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How are CKD stages 3 to 4 treated
How should treatment be approached for patients with CKD stages 3 to 4?
The earliest manifestations of CKD-MBD in the evolution of CKD are increases in FGF23, phosphate retention, decreases in calcitriol, then increases in PTH, and finally (in late stage 4, early stage 5 disease) hyperphosphatemia and eventually hypocalcemia.
Most patients are also calcidiol (25-hydroxy vitamin D) deficient. Unfortunately, adequate studies demonstrating clinical outcome benefit to various therapies are lacking.
Therefore treatment recommendations have been based on expert opinion and clinical judgment. The current approach to therapy should be aimed at reversing or preventing these perturbations in mineral metabolism.
A reasonable approach would be to prevent phosphate retention either through moderate phosphate restriction or the introduction of phosphate binders.
To date, the use of phosphate binders has not been approved in CKD stages 3 and 4, nor are there adequate studies demonstrating that the use of phosphate binders results in improved patient outcome.
Furthermore, there may be a risk of worsening coronary artery calcifications, especially with the use of calcium-containing phosphate binders. It is also reasonable to correct the calcidiol deficiency by replacing nutritional vitamin D, either with cholecalciferol (1200 to 2000 units/day) or ergocalciferol (50,000 units once monthly to once weekly).
Cholecalciferol is vitamin D 3 , which comes from animal sources, as opposed to ergocalciferol, vitamin D 2 , which comes from plants. Although cholecalciferol is more readily orally absorbed, once absorbed, both D 2 and D 3 compounds are essentially equivalent.
Extended-release (ER) calcifediol (25-hydroxycholecalciferol) may be more effective than nutritional vitamin D in correcting both the vitamin D deficiency and hyperparathyroidism. If PTH levels remain elevated after some degree of phosphate control and correction of vitamin D deficiency, then it would be reasonable to use a VDRA—calcitriol, paricalcitol, or doxercalciferol.
There does not appear to be a role for calcimimetics in CKD stages 3 and 4. Although the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (K/DOQI) and Kidney Disease: Improving Global Outcomes (K/DIGO) have suggested therapeutic targets for PTH concentrations, unfortunately there are insufficient data to support those targets, and patients should be treated using clinical judgment.
Characteristics of Commonly Used Phosphate Binders
| PHOSPHATE BINDER | BENEFITS | HAZARDS | BONE BIOPSY FINDINGS |
|---|---|---|---|
| Aluminum | Potent and effective Useful for short term in severe hyperphosphatemia | Dementia Low-turnover bone disease/osteomalacia Anemia Should not be used as maintenance therapy | Markedly decreases turnover, markedly impairs mineralization, and moderately decreases volume |
| Calcium salt based | Effective Inexpensive Treats hypocalcemia Antacid properties useful for reflux and peptic ulcer disease | High calcium load Hypercalcemia Development of adynamic bone disease Extraosseous/vascular calcifications | May slightly decrease bone turnover, no effect on mineralization or volume |
| Sevelamer | Effective No systemic absorption Lowers level of low-density lipoprotein cholesterol Lower risk of hypercalcemia Reduces aortic and coronary calcification versus calcium salts Lower risk of adynamic bone disease versus calcium salts | Expensive Binds bile acids May inhibit absorption of active vitamin D Not effective in acidic environment Gastrointestinal symptoms such as diarrhea/constipation High pill burden | May slightly increase bone turnover, no effect on mineralization, and may slightly increase bone volume |
| Lanthanum carbonate | Potent and effective over wide pH range Lack of hypercalcemia No evidence of increased risk of low bone turnover disease Reduced pill burden | Expensive Gastrointestinal symptoms such as dyspepsia | May increase bone turnover, no effect on mineralization, and increases in bone volume |
| Ferric citrate | Effective Significant absorption of iron that may decrease iron and ESA requirements Lack of hypercalcemia | Expensive Gastrointestinal symptoms such as diarrhea/dark stools High pill burden Potential for iron overload | Unknown |
| Sucroferric oxyhydroxide | Potent and effective over wide pH range Lack of hypercalcemia No significant systemic absorption Reduced pill burden | Expensive Gastrointestinal symptoms such as diarrhea/dark stools | Unknown |
Comparison of Kidney Disease Outcomes Quality Initiative With Kidney Disease: Improving Global Outcomes Mineral Guidelines
K/DIGO | K/DOQI | |
|---|---|---|
| Monitoring of Ca, phos, PTH | Starting at CKD stage 3 CKD stage 5 Ca and phos monthly PTH quarterly Include alkaline phosphatase: high or low levels may predict bone turnover | Same, no comment on alkaline phosphatase |
| Goal calcium | Normal range CKD stages 3–5 | Same, weighted to lower end of normal range (8.4–9.5 mg/dL) |
| Goal phosphorus | Normal range stages 3–5 | Range 2.7–4.6 mg/dL stages 3–4, 3.0–5.5 mg/dL for stage 5 |
| Goal PTH | Evaluate patients with PTH above upper limits of normal for correctable factors: low phos/ca, low vitamin D. Treat based on trends to achieve PTH between 2 and 9 times the upper limit of normal | Target ranges: CKD3 35–70 pg/mL CKD4 70–110 pg/mL CKD5 150–300 pg/mL |
| Bone biopsy | Reasonable in various settings and prior to bisphosphonate therapy in CKD-MBD | Should be considered |
Ca , Calcium; CKD , chronic kidney disease; CKD-MBD , chronic kidney disease–mineral and bone disorder; K/DIGO , Kidney Disease: Improving Global Outcomes; K/DOQI , Kidney Disease Outcomes Quality Initiative; phos , phosphorus; PTH , parathyroid hormone.
