Original Investigation Serum Phosphorus and Progression of CKD and Mortality: A Meta-analysis of Cohort Studies Jingjing Da, MD,1,2,* Xinfang Xie, MD,1,* Myles Wolf, MD,3 Sinee Disthabanchong, MD,4 Jinwei Wang, PhD,1 Yan Zha, MD,2 Jicheng Lv, MD,1 Luxia Zhang, MD, MPH,1 and Haiyan Wang, MD1,y Background: Recent studies have indicated that phosphorus may play an independent pathogenic role in chronic kidney disease (CKD) progression, but some of those studies were underpowered and yielded inconsistent results. Study Design: Systematic review and meta-analysis. Setting & Population: Non–dialysis-dependent patients with CKD (transplant recipients were excluded). Selection Criteria for Studies: Studies assessing the risk ratio of serum phosphorus level on kidney failure and mortality for non–dialysis-dependent patients with CKD published from January 1950 to June 2014 were included following systematic searching of MEDLINE, EMBASE, and the Cochrane Library. Predictor: Serum phosphorus level. Outcome: Kidney failure, defined as doubled serum creatinine level, 50% decline in estimated glomerular filtration rate, or end-stage kidney disease. Results: In 12 cohort studies with 25,546 patients, 1,442 (8.8%) developed kidney failure and 3,089 (13.6%) died. Overall, every 1-mg/dL increase in serum phosphorus level was associated independently with increased risk of kidney failure (hazard ratio, 1.36; 95% CI, 1.20-1.55) and mortality (hazard ratio, 1.20; 95% CI, 1.05-1.37). Limitations: Existence of potential residual confounding could not be excluded. Conclusions: This meta-analysis suggests an independent association between serum phosphorus level and kidney failure and mortality among non–dialysis-dependent patients with CKD and suggests that largescale randomized controlled trials should target disordered phosphorus homeostasis in CKD. Am J Kidney Dis. -(-):---. ª 2015 by the National Kidney Foundation, Inc. INDEX WORDS: Serum phosphorus; phosphorus homeostasis; kidney failure; renal outcome; mortality; chronic kidney disease (CKD); non–dialysis-dependent CKD; disease progression; disease trajectory; prognosis; meta-analysis.
C
hronic kidney disease (CKD) is a major public health problem worldwide, affecting 8% to 16% of the adult population.1 Early recognition2 and intervention against factors involved in the progression of CKD are key to improving outcomes of patients at risk. Unfortunately, progression of CKD varies substantially,3,4 while factors contributing to this heterogeneity are not fully understood. Besides well-established risk factors, including high blood pressure and proteinuria, accumulating evidence indicates an important role for serum phosphorus.5 Abnormal phosphorus homeostasis is a hallmark of CKD. Serum phosphorus level is used as a biomarker From the 1Renal Division, Department of Medicine, Peking University First Hospital; Peking University Institute of Nephrology; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China; 2Renal Division, Department of Medicine, Guizhou Provincial People’s Hospital; Guizhou Provincial Institute of Nephritic & Urinary Disease, Guiyang, Guizhou; 3Division of Nephrology and Hypertension, Department of Medicine, Division of Biostatistics, Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, Miami, FL; and 4Division of Nephrology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. Am J Kidney Dis. 2015;-(-):---
for phosphorus homeostasis and has been reported to be an important risk factor for both all-cause and cardiovascular mortality in individuals with CKD.6 Recent studies indicated that phosphorus also may play an independent pathogenic role in CKD progression,7 but some studies were underpowered and yielded inconsistent results.8 Furthermore, it is not clear whether a dose-response relationship exists in the association between phosphorus level and kidney disease outcomes, as is seen in the phosphorusmortality link. We therefore conducted a systematic review and meta-analysis of the effects of serum phosphorus level *
J.D. and X.X. contributed equally to this work. Deceased. Received May 23, 2014. Accepted in revised form January 4, 2015. Address correspondence to Luxia Zhang, MD, MPH, Renal Division, Peking University First Hospital, No. 8, Xishiku St, Xicheng District, Beijing China (e-mail: [email protected]) or Jicheng Lv, MD, Renal Division, Peking University First Hospital, 8, Xishiku St, Xicheng District, Beijing, China (e-mail: [email protected]). 2015 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2015.01.009 y
1
Da et al
on progression of CKD and all-cause mortality among non–dialysis-dependent patients with CKD.
METHODS Search Strategy and Selection Criteria We undertook a systematic review of the literature according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines.9 Relevant studies were identified by searching the following data sources: MEDLINE (Ovid; from January 1950 to June 2014), EMBASE (from January 1970 to June 2014), and the Cochrane Library database (Cochrane Central Register of Controlled Trials [CENTRAL]; no date restriction). We used Medical Subject Headings (MeSH) and text words of chronic kidney disease, cohort study, and all known spellings of phosphorus (see Item S1, available as online supplementary material). Studies were considered without language restrictions. Reference lists from identified trials and review articles were scanned manually to identify any other relevant studies. When detailed information that was needed for the analysis was not available, we wrote to the author for the data. We included studies that: (1) had a patient population comprising adults with CKD, (2) a cohort study or trial that reported associations between serum phosphorus level and kidney disease progression, and (3) reported the hazard ratio (HR) and its 95% confidence interval (CI) or standard errors for kidney failure or mortality associated with serum phosphorus level or each category of serum phosphorus level. We excluded cohorts with dialysis or kidney transplantation patients or studies without estimates of the HR of kidney failure associated with serum phosphorus level. We defined CKD as glomerular filtration rate (GFR) , 60 mL/min/1.73 m2, high serum creatinine level, albuminuria with albumin excretion . 30 mg/d, or abnormalities detected by histology. Kidney failure was defined as a composite of any of the following: doubling of serum creatinine level, 50% decline in estimated GFR (eGFR), or end-stage renal disease (ESRD) or comparable definitions used by individual authors.
Quality Assessment and Data Extraction The literature was searched and identified by 2 investigators (X.X. and J.D.) independently, and quality assessment (using 6 core quality criteria based on the standard principles of quality assessment10) also was undertaken independently by the 2 investigators using a standardized approach (Table S1). For all studies included, we extracted age, sex, history of diabetes mellitus, mean systolic (SBP) and diastolic blood pressure values, albuminuria or proteinuria value, serum phosphorus level, followup duration, sample size, ESRD events, composite kidney failure events, unadjusted and adjusted HRs of kidney failure per unit increase in baseline serum concentrations of phosphorus (1 mg/ dL) and those for each reported category of baseline serum phosphorus level. Similar data for all-cause mortality also were extracted. We defined the adjustment as adequate when models were adjusted for age, sex, eGFR, urine protein excretion, blood pressure, and comorbid conditions and as partial when adjusted for fewer covariates. For each category of serum phosphorus exposure, we assigned the numerical value for the risk category as the expected of the serum phosphorus value in each corresponding category.11 Any disagreement between the 2 investigators in the abstracted data was adjudicated by a third reviewer (J.L. or L.Z.).
Statistical Analysis Summary estimates of the HR and 95% CI were derived using a random-effects model. We used metaregression to assess the association between serum phosphorus level and kidney failure and 2
mortality with unadjusted and adjusted log HR per-unit exposure or that was estimable from category-specific estimates. Categoryspecific HRs of kidney failure by quartiles of serum phosphorus were pooled by metaregression, using the bottom quartile as the reference group. Subgroup analysis was conducted to assess the effect of adjustment for the key covariates of age, SBP, diastolic blood pressure, body mass index, GFR, serum calcium concentration, urinary protein excretion, plasma albumin level, and hemoglobin concentration. For studies that reported an HR for kidney failure per unit of serum phosphorus by Cox regression, we could directly use the natural logarithm of the hazard risk per unit of serum phosphorus. When this HR was not available for a study, we used the methods described by Hartemink et al12 to calculate HR estimates per unit of exposure based on the category-specific estimated HR, which assumed the association is approximately linear. The DerSimonian-Laird approach and the Hartung-KnappSidik-Jonkman method13,14 and Cochran Q test were used to assess heterogeneity between studies, and I2 was used to describe the percentage of variability that was due to heterogeneity instead of sampling error. A 2-sided P , 0.05 was considered statistically significant. SAS software, version 9.1 (SAS Institute Inc), and STATA software, version 13 (StataCorp LP), were used in the meta-analysis.
RESULTS Characteristics and Quality of Studies Our literature search returned 5,891 results for relevant articles. Of these, we reviewed the full text of 55 reports, from which we identified 12 cohort studies of adults with CKD in the meta-analysis (Fig 1). All cohort studies were published from 2005 to 2014 and involved a total of 25,546 patients with CKD.7,8,15-24 Characteristics of included studies are provided in Table 1. Of those patients, 0.6% were in CKD stage 1; 2%, stage 2; 85%, stage 3; and 12.4%, stages 4 and 5. Four studies (n 5 3,393 with 618 kidney failure events [doubling of serum creatinine level, 50% decline in eGFR, or ESRD])17,19,21,22 reported unadjusted and adjusted HRs of kidney failure per unit exposure of serum phosphorus. Three studies (n 5 11,947 with 566 events)8,18,20 reported adjusted HRs of kidney failure in each category of serum phosphorus, and one study (n 5 985 with 258 events) reported both.16 HRs of kidney failure per unit increased exposure of serum phosphorus with adjustment for eGFR were reported in all cohorts and adequate adjustments of HRs were reported in 3 cohorts.16,19,21 Association of Serum Phosphorus With KidneyRelated Adverse Outcomes The association of serum phosphorus level with risk of kidney failure was analyzed by metaregression with unadjusted, adequately adjusted, and partially adjusted log HR per unit exposure (Fig 2). Overall, serum phosphorus level was associated with risk of kidney failure, with HRs per 1-mg/dL increase in serum phosphorus level of 2.48 (95% CI, 1.57-3.92) in univariate analysis with evidence of extensive Am J Kidney Dis. 2015;-(-):---
Serum Phosphorus and CKD Progression
MEDLINE 1912 Citations
EMBASE 3595 Citations
CCRT 433 Citations
Total 5891 Citations
5836 citations excluded 1400 No exposure to serum phosphorus 1496 Not CKD population 461 Review article 97 Not cohort studies 141 Pediatric population 49 Not human population study 1059 Transplantation or dialysis 1133 Duplicate studies Full-text analysis 55 Articles
Figure 1. Identification process for eligible cohort studies. Results of a systematic literature search of the association of kidney failure and mortality with serum phosphorus level in non–dialysisdependent chronic kidney disease (CKD). Abbreviation: CCTR, Cochrane Central Register of Controlled Trials.
heterogeneity (I2 5 95.7%; P 5 0.002) and 1.36 (95% CI, 1.20-1.55) in combined adjustment analysis with moderate heterogeneity (I2 5 31.0%; P 5 0.001). In adequate and partial adjustment subtotals, risk of kidney failure increased by 41% and 33%, respectively, per 1-mg/dL increase in serum phosphorus level (HRs of 1.41 [95% CI, 1.03-1.94] and 1.33 [95% CI, 1.051.68]). Because the largest study (Mehrota et al8 from the KEEP [Kidney Early Evaluation Program] Study Investigators) did not report detailed data for HR of kidney failure per unit exposure of serum phosphorus, we used the method by Hartemink et al12 to calculate the HR per 1 mg/dL of serum phosphorus exposure. In a sensitivity analysis that excluded the KEEP Study, results were essentially unchanged (unadjusted HR, 2.17 [95% CI, 1.64-3.18]; combined adjusted HR, 1.36 [95% CI, 1.18-1.57]; Fig 2). Figure S1 shows results of subgroup analyses. Subgroup analyses showed that the association between serum phosphorus level and risk of kidney failure was not modified by age, sex, SBP, diastolic blood pressure, body mass index, GFR, serum calcium concentration, urinary protein excretion, plasma albumin level, or hemoglobin level (all P for heterogeneity . 0.1). Next, we pooled the category-specific HRs of kidney failure by quartiles of serum phosphorus to demonstrate the correlation of kidney failure risk Am J Kidney Dis. 2015;-(-):---
43 22 2 4 7 8
articles excluded No exposure to serum phosphorus Not CKD population Review article, commentary, or editorial Not cohort study Transplantation or dialysis
12 cohorts n=25546 Renal events =1442, 8 studies/16325 All-cause mortality events =3089, 7studies/22728
with serum phosphorus level. With the first category as the reference, serum phosphorus quartiles 2 to 4 were associated with higher risk of kidney failure in unadjusted models (HRs for quartiles 2, 3, and 4 of 1.39 [95% CI, 1.00-1.94], 1.69 [95% CI, 1.19-2.39], and 3.90 [95% CI, 1.84-8.25], respectively). In metaregression using adjusted HR in each category, the risk of kidney failure was significantly increased only in quartile 4 (HR, 1.38; 95% CI, 1.09-1.74; Fig S2). Association of Serum Phosphorus With Mortality All-cause mortality was reported in 7 studies involving 21,525 patients, among whom 3,089 deaths were observed. Summary estimates for risk of all-cause mortality are shown in Fig 3. The unadjusted HR of all-cause mortality per 1-mg/dL increase in serum phosphorus level was 1.23 (95% CI, 1.16-1.31) in non–dialysis-dependent patients with CKD with no heterogeneity. After adjustment, every 1-mg/dL increase in serum phosphorus level was associated with a 20% increased risk for death (HR, 1.20; 95% CI, 1.051.37), with moderate evidence of heterogeneity (I2 5 41.9%; P 5 0.1). Estimates of adequate adjustment showed a 21% increased risk of mortality (HR, 1.21; 95% CI, 1.09-1.34). Subgroup analysis showed that the association between serum phosphorus level and risk of all-cause mortality was modified by SBP; patients with CKD with SBP . 140 mm Hg had a 3
Da et al Table 1. Characteristics of Studies Reporting the Association of Serum Phosphorus With Kidney Failure and Mortality Among Non–Dialysis-Dependent CKD Patients
Study
Country
Cohort
Schwarz16 (2006) Fliser22 (2007) Smith21 (2010) Kovesdy19 (2010) Zoccali17 (2011) Scialla18 (2013) Mehrotra8 (2013) Chartsrisak20 (2013) Voormolen7 (2007) Kestenbaum15 (2005) Eddington23 (2010) Menon24 (2005)
US DE US US IT US US TH NL US US US
VAMC MMKD HMO VAMC REIN AASK KEEP
Mean Mean CKD Proteinuria Follow-up GFR Stage (g/d) Duration (y)
33.6 69.8 47.8 37 43.9 45.2 47.2 42.3 PREPARE 13 47.2 CRISIS 32 MDRD 33
1-5 1-5 3-5 1-5 2-4 2-5 3-5 2-4 4-5 1-5 3-5 3-4
0.905 0.923 0.694 3.034
1.012
4.6a
2.1 4 5 1.5 2.5 7.9 2.3 2 1.5 2.1 2.9 10
N
985 227 2,122 713 331 809 10,672 466 448 6,730 1,203 840
Mean Mean Serum P Age (y) (mg/dL)
65.3 45.65 68.49 70 49.34 55 70.59 65 60 71.2 64 52
3.83 3.38 3.61 3.9 3.48 3.5 3.74 3.8 4.71 3.72 3.8
No. of Kidney Disease Outcome Events (%)
258 65 176 293 84 234 194 74
(18.7%) (4.7%) (12.8%) (21.3%) (27.4%) (17.0%) (14.1%) (5.4%)
No. of Mortality Events (%)
625 (20.2%) 244 (7.9%)
578 (18.7%) 30 1,133 271 208
(1%) (36.7%) (8.8%) (6.7%)
Note: Kidney failure was defined as doubling of serum creatinine level or 50% decline in estimated GFR or end-stage renal disease. GFRs expressed in mL/min/1.73 m2. Conversion factor for serum P in mg/dL to mmol/L, 30.3229. Abbreviations: AASK, African American Study of Kidney Disease and Hypertension; CKD, chronic kidney disease; CRISIS, Chronic Renal Insufficiency Standards Implementation Study; DE, Germany; GFR, glomerular filtration rate; HMO, health maintenance organization; IT, Italy; KEEP, Kidney Early Evaluation Program; MDRD, Modification of Diet in Renal Disease Study; MMKD, Mild to Moderate Kidney Disease Study; NL, Netherlands; P, phosphorus; PREPARE, The Predialysis Patient Record; TH, Thailand; US, United States; VAMC, Veterans Affairs Medical Center. a Median.
35% increased risk for mortality (HR, 1.35; 95% CI, 1.18-1.55; Fig S3).
DISCUSSION Recent studies have indicated that phosphorus may play an independent pathogenic role in CKD progression,7 but some of those studies are underpowered and yield inconsistent results.8 To our knowledge, this is the first systematic review and meta-analysis of serum phosphorus level and outcomes in CKD and included 12 cohort studies with 25,546 patients with CKD. Our study indicates that higher serum phosphorus level is an independent risk factor for kidney disease progression and mortality among non– dialysis-dependent patients with CKD. Serum phosphorus level is used as a biomarker for phosphorus homeostasis and has been reported to be associated with cardiovascular events and mortality among patients with CKD.6,15,25 However, the relationship between serum phosphorus level and kidney disease outcome has been less certain. Several cohort studies have shown an association between higher serum phosphorus levels and kidney disease progression. For example, post hoc analyses of randomized controlled clinical trials (African American Study of Kidney Disease and Hypertension [AASK]18 and Ramipril Efficacy in Nephropathy [REIN]17), as well as a study of US male veterans,16 suggested that higher serum phosphorus levels were associated with higher risk of kidney disease progression. Meanwhile, a large cohort study consisting of patients with early4
stage CKD (the KEEP Study) did not observe an association between serum phosphorus levels (in quartiles) and risk for death or progression to ESRD.8 Compared with other studies, participants in the KEEP Study had fairly well-preserved kidney function (average serum creatinine, 1.3 mg/dL) and lower serum phosphorus levels.8 Even so, a trend toward increased risk of kidney failure was observed in the KEEP Study when serum phosphorus levels were .4.1 mg/dL. In our meta-analysis, the association between serum phosphorus level and kidney failure became statistically significant at the highest quartile of serum phosphorus. These findings are consistent with the trend observed in the KEEP Study. The association between higher serum phosphorus level and adverse prognosis could be explained by several mechanisms. First, increased phosphate load could lead to tubular injury, interstitial fibrosis, endothelial dysfunction, and vascular calcification by either the direct effect of phosphate or formation of calcium-phosphate crystals called calciprotein.26 Second, in hyperphosphatemic animal models of CKD, deposition of calcium phosphate crystals was found in either the renal interstitium or mitochondria of tubular cells, which in turn led to progressive loss of kidney function by mitogenesis of fibroblasts and cell damage.27,28 Restriction of dietary phosphorus or phosphate-binder treatment protects the residual nephron from damage in rat models of CKD.29,30 Finally, phosphorus homeostasis is regulated through multiple physiopathologic mechanisms. Fibroblast Am J Kidney Dis. 2015;-(-):---
Serum Phosphorus and CKD Progression
Study
HR (95% CI)
N of Events/N of Pts
Unadjusted Schwarz 2006
258/985
2.33 (1.99, 2.73)
Fliser 2007
65/227
1.31 (1.16, 1.48)
Smith 2010
176/2122
3.90 (3.19, 4.77)
Kovesdy 2010
293/713
1.62 (1.47, 1.79)
Zoccali 2011
84/331
2.87 (2.18, 3.77)
Scialla 2013
298/809
1.53 (1.27, 1.83)
KEEP 2013
194/10672
6.89 (4.70, 10.11)
74/466
3.11 (2.01, 4.81)
Unadj Overall HKSJ ( I2 = 95.7%, p = 0.002)
1442/16325
2.48 (1.57, 3.92)
Unadj w/o KEEP (HKSJ) (I2 = 94.9%, p = 0.003)
1248/5653
2.17 (1.48, 3.18)
258/985
1.29 (1.12, 1.48)
176/2122
1.69 (1.29, 2.21)
Kovesdy 2010
293/713
1.42 (1.15, 1.76)
Adequate adj subtotal ˄HKSJ˅ (I2 = 36.4%, p = 0.04)
727/3820
1.41 (1.03, 1.94)
Fliser 2007
65/227
1.17 (0.86, 1.59)
Zoccali 2011
84/331
1.66 (1.18, 2.33)
Scialla 2013
290/809
1.13 (0.94, 1.36)
KEEP 2013
194/10672
1.48 (1.02, 2.16)
74/466
1.63 (1.07, 2.46)
707/12506
1.33 (1.05,1.68)
Combined Overall (HKSJ) (I2 = 31.0%, p = 0.001)
1434/16325
1.36 (1.20, 1.55)
Combined w/o KEEP (HKSJ) (I2 = 39.1%, p = 0.002)
1240/5653
1.36 (1.18,1.57)
Chartsrisak 2013
Adequate adjustment Schwarz 2006 Smith 2010
Partial adjustment
Chartsrisak 2013 Partial adj subtotal (HKSJ) (I2 = 35.8%, p = 0.03)
Heterogeneity between groups p
C
hronic kidney disease (CKD) is a major public health problem worldwide, affecting 8% to 16% of the adult population.1 Early recognition2 and intervention against factors involved in the progression of CKD are key to improving outcomes of patients at risk. Unfortunately, progression of CKD varies substantially,3,4 while factors contributing to this heterogeneity are not fully understood. Besides well-established risk factors, including high blood pressure and proteinuria, accumulating evidence indicates an important role for serum phosphorus.5 Abnormal phosphorus homeostasis is a hallmark of CKD. Serum phosphorus level is used as a biomarker From the 1Renal Division, Department of Medicine, Peking University First Hospital; Peking University Institute of Nephrology; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China; 2Renal Division, Department of Medicine, Guizhou Provincial People’s Hospital; Guizhou Provincial Institute of Nephritic & Urinary Disease, Guiyang, Guizhou; 3Division of Nephrology and Hypertension, Department of Medicine, Division of Biostatistics, Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, Miami, FL; and 4Division of Nephrology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. Am J Kidney Dis. 2015;-(-):---
for phosphorus homeostasis and has been reported to be an important risk factor for both all-cause and cardiovascular mortality in individuals with CKD.6 Recent studies indicated that phosphorus also may play an independent pathogenic role in CKD progression,7 but some studies were underpowered and yielded inconsistent results.8 Furthermore, it is not clear whether a dose-response relationship exists in the association between phosphorus level and kidney disease outcomes, as is seen in the phosphorusmortality link. We therefore conducted a systematic review and meta-analysis of the effects of serum phosphorus level *
J.D. and X.X. contributed equally to this work. Deceased. Received May 23, 2014. Accepted in revised form January 4, 2015. Address correspondence to Luxia Zhang, MD, MPH, Renal Division, Peking University First Hospital, No. 8, Xishiku St, Xicheng District, Beijing China (e-mail: [email protected]) or Jicheng Lv, MD, Renal Division, Peking University First Hospital, 8, Xishiku St, Xicheng District, Beijing, China (e-mail: [email protected]). 2015 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2015.01.009 y
1
Da et al
on progression of CKD and all-cause mortality among non–dialysis-dependent patients with CKD.
METHODS Search Strategy and Selection Criteria We undertook a systematic review of the literature according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines.9 Relevant studies were identified by searching the following data sources: MEDLINE (Ovid; from January 1950 to June 2014), EMBASE (from January 1970 to June 2014), and the Cochrane Library database (Cochrane Central Register of Controlled Trials [CENTRAL]; no date restriction). We used Medical Subject Headings (MeSH) and text words of chronic kidney disease, cohort study, and all known spellings of phosphorus (see Item S1, available as online supplementary material). Studies were considered without language restrictions. Reference lists from identified trials and review articles were scanned manually to identify any other relevant studies. When detailed information that was needed for the analysis was not available, we wrote to the author for the data. We included studies that: (1) had a patient population comprising adults with CKD, (2) a cohort study or trial that reported associations between serum phosphorus level and kidney disease progression, and (3) reported the hazard ratio (HR) and its 95% confidence interval (CI) or standard errors for kidney failure or mortality associated with serum phosphorus level or each category of serum phosphorus level. We excluded cohorts with dialysis or kidney transplantation patients or studies without estimates of the HR of kidney failure associated with serum phosphorus level. We defined CKD as glomerular filtration rate (GFR) , 60 mL/min/1.73 m2, high serum creatinine level, albuminuria with albumin excretion . 30 mg/d, or abnormalities detected by histology. Kidney failure was defined as a composite of any of the following: doubling of serum creatinine level, 50% decline in estimated GFR (eGFR), or end-stage renal disease (ESRD) or comparable definitions used by individual authors.
Quality Assessment and Data Extraction The literature was searched and identified by 2 investigators (X.X. and J.D.) independently, and quality assessment (using 6 core quality criteria based on the standard principles of quality assessment10) also was undertaken independently by the 2 investigators using a standardized approach (Table S1). For all studies included, we extracted age, sex, history of diabetes mellitus, mean systolic (SBP) and diastolic blood pressure values, albuminuria or proteinuria value, serum phosphorus level, followup duration, sample size, ESRD events, composite kidney failure events, unadjusted and adjusted HRs of kidney failure per unit increase in baseline serum concentrations of phosphorus (1 mg/ dL) and those for each reported category of baseline serum phosphorus level. Similar data for all-cause mortality also were extracted. We defined the adjustment as adequate when models were adjusted for age, sex, eGFR, urine protein excretion, blood pressure, and comorbid conditions and as partial when adjusted for fewer covariates. For each category of serum phosphorus exposure, we assigned the numerical value for the risk category as the expected of the serum phosphorus value in each corresponding category.11 Any disagreement between the 2 investigators in the abstracted data was adjudicated by a third reviewer (J.L. or L.Z.).
Statistical Analysis Summary estimates of the HR and 95% CI were derived using a random-effects model. We used metaregression to assess the association between serum phosphorus level and kidney failure and 2
mortality with unadjusted and adjusted log HR per-unit exposure or that was estimable from category-specific estimates. Categoryspecific HRs of kidney failure by quartiles of serum phosphorus were pooled by metaregression, using the bottom quartile as the reference group. Subgroup analysis was conducted to assess the effect of adjustment for the key covariates of age, SBP, diastolic blood pressure, body mass index, GFR, serum calcium concentration, urinary protein excretion, plasma albumin level, and hemoglobin concentration. For studies that reported an HR for kidney failure per unit of serum phosphorus by Cox regression, we could directly use the natural logarithm of the hazard risk per unit of serum phosphorus. When this HR was not available for a study, we used the methods described by Hartemink et al12 to calculate HR estimates per unit of exposure based on the category-specific estimated HR, which assumed the association is approximately linear. The DerSimonian-Laird approach and the Hartung-KnappSidik-Jonkman method13,14 and Cochran Q test were used to assess heterogeneity between studies, and I2 was used to describe the percentage of variability that was due to heterogeneity instead of sampling error. A 2-sided P , 0.05 was considered statistically significant. SAS software, version 9.1 (SAS Institute Inc), and STATA software, version 13 (StataCorp LP), were used in the meta-analysis.
RESULTS Characteristics and Quality of Studies Our literature search returned 5,891 results for relevant articles. Of these, we reviewed the full text of 55 reports, from which we identified 12 cohort studies of adults with CKD in the meta-analysis (Fig 1). All cohort studies were published from 2005 to 2014 and involved a total of 25,546 patients with CKD.7,8,15-24 Characteristics of included studies are provided in Table 1. Of those patients, 0.6% were in CKD stage 1; 2%, stage 2; 85%, stage 3; and 12.4%, stages 4 and 5. Four studies (n 5 3,393 with 618 kidney failure events [doubling of serum creatinine level, 50% decline in eGFR, or ESRD])17,19,21,22 reported unadjusted and adjusted HRs of kidney failure per unit exposure of serum phosphorus. Three studies (n 5 11,947 with 566 events)8,18,20 reported adjusted HRs of kidney failure in each category of serum phosphorus, and one study (n 5 985 with 258 events) reported both.16 HRs of kidney failure per unit increased exposure of serum phosphorus with adjustment for eGFR were reported in all cohorts and adequate adjustments of HRs were reported in 3 cohorts.16,19,21 Association of Serum Phosphorus With KidneyRelated Adverse Outcomes The association of serum phosphorus level with risk of kidney failure was analyzed by metaregression with unadjusted, adequately adjusted, and partially adjusted log HR per unit exposure (Fig 2). Overall, serum phosphorus level was associated with risk of kidney failure, with HRs per 1-mg/dL increase in serum phosphorus level of 2.48 (95% CI, 1.57-3.92) in univariate analysis with evidence of extensive Am J Kidney Dis. 2015;-(-):---
Serum Phosphorus and CKD Progression
MEDLINE 1912 Citations
EMBASE 3595 Citations
CCRT 433 Citations
Total 5891 Citations
5836 citations excluded 1400 No exposure to serum phosphorus 1496 Not CKD population 461 Review article 97 Not cohort studies 141 Pediatric population 49 Not human population study 1059 Transplantation or dialysis 1133 Duplicate studies Full-text analysis 55 Articles
Figure 1. Identification process for eligible cohort studies. Results of a systematic literature search of the association of kidney failure and mortality with serum phosphorus level in non–dialysisdependent chronic kidney disease (CKD). Abbreviation: CCTR, Cochrane Central Register of Controlled Trials.
heterogeneity (I2 5 95.7%; P 5 0.002) and 1.36 (95% CI, 1.20-1.55) in combined adjustment analysis with moderate heterogeneity (I2 5 31.0%; P 5 0.001). In adequate and partial adjustment subtotals, risk of kidney failure increased by 41% and 33%, respectively, per 1-mg/dL increase in serum phosphorus level (HRs of 1.41 [95% CI, 1.03-1.94] and 1.33 [95% CI, 1.051.68]). Because the largest study (Mehrota et al8 from the KEEP [Kidney Early Evaluation Program] Study Investigators) did not report detailed data for HR of kidney failure per unit exposure of serum phosphorus, we used the method by Hartemink et al12 to calculate the HR per 1 mg/dL of serum phosphorus exposure. In a sensitivity analysis that excluded the KEEP Study, results were essentially unchanged (unadjusted HR, 2.17 [95% CI, 1.64-3.18]; combined adjusted HR, 1.36 [95% CI, 1.18-1.57]; Fig 2). Figure S1 shows results of subgroup analyses. Subgroup analyses showed that the association between serum phosphorus level and risk of kidney failure was not modified by age, sex, SBP, diastolic blood pressure, body mass index, GFR, serum calcium concentration, urinary protein excretion, plasma albumin level, or hemoglobin level (all P for heterogeneity . 0.1). Next, we pooled the category-specific HRs of kidney failure by quartiles of serum phosphorus to demonstrate the correlation of kidney failure risk Am J Kidney Dis. 2015;-(-):---
43 22 2 4 7 8
articles excluded No exposure to serum phosphorus Not CKD population Review article, commentary, or editorial Not cohort study Transplantation or dialysis
12 cohorts n=25546 Renal events =1442, 8 studies/16325 All-cause mortality events =3089, 7studies/22728
with serum phosphorus level. With the first category as the reference, serum phosphorus quartiles 2 to 4 were associated with higher risk of kidney failure in unadjusted models (HRs for quartiles 2, 3, and 4 of 1.39 [95% CI, 1.00-1.94], 1.69 [95% CI, 1.19-2.39], and 3.90 [95% CI, 1.84-8.25], respectively). In metaregression using adjusted HR in each category, the risk of kidney failure was significantly increased only in quartile 4 (HR, 1.38; 95% CI, 1.09-1.74; Fig S2). Association of Serum Phosphorus With Mortality All-cause mortality was reported in 7 studies involving 21,525 patients, among whom 3,089 deaths were observed. Summary estimates for risk of all-cause mortality are shown in Fig 3. The unadjusted HR of all-cause mortality per 1-mg/dL increase in serum phosphorus level was 1.23 (95% CI, 1.16-1.31) in non–dialysis-dependent patients with CKD with no heterogeneity. After adjustment, every 1-mg/dL increase in serum phosphorus level was associated with a 20% increased risk for death (HR, 1.20; 95% CI, 1.051.37), with moderate evidence of heterogeneity (I2 5 41.9%; P 5 0.1). Estimates of adequate adjustment showed a 21% increased risk of mortality (HR, 1.21; 95% CI, 1.09-1.34). Subgroup analysis showed that the association between serum phosphorus level and risk of all-cause mortality was modified by SBP; patients with CKD with SBP . 140 mm Hg had a 3
Da et al Table 1. Characteristics of Studies Reporting the Association of Serum Phosphorus With Kidney Failure and Mortality Among Non–Dialysis-Dependent CKD Patients
Study
Country
Cohort
Schwarz16 (2006) Fliser22 (2007) Smith21 (2010) Kovesdy19 (2010) Zoccali17 (2011) Scialla18 (2013) Mehrotra8 (2013) Chartsrisak20 (2013) Voormolen7 (2007) Kestenbaum15 (2005) Eddington23 (2010) Menon24 (2005)
US DE US US IT US US TH NL US US US
VAMC MMKD HMO VAMC REIN AASK KEEP
Mean Mean CKD Proteinuria Follow-up GFR Stage (g/d) Duration (y)
33.6 69.8 47.8 37 43.9 45.2 47.2 42.3 PREPARE 13 47.2 CRISIS 32 MDRD 33
1-5 1-5 3-5 1-5 2-4 2-5 3-5 2-4 4-5 1-5 3-5 3-4
0.905 0.923 0.694 3.034
1.012
4.6a
2.1 4 5 1.5 2.5 7.9 2.3 2 1.5 2.1 2.9 10
N
985 227 2,122 713 331 809 10,672 466 448 6,730 1,203 840
Mean Mean Serum P Age (y) (mg/dL)
65.3 45.65 68.49 70 49.34 55 70.59 65 60 71.2 64 52
3.83 3.38 3.61 3.9 3.48 3.5 3.74 3.8 4.71 3.72 3.8
No. of Kidney Disease Outcome Events (%)
258 65 176 293 84 234 194 74
(18.7%) (4.7%) (12.8%) (21.3%) (27.4%) (17.0%) (14.1%) (5.4%)
No. of Mortality Events (%)
625 (20.2%) 244 (7.9%)
578 (18.7%) 30 1,133 271 208
(1%) (36.7%) (8.8%) (6.7%)
Note: Kidney failure was defined as doubling of serum creatinine level or 50% decline in estimated GFR or end-stage renal disease. GFRs expressed in mL/min/1.73 m2. Conversion factor for serum P in mg/dL to mmol/L, 30.3229. Abbreviations: AASK, African American Study of Kidney Disease and Hypertension; CKD, chronic kidney disease; CRISIS, Chronic Renal Insufficiency Standards Implementation Study; DE, Germany; GFR, glomerular filtration rate; HMO, health maintenance organization; IT, Italy; KEEP, Kidney Early Evaluation Program; MDRD, Modification of Diet in Renal Disease Study; MMKD, Mild to Moderate Kidney Disease Study; NL, Netherlands; P, phosphorus; PREPARE, The Predialysis Patient Record; TH, Thailand; US, United States; VAMC, Veterans Affairs Medical Center. a Median.
35% increased risk for mortality (HR, 1.35; 95% CI, 1.18-1.55; Fig S3).
DISCUSSION Recent studies have indicated that phosphorus may play an independent pathogenic role in CKD progression,7 but some of those studies are underpowered and yield inconsistent results.8 To our knowledge, this is the first systematic review and meta-analysis of serum phosphorus level and outcomes in CKD and included 12 cohort studies with 25,546 patients with CKD. Our study indicates that higher serum phosphorus level is an independent risk factor for kidney disease progression and mortality among non– dialysis-dependent patients with CKD. Serum phosphorus level is used as a biomarker for phosphorus homeostasis and has been reported to be associated with cardiovascular events and mortality among patients with CKD.6,15,25 However, the relationship between serum phosphorus level and kidney disease outcome has been less certain. Several cohort studies have shown an association between higher serum phosphorus levels and kidney disease progression. For example, post hoc analyses of randomized controlled clinical trials (African American Study of Kidney Disease and Hypertension [AASK]18 and Ramipril Efficacy in Nephropathy [REIN]17), as well as a study of US male veterans,16 suggested that higher serum phosphorus levels were associated with higher risk of kidney disease progression. Meanwhile, a large cohort study consisting of patients with early4
stage CKD (the KEEP Study) did not observe an association between serum phosphorus levels (in quartiles) and risk for death or progression to ESRD.8 Compared with other studies, participants in the KEEP Study had fairly well-preserved kidney function (average serum creatinine, 1.3 mg/dL) and lower serum phosphorus levels.8 Even so, a trend toward increased risk of kidney failure was observed in the KEEP Study when serum phosphorus levels were .4.1 mg/dL. In our meta-analysis, the association between serum phosphorus level and kidney failure became statistically significant at the highest quartile of serum phosphorus. These findings are consistent with the trend observed in the KEEP Study. The association between higher serum phosphorus level and adverse prognosis could be explained by several mechanisms. First, increased phosphate load could lead to tubular injury, interstitial fibrosis, endothelial dysfunction, and vascular calcification by either the direct effect of phosphate or formation of calcium-phosphate crystals called calciprotein.26 Second, in hyperphosphatemic animal models of CKD, deposition of calcium phosphate crystals was found in either the renal interstitium or mitochondria of tubular cells, which in turn led to progressive loss of kidney function by mitogenesis of fibroblasts and cell damage.27,28 Restriction of dietary phosphorus or phosphate-binder treatment protects the residual nephron from damage in rat models of CKD.29,30 Finally, phosphorus homeostasis is regulated through multiple physiopathologic mechanisms. Fibroblast Am J Kidney Dis. 2015;-(-):---
Serum Phosphorus and CKD Progression
Study
HR (95% CI)
N of Events/N of Pts
Unadjusted Schwarz 2006
258/985
2.33 (1.99, 2.73)
Fliser 2007
65/227
1.31 (1.16, 1.48)
Smith 2010
176/2122
3.90 (3.19, 4.77)
Kovesdy 2010
293/713
1.62 (1.47, 1.79)
Zoccali 2011
84/331
2.87 (2.18, 3.77)
Scialla 2013
298/809
1.53 (1.27, 1.83)
KEEP 2013
194/10672
6.89 (4.70, 10.11)
74/466
3.11 (2.01, 4.81)
Unadj Overall HKSJ ( I2 = 95.7%, p = 0.002)
1442/16325
2.48 (1.57, 3.92)
Unadj w/o KEEP (HKSJ) (I2 = 94.9%, p = 0.003)
1248/5653
2.17 (1.48, 3.18)
258/985
1.29 (1.12, 1.48)
176/2122
1.69 (1.29, 2.21)
Kovesdy 2010
293/713
1.42 (1.15, 1.76)
Adequate adj subtotal ˄HKSJ˅ (I2 = 36.4%, p = 0.04)
727/3820
1.41 (1.03, 1.94)
Fliser 2007
65/227
1.17 (0.86, 1.59)
Zoccali 2011
84/331
1.66 (1.18, 2.33)
Scialla 2013
290/809
1.13 (0.94, 1.36)
KEEP 2013
194/10672
1.48 (1.02, 2.16)
74/466
1.63 (1.07, 2.46)
707/12506
1.33 (1.05,1.68)
Combined Overall (HKSJ) (I2 = 31.0%, p = 0.001)
1434/16325
1.36 (1.20, 1.55)
Combined w/o KEEP (HKSJ) (I2 = 39.1%, p = 0.002)
1240/5653
1.36 (1.18,1.57)
Chartsrisak 2013
Adequate adjustment Schwarz 2006 Smith 2010
Partial adjustment
Chartsrisak 2013 Partial adj subtotal (HKSJ) (I2 = 35.8%, p = 0.03)
Heterogeneity between groups p
