KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease


15.1 In CKD Stages 3, 4 and 5, the serum level of total CO2 should be measured.

15.1a The frequency of these measurements should be based on the stage of CKD as shown in Table 32. (OPINION)

15.2 In these patients, serum levels of total CO2 should be maintained at ≥22 mEq/L (22 mmol/L). (EVIDENCE) If necessary, supplemental alkali salts should be given to achieve this goal. (OPINION)


A fall in serum total CO2occurs during the course of CKD.504 An overt acidosis is present when the estimated GFR is below 30 mL/min/1.73 m2 in a large proportion of patients,478 and it progresses such that most patients on maintenance dialysis have an acidosis.505


Classical studies in humans demonstrated the powerful effect of chronic metabolic acidosis, induced experimentally or resulting from chronic kidney disease, on the loss of bone mineral.506-509 Experimental studies performed largely in animals fed excess mineral acid, or bone organ cultures exposed to varying pH environments, have investigated mechanisms whereby chronic metabolic acidosis alters bone composition. Chronic metabolic acidosis produces a change in the ionic composition of bone, with net reductions in apatite, sodium, and potassium.510 Cellular functions within bone are changed by chronic metabolic acidosis, such that matrix gene expression associated with osteoblastic activity is inhibited,511 while osteoclastic activities are increased.512 Additionally, the trophic effects of the growth hormone IGF-1 axis on bone growth and structure is blunted in chronic metabolic acidosis.513 Chronic metabolic acidosis reduces the kidney proximal tubule synthesis of 1,25(OH)2D3,514 and may thereby limit calcium absorbed from the diet. Chronic metabolic acidosis alters the homeostatic relationships between blood ionized calcium, PTH, and 1,25(OH)2D3 such that bone dissolution is exaggerated.515,516

Bone fractures are a relatively common manifestation of chronic metabolic acidosis.517 Recent studies utilizing dynamic histomorphometry have demonstrated a reduction in bone mineral density,518,519 and in bone formation rates. However, histomorphometric analyses of bone in patients with forms of chronic metabolic acidosis are quite limited, and remain controversial. Linear growth in children is reduced by chronic metabolic acidosis.520 Chronic metabolic acidosis contributes, in part, to the osteodystrophy in patients with chronic kidney disease.53

Strength of Evidence

There is scant evidence, in patients with kidney disease on maintenance dialysis, that either amelioration or improvement of osteodystrophy occurs through elimination of chronic metabolic acidosis per se. One study in 21 patients on maintenance dialysis found that, after 18 months of observation, a group with acidosis (total CO2 = 15 mmol/L) had progression of secondary hyperparathyroidism biochemically and on bone biopsy, when compared to the absence of worsening in the control group (total CO2 = 24 mmol/L), all of whom still had some degree of secondary hyperparathyroid bone disease.521 Additionally, a cross-sectional study of 76 patients studied with percutaneous, transiliac bone biopsy demonstrated that those with a normal biopsy result had a serum bicarbonate level of 23 mmol/L while those with either mild or advanced mixed osteodystrophy had serum bicarbonate levels below 20 mmol/L.53 It appears that the absence of acidosis renders therapy of osteodystrophy with a vitamin D metabolite more effective.522 Also, in children with renal tubular acidosis, normalization of serum bicarbonate is one component of the return of normal growth parameters.520

Clinical Applications

Measurement and monitoring of the serum levels of total CO2 is warranted in patients with CKD Stages 3, 4, and 5,478 or in patients on maintenance dialysis. Steps to keep the measured serum levels of CO2 above 22 mmol/L are warranted for improvement in bone histology, and to ameliorate excess protein catabolism.523 The clinician is reminded that the use of exogenous alkali salts containing citrate may increase the absorption of dietary aluminum in patients with CKD,521 both before dialysis and in those treated with dialysis524; therefore, citrate alkali salts should be avoided in CKD patients exposed to aluminum salts.

Recommendations for Research

Areas for future research into the effects of chronic metabolic acidosis and osteodystrophy should include a fuller understanding of the calcium-vitamin D-PTH and the growth hormone-IGF-1 axes in humans with CKD at the level of bone. The role of newer therapeutic agents for osteoporosis, such as bisphosphonates, selective estrogen-receptor modulators, or isoflavones in patients with CKD, with or without chronic metabolic acidosis, remains unknown and deserves exploration.