New Progress in Blood Phosphorus Management in Non-dialysis CKD Patients
Dec 23, 2022
Chronic kidney disease-mineral and bone metabolic abnormalities (CKD-MBD) is one of the common serious complications in patients with chronic kidney disease (CKD), and its management is crucial to the long-term prognosis of CKD patients. The 2019 "Guidelines for the Diagnosis and Treatment of Mineral and Bone Abnormalities in Chronic Kidney Disease in China" clearly pointed out that CKD-MBD needs to reduce the incidence of fractures and cardiovascular and cerebrovascular complications by managing the patient's serum calcium, phosphorus, parathyroid hormone (PTH) and other indicators, to achieve the long-term goal of improving the quality of life of patients and reducing mortality [1].
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Serum phosphorus management has long been considered a key link in the management of CKD-MBD [2]. Halfway through 2022, we invited Professor Peng Hui from the Third Affiliated Hospital of Sun Yat-sen University to review the latest progress in blood phosphorus management of non-dialysis CKD patients in the first half of 2022.
1 Hyperphosphatemia is an independent risk factor for CKD progression and cardiovascular events
Analysis of the NEPHRONA cohort study | CKD patients without previous cardiovascular disease history | 2445 cases
Research purposes and methods: A cohort study included 2445 patients with CKD stage 3-5D without cardiovascular history from the NEPHRONA cohort study (950 cases in stage 3, 612 cases in stage 4, 195 cases in stage 5, and 688 cases on dialysis). Multivariate logistic and competing risk model regression analysis methods were used to analyze the independent risk factors for CKD progression (2-year follow-up observation time) or cardiovascular events (CVE) (4-year follow-up observation time)[3].
Results: After 2 years, 301 patients developed CKD progression, hyperphosphatemia accounted for 34.3% of CKD progression, and 7.8% of non-CKD progression, odds ratio (OR) 6.16 [95% Confidence Interval (CI) 4.39-8.68, P<0.001]; during the 4-year follow-up, 203 patients developed CVE, and hyperphosphatemia accounted for 36% of those with CVE, and 28.3% of those without CVE. OR 2.00 (95%CI 1.49-2.67, P<0.001). Hyperphosphatemia is an independent risk factor for the progression of CKD and the occurrence of CVE. In addition, secondary hyperparathyroidism (SHPT) is also an independent risk factor for the progression of CKD and the occurrence of CVE [3].
Odds ratio (OR) of secondary hyperparathyroidism (SHPT), hypercalcemia, and hyperphosphatemia in a logistic model of chronic kidney disease progression. Model 1: Analysis including three variables. Model 2: Adjusted for age and gender. Model 3: Adjusted for age, sex, body mass index, diabetes, hypertension, smoking status, and proteinuria.
Cardiovascular event (CVE) hazard ratios (HR) for secondary hyperparathyroidism, hypercalcemia, and hyperphosphatemia in a competing risks model. Model 1: Analysis including three variables. Model 2: Adjusted for age and gender. Model 3: Adjusted for age, sex, body mass index, diabetes, hypertension, dyslipidemia, smoking status, chronic kidney disease stage, and 25-hydroxyvitamin D level.
2 Cannot reduce phosphorus, but can improve indicators such as uremic toxins and atherosclerotic toxins in non-dialysis CKD patients, and is closely related to compliance
The guidelines recommend that non-dialysis CKD patients should adopt the 2D phosphorus reduction principle of dietary phosphorus control (Diet) and reasonable selection of phosphorus binders (Drugs)[1]. Phosphorus-restricted diet is the cornerstone of blood phosphorus management in CKD patients and one of the important means to reduce phosphorus in non-dialysis CKD patients. However, the implementation is full of challenges, including compliance, accurate assessment of phosphorus content in food, and malnutrition. , currently has little effect on the control of blood phosphorus in patients with advanced CKD [1]. New research shows again that a low-protein diet can improve indicators of uremic toxins and atherogenic toxins in non-dialysis CKD patients, and is closely related to adherence.
Clinical study of low-protein diet | non-dialysis severe CKD patients | 57 cases
Research purposes and methods: A clinical study included 57 non-dialysis patients with severe CKD [estimated glomerular filtration rate (eGFR) 6-25 ml/min/1.73m2], given a low-protein diet (0.6g protein/kg target weight) for 2 months, evaluate the patient's adherence (adherence) and consistency (concordance), and observe nutrition-related indicators [blood lipids, blood phosphorus, normalized proteolysis rate (nPCR), etc.], uremic toxins [total sulfuric acid Changes in the levels of p-cresol (PCS) and free PCS, total indoxyl sulfate (IS) and free IS] and atherogenic toxin [lipoprotein-associated phospholipase A2 (Lp-PLA2)] [4].
Research results: After 2 months of low-protein diet treatment, nPCR, blood urea nitrogen, total cholesterol, and triglycerides of all patients decreased significantly, while blood phosphorus did not change significantly; the level of free PCS decreased significantly in adherents; the consistency was high The levels of Lp-PLA2, total PCS, free PCS and total IS decreased in patients with low consistency, while the levels of Lp-PLA2 and total PCS increased in patients with low consistency [4].
A low-protein diet improves uremic and atherogenic toxins in nondialysis CKD patients, but only in patients with high compliance and consistency.
3 Phosphorus binders
The Chinese CKD-MBD guidelines recommend restricting the use of calcium- and phosphate-containing binders, and recommend non-calcium- and phosphate-containing binders as first-line drugs. Non-calcium-containing phosphate binders commonly used in clinical practice are mainly sevelamer and lanthanum carbonate. At present, lanthanum carbonate does not indicate non-dialysis patients in China. In the first half of this year, non-calcium-containing phosphate binders released important studies on the long-term prognosis of non-dialysis CKD patients. Next, we will take stock one by one.
3.1 Two new pieces of evidence have been added for the long-term benefits of sevelamer on non-dialysis CKD patients
PECERA study｜Prospective, multicenter, open cohort study｜Non-dialysis CKD stage 4-5 | 966 cases
Research purposes and methods: A 3-year prospective multicenter open cohort study, including 966 non-dialysis CKD stage 4-5 adult patients, compared calcium and/or non-calcium phosphate binders in the risk of all-cause mortality benefits. 515 patients (53%) received phosphate binders, 37% used calcium-containing phosphate binders (n=360), 11% used non-calcium phosphate binders (n=111), and 5% used a combination of both (n=360). =44), of which sevelamer was the only non-calcium phosphate binder prescribed during the study period.
Results: Sevelamer-treated patients had a significant 53% reduction in overall all-cause mortality [hazard ratio (HR) 0.47, 95% CI 0.27-0.84], whereas no significant reduction was seen in patients treated with calcium-phosphate binders ( HR 0.77, 95% CI 0.57-1.03) [5]. Studies have shown that sevelamer can reduce the risk of all-cause mortality in non-dialysis CKD patients with hyperphosphatemia.
Large retrospective real-world cohort study | non-dialysis CKD stage 1-5 | 9047 cases
Research objectives and methods: A retrospective real-world cohort study of 9047 adults with nondialysis CKD hyperphosphatemia who received sevelamer or calcium-containing phosphate binders (CPB) was included in the Optum Clinformatics® administrative claims database in the United States. For patients, the 1:1 propensity score matching (PSM) method was used to correct the differences in confounding variables between groups. After PSM, there were 2399 patients in the sevelamer group and CPB group, and the average follow-up time was 1032.1±985.9 days. The primary endpoint is renal replacement therapy (RRT, including hemodialysis, peritoneal dialysis, and kidney transplantation), and the secondary endpoints are major cardiovascular events (MACE, including all-cause death, acute non-fatal myocardial infarction, stroke), MACE+ (including MACE, unstable angina and heart failure) and all-cause death[6]
Results: During the 3-year follow-up period, Sevelamer significantly reduced the incidence of RRT in non-dialysis CKD patients by 16% (HR 0.84, 95%CI 0.79-0.91, P<0.001), compared with calcium-phosphate binders. The reduction in the incidence of MACE and MACE+ was 9% (HR 0.91, 95%CI 0.84-0.99, P=0.0249) and 12% (HR 0.88, 95%CI 0.81-0.95, P= 0.0009) respectively [6].
Studies have shown that Sevelamer can significantly reduce the use of renal replacement therapy in CKD patients and reduce the occurrence of major cardiovascular events.
3.2 The long-term benefits of lanthanum carbonate on non-dialysis CKD patients did not yield positive results
IMPROVE-CKD Study｜Multicenter, Randomized Double-blind Controlled Trial | CKD Phase 3b~4 | 278 Cases
Research endpoint: A multi-center, randomized double-blind trial, including 278 patients with CKD stage 3b~4 with blood phosphorus >1.00mmol/L, were randomly assigned to the lanthanum carbonate group (500mg/time, 3 times a day; n=138) or The placebo group (n=140) was treated for 96 weeks. The primary endpoint was carotid-femoral pulse wave velocity (PWV) [7]. Relevant research results have been published in 2020, and this year, the latest post-hoc analysis using the level of calcium protein particles (CPP) as the research endpoint was released [8].
Research results: For non-dialysis patients with advanced CKD with normophosphatemia, compared with placebo, there was no significant difference in PWV and serum phosphorus levels after 96 weeks of lanthanum carbonate treatment[7], and there was no change in CPP[8].
Studies have shown that lanthanum carbonate did not significantly improve PWV and blood phosphorus levels in non-dialysis patients, and more research is expected.
summary
CKD-MBD needs to reduce the incidence of fractures and cardiovascular and cerebrovascular complications through the management of serum calcium, phosphorus, PTH, and other indicators in patients, to achieve the long-term goal of improving the quality of life of patients and reducing the risk of death. Hyperphosphatemia is the key to the management of CKD-MBD.
This year, a new study published in Nephrology Dialysis Transplantation once again confirmed that hyperphosphatemia is an independent risk factor for CKD progression and cardiovascular events, and early management of blood phosphorus should be paid attention to in clinical work.
The long-term benefits of phosphorus-restricted diets in non-dialysis CKD patients have been controversial. The Chinese CKD-MBD guidelines point out that restricting dietary phosphorus intake is an important means of reducing phosphorus in non-dialysis CKD patients, but according to the existing evidence, it has little effect on blood phosphorus control in advanced CKD patients. And this year's newly released clinical research has once again confirmed that for non-dialysis CKD patients, a phosphorus-restricted diet cannot reduce blood phosphorus levels, and only improves uremic toxins and atherosclerosis in non-dialysis CKD patients with high compliance and consistency. Toxin accumulation. This study suggests that in our clinical work if patients with poor compliance or non-compliance are expected, phosphorus binders should be added as soon as possible.
Current domestic and foreign guidelines recommend limiting the use of calcium-phosphate binders. Chinese CKD-MBD guidelines recommend non-calcium-containing phosphate binders as the first-line drug. Non-calcium-containing phosphorus binders commonly used in my country include sevelamer and lanthanum carbonate. Currently, only sevelamer carbonate has indications for non-dialysis CKD patients in China. Both have released important studies on the long-term prognosis of non-dialysis CKD patients this year. Among them, two studies of sevelamer respectively confirmed that compared with calcium-phosphate binders, it can reduce the risk of all-cause mortality, the risk of entering RRT, and the risk of cardiovascular events in non-dialysis CKD patients. The IMPROVE-CKD study of lanthanum carbonate has not yet yielded positive results.
for more information:ali.ma@wecistanche.com
