JOURNAL CLUB
“Hormone Linked to Premature Death in Kidney Patients”: Hype or Reality?

FGF-23

A paper by Kendrick and co-workers (1) published in JASN Express, as an advanced online publication this week, is currently receiving considerable coverage in the popular press. The most widely circulated quote in the lay press is: "This discovery allows us to predict at-risk patients before they require dialysis," lead investigator Dr. Michel Chonchol, an associate professor of medicine specializing in nephrology, told ScienceDaily. "This has provided us a critical marker to look for, a marker that could save lives."

Are these conclusions hype or reality? This is the topic of our Journal Club. 

Background information on FGF-23 can be obtained elsewhere in excellent reviews and commentaries by Myles Wolf and others (3,4).

Kendrick and co-workers conducted a retrospective study on the HOST cohort. The HOST study was a multicenter, prospective, randomized, double-blind, placebo-controlled trial examining the effects of folate, pyridoxine hydrochloride (vitamin B6), and cyanocobalamin (vitaminB12) replacement on all-cause mortality and cardiovascular events inpatients with advanced kidney disease with elevated plasma total homocysteine concentrations (2). 

The primary publication from HOST was published in JAMA in 2007(2). The design of the study is in a paper in Clinical Trials.

HOST originally enrolled a total of 2056 participants aged 21 yr of age or older, with ESRD receiving either maintenance hemodialysis or peritoneal dialysis (n =751), or with an estimated creatinine clearance (calculated by the Cockcroft-Gault formula) of less than 30 ml/min (n =1305) not requiring chronic dialysis.  

The cohort of 1305 subjects represent the CKD sample of patients from HOST, and it was whittled down a bit more after subjects with CKD who had initiated chronic hemodialysis within 3 mo after randomization (n=34; 2.6%) or for whom a plasma sample was not available for FGF-23 measurement (n =172, 13.2%) were excluded. This resulted in a final sample of 1099 subjects for the present study (Figure 1). 

Since one of the key inclusion criteria was a plasma homocysteine concentration of 15 µmol/L or higher, i.e., all of the patients in the original HOST cohort as well those in the Kendrick study were hyperhomocysteneimic.

Participants in HOST were also excluded if they were pregnant; had a life expectancy of less than 6 mo; had end-stage liver disease or metastatic cancer; were taking methotrexate, antifolate medication, or anticonvulsants; expected to receive a living-related kidney donation in the next 6 months, and were noncompliant with medications.

Participants in HOST were randomly assigned to receive a once-daily capsule containing 40mgof folic acid, 100 mg of vitamin B6, and 2 mg of vitamin B12 or a daily placebo capsule.

Participant enrollment in HOST began in September 2001 and ended in October 2003

Key characteristics of participants in the Kendrick study were:

• 98% male
• age of the participants was 69+/-11 yr
• Mean estimated Modified Diet Renal Disease-GFR (MDRD-GFR) was 18 +/-6 ml/ min/1.73m2, and most participants (n = 718; 65%) had an estimated MDRD-GFR of 15 to 29 ml/min/1.73m.2
• All patients had elevated plasma homocysteine levels of >15 µmol/L

The exposure variable

• The plasma FGF-23 concentration measured 3 months after randomization was the primary exposure variable in this analysis. 
• Graphical methods and measures of skewness and kurtosis were used to determine the distribution of FGF-23 concentrations in the plasma samples.
• Given the positively skewed distribution of FGF-23 concentrations, the values were transformed to the log base of 10. 
• Quartiles of FGF-23 concentrations were chosen with the lowest quartile serving as the reference category. FGF-23: Quartile (Q)1< 216 RU/ml, Q2 217–380 RU/ml, Q3 381–945 RU/ml and, Q4 >946 RU/ml

Major Findings

1. Association between FGF-23 and Mortality

• Increased deaths associated with higher FGF-23 levels.
• 453 deaths from all causes.  The number of deaths increased across FGF 23 quartiles:  82, 104, 132, and 135 deaths, corresponding to crude death rates of 10.2, 13.4, 18.1, and 19 per 100 person-years, respectively.
• Higher plasma FGF-23 concentrations were associated with greater risk of all-cause mortality in crude analysis P<0.0001 by the log-rank test for the overall comparison among the subgroups. 
• In models adjusted for various factors, the association remained -- highest quartile remained associated with an approximately twofold greater risk for death.
• The first and second quartile of FGF-23 concentrations had a similar mortality rate, the third quartile was associated with significantly increased risk of death, and the fourth quartile was associated with an approximate tripling of mortality
• When plasma FGF-23 concentrations were evaluated as a continuous variable, higher concentrations of FGF-23 were associated with an increased risk of all-cause mortality, with a hazard ratio (HR) of 1.63 (95% CI 1.29 to 2.07; P<0.0001) per SD increase in log FGF-23 concentrations in the fully adjusted model.

FGF-23 was the strongest risk factor for death.

2. Association between FGF-23 and Initiation of Dialysis

      In the HOST study CKD cohort, 56% (n =615) of participants initiated chronic dialysis.

• A higher incidence of dialysis initiation across increasing FGF-23 quartiles (P<0.0001).
• After adjustments for demographics, traditional cardiovascular risk factors, baseline kidney function, and other variables of mineral metabolism, the two highest quartiles (381 to 945 RU/ml and >946 RU/ml) of FGF-23 concentrations remained significantly associated with incident chronic dialysis

Limitations of the study

1. Generalizibility: Participants were almost exclusively male subjects (98%), and older (mean age 69+/-11 years), with high homocysteine levels in the VA system.
2. The cohort was dated -- from 2001 to 2003 – 10 years ago use of various metabolic bone disease (MBD) medications, such as phosphate binders and vitamin D or its analogues was limited. How valid are observations from a cohort that reflects care that took place over 10 years ago?
3. Confounding: albuminuria was not measured. Therefore, albuminuria could not be included in the models. Many previous studies have demonstrated that albuminuria is a powerful factor influencing both kidney disease progression and mortality. Also, the issue of residual confounding: there may be other key factors that were not measured that could have been important
4.  eGFR was used as the measure for kidney function – this is less precise as a longitudinal measure of kidney function that actual measurement of GFR.
5. Assessment of outcomes: In the original HOST study, after the return visit at 3 months, further contact was not in person; thus, ascertainment of outcomes such as death and initiation of dialysis might have been incomplete.
   
   

Bottom-line

While the study is nicely done, I suggest that the interpretation of the results should be hypothesis generating, i.e., patients should not be rushing out to their nephrologists asking to have FGF-23 measured as a validated predictive biomarker for mortaility or need to initiate dialysis.

• This study doesn't prove that FGF-23 predicts the initiation of dialysis -- it suggests that higher FGF-23 levels are independently associated with an increased rate of dialysis initiation in a VA cohort dating back 10 years comprising mostly men with high homocysteine levels. One would need to do a validation study in a different cohort.
• The association between increased FGF-23 levels and mortality has been demonstrated before in other patient populations, including a dialysis cohort (5,6). Yes, FGF-23 is an exciting molecule, but so far most of the studies have been observational in nature. To argue that elevated FGF is a valid surrogate for hard endpoints we need a properly powered randomized controlled study designed to evaluate whether reduction in FGF-23 level improves outcomes.
• There is a push to perform randomized trials with FGF-23. This study should be one more impetus.

References

1. Kendrick J, Cheung AK, Kaufman JS, Greene T, Roberts WL, Smits G, Chonchol M; the HOST Investigators. FGF-23 Associates with Death, Cardiovascular Events, and Initiation of Chronic Dialysis. J Am Soc Nephrol. 2011 Sep 7. [Epub ahead of print]

2. Jamison RL, Hartigan P, Kaufman JS, Goldfarb DS, Warren SR, Guarino PD, Gaziano JM; Veterans Affairs Site Investigators: Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: A randomized controlled trial. JAMA 298: 1163–1170, 2007

3. Zisman AL, Wolf M. Recent advances in the rapidly evolving field of fibroblast growth factor 23 in chronic kidney disease. Curr Opin Nephrol Hypertens. 2010 Jul;19(4):335-42. Review. PubMed PMID: 20583336.

4. Wolf M. Forging forward with 10 burning questions on FGF23 in kidney disease. J Am Soc Nephrol. 2010 Sep;21(9):1427-35. Epub 2010 May 27. 

5. Wolf M, Molnar MZ, Amaral AP, Czira ME, Rudas A, Ujszaszi A, Kiss I, Rosivall L, Kosa J, Lakatos P, Kovesdy CP, Mucsi I. Elevated fibroblast growth factor 23 is a risk factor for kidney transplant loss and mortality. J Am Soc Nephrol. 2011 May;22(5):956-66. Epub 2011 Mar 24. PubMed PMID: 21436289

6. Gutiérrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, Smith K, Lee H, Thadhani R, Jüppner H, Wolf M. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008 Aug 7;359(6:584-92. PubMed PMID: 18687639;