**The New Kidney and Bone Disease: Chronic Kidney Disease – Mineral and Bone Disorder (CKD–MBD)**

Igor G. Nikolov1, Ognen Ivanovski2 and Nobuhiko Joki3 *1University Clinic of Nephrology, Medical Faculty - Skopje, 2University Clinic of Urology, Medical Faculty - Skopje, 3Division of Nephrology, Toho University Ohashi Medical Center, Tokyo, 1,2Republic of Macedonia 3Japan* 

### **1. Introduction**

24 Chronic Kidney Disease

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Kidney is one of the most important organs in the regulation of mineral metabolism (Fukagawa et al., 2006). Chronic kidney disease (CKD) is a worldwide public health problem that affects 5% to 10% of the world population, with increasing prevalence and adverse outcomes, including progressive loss of kidney function, cardiovascular disease, and premature death (Eknoyan et al., 2004). Calcium and phosphorus are fundamentally important in a wide array of biological functions. Abnormalities in calcium, phosphorus, parathyroid hormone (PTH), and vitamin D metabolism (usually referred to as disordered mineral metabolism) are common in patients with (CKD) (Block et al., 1998). Cardiovascular disease is the leading cause of death in patients with CKD (London et al., 2003). It has been shown that in individuals with kidney failure on maintenance dialysis who are younger than 65 years, cardiovascular mortality is 10 to 500 times higher than in the general population, even after adjustment for sex, race, and presence of diabetes (Foley RN et al., 1998). Disturbances in mineral metabolism are common complications of CKD and an important cause of morbidity and decreased quality of life. Importantly, increasing evidence suggests that these disturbances are associated with changes in arterial compliance, cardiovascular calcification, bone disorders and all-cause and cardiovascular mortality (Palmer SC et al., 2005, Drueke et al., 2010). Traditionally, when defining bone diseases in CKD patients, this group of disorders has been usually termed renal osteodystrophy. However, beside strictly defined, the term renal osteodystrophy means only bone abnormalities. Recently, the KDIGO (Kidney Disease: Improving Global Outcomes) conference group agreed that the definition of renal osteodystrophy should be only specific to bone pathology found in patients with CKD (Moe S. et al., 2006). It has been concluded that renal osteodystrophy is one component of the mineral and bone disorders that occur as a complication of CKD. It has been proposed that the evaluation and definitive diagnosis of renal osteodystrophy requires performing a bone biopsy. Histomorphometry is not essential for clinical diagnosis, but should be performed in research studies. There was an agreement that histomorphometric results are to be reported by use of the standard nomenclature

The New Kidney and Bone Disease:

calcium measurement.

(Slatopolsky and Delmez, 1994).

**2.3 Parathyroid hormone** 

**2.2 Phosphorus** 

Chronic Kidney Disease – Mineral and Bone Disorder (CKD–MBD) 27

phosphate, and is therefore not physiologically active. In the presence of hypoalbuminemia, there is an increase in ionized calcium relative to total calcium; thus, total serum calcium may underestimate the physiologically active (ionized) serum calcium. The most commonly used formula for estimating ionized calcium from total calcium is the addition of 0.2 mmol/l for every 1 g decrease in serum albumin below 40 g/l. Unfortunately, recent data have shown that it offers no superiority over total calcium alone and is less specific than ionized calcium measurements. In addition, the assay used for albumin may affect the corrected

It has been shown that inorganic phosphorus is critical for numerous normal physiological functions, including skeletal development, mineral metabolism, cell-membrane phospholipid content and function, cell signaling, platelet aggregation, and energy transfer through mitochondrial metabolism. Owing to its importance, normal homeostasis maintains serum concentrations between 0.81–1.45 mmol/l. The terms, phosphorus and phosphate, are often used interchangeably, but strictly speaking, the term phosphate means the sum of the two physiologically occurring inorganic ions in the serum, and in other body fluids, hydrogenphosphate (HPO42) and dihydrogenphosphate (H2PO4). However, most laboratories report this measurable, inorganic component as phosphorus. Unlike calcium, a major component of phosphorus is intracellular, and factors such as pH and glucose can cause shifts of phosphate ions into or out of cells, thereby altering the serum concentration without changing the total body phosphorus. Phosphorus is routinely measured in clinical laboratories with colorimetric methods in automated machines. Serum phosphorus levels reach the lowest level in the early hours of the morning, increasing to a plateau at the

afternoon, and further increasing to a peak late in the evening (Portale et al., 1987).

Hyperphosphatemia occurs as a consequence of diminished phosphorus filtration and excretion with the progression of CKD. Decreased phosphorus excretion can initially be overcome by increased secretion of parathyroid hormone (PTH), which decreases proximal phosphate reabsorption (Slatopolsky and Delmez, 1994). Hence, phosphorus levels are usually within normal range until the GFR falls below approximately 30 ml/min, or stage IV. CKD according to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF–K/DOQI) classification (National Kidney Foundation: K/DOQI). In more advanced stages of CKD, the blunted urinary excretion of phosphorus can no longer keep pace with the obligatory intestinal phosphate absorption, resulting in hyperphosphatemia. Therefore, it is not surprising that the majority of patients with CKD stage 4 and stage 5 have a significant hyperphosphatemia (Block et al., 1998). It has been shown that in patients with advanced CKD high serum calcium, phosphate, and calcium-phosphate product levels are associated with unaccountably high rates of cardiovascular disease (Ganesh et al., 2001; Stevens et al., 2004; Slinin et al., 2005). Moreover, it has been shown also that these derangements in mineral metabolism could occur as well during the early stages of CKD

The parathyroid gland plays an important role in the regulation of mineral homeostasis by effects trough other organs such as the kidney and bone. Fluctuation in extracellular calcium

recommended by the American Society for Bone and Mineral Research (Parfitt et al., 1987)**,**  and investigators would supply primary measurements used to report any derived parameters. Based on all of this a new term has been proposed and coined "Chronic kidney disease – mineral and bone disorder (CKD-MBD)" willing to describe the systemic consequences of mineral metabolism disturbances in CKD patients which can no longer be considered restricted only to bone disease. CKD-MBD defines a triad of interrelated abnormalities of serum biochemistry, bone and the vasculature associated with CKD. The adverse effects of high serum phosphorus and an increase of serum calcium due to calcium overload which are present late in CKD are important component of CKD-MBD as well as vascular changes. Furthermore, to clarify the interpretation of bone biopsy results in the evaluation of CKD-MBD, it has been proposed to use three key histologic descriptors—bone turnover, bone mineralization, and bone volume (so called TMV system)— with any combination of each of the descriptors possible in a given specimen. The TMV classification scheme provides a clinically relevant description of the underlying bone pathology, as assessed by histomorphometry, which, in turn, helps to define the pathophysiology, and, thereby, probably to guide the therapy (Moe S. et al., 2006).
