Overview of Renal Osteodystrophy and Current Therapeutic Approach

Introduction: ROD includes all the disorders of bone and mineral metabolism, caused by impaired renal function. It represents a spectrum of bony disorders ranging from high turnover lesions of secondary hyperparathyroidism to low turnover lesions of adynamic bone and osteomalacia. In children with end stage renal failure, the most common skeletal pathology is that of secondary hyperparathyroidism.1 Adynamic bone lesions that are not associated with aluminium deposition in bone are more common in adults with advanced renal failure. This disorder is less common in children and most such cases are due to treatment with large doses of calcitriol to control secondary hyperparathyroidism (SHPT). That means, in children ROD is mainly a consequence of impaired metabolism of Ca++, PO4 and Vitamin D and their complex interaction with parathyroid hormone, eventually causing secondary hyperparathyroidism. As the new studies suggest, the complex interaction causing the development of ROD can be summarized as follows.


Introduction:
ROD includes all the disorders of bone and mineral metabolism, caused by impaired renal function.It represents a spectrum of bony disorders ranging from high turnover lesions of secondary hyperparathyroidism to low turnover lesions of adynamic bone and osteomalacia.In children with end stage renal failure, the most common skeletal pathology is that of secondary hyperparathyroidism. 1 Adynamic bone lesions that are not associated with aluminium deposition in bone are more common in adults with advanced renal failure.This disorder is less common in children and most such cases are due to treatment with large doses of calcitriol to control secondary hyperparathyroidism (SHPT).That means, in children ROD is mainly a consequence of impaired metabolism of Ca ++ , PO 4 and Vitamin D and their complex interaction with parathyroid hormone, eventually causing secondary hyperparathyroidism.As the new studies suggest, the complex interaction causing the development of ROD can be summarized as follows.
1) There is already some degree of phosphate retention even at GFR of 50-70ml/per minute/1.73m 2 .More phosphate retention develops as the GFR keeps falling.
Retention of phosphate inhibits one-α hydroxylase enzyme needed for the synthesis of calcitriol.It also causes increased PTH secretion by a direct stimulation of the parathyroid gland (through phosphorus sensors?).
2) Decreased calcitriol in blood, thus decreases calcium absorption from the intestine and increases PTH secretion through vitamin D receptors in the gland.
3) Also decreased ionized calcium increases PTH secretion through calcium sensors in the gland.Two other syndromes are also seen to add further morbitity and ultimate mortality from ROD.They are coronary artery calcification and calciphylaxis.Calciphylaxis include both soft tissue and vascular calcifications.Both these syndromes are seen in ROD patients with high Ca x PO 4 product (Ca x PO 4 > 70 mg/dl).These syndromes are still being evaluated and need further discussion elsewhere.In brief, the consequences of treatment failure for ROD can be summarized as follows: 1) Predisposes to soft tissue calcification that can be visceral, periarticular and most importantly cardivascular.
2) Causes a significant positive Ca + PO 4 balance, thus increasing the morbitity and mortality of patients with end-stage renal disease.
3) Studies in adult CKD patients have shown that patients with serum PO 4 > 6.5 mg/dl and Ca x PO 4 > 72 mg/dl have higher mortality than patients with serum PO 4 < 6.5 mg/dl and Ca x PO 4 < 52 mg/dl.
Ganesh et al have shown in their study on a large patient population on dialysis (>12,000 ESRD patients) that the patients with plasma PO 4 > 6.5 mg/dl have 56% higher mortality risk, mostly due to coronary artery disease and 27% have increased risk of sudden death.Furthermore, for each 10mg/dl increase in the Ca x PO 4 product, there is an 11% increase in risk for sudden death. 2 Ideal goals to achieve in the management of renal bone disease: Considering all the consequences described above, the strategies for the management of ROD should include the following: 1) Prevention of parathyroid gland hyperplasia.
2) Optimize the serum PTH level in the range that ensures normal bone formation and corresponds with a normal rate of skeletal remodelling.PTH level should be kept in the normal range in predialysis patients and 2-3 times over upper normal limit in patients on dialysis.
3) Avoidance of positive balance of calcium x phosphate.
4) Therapy should start at the very early stage of CKD.
When the creatinine clearance falls < 60-70 ml/min/1.73m 2 , serum PTH starts to rise due to decrease level of calcitriol, so therapuetic intervention should be undertaken at this stage.

New strategy for the treatment of ROD:
Prevention and treatment of ROD have always been great challeges for the nephrologists.From the discussion above, it is apparent that many consequences were unknown that we know now.Thus, it has become even more challenging now to especially prevent the occurrence of such consequences.We have, however, the following advantages in these days: 1) Better understanding of the disease process With the use of newer drugs, strategies are being formulated at different renal centers.It is important to note that any such strategy must be created as an individual basis, the factors need to be considered are age, type of primary disease, rate of progress of renal failure, nutrition, acidosis, dialysis or predialysis, type of dialysis and medication like steroid and growth hormone.
There may still some debates as to when to start treatment, however most nephrologists find it rational to initiate therapy at the early stage of CKD.Studies have found an increase in PTH secretion as creatine clearance falls to <60-70 ml/min/ 1.73 m 2 .In addition, there is already a significant decrease in calcitriol level even at an early stage of CKD, which suggests that decrease in calcitriol level maybe a factor to cause secondary hyperparathyroidism.Thus, it may seem to be rational to start treatment at the early stage of CKD.However, the problem is that admisistration of calcitriol may result in an increase in the Ca x P burden.Dietary PO A wide variety of vitamin D analogs were screened for the same purpose and in addition to paricalcitol, the other analogs used are 1) Doxercalciferol (Hecterol) -a hydroxy vitamin D2 that undergoes 25 hydroxylation in liver to form active 1-25 dihydroxy vit D2.
Among all these, the most commonly used vitamin D analog is paricalcitol.

Growth Hormone and ROD:
As a whole, the use of growth hormone in children with chronic renal failure remains controversial.It is known from animal models that growth hormone stimulates chondrocyte proliferation.Patients of CKD who receive growth hormone should be monitored for signs of ROD, slipped capital femoral epiphysis and avascular necrosis on serial radiographs, serum Ca, PO 4 , alkaline phosphatase and PTH levels should also be monitored.Long-term effects of growth hormone were studied in 45 pre-pubertal Dutch children with chronic renal insufficiency and no adverse effects related to PTH concentration or development of radiological of ROD were reported in that study. 4

Parathyroidectomy in ROD:
Surgical exicion of parathyroid gland is better than ethanol injection into the gland, but parathyroidectomy is rarely done nowadays as medical treatment of SHPT has improved significantly over the last decade.Current indications for parathyroidectomy are: 13,14 1) Severe episodes of hypercalcemia and hyperphosphatemia with high levels of serum PTH, not responding at all to medical treatment.2) Recurrent bony fractures with severe ROD.

2 )
Development of new drugs, like (a) Calcium and aluminium free phophate binders (b) Paricalcitrol, a non-hypercalcemic Vitamin D analogue (c) Calcimimetics-e.g,cinacalcet HCL, which directly stimulate calcium sensing receptors and potentially supress PTH secretion without increasing serum Ca ++ . 5,6 Dietary PO 4 restriction in advisable, but associated protein restriction may not be good for growth in children and it is practically very difficult.However, most practitioners would advise to decrease phosphate intake when the creatinine clearance falls below 50-ml/min/1.73m 2 .Phosphate restriction decreases serum PTH level and may help to maintain normal calcitriol level; however, there is already parathyroid gland hyperplasia when it is usually advised.So, early advice on dietary phosphate restriction to 800-1000 mg/day maybe useful.
7,8striction can normalize plasma calcitriol level and thus decrease serum PTH level.However, PO 4 restriction may not always be practical, especially in children; associated protein restriction may have deleterious effect on growth.In this situation, a new alternative vitamin D analog maybe very much useful.This analog is 'Paricalcitol (zemplar)', which has minimal effects on gut absorption of Ca and PO 4. It is an active analog based on vitamin D 2 structure (19-nor-1, 25-dihydroxy vit D 2 ) that supresses PTH secretion but has minimal effect on serum level of Ca and PO 4 .It is not a non-calcemic vitamin D, but has less calcemic effect.The result would be to correct secondary hyperparathyroidism while minimizing the toxicity resulting from increased level of Ca and PO 4 .7,8 its effects on their function.In this regard, a skeleton in growing children is very important since CaSRs are expressed in the epiphyseal plate of chondrocytes.However, the role of CaSR in the chondrocyte proliferation and differentiation is not yet clear.