Invited commentary by Dr. Edgar Lerma
In recent years, the epidemic of chronic kidney disease (CKD) and its association with increased cardiovascular morbidity and mortality has become clear. As nephrologists, we are responsible for instituting measure to delay progression of CKD, including control of hypertension and diabetes, and avoidance of nephrotoxic agents. Several studies have demonstrated so-called “secondary risk factors” that may be unrelated to the development of CKD, but contribute significantly to CKD progression. These include intraglomerular hypertension and hypertrophy, altered phosphate metabolism (with interstitial calcium-phosphate deposition), increased prostaglandin synthesis, hyperlipidemia, metabolic acidosis, proteinuria, tubulointerstitial disease, retained uremic toxins, and filtered iron.
In a recent article in AJKD, Cozzolino et al attempt to describe a distinct interrelationship between hypertension and proteinuria (well-established risk factors) with altered phosphate metabolism, on the basis of recently published experimental studies and clinical trials. It has been well-established that reducing proteinuria is an important intervention to slow CKD progression. It has also been demonstrated that multiple therapeutic strategies to reduce proteinuria have a greater effect on slowing progression than any individual approach. This has been the impetus for combining lifestyle modifications (weight reduction, dietary Na restriction, smoking cessation, etc.) and use of RAAS blocking agents.
The recent understanding of the FGF-23/klotho system and its pivotal role in the phosphate-regulating endocrine axis has brought forth some insight into how altered phosphate metabolism may contribute to CKD progression, and represent another opportunity to delay GFR loss. The authors describe the relationship between the FGF-23/klotho system and the RAAS (see Fig 1 from the article below), and their impact on pathways of CKD progression.
In this connection, it has been suggested that the renoprotective effects of RAAS blockers are somehow minimized by altered phosphate metabolism, eg, serum phosphate > 4.5 mg/dL. Additionally, it is suggested that phosphate binding agents may have an additional long-term renoprotective role that is additive to RAAS blockers. This study gives us more reason to push for aggressive phosphate control in our CKD patients.
Edgar V. Lerma, MD
Clinical Professor of Medicine
University of Illinois at Chicago College of Medicine