Diabetes and Chronic Kidney Disease
Diabetes and Chronic Kidney Disease
In the US, diabetic nephropathy accounts for the majority of chronic kidney disease (CKD). It contributes significantly to morbidity and mortality among the diabetic population1,2 and accounts for approximately 40% of patients with end-stage renal disease.3 The earliest manifestation of renal involvement in diabetes is the presence of microalbuminuria, as defined by urine albumin excretion of 30–300mg/day.4 Progression to overt proteinuria (urine albumin excretion greater than 300mg/day) and diabetic nephropathy occur more frequently in those with poor glycemic control, glomerular hyperfiltration, and hypertension.5
Diabetes and Chronic Kidney Disease
In the US, diabetic nephropathy accounts for the majority of chronic kidney disease (CKD). It contributes significantly to morbidity and mortality among the diabetic population1,2 and accounts for approximately 40% of patients with end-stage renal disease.3 The earliest manifestation of renal involvement in diabetes is the presence of microalbuminuria, as defined by urine albumin excretion of 30–300mg/day.4 Progression to overt proteinuria (urine albumin excretion greater than 300mg/day) and diabetic nephropathy occur more frequently in those with poor glycemic control, glomerular hyperfiltration, and hypertension.5 Not all kidney disease in diabetics is attributable to diabetic nephropathy. Despite an increasing population of diabetics in the population, advances in the care of the diabetic patient have reduced the incidence of overt progression to diabetic nephropathy.6,7 The natural history of diabetic nephropathy, which had previously been characterized by a decline in glomerular filtration rate (GFR) by approximately 10–15ml/min per year,8 can be reduced to a rate of decline of 3.7ml/min per year with antihypertensive therapy alone.9 In one series of type 1 diabetics in Sweden, the incidence of diabetic nephropathy after 20 years was found to decrease from 28% to 5.8%.10 However, a study by Kramer et al. found that 30% of diabetics with estimated GFR of <60ml/min had neither albuminuria nor retinopathy.11 This illustrates the important principle that diabetics continue to be susceptible to other types of renal disease and the manifestation of chronic kidney disease in this population may be due to causes other than diabetic nephropathy.
The management of chronic kidney disease, including diabetic nephropathy, consists not only of protecting residual renal function and instituting renal replacement therapy when necessary, but also in treating the myriad complications of kidney disease, including renal osteodystrophy.The impact of these complications on the health and survival of patients with chronic kidney disease is significant. Elevations in the serum phosphorus, the calcium-phosphorus product, and parathyroid hormone (PTH) levels are associated with vascular calcifications, an increase in cardiovascular morbidity and mortality, and an overall increase in the relative risk of death from all causes in the CKD population.12,13 Pathophysiology of Secondary Hyperparat hyroidism
Renal osteodystrophy refers to a variety of bone diseases that occur as a result of distortions in mineral metabolism from kidney disease. In the CKD population, it is most commonly manifest as secondary hyperparathyroidism, a disease of high bone turnover.Secondary hyperparathyroidism is present in 30% to 40% of stage 3 CKD patients and 50% to 80% of stage 4 CKD patients. Phosphorus retention and declining calcitriol production, both sequelae of reduced functional renal mass, stimulate excess secretion of the parathyroid hormone and promotes parathyroid tissue hyperplasia.14,15 The resulting bone disease, also termed osteitis fibrosa, is characterized by accelerated bone formation and resorption due to increased osteoclastic and osteoblastic activity. Marrow fibrosis may also occur. The severity of secondary hyperparathyroidism is variable but roughly proportional to the degree and duration of PTH elevation. These patients become susceptible to frequent fractures, pruritis, and ectopic calcifications. Secondary hyperparthyroidism and the concomitant distortions in mineral metabolism— specifically, the elevations in serum phosphorus and calcium-phosphorus products—are linked to vascular calcifications16,17 and are associated with higher cardiovascular mortality.18,19 Furthermore, moderate to severe hyperparathyroidism is independently associated with an increase in the relative risk of death as well as cardiovascular hospitalizations in hemodialysis patients.20
Identification of abnormalities in mineral metabolism may be difficult in early kidney disease. Data from Gutierrez et al. shows that significant increases in serum phosphorus and decreases in serum calcium are not manifest in patients with chronic kidney disease until GFR is less than 30ml/min.21 This is likely due to normalization of calcium and phosphorus levels by increased parathyroid hormone secretion. However, the compensatory hyperparathyroidism is detrimental to bone health and may be independently associated with mortality and cardiovascular complications.22,23 Current treatment guidelines established by the National Kidney Foundation Kidney Disease Outcome and Quality Initiative (K/DOQI) recommend routine screening of calcium, phosphorus, and PTH levels with frequency based on stage of CKD. Patients with stage 3 kidney disease (GFR 30–59) should have PTH, calcium, and phosphorus checked every 12 months, while those with stage 4 disease (GFR 15–29) should have the same serum values checked every three months.Those with stage 5 disease (GFR <15) should have PTH checked every three months, and calcium and phosphorus checked monthly.24
To minimize the risk of death and cardiovascular complications from renal osteodystrophy, target goals for the therapy of secondary hyperparathyroidism have been developed. K/DOQI guidelines recommend a target intact PTH of 35–70pg/ml for stage 3 CKD, 70–110pg/ml for stage 4 CKD, and 150–300pg/ml for stage 5 CKD,25 reflecting the increasing bone resistance to PTH with declining renal function.As PTH secretion is stimulated by hyperphosphatemia and vitamin D deficiency, control of secondary hyperparathyroidism begins with the reduction of serum phosphorus levels and normalization of vitamin D stores.
Dietary phosphorus restriction is an important initial treatment that has been shown to reduce secondary hyperparathyroidism in patients with chronic kidney disease, provided that patients comply with the diet.26–28 Foods that are especially high in phosphorus include dairy products (milk, yogurt, cheese), liver, meat, beans, nuts, whole-grain breads and cereals, and many soft drinks. Because it may be difficult for patients to find practical ways to construct a satisfying diet given these restrictions, the assistance of a knowledgable dietician is usually necessary and helpful.29
Phosphorus binders decrease serum phosphorus levels by binding dietary phosphorus and preventing its absorption in the gut. Calcium-based phosphorus binders are the first line of treatment based on a profile of easy availability, effectiveness, and low cost. In addition, they act as a source of calcium supplementation, which may further suppress PTH secretion. However, in order to prevent excessive calcium loading, the K/DOQI guidelines recommend limiting daily calcium supplementation to 1.5 grams per day. A higher ingested calcium load predisposes patients to ectopic and vascular calcifications.30 These patients may also have an increase in urinary calcium excretion, suggesting that excessive calcium supplementation may not be incorporated into bone and may contribute to the serum calcium burden and increased filtered load at the kidney. Sustained hypercalciuria may accelerate functional renal loss in the CKD population and may prove to be detrimental in this population.
Additional agents such as lanthanum carbonate and sevelamer hydrochloride have been developed to bind phosphorus without the co-absorption of a potentially toxic substance. Both are significantly more expensive than calcium-based agents and contribute to the high cost of care in the end stage renal disease (ESRD) population.31 Thus far, there has been no evidence of toxic accumulation or adverse effects on bone metabolism from lanthanum in human subjects,32 though animal studies have raised concerns about lanthanum deposition in a number of tissues including liver, lung, and kidney.33 There has been no evidence of similar tissue deposition in humans to date. Sevelamer has been associated with the development of a metabolic acidosis and, in general, should be used sparingly and cautiously in the CKD population.34,35
Active vitamin D therapy is used to further suppress PTH into the target range. Calcitriol, the naturally occurring active form of vitamin D, suppresses PTH and reverses renal osteodystrophy. While both oral and intravenous forms have been shown to be effective,36,37 calcitriol is limited to a narrow therapeutic index by side effects.Vitamin D receptors are present on a variety of tissues besides the parathyroid gland, including the intestines, kidneys, bone, immune cells, skin, heart, and brain.38,39 As a result, calcitriol stimulates intestinal reabsorption of calcium and phosphorus and may cause hypercalciuria, hyperphosphatemia, and an elevated calcium-phosphorus product.40–43
Vitamin D analogs such as paricalcitol (19-nor- 1,25(OH)2D2) and doxercalciferol (1α(OH)D2) have been developed to decrease PTH levels with minimal hypercalcemia and hyperphosphatemia.44–46 Doxercalciferol is a prohormone that is metabolized by the liver to active 1,25(OH)2D2,47 while paricalcitol has modifications to the A ring and the presence of a D2 side chain through which it achieves receptor and site selectivity.48 Paricalcitol has been shown to suppress PTH more rapidly and with fewer side effects than calcitriol.49 In a study by Sprague et al., a 50% reduction in PTH levels was attained at week 15 compared with week 23 in the paricalcitol and calcitriol treatment groups, respectively. Patients treated with paricalcitol had reduced mean PTH levels to K/DOQI goals at week 18, while patients treated with calcitriol did not attain target goals during the study. Furthermore, the incidence of sustained hypercalcemia and/or an elevated calciumphosphorus product was noted in 18% of patients on paricalcitol versus 33% of patients on calcitriol (p=0.008). In a separate study by Teng et al., paricalcitol was associated with a lower mortality rate than calcitriol among patients on hemodialysis.50 An oral preparation of paricalcitol was recently approved for the treatment of secondary hyperparathyroidism in chronic kidney disease patients and can be used safely in the CKD population.51
Renal osteodystrophy also includes conditions of low bone turnover, such as adynamic bone disease. This type of disease is seen infrequently in the chronic kidney disease population. However, among patients with end-stage renal disease on dialysis, diabetics have a higher percentage of low turnover bone disease than non-diabetics.52,53 Insulin deficiency and the accumulation of advanced glycation end products have been proposed as modulators of osteoblastic and osteoclastic activity and may blunt parathyroid response to hypocalcemia.54–56 While the exact pathophysiology is not completely understood, the management of low turnover bone disease begins with diabetic control and normalization of low PTH values (typically an intact PTH <100pg/ml) to target goal. Low serum calcium in these patients is a potent stimulus to PTH secretion and gland hyperplasia and, therefore, should generally be tolerated in this low PTH state. In this group of patients the serum calcium should be maintained in the low normal range (8.4 to 9.5mg/dl) or even below this range to stimulate PTH secretion. The dialysate calcium concentration should not exceed 2.5mEq/L in these patients, and calciumbased phosphorus binders should be avoided. PTH secretion is also inhibited by vitamin D and low serum phosphorus levels. Phosphorus binders should be reduced or discontinued to allow serum phosphorus to rise to 4.5 and 5.5mg/dL, and calcium-based binders should generally be avoided. Due to the reduced buffering capacity of bone in these patients, they are at particular risk of developing increased calcium, phosphorus, and calcium-phosphorus products. Active vitamin D is not recommended in this population as it will further suppress PTH and inhibit parathyroid gland hyperplasia. Conclusions
While diabetic nephropathy remains the leading cause of renal failure in adults, the diabetic population remains susceptible to kidney disease from other causes. Renal impairment of any severity increases the allcause and cardiovascular mortality of diabetics,57 therefore every effort should be made to preserve renal function with aggressive glycemic and antihypertensive therapy. The development of diabetic nephropathy may expose these patients to further increases in cardiovascular risk and death due to complications of abnormal mineral metabolism and renal osteodystrophy.58,59 Secondary hyperparathyroidism, which is prevalent in the CKD population, requires attentive normalization of PTH to target goal through dietary and pharmacological means. Phosphorus reduction through dietary restrictions and phosphate binders play a crucial role in the management of secondary hyperparathyroidism and require careful patient education and compliance. Calcitriol can suppress PTH in a dose-dependent manner, but can cause hypercalcemia and hyperphosphatemia. Newer vitamin D analogs, paricalcitol in particular, potently suppress PTH with minimal effects on serum calcium and phosphorus. Through the diverse actions of vitamin D, use of active vitamin D may also reduce the risk of cardiovascular events and death in diabetics.■