSIONS: Bowel symptoms occur in association with, but are only partly explained by, stool form disturbances. These observations support a role for other pathophysiological mechanisms in functional bowel disorders.

Risk factors for fecal incontinence: a population-based study in women.

BACKGROUND: In women with "idiopathic" fecal incontinence (FI), consensus guidelines recommend anal sphincter imaging and surgical repair, when feasible, of anal sphincter defects believed to cause FI. However, the relative contributions of obstetric trauma and bowel symptoms to FI in the community are unknown. METHODS: To assess risk factors for FI during the past year, a previously validated questionnaire was mailed to an age-stratified random sample of 5,300 women residing in Olmsted County, Minnesota. RESULTS: Altogether, 2,800 women (53%) responded. The risk of fecal incontinence increased with age (odds ratio [OR] per decade 1.3, 95% CI 1.2-1.4). The risk of fecal incontinence was higher among women with rectal urgency (OR 8.3, 95% CI 4.8-14.3) whether or not they also had other bowel disturbances (i.e., constipation, diarrhea, or abdominal pain) or had a vaginal delivery with forceps or stitches (OR 9.0, 95% CI 5.6-14.4). Among women with FI, rectal urgency and age were also risk factors for symptom severity. In contrast, obstetric risk factors for anorectal trauma did not increase the risk for FI. The risk for FI was not significantly different among women with cesarean section, vaginal delivery with or without forceps or stitches, or anorectal surgery, compared with nulliparous women without any of these risk factors. CONCLUSIONS: Rectal urgency rather than obstetric injury is the main risk factor for FI in women. These observations reinforce the importance of behavioral, dietary, and pharmacological measures to ameliorate bowel disturbances before anal imaging in women with "idiopathic" FI.

Differences between painless and painful constipation among community women.

BACKGROUND: In the Rome II criteria, patients with both constipation and abdominal pain (AP) (i.e., "painful constipation" (PC)), who do not satisfy criteria for irritable bowel syndrome (IBS) are included in the same functional constipation (FC) category as patients with constipation without AP (i.e., "painless constipation" (PLC)). What differences, if any, exist between FC without (i.e., PLC) and with AP (i.e., PC) are unclear. METHODS: To compare clinical features among PLC, PC, constipation-predominant IBS (C-IBS), and non-C-IBS, a validated questionnaire was mailed (with telephone follow-up of nonresponders) to an age-stratified random sample of 5,200 adult women in Olmsted County, Minnesota. RESULTS: Altogether, 2,800 women (53%) responded. The age-adjusted prevalence of PLC (7.1 per 100; 95% confidence interval (95% CI), 6.2-8.0) was higher compared to PC (0.9 per 100; 95% CI, 0.6-1.2). Compared to PLC, patients with PC reported worse general health (i.e., excellent or very good = 37.5% vs 51.2%), more somatic symptoms (mean score = 1.3 vs 0.9), and urinary urgency (% often = 58% vs 32%), and had a higher prevalence of hysterectomy. Bowel symptoms significantly impacted > or =1 domain of quality of life (QOL) in 18% of PC versus 9% of PLC. In a logistic discriminant model, age, general health, impact of bowel symptoms on QOL, somatic symptoms, and urinary urgency independently discriminated between bowel subtypes. CONCLUSIONS: Patients with PC more closely resemble those with C-IBS than PLC. Consideration should be given to separating PC from PLC in the Rome criteria and in therapeutic trials.

Comparison of rectoanal axial forces in health and functional defecatory disorders.

Anal manometry measures circumferential pressures but not axial forces that are responsible for defecation and contribute to fecal continence. Our aims were to investigate these mechanisms by measuring axial rectoanal forces with an intrarectal sphere or a latex balloon fixed at 8, 6, or 4 cm from the anal verge and connected to axial force and displacement transducers. Rectoanal forces and rectal pressures within a latex balloon were measured at baseline (i.e., at rest) and during maneuvers (i.e., squeeze, simulated evacuation, and a Valsalva maneuver) in 12 asymptomatic women and 12 women with symptoms of difficult defecation. Anal resting and squeeze pressures were also assessed by manometry and were similar in control patients and experimental patients. At rest, axial rectoanal forces were directed inward and increased as the device approached the anal verge. Control patients augmented this inward force when they squeezed and exerted an outward force during simulated expulsion and a Valsalva maneuver. The force change during maneuvers was also affected by device location and was highest at 4 cm from the verge. In experimental patients, the force at rest and the change in force during all maneuvers was lower than in control patients. The rectal pressure during a Valsalva maneuver was also lower in experimental patients than in control patients, suggestive of impaired propulsion. In conclusion, a subset of women with defecatory symptoms had weaker axial forces not only during expulsion but also during a Valsalva maneuver and when they squeezed (i.e., contracted) their pelvic floor muscles, suggestive of generalized pelvic floor weakness.

Prevalence and burden of fecal incontinence: a population-based study in women.

BACKGROUND & AIMS: The epidemiology of fecal incontinence (FI) is incompletely understood. We report the prevalence, clinical spectrum, health care-seeking behavior, and quality of life (QOL) in community women with FI. METHODS: A questionnaire was mailed to an age-stratified random sample of 5300 Olmsted County, Minnesota, women identified by the Rochester Epidemiology Project. Symptom severity was assessed by a validated scale, and impact on QOL was evaluated for subjects who had any FI during the past year. The prevalence of FI was calculated with direct age adjustment to the 2000 US white female population. RESULTS: Altogether, 2800 of 5300 women (53%) responded to the survey. The overall age-adjusted prevalence of FI in the past year was 12.1 per 100 (95% confidence interval, 11.0-13.1). The prevalence increased with age from 7 (third decade) to 22 (sixth decade) per 100 and was steady thereafter. Symptoms were mild (45%), moderate (50%), or severe (5%), and symptom severity was related to the impact of FI on QOL and physician-consulting behavior. Moderate to severe impact on >/=1 domain of QOL was reported by 6% with mild, 35% with moderate, and 82% with severe symptoms, whereas 5% with mild, 10% with moderate, and 48% with severe FI had consulted a physician for FI in the past year. CONCLUSIONS: More than 1 of 10 adult women in the population have FI; almost 1 of 15 have moderate to severe FI. FI significantly impacts QOL and prompts health care utilization predominantly in women with moderate to severe symptoms.