Hyperphosphatemia(also acute phosphate nephropathy)

Data from

• Overview of the causes and treatment of hyperphosphatemia
• Tumor lysis syndrome: Definition, pathogenesis, clinical manifestations, etiology and risk factors-Hyperphosphatemia
• Tumor lysis syndrome: Prevention and treatment-Indications for renal replacement therapy
• Acute phosphate nephropathy
• Neonatal hypocalcemia
• Management of hyperphosphatemia in chronic kidney disease-Specific treatment
• Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)
• Management of secondary hyperparathyroidism in dialysis patients
• Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease
• Overview of the management of acute kidney injury in adults-Hyperphosphatemia

1.Normal physiology#

• 見HypophosphatemiaHypophosphatemia-1.Physiology

2.Etiologies#

• Pseudohyperphosphatemia(因為某些分析方法)
  • Hyperglobulinemia(MM, Waldenström macroglobulinemia...), hyperlipidemia, hyperbilirubinemia, hemolysis, drugs(high dosage Ambisome, heparin, tPA)
• Extracellular shifting(感覺和hyperkalemia類似但少了β-blocker)
  • Insulin deficiency
  • Metabolic acidosis
    • Intracellular pH↓-->phosphofructokinase activity↓-->glycolysis↓-->phosphate utilization↓-->hyperphosphatemia
    • Extracellular shifting of P
    • 尤其DKA or lactic acidosis
      • DKA因為還有insulin deficiency(and osmotic diuresis(所以DKA總P量是↓的, 但serum concentration可高可低)); lactic acidosis因為尚有cell deaths/hypercatabolism
  • Respiratory acidosis
• Phosphate loading
  • Vitamin D intoxications(因為1.↑GI uptake Ca, P; 2.bone放出Ca-P; 3.(↑SCa+Vitamin D-->↓PTH); 4.本身似乎也↑p. tubule Pi resorption; 上述effects總和比(Vitamin D↑導致FGF-23↑)大)
  • Drugs
    • Fleet enema
      • 還是常用於preparation for colonoscopy, 因為(less expensive, better tolerated, more effective in colonic cleansing; reference:Which is the optimal bowel preparation for colonoscopy - a meta-analysis.(2006 Colorectal Dis.)
      • For acute phosphate nephropathy
        • Incidence:unknown
        • Pathogenesis
          • Phosphate loading
            • 用fleet者即使GFR>70ml/min一樣可以使serum P>8mg/dL(even 30-40%; 尤其elderly, 可能是因為老人volume少, bowel motility problems, GI absorption↑...)
          • Nephrocalcinosis
            • Ca-P depositions in distal and collecting ducts-->TN-->peritubular interstitial deposits-->IN
              • 所以是ATIN or cTIN
        • Risk factors
          • Old age(volume少, bowel motility problems, GI absorption↑), female(TBW較少?)
          • Ulceration of bowel mucosa, bowel obstruction/ileus(GI吸收多?)
          • Volume depletion
            • Due to diarrhea(+NPO for colonoscopy)
          • ACEI/ARB
            • Due to 1.↓GFR 2.↓ angiotensin II-dependent proximal tubule HCO3 reabsorption(=↓NHE3?)(所以Ca-P容易沉澱)
          • Diuretics/NSAID
          • Poor GFR(<60ml/min?), 不過normal GFR者也可acute phosphate nephropathy
          • HTN, DM
            • why?
        • S/S
          • Increasing Cre after days-months(Median:1M) after fleet when SCa and SP are both normal !!!!!!!
          • U/A多bland but可hematuria(不常見), pyuria, trivial proteinuria
          • Poor prognosis!!!(多CKD, 可ESRD), 不太會recover to baseline!!
        • If AKI within hrs + hyperphosphatemia + hypocalcemia; 多會recover
          • 此種狀況比較不像acute phosphate nephropathy, 比較像pre-renal AKI or dehydration related ATN
        • Tx
          • Avoid fleet if eGFR<60ml/min、高齡、脫水、使用 ACEI/ARB/NSAID/利尿劑者絕對禁用口服磷酸鹽清腸劑，應改用 PEG 等非吸收型配方
          • Consider HD to remove phosphate if acute phosphate nephropathy with still hyperphosphatemia within 12-24hrs after fleet use
    • Fosphenytoin(metabolized to phenytoin, phosphate, and formaldehyde)
  • Osteolytic metastasis, cell lysis(tumor lysis, rhabdomyolysis, hemolysis/transfusion of stored blood, fulminant hepatitis(Brenner(p814)))
    • For tumor lysis syndrome
      • 大多在C/T D-3~D7
      • Malignant lymphoid cell內P的含量為normal lymphoid cell的4X所以lysis容易hyperphosphatemia
      • 若Ca-P乘積>60(mg^2)/(dL^2)容易Ca-P deposition而AKI, arrhythmia
      • 若Ca-P乘積>70(mg^2)/(dL^2), 可能需要RRT(且因為P較難移除, 有可能需要QD HD)
• ↓renal clearance
  • GFR↓(多要CKD stage IV以上)
    • 見-hypophosphatemiahypophosphatemia-當hyperphosphatemia
  • Increased tubular resorption
    • Acromegaly(GH and IGF-1直接↑proximal tubules的NaPi IIa)
      • 也會hypercalcemia(due to concurrent ↑PTH(MEN I?) or ↑1,25-OH vitamin D)
    • Hypoparathyroidism
      • 見-hypocalcemiahypocalcemia-hypoparathyroidism
      • Hypoparathyroidism Tx 用 calcitriol 常規上會↑GI磷吸收而惡化高磷(需監測P/Ca、配磷結合劑與低磷飲食; 且無PTH時FGF23的phosphaturic效果也變差); (原筆記曾寫「calcitriol反而↓高磷」之孤例觀察, 與主流生理矛盾且同庫vitamin D intoxication→磷↑不符, 已標記存疑)
    • Pseudohypoparathyroidism(congenital)
      • Due to renal PTH resistance
      • 見-hypocalcemiahypocalcemia-Pseudohypoparathyroidism
    • Drugs
      • Bisphosphonate
        • P可高可低; 因為1.抑制bone resorption and 可Ca↓->iPTH↑->urine排P↑, 2.但也刺激renal tubules再吸收P
    • Familial tumoral calcinosis(AR)(mirror image of ADHR)
      • Due to GALNT3 gene loss of function mutation(encodes a glycosyltransferase which ↓ FGF23 degradation)==>FGF 23↓; 也可以是Klotho(coreceptor of FGF 23) loss of functional mutation導致FGF 23 resistance or FGF 23本身loss of functional mutation
        • Calcitriol↑↑; iPTH, ALP, SCa WNL
          • Ca*P乘積↑導致鈣磷沉積, soft tissue calcifications(故名tumoral calcinosis)
      • Tx
        • Phosphate binders
        • Azol(phosphaturic effects)
          • Increased proximal tubules PTH sensitivity
          • 導致proximal renal tubules intracellular alkalosis(?)導致phosphate resorption↓

3.Tx#

• Tx of underlying diseases
  • CKD者見-CKD-MBD(2017 KDIGO) (4.2) (also bone physiology); CKD/ESRD-Tx(Anemia/Ca/P/Vitamin D/iPTH/drugs/comorbidities)-Ca/P/iPTH-P
• Phosphate binders
  • CKD non-G5D P goal:normal
  • ESRD P goal:3.5-5.5mg/dL(KDOQI and uptodate), toward normal(KDIGO)
  • AKI goal:<6mg/dL(不過AKI沒evidence support這樣做improves outcomes)
  • 飲食限磷(first-line):目標約800-1000mg/day; 重點在有機磷 vs 無機磷——無機磷(加工食品/可樂/加工肉品中的phosphate additives)吸收率>90%且不受vitamin D調控, 應優先避免(很多磷藏在添加物, 衛教很重要); 植物性有機磷(phytate)吸收率最低(~40-50%), 動物性次之(~60%); 不應為限磷而過度限制蛋白質(會malnutrition)
  • Phosphate binders(務必隨餐服用才有效), 分類:
    • Calcium-based:CaCO3(碳酸鈣)、Ca acetate(醋酸鈣, PhosLo; 結合磷效力較CaCO3佳且釋出Ca較少)
      • 便宜有效, 但risk:hypercalcemia, 加重vascular calcification; 建議elemental Ca<1500mg/day(KDIGO 2017建議限制calcium-based binders用量)
    • Non-calcium, non-metal:Sevelamer(carbonate or HCl; HCl form會加重metabolic acidosis故ESRD多用carbonate); 額外好處↓LDL、↓uric acid、可能↓vascular calcification與發炎; 無hypercalcemia風險; 缺點pill burden大、GI S/E
    • Lanthanum carbonate(Fosrenol):咀嚼錠, 效力強、pill burden較低; 微量GI/骨沉積(長期安全性大致良好)
    • Iron-based:Ferric citrate(同時補鐵, 可↓ESA/IV iron需求, 但小心iron overload)、Sucroferric oxyhydroxide(Velphoro; pill burden低, 幾乎不吸收鐵)
    • Aluminum hydroxide:效力最強, 但Al毒性(encephalopathy, osteomalacia, microcytic anemia), 僅短期(<4W)救援用
    • (Magnesium-based少用)
  • Tenapanor(NHE3 inhibitor; 2023 FDA核准用於透析病人控磷): 抑制腸道NHE3→↓細胞內pH→緊縮tight junction→↓paracellular磷吸收(非結合劑全新機轉); 可單用或與binder併用顯著降pill burden，主S/E為腹瀉；NORMALIZE (Kidney360 2023; PMID 37853560)：透析高血磷使用 tenapanor 顯著降結合劑負擔並助達標｜33.7% 患者達目標血磷(2.5-4.5 mg/dL)〔PMID 37853560〕
  • 同步治療secondary hyperparathyroidism(vitamin D analogs如calcitriol/paricalcitol、calcimimetics如cinacalcet/etelcalcetide), 因為iPTH↑會動員骨中Ca-P; 詳見CKD-MBD
• N/S infusion
• Azol：→ 見上方 Familial tumoral calcinosis段（phosphaturic機轉同上）
• Dialysis(移除磷)
  • HD每次移除磷有限(磷主要在ICF, 透析中後段血磷↓→濃度梯度↓→移除變慢, 呈rebound/redistribution-limited; 單次HD約移除~800mg), 故單靠HD常不足以控磷, 需搭配限磷+binder
  • 延長/頻繁透析(nocturnal HD、short daily HD、HDF)移除較多磷, 是控制頑固高磷的有效手段
  • if poor GFR and symptomatic hypocalcemia(or 急性嚴重高磷如tumor lysis/AKI)
    • HD(必要時CRRT)

---

相關章節#

• CKD-MBD、Hypocalcemia、Vitamin D deficiency、Peritoneal dialysis(PD)、Hemodialysis(HD)