Article Predictors of Incident ESRD Among Patients with Primary Hyperoxaluria Presenting Prior to Kidney Failure
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Article Predictors of Incident ESRD among Patients with Primary Hyperoxaluria Presenting Prior to Kidney Failure Fang Zhao,* Eric J. Bergstralh,† Ramila A. Mehta,† Lisa E. Vaughan,† Julie B. Olson,* Barbara M. Seide,* Alicia M. Meek,* Andrea G. Cogal,* John C. Lieske,*‡ and Dawn S. Milliner*§ on behalf of the Investigators of the Rare Kidney Stone Consortium Abstract *Division of Nephrology and Background and objectives Overproduction of oxalate in patients with primary hyperoxaluria (PH) leads to Hypertension, calcium oxalate deposition in the kidney and ESRD in a substantial number of cases. However, the key †Division of determinants for renal outcome remain unclear. Thus, we performed a retrospective analysis to identify Biostatistics, ‡ predictors for renal outcome among patients with PH participating in the Rare Kidney Stone Consortium (RKSC) Department of Laboratory Medicine PH Registry. and Pathology, and §Division of Pediatric Design, setting, participants, & measurements We characterized clinical and laboratory features of patients Nephrology, Mayo enrolled in the RKSC PH Registry. We assessed correlation between urinary measures and eGFR at diagnosis by Clinic, Rochester, Spearman rank correlation and estimated renal survival using the Kaplan–Meier method. We determined factors Minnesota associated with renal survival by Cox proportional hazard models. Correspondence: Dr. Dawn S. Milliner, Results Of 409 patients enrolled in the RKSC Registry as of March 2014, we excluded 112 patients who had ESRD Division of at PH diagnosis from analysis. Among the remaining 297 patients, 65% had PH type 1, 12% had type 2, 13% had Nephrology and type 3, and 11% had unclassified PH. Median (25th, 75th percentile) age at PH diagnosis was 8.1 (4.0, 18.2) years Hypertension, Mayo with an eGFR of 73.0 (56.4, 97.5) ml/min per 1.73 m2 and urinary oxalate excretion rate of 1.64 (1.11, 2.44) mmol/ Clinic, 200 First Street SW, Rochester, MN 2 1.73 m per 24 hours. During a median follow-up of 3.9 (1.0, 12.8) years, 59 (20%) patients developed ESRD. 55905. Email: Urinary oxalate excretion at diagnosis stratified by quartile was strongly associated with incident ESRD (hazard milliner.dawn@mayo. ratio [HR], 3.4; 95% confidence interval [95% CI], 1.4 to 7.9). During follow-up there was a significant association edu between urinary oxalate quartile (Q) and incident ESRD (Q4 versus Q1: HR, 3.3; 95% CI, 1.2 to 9.3). This asso- ciation 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. Clin J Am Soc Nephrol 11: 119–126, 2016. doi: 10.2215/CJN.02810315 Introduction (normal ,0.5 mmol [,45 mg]/1.73 m2 per 24 hours; The primary hyperoxalurias (PHs) are autosomal conversion factor for oxalate: 1 mmol=88 mg) (5), recessive disorders characterized by enzymatic de- which results in calcium oxalate (CaOx) supersatura- fects in glyoxylate metabolism, which ultimately re- tion in the urine and subsequent urolithiasis and/or sult in overproduction of oxalate (1–4). Three types of nephrocalcinosis. Progressive crystal deposition, ac- PH have been identified: primary hyperoxaluria type companied by parenchymal inflammation and fibro- 1 (PH1) is caused by a deficiency of the liver-specific sis, may eventually progress to ESRD (6). peroxisomal enzyme alanine-glyoxylate aminotrans- Clinical manifestations of PH are heterogenous with ferase (AGT), which is encoded by the AGXT gene; respect to age at onset, type of presentation, severity primary hyperoxaluria type 2 (PH2) is secondary to of hyperoxaluria, and rate of progression to renal glyoxylate reductase/hydroxypyruvate reductase insufficiency (7). PH1 outcome appears, in part, to be (GRHPR) deficiency and caused by mutations in the associated with genotype, with the pGly170Arg mu- GRHPR gene; and primary hyperoxaluria type 3 tation in particular associated with better renal sur- (PH3) is caused by mutations in the HOGA1 gene, vival (8,9). Nevertheless, patients with the same which encodes the mitochondrial 4-hydroxy-2-oxo- genotype can present with very disparate symptoms glutarate aldolase (HOGA) enzyme. Humans cannot and disease course (10). Therefore, factors that deter- degrade oxalate, and it is primarily eliminated by the mine renal outcome remain incompletely defined. kidneys. Hence, endogenous overproduction leads to The Rare Kidney Stone Consortium (RKSC) PH substantial elevations in urinary oxalate excretion, Registry was developed in 2002 to advance under- typically .1mmol(.88 mg)/1.73 m2 per 24 hours standing of the natural history of PH and to elucidate www.cjasn.org Vol 11 January, 2016 Copyright © 2016 by the American Society of Nephrology 119 120 Clinical Journal of the American Society of Nephrology factors that influence outcomes (11). In the current study dialysis or renal transplantation. A cohort of nonstone- we used the RKSC PH Registry to evaluate PH type and forming adults in good general health without any kidney the effect of urinary constituents that influence CaOx crys- disease or diabetes (52 women and 49 men; age 18–83 tal formation (oxalate, calcium, citrate, phosphorus, vol- years) who completed 24-hour urine collections on a ume) on renal outcomes and determine whether there free-choice diet were used for a reference range popula- are cut points that stratify risk. tion. Materials and Methods Statistical Analyses Study Population Results were expressed in terms of the median (25th, 75th Clinical and laboratory information were collected from percentiles) for continuous variables and as percentages for patients with PH enrolled in the RKSC PH registry (11). The categorical variables. Spearman rank correlation was used first patient was enrolled in 2003. As of March 2014, 13 to analyze correlations between baseline clinical and patients had died. Total person-years of follow-up was laboratory variables and eGFR at diagnosis. To maximize 2483. General information and clinical manifestations available data, the diagnosis reading was defined as the were abstracted from registry data. Symptoms included closest reading within 3 years before PH diagnosis and up stone-related pain, stone passage, hematuria, or failure to to 60 days after diagnosis. thrive. PH1 was confirmed by mutations of the AGXT The percentage of patients who were free of renal failure gene, liver biopsy confirming deficiency of AGT, or by after PH diagnosis was estimated using the Kaplan–Meier marked hyperoxaluria in combination with hyperglycolic method. Factors associated with renal survival were esti- aciduria in a patient with no identifiable secondary causes. mated by univariate analyses using the Cox proportional PH2 was established by mutations of GRHPR, liver biopsy hazard model with log-rank tests and trend tests used for confirming deficiency of GRHPR enzyme, or hyperoxalu- comparison between subgroups. The outcome of interest ria in combination with hyperglyceric aciduria without was time to ESRD and was censored on death or loss to identifiable secondary cause. PH3 was diagnosed by mu- follow-up. To display the effect of quantitative factors on tations of HOGA1. Patients considered to have PH of un- ESRD, data were split into four groups based on quartiles classified type met the same clinical criteria as those with of urine oxalate. Hazard ratios (HRs) and 95% confidence other types; had no identifiable enteric hyperoxaluria; and intervals (95% CIs) were presented. We further used a were negative on testing for mutations of AGXT, GRHPR, time-dependent Cox model to explore the effect of urinary and HOGA1. oxalate excretion level on renal outcome during follow-up. Laboratory results, including 24-hour urine volume, Oxalate was first evaluated as a continuous factor and oxalate, calcium, citrate, and phosphorus and serum then as quartiles derived from all follow-up readings. creatinine, were extracted from registry data. All 24-hour Times to ESRD by oxalate quartile were estimated by di- urine values were from baseline (0–60 days after diagnosis) viding individual-patient follow-up time into intervals or during follow-up (.60 days until last available before based on the quartile of latest oxalate reading and noting ESRD). Renal function was assessed by serum creatinine whether the interval ended in ESRD. Person-time and values to estimate GFR using the Schwartz formula (12) in ESRD events were summed within oxalate quartiles with children ,18 years and the Modification of Diet in Renal the rate=1003(events/person-time). P values ,0.05 were Disease formula (13) in adults. ESRD or renal failure was considered to indicate statistically significant differences. definedasaneGFR,15 ml/min per 1.73 m2 or start of All calculations were done using SAS software, version 9. Table 1. Clinical characteristics of patients with primary hyperoxaluria who had or did not have ESRD at or before diagnosis Characteristics Without ESRD (n=297) With ESRD (n=112) P Value Type of PH, % (n) ,0.001 PH1 64.6 (192) 93.8 (105) PH2 11.8 (35) 3.6 (4) PH3 12.8 (38) 0 (0) Unclassified 10.8 (32) 2.7 (3) Sex, % (n) 0.05 Female 42.8 (127) 53.6 (60) Male 57.2 (170) 46.4 (52) Median age, y At diagnosis 8.1 (4.0, 18.2) 25.3 (6.8, 42.0) ,0.001 At symptom onset 4.5 (1.7, 11.3) 9.4 (2.0, 21.6) 0.02 Median time between initial 1.4 (0.1, 7.5) 3.5 (0.3, 21.0) ,0.001 symptoms and diagnosis, y Median eGFR, ml/min per 1.73 m2 73.0 (56.4, 97.5) 6.6 (3.9, 13.8) ,0.001 Median values are expressed with 25th, 75th percentiles. PH, primary hyperoxaluria; PH1, primary hyperoxaluria type 1; PH2, primary hyperoxaluria type 2; PH3, primary hyperoxaluria type 3. Clin J Am Soc Nephrol 11: 119–126, January, 2016 Predictors of Incident ESRD in Primary Hyperoxaluria, Zhao et al.