Phosphate Control: The Next Frontier in Dialysis Cardiovascular Mortality

<b><i>Background:</i></b> Cardiovascular disease (CVD) is a major cause of death in patients with chronic kidney disease (CKD) on dialysis. Mortality rates are still unacceptably high even though they have fallen in the past 2 decades. Hyperphosphatemia (elevated serum phosphate levels) is seen in almost all patients with advanced CKD and is by far the largest remaining modifiable contributor to CKD mortality. <b><i>Summary:</i></b> Phosphate retention drives multiple physiological mechanisms linked to increased risk of CVD. Fibroblast growth factor 23 and parathyroid hormone (PTH) levels, both of which have been suggested to have direct pathogenic CV effects, increase in response to phosphate retention. Phosphate, calcium, and PTH levels are linked in a progressively worsening cycle. Maladaptive upregulation of phosphate absorption is also likely to occur further exacerbating hyperphosphatemia. Even higher phosphate levels within the normal range may be a risk factor for vascular calcification and, thus, CV morbidity and mortality. A greater degree of phosphate control is important to reduce the risk of CV morbidity and mortality. Improved phosphate control and regular monitoring of phosphate levels are guideline-recommended, established clinical practices. There are several challenges with the current phosphate management approaches in patients with CKD on dialysis. Dietary restriction of phosphate and thrice-weekly dialysis alone are insufficient/unreliable to reduce phosphate to &#x3c;5.5 mg/dL. Even with the addition of phosphate binders, the only pharmacological treatment currently indicated for hyperphosphatemia, the majority of patients are unable to achieve and maintain phosphate levels &#x3c;5.5 mg/dL (or more normal levels) [PhosLo® gelcaps (calcium acetate): 667 mg (prescribing information), 2011, VELPHORO®: (Sucroferric oxyhydroxide) (prescribing information), 2013, FOSRENAL®: (Lanthanum carbonate) (prescribing information), 2016, AURYXIA®: (Ferric citrate) tablets (prescribing information), 2017, RENVELA®: (Sevelamer carbonate) (prescribing information), 2020, RealWorld dynamix. Dialysis US: Spherix Global Insights, 2019]. Phosphate binders do not target the primary pathway of phosphate absorption (paracellular), have limited binding capacity, and bind nonspecifically [PhosLo® gelcaps (calcium acetate): 667 mg (prescribing information). 2013, VELPHORO®: (Sucroferric oxyhydroxide) (prescribing information), 2013, FOSRENAL®: (Lanthanum carbonate) (prescribing information), 2016, AURYXIA®: (Ferric citrate) tablets (prescribing information), 2017, RENVELA®: (Sevelamer carbonate) (prescribing information) 2020]. <b><i>Key Messages:</i></b> Despite current phosphate management strategies, most patients on dialysis are unable to consistently achieve target phosphate levels, indicating a need for therapeutic innovations [RealWorld dynamix. Dialysis US: Spherix Global Insights, 2019]. Given a growing evidence base that the dominant mechanism of phosphate absorption is the intestinal paracellular pathway, new therapies are investigating ways to reduce phosphate levels by blocking absorption through the paracellular pathway.

Uremic Cardiomyopathy

Chronic Kidney Disease (CKD) affects approximately 10% of the general population. CKD itself is a risk factor for cardiovascular mortality and morbidity. Large epidemiological studies have clearly established a clear relationship between severity of CKD and cardiovascular event rates. Sudden cardiac death accounts for approximately 40% mortality in dialysis patients and it is usually secondary to an underlying cardiomyopathy, with left ventricular hypertrophy mostly evident on echocardiography. Several risk factors play an important role in pathogenesis of uremic cardiomyopathy including vitamin D deficiency, secondary hyperparathyroidism, phosphate retention, increased FGF23 and decreased Klotho levels. The mortality due to cardiovascular events in early stage CKD is relatively higher in comparison to progression to ESRD, so early diagnosis and treatment with dialysis should be focused.

Hyperphosphatemia with elevated serum PTH and FGF23, reduced 1,25(OH)2D and normal FGF7 concentrations characterize patients with CKD

Background Hyperphosphatemia confers adverse cardiovascular outcomes, and commonly occurs in late-stage CKD. Fibroblast growth factor 7 (FGF7) is a phosphaturic peptide which decreases renal phosphate transport in vitro and in vivo. Serum FGF7 concentrations are reduced in hyperphosphatemic patients with hypophosphatasia and are elevated in some hypophosphatemic patients with tumor-induced osteomalacia. No data, however, are available on whether circulating FGF7 concentrations increase to compensate for phosphate retention in CKD patients. Methods This was a cross-sectional study performed among 85 adult patients with varying estimated glomerular filtration rates (eGFR). We measured serum intact FGF7 (iFGF7) concentration using an iFGF7 immunoassay and determined its associated factors. Relationships between eGFR and mineral metabolism biomarkers [phosphate, iFGF7, iFGF23, parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D (1,25(OH)2D)] were explored. Results For eGFRs of ≥ 60 (n = 31), 45–59 (n = 16), 30–44 (n = 11), 15–29 (n = 15), and < 15 mL/min/1.73 m2 (n = 12), median (IQ25-75) iFGF7 concentrations were 46.1 (39.2–56.9), 43.1 (39.0-51.5), 47.3 (38.3–66.5), 47.7 (37.7–55.8), and 49.6 (42.5–65.6) pg/mL, respectively (P = 0.62). Significant increases in serum iFGF23, PTH, and phosphate were observed at eGFRs of < 33 (95 % CI, 26.40-40.05), < 29 (95 % CI, 22.51–35.36), and < 22 mL/min/1.73 m2 (95 % CI, 19.25–25.51), respectively, while significant decreases in serum 1,25(OH)2D were observed at an eGFR of < 52 mL/min/1.73 m2 (95 % CI, 42.57–61.43). No significant correlation was found between serum iFGF7 and phosphate, iFGF23, PTH or 1,25(OH)2D. In multivariable analyses, body mass index (per 5 kg/m2 increase) was independently associated with the highest quartile of serum iFGF7 concentration (OR, 1.20; 95 % CI, 1.12–1.55). Conclusions Compensatory decreases in circulating 1,25(OH)2D and increases in circulating iFGF23 and PTH, but not iFGF7, facilitate normalization of serum phosphate concentration in early stages of CKD. Whether other circulating phosphaturic peptides change in response to phosphate retention in CKD patients deserves further study.

Phosphorus retention by granulated apatite: assessing maximum retention capacity, kinetics and retention processes

Natural apatites have previously shown a great capacity for phosphate retention from wastewater. However, its fine particle size distribution may lead to a premature clogging of the filter. Accordingly, a granulated apatite product was developed and manufactured in order to control the particle size distribution of the media. Experiments were conducted on laboratory columns to assess their phosphorus retention capacity, to identify the processes involved in phosphorus retention and to evaluate their kinetic rates. The results showed phosphorus retention capacities of 10.5 and 12.4 g PO4-P·kg−1 and kinetic rate coefficients in the range of 0.63 and 0.23 h−1 involving lower values than those found for natural apatites in previous studies. Scanning Electron Microscopy images showed that apatite particles in the granules were embedded in the binder and were not readily accessible to act as seeds for calcium phosphate precipitation. The retention processes differ depending on the supersaturation of the solution with respect to calcium phosphate phases: at low calcium concentrations (69.8 ± 3.9 mg·L−1), hydroxyapatite precipitates fill up the porosity of the binder up to a depth of 100–300 μm from the granule surface; at higher calcium concentrations (112.7 ± 7.4 mg·L−1) precipitation occurs at the granule surface, forming successive layers of hydroxyapatite and carbonated calcium phosphates.

Renal Phosphate Handling in Antiretroviral-naïve HIV-infected Patients

Background: Human immunodeficiency virus (HIV) infection impairs renal function, thereby affecting renal phosphate metabolism. Objectives: We prospectively estimated the prevalence of phosphate abnormalities (mild, moderate to life-threatening hypophosphataemia, and hyperphosphataemia) before initiating antiretroviral therapy (ART). Methods: A cross-sectional analysis was performed on 170 consecutive newly diagnosed ART-naïve, HIV-infected patients attending our HIV/AIDS clinics over a period of one year. Fifty (50) screened HIV-negative blood donors were used for comparison (controls). Blood and urine were collected simultaneously for phosphate and creatinine assay to estimate fractional phosphate excretion (FEPi %) and glomerular filtration rate (eGFR). Results: eGFR showed significant difference between patients’ and controls’ medians (47.89ml/min/1.73m2 versus 60ml/min/1.73m2, p <0.001); which denotes a moderate chronic kidney disease in the patients. Of the 170 patients, 78 (45.9%) had normal plasma phosphate (0.6-1.4 mmol/L); 85 (50%) had hyperphosphataemia. Grades 1, 2 and 3 hypophosphataemia was observed in 3 (1.8%), 3 (1.8%), and 1(0.5%) patient(s) respectively. None had grade 4 hypophosphataemia. Overall, the patients had significantly higher median of plasma phosphate than the controls, 1.4 mmol/L (IQR: 1.0 – 2.2) versus 1.1 mmol/L (IQR: 0.3 – 1.6), p <0.001, implying hyperphosphataemia in the patients; significantly lower median urine phosphate than the controls, 1.5 mmol/L (IQR: 0.7 -2.1) versus 8.4 mmol/L (IQR: 3.4 – 16), p <0.001), justifying the hyperphosphataemia is from phosphate retention; but a non-significantly lower median FEPi% than the controls, 0.96 % (IQR: 0.3 -2.2) versus 1.4% (IQR: 1.2 -1.6), p > 0.05. Predictors of FEPi% were age (Odds ratio, OR 0.9, p = 0.009); weight (OR 2.0, p < 0.001); CD4+ cells count predicted urine phosphate among males (p = 0.029). Conclusion: HIV infection likely induces renal insufficiency with reduced renal phosphate clearance. Thus, hyperphosphataemia is highly prevalent, and there is mild to moderate hypophosphataemia but its life-threatening form (grade 4) is rare among ART-naïve HIV patients.