Mineral Bone Disorder (CKD-MBD)

• Note: these are guidelines based on expert opinion and evidence (where there is any available). Lab frequency should be adjusted depending on rate of progression or when medication doses are adjusted

• CKD stage 1 (GFR ≥90): measurements not routinely indicated

  • Ca, PO4 usually assessed every 1-2 years with assessment of kidney function

• CKD stage 2 (GFR 60-89)

  • Measure Ca, PO4 every 12 months, PTH based on baseline and CKD progression (usually every 1-3 years)

• CKD stage 3 (GFR 30-59)

  • Measure Ca, PO4 every 6-12 months, PTH based on baseline and CKD progression (usually every 12-24 months)

  • Target intact PTH: 35-70 pg/mL (3.85-7.7 pmol/L)

• CKD stage 4 (GFR 15-29)

  • Measure Ca, PO4 every 3-6 months, PTH every 6-12 months

  • Target intact PTH 70-110 pg/mL (7.7-12.1 pmol/L)

• CKD stage 5 (GFR <15)

  • Measure Ca, PO4 every month and PTH every 3 months

  • Target intact PTH 150-300 pg/mL (16.5-33.0 pmol/L)

• Calcium - Normally runs low in ESRD and CKD patients due to high phosphorus levels. Important to make sure kids are getting the DRI of calcium and Vit D and are on supplements if needed.

  • Often, we will choose calcium containing Phos binders for these kids (Calcium Carbonate/TUMS, Calcium Acetate/PhosLo).

  • For older kids (teens and above), we tend to avoid calcium containing binders since they are at higher risk for vascular calcifications.

  • Rarely, a child will be hypercalcemic. Sometimes that is due to medications (hypervitaminosis D), elevated Vitamin A (high doses in kidney formulas), or inactivity and bone turnover.

• Phosphorus - Different normals for different ages, but we adhere to KDOQI guidelines

  • First step is dietary management. See Table 23 for recommended DRI for phosphorus based on levels and PTH

  • Phos is one of the first signals for hyperparathyroidism. Decreased clearance of phosphorus in the kidney with advancing kidney disease leads to rising blood levels.

  • This decreases calcium levels and drives PTH to increase.

  • We use phos binders once dietary control is insufficient. For the formula fed children, we can decant with Renvela (sevelamer) just like we do with Kayexalate.

  • Be mindful of pt’s age and preferentially use calcium containing binders (easier, no decanting required!). Young kids need to be in positive calcium balance for good growth, so we prefer TUMS or PhosLo for them.

• Vitamin D - Target normal levels (most attendings are ok with > 20ng/dL, but some want them > 30ng/dL) provided they are not hypercalcemic

  • Vitamin D is modified in the kidney to activated 1,25 VitD. This will act in multiple places, including the gut to enhance absorption of Calcium AND Phos. It also increases bone resorption (via PTH) and decreases kidney Ca and Phos excretion.

  • We start by supplementing cholecalciferol (basic vitamin D) or ergocalciferol (plant-derived Vitamin D, only has to be given weekly). We should make sure substrates are first replete before giving activated Vit D.

  • As kidney disease advances, activated Vit D reduces in the blood and we can start replacing that. These include calcitriol (Rocaltrol), paricalcitol (Zemplar), and doxercalciferol (Hectorol). They act on the Vitamin D receptor in the parathyroid glands to help suppress PTH.

• PTH - Target levels are debated. But KDOQI has published these numbers. Most recent guidelines say for dialysis patients to be less than 2-9x the upper limit of normal (huge range), but CKD PTH targets are still debated.

  • We use Phos management as first line for PTH reduction

  • Then Vit D supplementation (activated Vit D)

  • Last case, consider Sensipar (cinacalcet). Since it is an antagonist to the Ca-sensing receptor, it can result in profound hypocalcemia and needs to be closely monitored.

  • If there is still significant hyperPTH, especially with hypercalcemia, consider primary hyperPTH workup (will need a nuclear sestamibi scan to evaluate for adenoma; done through adult Stanford side)

Alk Phos - Monitor levels with growth hormone and PTH to make sure not rising or elevated. Concern for bone abnormalities.

Calcium homeostasis: https://i0.wp.com/nephsim.com/wp-content/uploads/2019/02/Picture1-2.png

Phosphorus

• Goal: predialysis level toward the normal range (2.5- 4.5 mg/dL, or say 3.5-5.0)

• Modeling goals:

  • Predict change in predialysis serum P with change in dialysis therapy (longer treatment, extra treatments, hemodiafiltration )

  • Estimated phosphate binder equivalent dose (PBED) needed to achieve a given predialysis serum P

• How is phosphorus removal by hemodialysis different from urea removal?

  • Diffusion effect

    • Phosphate (MW 95) diffuses more slowly than urea (MW 60), and it is charged

    • K0A = maximum in vitro clearance through a dialyzer at infinite blood and dialysate flow rates

    • Different for each solute, and depends on dialyzer membrane permeability (L0) and dialyzer membrane surface area (A)

    • K0A urea typically ~1500 mL/min for a high efficiency, large dialyzer

    • K0A for phosphorus ~0.6 x K0A for urea (for modern high efficiency dialyzers)

      • The 0.6 K0A multiple in vitro accounts for a 0.85 lower clearance in vitro (i.e., diffusion effect accounts for 15% lower clearance)

  • Flow effect

    • Phosphate is removed from plasma water; urea is removed from blood water (RBCs and plasma)

      • Hematocrit 33%, plasma 67%

      • Blood water = 0.80 * 0.33 + 0.93 * 0.67 = 0.264 + 0.623 = 0.89 x Qb

        • For Qb 400, Qbw = 356 mL/min

      • Plasma water = 0.93 x 0.67 = 0.62 * Qb

        • For Qb 400, Qpw = 248 mL/min

      • Only spends 15 seconds in the dialyzer

      • Qpw/Qbw = 0.62/0.89 = 0.70

        • The flow from which you are removing phos is 70% of the flow of urea

      • Overall combing diffusion and flow effects, Kd phosphate is about 60% of that of Kd-urea

      • Of course when you remove fluid, the hematocrit can go up markedly in some patients, further restricting phosphorus removal

    • Plateau effect

      • Phosphate levels during dialysis plateau and don't keep going down (after ~2-2.5 hours)

        • Treatment implication: dialysis session length extension is more beneficial for removal of phosphate than for urea

      • Two pool model of solute removal

        • Central compartment and peripheral compartment

        • The "door" (Kc, intercompartmental clearance) between compartments for urea is small

          • To account for this in modeling, Phos = 3x TBW; for Urea is 0.67 x TBW

        • The door "opens up" when plasma levels get to about 3 mg/dL [*** check slides]

      • Time averaged value multiplied by clearance = how much phos is removed by clearance

    • How much P is absorbed per week?

      • Dietary phosphorus intake/day = 1100 mg (men), 900 mg (women)

        • 2/3 is absorbed, so 773 mg (men) or 600 mg (women) per day

      • Per week: P absorbed = 5.1 g/week in men or 4.2 g/week in women

    • How much P is removed during an average dialysis treatment?

      • Depends a lot on predialysis serum phosphorus level

        • Removal = dialyzer clearance x intradialytic average P level x session length

        • Intradialytic average P level (and hence P removal) depends on prephos: plateau is higher if serum phosphorus is higher

          • Clearance per treatment is ~1000 mg when prephos = 4.0 mg/dL

          • Problem:

            • Weekly P removed = 3 g, means there is a deficit of 2.1 g (men) and 1.2 g (women) that needs to be removed, which is accomplished with binders

Phosphate binder equivalent dose

• PBED: calculator at ureakinetics.org (username solute/password solvent)

  • 1 g PBED will bind 45 mg phosphorus

    • This is the case for calcium carbonate and calcium acetate

• Common binders [***conversions in screenshot]

  • Calcium carbonate

    • 40% elemental calcium by weight

  • Calcium acetate (Phoslo)

    • 25% elemental calcium by weight

  • Lanthanum carbonate (Fosrenol)

  • Sevelamer (Renvela)

  • Ferric citrate (auryxia)

  • Sucroferric oxyhydroxide

• Average PBED requirements

  • Depends on phosphate content of diet, dialysis amount, and residual kidney function, and on desired prephos value

    • Anuric men: ~6.0 g/day; anuric women: ~5.5 g/day; with residual kidney function these are about 25% lower

    • 5.0 g/day PBED will bind 5 x 45 = 225 mg P/dday = 1.6 g P/week

• What happens if the patient stops taking binders?

  • When PBED = 0, prephos will rise to around 8.0 mg/dL

    • Assuming no residual function: now dialyzer removal is ~1600 mg/session, or 4.8 g/week. There is no longer a P removal deficit assuming standard phosphorus intake (which is often not the case)

• Phosphate solver model: calculator at ureakinetics.org

  • Assume prephos = 6.0 mg/dL; PBED is 5.2 g/day

  • We want prephos to 4.0, dialysis schedule 3/week x3.5 hours. Assuming P intake 1200 mg/day, PBED would be 5.2 g day with prephos of 6.0.

  • If we increase session length from 3.5 to 4.5 hours, prephos would decrease to 4.51 mg/dL

  • Adding a 4th treatment would lower phos to 4.17 mg/dL

  • Adding a 4th treatment but keeping total dialysis time/week at 10.5 h (157 min/session): predicted prephos 5.7 mg/dL

  • Reducing phos intake from 1200 to 955 mg/day would lower prephos from 6.0 to 4.0 mg/dL

  • Increasing PBED from 5.2 g/day to 10.6 g/day would lower prephos to 4.0 mg/dL

• Conclusions:

  • Phosphate control can be approached from diet, binders, or treatment

  • Dialysis session length increases or adding 4th treatment can markedly lower predialysis serum phosphorus

  • Weekly time on dialysis is more important than frequency

  • A kinetic model can be used to make "what-if" predictions, but model still needs clinical validation before being clinically applied