The increase in FGF23, decrease in Klotho, and decrease in renal mass are possible early events in the etiology of CKD-MBD.
These alterations favor the lowering of 1–hydroxylase in the kidney, resulting in low calcitriol levels. This results in reduction of intestinal calcium absorption and so the decrease in serum calcium.
Hypocalcemia stimulates the synthesis and release of PTH. The generation of 1–hydroxylase is stimulated by an increase in PTH. All of these pathways result in compensatory increases in to normalize serum calcium. Additionally, the increase in FGF23 and PTH causes phosphaturia, serum phosphate levels normal until stages 3-4. When GFR gradually decreases, these complex and interconnected processes fail to appropriately manage mineral metabolism, and despite increases in FGF23 and PTH, serum phosphate rises while serum calcitriol falls.
This situation worsens in advanced stages of CKD-MBD. As a result of the decrease in calcium and calcitriol and the increase in phosphate. The parathyroid gland is subjected to a permanent proliferative stimulus, triggering severe forms of secondary hyperparathyroidism with gland hyperplasia, first diffuse and then nodular, with a significant reduction in CaSR, VDR, and FGFR/Klotho expression, resulting in poor response of the parathyroid glands to calcium, VDR activators (VDRA) and FGF23
As the nephron mass gets reduced in CKD, there is initial rise in FGF23 with reduced Klotho. FGF23 reduces the activity of 1a-hydroxylase and active vitamin D levels gets reduced. CaSR senses the reduced serum Ca and increase the production of PTH.
PTH stimulate 1a-Hydroxylase attempting to normalize serum Ca.
Both PTH and FGF23 are phosphaturic, so these mechanisms maintain normal Ca and PO4 in the early stages of CKD.
As CKD progresses, continuous stimulation of Parathyroid gland leads to SHPTH and Ca tends to go down and PO4 accumulates because of further reduction in nephron mass.
The Parathyroid undergoes diffuse then nodular hyperplasia during this process
Pathogenisis of CKD MBD
biochemical changes occurs as early as CKD G2 with reduction of functioning kidneymass & phosphorusretention & decreasedklotho coreceptor expression & increasedFGF23 aiming to normalize S.phosphorus via its phosphaturic effect (FGF23 inhibits NaPi2a,c– decreasing phosphorus reabsorption in PCT-, and NaPi2b in intestine – decreasing intestinal absorption of phosphorus-, inhibit 1alphahydroxylase– inhibiting calcidiol activation hence intestinal absorption of phosphorus-, also stimulate PTH secretion with synergistic effect on urinary phosphorus excretion). PTH activates calcidiol which increases both calcium absorption & reabsorption till late stages of CKD where these compensatory mechanisms fail to mention normal values of calcium and phosphorus. With sustained stimulation of PTH gland with hyperplasia ( diffused then nodular), the gland show receptor (CaSR, VDR, FGF23R) hyporesponsiveness and become resistant to calcium & vitamin D and FGF23 with sustained SHPT. This results in promoting bone resorbtion in expence of bone formation.
increase in FGF23 ,decrease of Klotho leads to loss of renal mass,these abnormaities accommodate the reduction of alpha 1 hydroxylase in the kidneys which leads to decrease of calcitorial which leads to reduction of intestinal calcium absorption and low serum calcium .hypocalcemia stimulates the release of PTH which increase the alpha 1 hydroxylase. all these mechanisms accelerate to normalise the calcium
It is currently accepted that increase in FGF23, the decrease of Klotho, and the reduction of renal mass are possibly the earliest events in the pathogenesis of CKD-MBD. These changes favor the reduction of 1-α-hydroxylase in the kidney, which results in low levels of calcitriol, the most active natural activator of VDR, a fact that reduces the absorption of calcium in the intestine and favors the decrease in serum calcium, which in turn acts as a stimulus for the synthesis and release of PTH. The increase in PTH favors bone turnover and resorption and stimulates the production of 1-α-hydroxylase. All of these mechanisms translate into compensatory increases to normalize serum calcium. Furthermore, the increase in FGF23 and PTH favor urinary phosphate excretion, maintaining normal serum phosphate levels until stages 3–4 of CKD .Despite the compensatory increases in PTH, it is well known that in CKD there is currently a hyporesponsiveness to PTH which limits its action .
Despite the fact that FGF23 and PTH have synergistic effects in relation to the renal excretion of phosphate, they have opposite effects on calcitriol synthesis. FGF23 inhibits 1-α-hydroxylase by decreasing the synthesis of calcitriol, whereas PTH stimulates the production of 1-α-hydroxylase, increasing calcitriol synthesis .FGF23 exerts its tubular effect by binding to its Klotho co-receptor and activating its FGFR-1 FGFR-3 receptors, while PTH does so by binding to its specific receptor. Both increase the phosphate excretion by reducing the concentration of the sodium cotransporters NaPi2a and NaPi2c, through Protein Kinase A and C -dependent pathways .
Calcium and calcitriol exert their actions on the parathyroid cells through their specific receptors, the calcium- sensing receptor (CaSR), and the vitamin D receptor (VDR), respectively .CaSR is a G protein-coupled membrane receptor, while VDR is a nuclear receptor that, when bound to its activator (any active form of active vitamin D (VDRA), acts as a transcription factor. Differences in the nature of the VDRAs and their receptors can induce different actions and a synergistic effect on the parathyroid cells.
When kidney function progressively decreases, these complex and tightly interrelated mechanisms fail to adequately control the mineral metabolism, and despite increases in FGF23 and PTH, serum phosphate increase and serum calcitriol decrease. In advanced stages of CKD-MBD, this situation worsens, and as a consequence of the decrease in calcium and calcitriol and the increase in phosphate, the parathyroid gland is subjected to a permanent proliferative stimulus that triggers severe forms of secondary hyperparathyroidism with hyperplasia of the gland, first diffuse and then nodular, with a significant reduction in the CaSR, VDR and FGFR/Klotho expression which ends in a poor response of the parathyroid glands to calcium, VDR activators (VDRA) and FGF23 .
according pathogenesis of CKD-MBD
before the old modle
with early stag of CKD
>>hyperphosphatemia and hypocalcemia sensitize parathyroid gland to produce PTH
which increase 1-alfa calcidoil and its effect on ca absorption from intestine and increase of phosphate excretion and change in bone turn over
>>>but recently many factors involved in the pathogenesis in CKD -MBD
as FGF23/KLOTHO which appear in early stag of CKD as phosphaturic effect
wnt inhibitor ( sclerostin . dkk1 )
fuetin
activin A
uremic toxins
All these factor Lead to>>> High turnover bone disease –vascular calcification-valvular calcification –cardiac fibrosis –anemia – )-and clinical outcome bon fragility and fracture
Increase in FGF23, Decrease of Klotho, Reduction of renal mass. These changes favor the low levels of calcitriol due to reduction of 1-α-hydroxylase in the kidney. This results in reduction of intestinal calcium absorption and so the decrease in serum calcium. Hypocalcemia leads to stimulation of the synthesis and release of PTH. The increase in PTH stimulates the production of 1-α-hydroxylase. All of these mechanisms translate into compensatory increases to normalize serum calcium. Furthermore, the increase in FGF23 and PTH increase phosphaturia, thus serum phosphate levels are maintained normal until stages 3–4. When GFR progressively reduces, these complex and tightly interrelated mechanisms fail to adequately control the mineral metabolism, and despite increases in FGF23 and PTH, serum phosphate increase, and serum calcitriol decrease.
In advanced stages of CKD-MBD, this situation worsens, and as a consequence of the decrease in calcium and calcitriol and the increase in phosphate, the parathyroid gland is subjected to a permanent proliferative stimulus that triggers severe forms of secondary hyperparathyroidism with hyperplasia of the gland, first diffuse and then nodular, with a significant reduction in the CaSR, VDR and FGFR/Klotho expression which ends in a poor response of the parathyroid glands to calcium, VDR activators (VDRA) and FGF23.
Parallel to the decrease in renal mass the klotho synthesis decreases. FGF-23 synthesis starts in the early stages of CKD. the FGF-23 promotes phosphate secretion. hyperphosphatemia is known to have an important role in CKD-MBD. Till CKD stage IIIa, compensatory mechanisms try to compensate for this so we do not observe high phosphate in the early stages of CKD. With progression hypocalcemia starts. while trying to secrete phosphate through the increase in FGF-23 and a compensatory increase in PTH (which also tries to compensate for hypocalcemia) a progressive increase in PTH can be seen. With the progression of CKD, secondary hyperparathyroidism is seen, markedly after stage 4 all patients have very high PTH. This increase in dialysis patients is either in form of hyperplasia or an increase in nodularity. With the advance in hyperparathyroidism, the VDR receptors become less in number and sensitivity and may entail surgical removal of autonomous nodules to control hyperparathyroidism
When Kidney function start to decrease even in early of disease some changes hoccur like increase koltho secrearion and fgf23 leading increase excretion of po4 in urine also decrease activation of vit d leading activation of pth secretion causing bone resorption to compansate hypocalcemia
Increase in FGF23, Decrease of Klotho, Reduction of renal mass. These changes favor the low levels of calcitriol due to reduction of 1-α-hydroxylase in the kidney. This results in reduction of intestinal calcium absorption and so the decrease in serum calcium. Hypocalcemia leads to stimulation of the synthesis and release of PTH. The increase in PTH stimulates the production of 1-α-hydroxylase. All of these mechanisms translate into compensatory increases to normalize serum calcium. Furthermore, the increase in FGF23 and PTH increase phosphaturia, thus serum phosphate levels are maintained normal until stages 3–4. When GFR progressively reduces, these complex and tightly interrelated mechanisms fail to adequately control the mineral metabolism, and despite increases in FGF23 and PTH, serum phosphate increase, and serum calcitriol decrease.
In advanced stages of CKD-MBD, this situation worsens, and as a consequence of the decrease in calcium and calcitriol and the increase in phosphate, the parathyroid gland is subjected to a permanent proliferative stimulus that triggers severe forms of secondary hyperparathyroidism with hyperplasia of the gland, first diffuse and then nodular, with a significant reduction in the CaSR, VDR and FGFR/Klotho expression which ends in a poor response of the parathyroid glands to calcium, VDR activators (VDRA) and FGF23.
The key players of CKD-MBD) are calcium, phosphate, PTH, FGF23, and the vitamin D hormonal system.with progression in kidney disease many changes will occur in these parameters with diffirent feedback mechanisms .
in summary early in CKD increase FGF23 klotho then pth increse , phosphate keep norml and calcium late CKD nephro loss derease in klotho expressiom, increase in FGF23, increase in PTH, low calcitriol, low calcium, high phosphate As a result, important changes occur in the bone and mineral hormonal axis, leading to changes in bone turnover and clinical outcomes, such as decrease in bone mass with increased bone fragility and bone fractures and increased vascular and valvular calcification, also with great impact in the cardiovascular outcomes.
The bone turnover rate affects both the cancellous (trabecular) and the compact (cortical) bone, and it depends on the activity of the bone remodeling units regulated by multiple factors, including PTH, which plays a key role in the remodeling process. The cortical (85% of the skeleton), is the highest metabolic activity is the trabecular bone. Both decrease in CKD patients, by time the loss of cortical bone is predominant and leads to a thin, trabecularized and more porous cortex, which increases bone fragility, especially in long bones. High serum PTH levels accelerates bone turnover, PTH stimulates bone cell proliferation and the activity of each remodeling unit, and the recruitment of the new bone remodeling units. As a result of these two mechanisms, bone activity increases, osteoid formation is abnormal, immature and non-lamellar, and although this abnormal matrix formed is mineralized, it results in a bone with a lower strength and a greater fragility. The quantification of serum PTH, associated with bone alkaline phosphatase, are the most widely used biochemical parameters to evaluate non-invasively bone activity, although PTH serum values has many limitations. Very high serum PTH levels,usually have a reasonable good histological predictive value of accelerated bone turnover, but moderately high PTH values do not have good correlation with bone turnover. Low PTH levels are associated with poor cell activity
The pathophysiology of CKD-MBD involves feedback loops between different organs (the kidney, the parathyroid glands, the bone, the intestine, and the vasculature). This system’s primary goal is maintaining calcium and phosphorus balance.
When the renal function falls below 40 mL/min, some components may be observed earlier in the course of CKD and precede the onset of clinically detectable abnormalities in serum phosphorus, calcium, PTH, and vitamin D. These include loss of klotho, increased FGF23 secretion, decreased bone formation rates, and vascular calcification.
Changes and abnormalities:
Biochemical abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism.
Bone changes: abnormalities in bone turnover, mineralization, linear volume growth, or strength.
Extraskeletal calcification
Most of the biochemical abnormalities that characterize CKD-MBD are due to SHPT.
SHPT result from:
Phosphate retention
Decreased calcium
Decreased calcitriol
Reduced expression of VDRs, CaSR, FGFRs, and klotho in the parathyroid glands.
These three interrelated processes account for morbidity and mortality in CKD.
pathogenesis of CKD :
the regulation of mineral and bone metabolism and regulation of calcium and phosphate depends on the action of PTH ,FGF23/KLOTHO/CALCITRIOL/CALCITONIN ==========
the main alteration ocuur in calcium ,phosphate ,PTH ,FGF23/KLOTHO and the vitamin D
which lead to important changes in bone and vascular metabolism
================
the increase in FGF23 ,the decrease of klotho and the reduction of renal mass are the earliest events in the pathogenesis of CKD -MBD
with reduction of 1-alfa hydroxylase in the kidney which result in low levels of calcitriol which reduce calcium absorption in the intestine and >>hypocalcemia which in turn stimulate the release of PTH
The increase in FGF23 and PTH increase phosphaturia, thus serum phosphate levels are maintained normal until stages 3–4. When GFR progressively reduces, these complex and tightly interrelated mechanisms fail to adequately control the mineral metabolism, and despite increases in FGF23 and PTH, serum phosphate increase, and serum calcitriol decrease.
In advanced stages of CKD-MBD, this situation worsens, and as a consequence of the decrease in calcium and calcitriol and the increase in phosphate, the parathyroid gland is subjected to a permanent proliferative stimulus that triggers severe forms of secondary hyperparathyroidism with hyperplasia of the gland, first diffuse and then nodular, with a significant reduction in the CaSR, VDR and FGFR/Klotho expression which ends in a poor response of the parathyroid glands to calcium, VDR activators (VDRA) and FGF23.
Early in CKD:
Increase in phosphate level because of phosphate retention
FGF23 increase
Klotho expression level decreases,
Decrease the level of 1-alpha-hydroxylase level
Hyperphosphatemia and hypocalcemia.
Hyperphosphatemia and hypocalcemia with decreased Vitamin D level lead to activation of PTH via activation of CaSR by hypocalcemia and hyperphosphatemia
And increase PTH expression by Vitamin D deficiency via VDR in the parathyroid gland.
The increase in PTH serum level leads to bone calcium resorption to keep calcium in normal level. In advanced stages of CKD:
Increase PTH resistance, in the bone, lead to continuing deteriorating imbalance and persistently defective homeostasis, this will lead to persistently activated parathyroid gland
Proliferation and diffuse enlargement
Nodular formation
Reduced CaSR and VDR in the new parathyroid glandular tissue.
Clinical and laboratory evidence of CKD-MBD.
In ckd as there are decrease in phosphorous excretion there will be increase in secretion of FGF23 from the osteocyte which increase the excretion of phosphate through tubular Klotho co R and decrease the activity of the 1 alfa hydrxylase subsequently decrease in calcitriol (active form vitamin D) which is important to increase intestinal absorption of calcium lead to hypocalcimia. Hyperphosphatemia, hypocalcimia and low calcitriol will cause simulation of PTH through CasR and VDR in PT gland, PTH causes increase phosphate excretion, increase secretion of 1 alfa hydrxylase with increase calcitriol production and increase bone turnover to increase S. Calcium level.
with persistent decrease in Calcitriol and Calcium stimulation of PTH there will be polyclonal proliferation of the gland and then become monoclonal proliferation which is become nodular with decrease CasR, VDR, FGFR1 in the gland and decrease the response to hypocalcimia, low calcitriol and subsequently progress to secondary and the tertiary hyperparathyroidism.
The aging of ckd population, increase prevalence of DM as a cause of ckd, excessive use of calcium and vitamin D and aluminum load all these will cause increase incidence of a dynamic bone disease.
Both high and low turnover bone disease increase risk of bone fragility, cardio-vascular disease and valvular and vascular calcification.
Bone : is a dynamic tissue with cycles of building
and demolition . Osteoclasts cells resorb bone, whereas osteoblasts cells fill in the resorptive cavities with new extracellular matrix that undergoes mineralization.
This process is regulated by physiochemical properties .
IN Chronic kidney disease (CKD) there is:
1-hyperphosphtemia.
2- decrease klotho expression.
3-Increase FGF23.
4-low vit -D.
5-low s.Ca
6- HPT.
7-soft tissue calcifications. 8-metabolic bone disease
Bone disease associated with CKD classified histologically according to the degrees of: 1- abnormal bone turnover
2- impaired mineralization of the extracellular matrix. classification are:
1. Secondary hyperparathyroidism (high-turnover bone disease or osteitis fibrosa).
2. Osteomalacia (defective mineralization).
3. Mixed uremic bone disease (a mixture of high-turnover bone disease and Osteomalacia).
4. A dynamic bone disease (decreased rates of bone formation without a mineralization defect).
High-turnover bone disease:
caused by excess PTH is characterized by greater number and size of osteoclasts and an increase in the resorption . There is an increased amount of osteoid (unmineralized bone). Osteomalacia :
characterized by prolongation of the mineralization lag time as well as by increased thickness, surface area, and volume of osteoid.
that may be present in CKD patients include 25-hydroxyvitamin D deficiency and hypophosphatemia .
Adynamic Bone Disease
the amount of osteoid thickness is normal or reduced and there is no mineralization defect.
The main findings are decreased numbers of osteoclasts and osteoblasts and very low rates of bone formation.
Early in CKD:
increase in phosphate level as a consequence of phosphate retention
FGF23 increase
Klotho expression level decreases,
decrease the level of 1-alpha-hydroxylase level
hyperphosphatemia and hypocalcemia.
Hyperphosphatemia and hypocalcemia with decreased viD level lead to activation of PTH via activation of CaSR by hypocalcemia and hyperphosphatemia
and increase PTH expression by vitD deficiency via VDR in the parathyroid gland.
The increase in PTH serum level leads to bone calcium resorption to keep normcalcemia.
In advanced stages of CKD:
increase PTH resistance, in the bone, lead to continuing deteriorating imbalance and persistently defective homeostasis,this will lead to persistently activated parathyroid gland
proliferation and diffuse enlargement
nodular formation
reduced CaSR and VDR in the new parathyroid glandular tissue.
clinical and laboratory evidence of CKD-MBD.
the pathophysiology changed as discovering of FGF23. the plasma FGF23 levels become elevated with progressively worsening renal function, likely to occur before observed changes in the levels of phosphate and PTH, Fibroblast growth factor 23 (FGF23) is derived from osteocytes and plays a vital role in vitamin D and phosphate metabolism. It requires klotho (a transmembrane protein) to enable it to bind to the FGF receptor (FGFR) in classic target organs such as kidneys and parathyroid glands. Plasma FGF23 enhances phosphate excretion in the proximal renal tubule by decreasing the expression of luminal sodium-dependent phosphate transporters and may also decrease intestinal phosphate absorption by inhibiting NaPi cotransporter activity. In addition, it reduces the synthesis of 1,25-dihydroxyvitamin D [1,25(OH)2D3] by down-regulating the activity of 1α-hydroxylase In the early stages of CKD, high levels of FGF23 attenuate hyperphosphatemia at the expense of 1,25(OH)2 vitamin D suppression, thus initiating the development of secondary hyperparathyroidism. The decrease in serum 1,25(OH)2D3 leads to decreased intestinal calcium absorption. The triad of low levels of calcium, calcitriol and hyperphosphatemia further enhances excessive PTH secretion. consequences of progressive worsening of kidney function include hypo-responsiveness of the vitamin D receptor (VDR) on the parathyroid gland with further enhancement of production of PTH and reduced expression of the calcium-sensing receptor on the parathyroid gland leading to parathyroid gland hyperplasia. parathyroid gland undergoes hypertrophy and becomes autonomous in advanced cases, loss of the ability to maintain mineral hemostasis hyperphosphatemia and secondary hyperparathyroidism with PTH hypo responsiveness all lead to bone resorption, and abnormal bone turnover, PTH increased in early CKD stages with subsequent activate on bone remodeling exert bone changes in early disease and may be silent process, The bone turnover rate affects both the cancellous (trabecular) and the compact (cortical) bone, and it depends on the activity of the bone remodeling units regulated by multiple factors, including PTH, which plays a key role in the remodeling process. high serum PTH levels accelerates bone turnover, PTH stimulates bone cell proliferation and the activity of each remodeling unit, and also increases the recruitment of new bone remodeling units As a result bone activity increases, osteoid formation is abnormal, immature and non-lamellar, and although this abnormal
matrix formed is mineralized, results in a bone with a lower strength and a greater fragility. serum PTH and bone alkaline phosphatase, are most widely used biochemical parameters to evaluate non-invasively bone activity. serum PTH levels, usually greater than 450 pg/ml, have a reasonable good histological predictive value of accelerated bone turnover, but moderately high PTH values (300–450 pg/ml) do not have good correlation with bone turnover.
First incidence : increase in FGF23, decrease Klotho and decrease in renal mass
2nd incidence: these changes decrease or inhibit the 1alpha hydroxylase and subsequently the production of vitamin D3.
3rd incidence: low vitamin D will cause hypocalcemia because of decreased calcium absorption.
4th: hypocalcemia and hyperphosphatemia (that happens because of decreased renal excretion with renal failure progression)will stimulate PTH secretion through CaSR.
5th: PTH will COMPENSATE the calcium phosphorus hemostasis :
– it will exercise a phosphaturic effect
-it will increase release of calcium from bone and will activate 1 alpha hydroxylase to lroduce more calcitriol what will cause a balance in calcium level.
6th : with progression of renal deterioration , there will be PTH hyporesponsivness , the Parathyroid gland will undergo monoclonal proliferation what cause a resistance of CaSR and VDR to serum calcium and phosphate level. Because of this there will be decompensation of the compensatory mechanism and the Parathyroid gland will not be more able to normalize calcium and phosphorus levels.
The increased level of PTH overtime (especially pth over 450)will cause increased bone activity, abnormal osteoid formation, immature and non lamellar so that this although mineralized, it results a bone with low strength and great fragility( predominantly cortical bone loss because it is more abundant).
At the end: the increased fgf23 and decreased klotho over time will cause LV hypertrophy andincrease in vascular and valvular calcification
Fibroblast growth factor 23 (FGF23) is derived from osteocytes and plays a vital role in vitamin D and phosphate metabolism. It requires klotho (a transmembrane protein) to enable it to bind to the FGF receptor (FGFR) in classic target organs such as kidneys and parathyroid glands.
Plasma FGF23 enhances phosphate excretion in the proximal renal tubule by decreasing the expression of luminal sodium-dependent phosphate transporters and may also decrease intestinal phosphate absorption by inhibiting NaPi cotransporter activity.
In addition, it reduces the synthesis of 1,25-dihydroxyvitamin D [1,25(OH)2D3] by down-regulating the activity of 1α-hydroxylase and accentuating the activity of 24-hydroxylase.
In the early stages of CKD, high levels of FGF23 attenuate hyperphosphatemia at the expense of 1,25(OH)2vitamin D suppression, thus initiating the development of secondary hyperparathyroidism.
The decrease in serum 1,25(OH)2D3 leads to decreased intestinal calcium absorption. The triad of low levels of calcium, calcitriol and hyperphosphatemia further enhances excessive PTH secretion.
This excess PTH leads to mobilization of calcium from the bone and osteitis fibrosa.
Other consequences of progressive worsening of kidney function include hypo-responsiveness of the vitamin D receptor (VDR) on the parathyroid gland with further enhancement of production of PTH and reduced expression of the calcium-sensing receptor on the parathyroid gland leading to parathyroid gland hyperplasia. In some subsets of patients, the parathyroid gland undergoes hypertrophy and becomes autonomous.
FGF23, Klotho, and renal mass decreases may be the first events in CKD-MBD pathophysiology. These modifications limit kidney 1–hydroxylase, which lowers calcitriol, the most potent natural activator of VDR, which decreases intestinal calcium absorption and serum calcium, which stimulates PTH production and release. PTH increases bone turnover and 1–hydroxylase production.
These pathways cause compensatory calcium increases. FGF23 and PTH stimulate urinary phosphate excretion, preserving normal serum phosphate levels until CKD stages 3–4. In CKD, PTH hyporesponsiveness restricts its activity despite compensatory increases.
FGF23 and PTH synergistically excrete phosphate, although they oppose calcitriol production. PTH increases calcitriol synthesis, whereas FGF23 inhibits it. PTH binds to its receptor, whereas FGF23 binds to its Klotho co-receptor and activates its FGFR-1 and FGFR-3 receptors. Both reduce the sodium cotransporters NaPi2a and NaPi2c via Protein Kinase A and C-dependent pathways to promote phosphate excretion.
Calcium and calcitriol act on para-thyroid cells through their receptors, the CaSR and VDR, respectively. VDR is a nuclear receptor that operates as a transcription factor when attached to any active form of vitamin D (VDRA). CaSR is a G protein-coupled membrane receptor. VDRAs and receptors may operate differently and synergistically on parathyroid cells.
The CaSR detects minor drops in extracellular calcium concentrations and releases stored PTH within seconds or minutes. If the stimulus is reversed, it suppresses hormone release.
PTH production rises post-transcriptionally if calcium decreases for hours or days, affecting mRNA stability. The reduction in serum calcium increases PTH mRNA stability and half-life, whereas the rise decreases it. PTH mRNA stability and half-life increase with phosphate and vice versa. Phosphate affects the CaSR. Calcitriol, unlike calcium and phosphate, binds to VDR and reduces PTH gene transcription and production.
Increase in FGF23, Decrease of Klotho, Reduction of renal mass. These changes favor the low levels of calcitriol due to reduction of 1-α-hydroxylase in the kidney. This results in reduction of intestinal calcium absorption and so the decrease in serum calcium. Hypocalcemia leads to stimulation of the synthesis and release of PTH. The increase in PTH stimulates the production of 1-α-hydroxylase. All of these mechanisms translate into compensatory increases to normalize serum calcium. Furthermore, the increase in FGF23 and PTH increase phosphaturia, thus serum phosphate levels are maintained normal until stages 3–4. When GFR progressively reduces, these complex and tightly interrelated mechanisms fail to adequately control the mineral metabolism, and despite increases in FGF23 and PTH, serum phosphate increase, and serum calcitriol decrease.
In advanced stages of CKD-MBD, this situation worsens, and as a consequence of the decrease in calcium and calcitriol and the increase in phosphate, the parathyroid gland is subjected to a permanent proliferative stimulus that triggers severe forms of secondary hyperparathyroidism with hyperplasia of the gland, first diffuse and then nodular, with a significant reduction in the CaSR, VDR and FGFR/Klotho expression which ends in a poor response of the parathyroid glands to calcium, VDR activators (VDRA) and FGF23.
The pathogenesis of CKD-MBD: the pathogenesis of CKD-MBD implies the mechanisms of calcium and phosphorus homeostasis, which depends on the action of calcitrophic hormones;
PTH.
Calcitriol.
calcidol.
FGF23/Klotho.
Calcitonin.
All are modulated and regulated via absorption, elimination, and deposition of calcium and phosphate, to maintain the birth elements of sustained level. Kidneys, intestines, parathyroid glands, and bones all maintain this balanced level. At the early stage of CKD with an increase in phosphate level as a consequence of phosphate retention, FGF23 increase, and Klotho expression level decreases, and decrease the level of 1-alpha-hydroxylase level and the resultants hyperphosphatemia and hypocalcemia. Hyperphosphatemia and hypocalcemia with decreased viD level lead to activation of PTH via activation of CaSR by hypocalcemia and hyperphosphatemia and increase PTH expression by vitD deficiency via VDR in the parathyroid gland. The increase in PTH serum level leads to bone calcium resorption to keep normcalcemia. In advanced stages of CKD 3-5, with reduced levels of GFR, and increase PTH resistance, in the bone, lead to continuing deteriorating imbalance and persistently defective homeostasis, this will lead to persistently activated parathyroid gland proliferation and diffuse enlargement and nodular formation with reduced CaSR and VDR in the new parathyroid glandular tissue. The persistent imbalance and defective homeostasis lead to clinical and laboratory evidence of CKD-MBD. The timing of follow-up and management should be individualized and according to the CKd stage by KDIGO recommendation, and keeping all elements within the targeted level. Assessment of CKD should be started as early as stage 2-3a. Pathology of CKD metabolic disorder not only implies the ROD but should include all associated metabolic and systemic effects such as;
The increase in FGF23, decrease in Klotho, and decrease in renal mass are possible early events in the etiology of CKD-MBD.
These alterations favor the lowering of 1–hydroxylase in the kidney, resulting in low calcitriol levels. This results in reduction of intestinal calcium absorption and so the decrease in serum calcium.
Hypocalcemia stimulates the synthesis and release of PTH. The generation of 1–hydroxylase is stimulated by an increase in PTH. All of these pathways result in compensatory increases in to normalize serum calcium. Additionally, the increase in FGF23 and PTH causes phosphaturia, serum phosphate levels normal until stages 3-4. When GFR gradually decreases, these complex and interconnected processes fail to appropriately manage mineral metabolism, and despite increases in FGF23 and PTH, serum phosphate rises while serum calcitriol falls.
This situation worsens in advanced stages of CKD-MBD. As a result of the decrease in calcium and calcitriol and the increase in phosphate. The parathyroid gland is subjected to a permanent proliferative stimulus, triggering severe forms of secondary hyperparathyroidism with gland hyperplasia, first diffuse and then nodular, with a significant reduction in CaSR, VDR, and FGFR/Klotho expression, resulting in poor response of the parathyroid glands to calcium, VDR activators (VDRA) and FGF23
Pathogenesis of CKD-MBD
As the nephron mass gets reduced in CKD, there is initial rise in FGF23 with reduced Klotho. FGF23 reduces the activity of 1a-hydroxylase and active vitamin D levels gets reduced. CaSR senses the reduced serum Ca and increase the production of PTH.
PTH stimulate 1a-Hydroxylase attempting to normalize serum Ca.
Both PTH and FGF23 are phosphaturic, so these mechanisms maintain normal Ca and PO4 in the early stages of CKD.
As CKD progresses, continuous stimulation of Parathyroid gland leads to SHPTH and Ca tends to go down and PO4 accumulates because of further reduction in nephron mass.
The Parathyroid undergoes diffuse then nodular hyperplasia during this process
Pathogenisis of CKD MBD
biochemical changes occurs as early as CKD G2 with reduction of functioning kidney mass & phosphorus retention & decreased klotho coreceptor expression & increased FGF23 aiming to normalize S.phosphorus via its phosphaturic effect (FGF23 inhibits NaPi2a,c– decreasing phosphorus reabsorption in PCT-, and NaPi2b in intestine – decreasing intestinal absorption of phosphorus-, inhibit 1alpha hydroxylase– inhibiting calcidiol activation hence intestinal absorption of phosphorus-, also stimulate PTH secretion with synergistic effect on urinary phosphorus excretion).
PTH activates calcidiol which increases both calcium absorption & reabsorption till late stages of CKD where these compensatory mechanisms fail to mention normal values of calcium and phosphorus. With sustained stimulation of PTH gland with hyperplasia ( diffused then nodular), the gland show receptor (CaSR, VDR, FGF23R) hyporesponsiveness and become resistant to calcium & vitamin D and FGF23 with sustained SHPT. This results in promoting bone resorbtion in expence of bone formation.
increase in FGF23 ,decrease of Klotho leads to loss of renal mass,these abnormaities accommodate the reduction of alpha 1 hydroxylase in the kidneys which leads to decrease of calcitorial which leads to reduction of intestinal calcium absorption and low serum calcium .hypocalcemia stimulates the release of PTH which increase the alpha 1 hydroxylase. all these mechanisms accelerate to normalise the calcium
It is currently accepted that increase in FGF23, the decrease of Klotho, and the reduction of renal mass are possibly the earliest events in the pathogenesis of CKD-MBD. These changes favor the reduction of 1-α-hydroxylase in the kidney, which results in low levels of calcitriol, the most active natural activator of VDR, a fact that reduces the absorption of calcium in the intestine and favors the decrease in serum calcium, which in turn acts as a stimulus for the synthesis and release of PTH. The increase in PTH favors bone turnover and resorption and stimulates the production of 1-α-hydroxylase. All of these mechanisms translate into compensatory increases to normalize serum calcium. Furthermore, the increase in FGF23 and PTH favor urinary phosphate excretion, maintaining normal serum phosphate levels until stages 3–4 of CKD .Despite the compensatory increases in PTH, it is well known that in CKD there is currently a hyporesponsiveness to PTH which limits its action .
Despite the fact that FGF23 and PTH have synergistic effects in relation to the renal excretion of phosphate, they have opposite effects on calcitriol synthesis. FGF23 inhibits 1-α-hydroxylase by decreasing the synthesis of calcitriol, whereas PTH stimulates the production of 1-α-hydroxylase, increasing calcitriol synthesis .FGF23 exerts its tubular effect by binding to its Klotho co-receptor and activating its FGFR-1 FGFR-3 receptors, while PTH does so by binding to its specific receptor. Both increase the phosphate excretion by reducing the concentration of the sodium cotransporters NaPi2a and NaPi2c, through Protein Kinase A and C -dependent pathways .
Calcium and calcitriol exert their actions on the parathyroid cells through their specific receptors, the calcium- sensing receptor (CaSR), and the vitamin D receptor (VDR), respectively .CaSR is a G protein-coupled membrane receptor, while VDR is a nuclear receptor that, when bound to its activator (any active form of active vitamin D (VDRA), acts as a transcription factor. Differences in the nature of the VDRAs and their receptors can induce different actions and a synergistic effect on the parathyroid cells.
When kidney function progressively decreases, these complex and tightly interrelated mechanisms fail to adequately control the mineral metabolism, and despite increases in FGF23 and PTH, serum phosphate increase and serum calcitriol decrease. In advanced stages of CKD-MBD, this situation worsens, and as a consequence of the decrease in calcium and calcitriol and the increase in phosphate, the parathyroid gland is subjected to a permanent proliferative stimulus that triggers severe forms of secondary hyperparathyroidism with hyperplasia of the gland, first diffuse and then nodular, with a significant reduction in the CaSR, VDR and FGFR/Klotho expression which ends in a poor response of the parathyroid glands to calcium, VDR activators (VDRA) and FGF23 .
according pathogenesis of CKD-MBD
before the old modle
with early stag of CKD
>>hyperphosphatemia and hypocalcemia sensitize parathyroid gland to produce PTH
which increase 1-alfa calcidoil and its effect on ca absorption from intestine and increase of phosphate excretion and change in bone turn over
>>>but recently many factors involved in the pathogenesis in CKD -MBD
as FGF23/KLOTHO which appear in early stag of CKD as phosphaturic effect
wnt inhibitor ( sclerostin . dkk1 )
fuetin
activin A
uremic toxins
All these factor Lead to>>> High turnover bone disease –vascular calcification-valvular calcification –cardiac fibrosis –anemia – )-and clinical outcome bon fragility and fracture
Thanks Dr. Elsayed.
Here is a simplified answer:
Increase in FGF23, Decrease of Klotho, Reduction of renal mass. These changes favor the low levels of calcitriol due to reduction of 1-α-hydroxylase in the kidney. This results in reduction of intestinal calcium absorption and so the decrease in serum calcium. Hypocalcemia leads to stimulation of the synthesis and release of PTH. The increase in PTH stimulates the production of 1-α-hydroxylase. All of these mechanisms translate into compensatory increases to normalize serum calcium. Furthermore, the increase in FGF23 and PTH increase phosphaturia, thus serum phosphate levels are maintained normal until stages 3–4. When GFR progressively reduces, these complex and tightly interrelated mechanisms fail to adequately control the mineral metabolism, and despite increases in FGF23 and PTH, serum phosphate increase, and serum calcitriol decrease.
In advanced stages of CKD-MBD, this situation worsens, and as a consequence of the decrease in calcium and calcitriol and the increase in phosphate, the parathyroid gland is subjected to a permanent proliferative stimulus that triggers severe forms of secondary hyperparathyroidism with hyperplasia of the gland, first diffuse and then nodular, with a significant reduction in the CaSR, VDR and FGFR/Klotho expression which ends in a poor response of the parathyroid glands to calcium, VDR activators (VDRA) and FGF23.
Parallel to the decrease in renal mass the klotho synthesis decreases. FGF-23 synthesis starts in the early stages of CKD. the FGF-23 promotes phosphate secretion. hyperphosphatemia is known to have an important role in CKD-MBD. Till CKD stage IIIa, compensatory mechanisms try to compensate for this so we do not observe high phosphate in the early stages of CKD. With progression hypocalcemia starts. while trying to secrete phosphate through the increase in FGF-23 and a compensatory increase in PTH (which also tries to compensate for hypocalcemia) a progressive increase in PTH can be seen. With the progression of CKD, secondary hyperparathyroidism is seen, markedly after stage 4 all patients have very high PTH. This increase in dialysis patients is either in form of hyperplasia or an increase in nodularity. With the advance in hyperparathyroidism, the VDR receptors become less in number and sensitivity and may entail surgical removal of autonomous nodules to control hyperparathyroidism
Great Dr. Mahmud
When Kidney function start to decrease even in early of disease some changes hoccur like increase koltho secrearion and fgf23 leading increase excretion of po4 in urine also decrease activation of vit d leading activation of pth secretion causing bone resorption to compansate hypocalcemia
Thanks Dr. Rabab
Here is a simplified answer:
Increase in FGF23, Decrease of Klotho, Reduction of renal mass. These changes favor the low levels of calcitriol due to reduction of 1-α-hydroxylase in the kidney. This results in reduction of intestinal calcium absorption and so the decrease in serum calcium. Hypocalcemia leads to stimulation of the synthesis and release of PTH. The increase in PTH stimulates the production of 1-α-hydroxylase. All of these mechanisms translate into compensatory increases to normalize serum calcium. Furthermore, the increase in FGF23 and PTH increase phosphaturia, thus serum phosphate levels are maintained normal until stages 3–4. When GFR progressively reduces, these complex and tightly interrelated mechanisms fail to adequately control the mineral metabolism, and despite increases in FGF23 and PTH, serum phosphate increase, and serum calcitriol decrease.
In advanced stages of CKD-MBD, this situation worsens, and as a consequence of the decrease in calcium and calcitriol and the increase in phosphate, the parathyroid gland is subjected to a permanent proliferative stimulus that triggers severe forms of secondary hyperparathyroidism with hyperplasia of the gland, first diffuse and then nodular, with a significant reduction in the CaSR, VDR and FGFR/Klotho expression which ends in a poor response of the parathyroid glands to calcium, VDR activators (VDRA) and FGF23.
The key players of CKD-MBD) are calcium, phosphate, PTH, FGF23, and the vitamin D hormonal system.with progression in kidney disease many changes will occur in these parameters with diffirent feedback mechanisms .
in summary early in CKD increase FGF23 klotho then pth increse , phosphate keep norml and calcium
late CKD nephro loss derease in klotho expressiom, increase in FGF23, increase in PTH, low calcitriol, low calcium, high phosphate
As a result, important changes occur in the bone and mineral hormonal axis, leading to changes in bone turnover and clinical outcomes, such as decrease in bone mass with increased bone fragility and bone fractures and increased vascular and valvular calcification, also with great impact in the cardiovascular outcomes.
The bone turnover rate affects both the cancellous (trabecular) and the compact (cortical) bone, and it depends on the activity of the bone remodeling units regulated by multiple factors, including PTH, which plays a key role in the remodeling process.
The cortical (85% of the skeleton), is the highest metabolic activity is the trabecular bone. Both decrease in CKD patients, by time the loss of cortical bone is predominant and leads to a thin, trabecularized and more porous cortex, which increases bone fragility, especially in long bones.
High serum PTH levels accelerates bone turnover, PTH stimulates bone cell proliferation and the activity of each remodeling unit, and the recruitment of the new bone remodeling units.
As a result of these two mechanisms, bone activity increases, osteoid formation is abnormal, immature and non-lamellar, and although this abnormal matrix formed is mineralized, it results in a bone with a lower strength and a greater fragility.
The quantification of serum PTH, associated with bone alkaline phosphatase, are the most widely used biochemical parameters to evaluate non-invasively bone activity, although PTH serum values has many limitations.
Very high serum PTH levels,usually have a reasonable good histological predictive value of accelerated bone turnover, but moderately high PTH values do not have good correlation with bone turnover. Low PTH levels are associated with poor cell activity
Good answer Dr. Rola
The pathophysiology of CKD-MBD involves feedback loops between different organs (the kidney, the parathyroid glands, the bone, the intestine, and the vasculature). This system’s primary goal is maintaining calcium and phosphorus balance.
When the renal function falls below 40 mL/min, some components may be observed earlier in the course of CKD and precede the onset of clinically detectable abnormalities in serum phosphorus, calcium, PTH, and vitamin D. These include loss of klotho, increased FGF23 secretion, decreased bone formation rates, and vascular calcification.
Changes and abnormalities:
Most of the biochemical abnormalities that characterize CKD-MBD are due to SHPT.
SHPT result from:
These three interrelated processes account for morbidity and mortality in CKD.
Good answer Dr. Amna
pathogenesis of CKD :
the regulation of mineral and bone metabolism and regulation of calcium and phosphate depends on the action of PTH ,FGF23/KLOTHO/CALCITRIOL/CALCITONIN ==========
the main alteration ocuur in calcium ,phosphate ,PTH ,FGF23/KLOTHO and the vitamin D
which lead to important changes in bone and vascular metabolism
================
the increase in FGF23 ,the decrease of klotho and the reduction of renal mass are the earliest events in the pathogenesis of CKD -MBD
with reduction of 1-alfa hydroxylase in the kidney which result in low levels of calcitriol which reduce calcium absorption in the intestine and >>hypocalcemia which in turn stimulate the release of PTH
Thanks Dr. Emad
In addition to your answer:
The increase in FGF23 and PTH increase phosphaturia, thus serum phosphate levels are maintained normal until stages 3–4. When GFR progressively reduces, these complex and tightly interrelated mechanisms fail to adequately control the mineral metabolism, and despite increases in FGF23 and PTH, serum phosphate increase, and serum calcitriol decrease.
In advanced stages of CKD-MBD, this situation worsens, and as a consequence of the decrease in calcium and calcitriol and the increase in phosphate, the parathyroid gland is subjected to a permanent proliferative stimulus that triggers severe forms of secondary hyperparathyroidism with hyperplasia of the gland, first diffuse and then nodular, with a significant reduction in the CaSR, VDR and FGFR/Klotho expression which ends in a poor response of the parathyroid glands to calcium, VDR activators (VDRA) and FGF23.
Early in CKD:
Increase in phosphate level because of phosphate retention
FGF23 increase
Klotho expression level decreases,
Decrease the level of 1-alpha-hydroxylase level
Hyperphosphatemia and hypocalcemia.
Hyperphosphatemia and hypocalcemia with decreased Vitamin D level lead to activation of PTH via activation of CaSR by hypocalcemia and hyperphosphatemia
And increase PTH expression by Vitamin D deficiency via VDR in the parathyroid gland.
The increase in PTH serum level leads to bone calcium resorption to keep calcium in normal level.
In advanced stages of CKD:
Increase PTH resistance, in the bone, lead to continuing deteriorating imbalance and persistently defective homeostasis, this will lead to persistently activated parathyroid gland
Proliferation and diffuse enlargement
Nodular formation
Reduced CaSR and VDR in the new parathyroid glandular tissue.
Clinical and laboratory evidence of CKD-MBD.
Great Dr. Ahmed
In ckd as there are decrease in phosphorous excretion there will be increase in secretion of FGF23 from the osteocyte which increase the excretion of phosphate through tubular Klotho co R and decrease the activity of the 1 alfa hydrxylase subsequently decrease in calcitriol (active form vitamin D) which is important to increase intestinal absorption of calcium lead to hypocalcimia. Hyperphosphatemia, hypocalcimia and low calcitriol will cause simulation of PTH through CasR and VDR in PT gland, PTH causes increase phosphate excretion, increase secretion of 1 alfa hydrxylase with increase calcitriol production and increase bone turnover to increase S. Calcium level.
with persistent decrease in Calcitriol and Calcium stimulation of PTH there will be polyclonal proliferation of the gland and then become monoclonal proliferation which is become nodular with decrease CasR, VDR, FGFR1 in the gland and decrease the response to hypocalcimia, low calcitriol and subsequently progress to secondary and the tertiary hyperparathyroidism.
The aging of ckd population, increase prevalence of DM as a cause of ckd, excessive use of calcium and vitamin D and aluminum load all these will cause increase incidence of a dynamic bone disease.
Both high and low turnover bone disease increase risk of bone fragility, cardio-vascular disease and valvular and vascular calcification.
Great Dr. Israa
Summarize the pathogenesis of CKD-MBD
Bone : is a dynamic tissue with cycles of building
and demolition . Osteoclasts cells resorb bone, whereas osteoblasts cells fill in the resorptive cavities with new extracellular matrix that undergoes mineralization.
This process is regulated by physiochemical properties .
IN Chronic kidney disease (CKD) there is:
1-hyperphosphtemia.
2- decrease klotho expression.
3-Increase FGF23.
4-low vit -D.
5-low s.Ca
6- HPT.
7-soft tissue calcifications.
8-metabolic bone disease
Bone disease associated with CKD classified histologically according to the degrees of:
1- abnormal bone turnover
2- impaired mineralization of the extracellular matrix.
classification are :
1. Secondary hyperparathyroidism (high-turnover bone disease or osteitis fibrosa).
2. Osteomalacia (defective mineralization).
3. Mixed uremic bone disease (a mixture of high-turnover bone disease and Osteomalacia).
4. A dynamic bone disease (decreased rates of bone formation without a mineralization defect).
High-turnover bone disease:
caused by excess PTH is characterized by greater number and size of osteoclasts and an increase in the resorption . There is an increased amount of osteoid (unmineralized bone).
Osteomalacia :
characterized by prolongation of the mineralization lag time as well as by increased thickness, surface area, and volume of osteoid.
that may be present in CKD patients include 25-hydroxyvitamin D deficiency and hypophosphatemia .
Adynamic Bone Disease
the amount of osteoid thickness is normal or reduced and there is no mineralization defect.
The main findings are decreased numbers of osteoclasts and osteoblasts and very low rates of bone formation.
Good answer Dr. Ahmed
Early in CKD:
increase in phosphate level as a consequence of phosphate retention
FGF23 increase
Klotho expression level decreases,
decrease the level of 1-alpha-hydroxylase level
hyperphosphatemia and hypocalcemia.
Hyperphosphatemia and hypocalcemia with decreased viD level lead to activation of PTH via activation of CaSR by hypocalcemia and hyperphosphatemia
and increase PTH expression by vitD deficiency via VDR in the parathyroid gland.
The increase in PTH serum level leads to bone calcium resorption to keep normcalcemia.
In advanced stages of CKD:
increase PTH resistance, in the bone, lead to continuing deteriorating imbalance and persistently defective homeostasis,this will lead to persistently activated parathyroid gland
proliferation and diffuse enlargement
nodular formation
reduced CaSR and VDR in the new parathyroid glandular tissue.
clinical and laboratory evidence of CKD-MBD.
Great Dr. Mahmoud
-Summarize the pathogenesis of CKD-MBD?
The old theory:
The current concept:
Great Dr Ben
Thnxs prof
-Summarize the pathogenesis of CKD-MBD ?
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
Apology, some thing went wrong
the pathophysiology changed as discovering of FGF23. the plasma FGF23 levels become elevated with progressively worsening renal function, likely to occur before observed changes in the levels of phosphate and PTH, Fibroblast growth factor 23 (FGF23) is derived from osteocytes and plays a vital role in vitamin D and phosphate metabolism. It requires klotho (a transmembrane protein) to enable it to bind to the FGF receptor (FGFR) in classic target organs such as kidneys and parathyroid glands. Plasma FGF23 enhances phosphate excretion in the proximal renal tubule by decreasing the expression of luminal sodium-dependent phosphate transporters and may also decrease intestinal phosphate absorption by inhibiting NaPi cotransporter activity. In addition, it reduces the synthesis of 1,25-dihydroxyvitamin D [1,25(OH)2D3] by down-regulating the activity of 1α-hydroxylase In the early stages of CKD, high levels of FGF23 attenuate hyperphosphatemia at the expense of 1,25(OH)2 vitamin D suppression, thus initiating the development of secondary hyperparathyroidism. The decrease in serum 1,25(OH)2D3 leads to decreased intestinal calcium absorption. The triad of low levels of calcium, calcitriol and hyperphosphatemia further enhances excessive PTH secretion. consequences of progressive worsening of kidney function include hypo-responsiveness of the vitamin D receptor (VDR) on the parathyroid gland with further enhancement of production of PTH and reduced expression of the calcium-sensing receptor on the parathyroid gland leading to parathyroid gland hyperplasia. parathyroid gland undergoes hypertrophy and becomes autonomous in advanced cases, loss of the ability to maintain mineral hemostasis hyperphosphatemia and secondary hyperparathyroidism with PTH hypo responsiveness all lead to bone resorption, and abnormal bone turnover, PTH increased in early CKD stages with subsequent activate on bone remodeling exert bone changes in early disease and may be silent process, The bone turnover rate affects both the cancellous (trabecular) and the compact (cortical) bone, and it depends on the activity of the bone remodeling units regulated by multiple factors, including PTH, which plays a key role in the remodeling process. high serum PTH levels accelerates bone turnover, PTH stimulates bone cell proliferation and the activity of each remodeling unit, and also increases the recruitment of new bone remodeling units As a result bone activity increases, osteoid formation is abnormal, immature and non-lamellar, and although this abnormal
matrix formed is mineralized, results in a bone with a lower strength and a greater fragility. serum PTH and bone alkaline phosphatase, are most widely used biochemical parameters to evaluate non-invasively bone activity. serum PTH levels, usually greater than 450 pg/ml, have a reasonable good histological predictive value of accelerated bone turnover, but moderately high PTH values (300–450 pg/ml) do not have good correlation with bone turnover.
Good Dr. Ahmed
First incidence : increase in FGF23, decrease Klotho and decrease in renal mass
2nd incidence: these changes decrease or inhibit the 1alpha hydroxylase and subsequently the production of vitamin D3.
3rd incidence: low vitamin D will cause hypocalcemia because of decreased calcium absorption.
4th: hypocalcemia and hyperphosphatemia (that happens because of decreased renal excretion with renal failure progression)will stimulate PTH secretion through CaSR.
5th: PTH will COMPENSATE the calcium phosphorus hemostasis :
– it will exercise a phosphaturic effect
-it will increase release of calcium from bone and will activate 1 alpha hydroxylase to lroduce more calcitriol what will cause a balance in calcium level.
6th : with progression of renal deterioration , there will be PTH hyporesponsivness , the Parathyroid gland will undergo monoclonal proliferation what cause a resistance of CaSR and VDR to serum calcium and phosphate level. Because of this there will be decompensation of the compensatory mechanism and the Parathyroid gland will not be more able to normalize calcium and phosphorus levels.
The increased level of PTH overtime (especially pth over 450)will cause increased bone activity, abnormal osteoid formation, immature and non lamellar so that this although mineralized, it results a bone with low strength and great fragility( predominantly cortical bone loss because it is more abundant).
At the end: the increased fgf23 and decreased klotho over time will cause LV hypertrophy andincrease in vascular and valvular calcification
Great Dr. Nour
Fibroblast growth factor 23 (FGF23) is derived from osteocytes and plays a vital role in vitamin D and phosphate metabolism. It requires klotho (a transmembrane protein) to enable it to bind to the FGF receptor (FGFR) in classic target organs such as kidneys and parathyroid glands.
Plasma FGF23 enhances phosphate excretion in the proximal renal tubule by decreasing the expression of luminal sodium-dependent phosphate transporters and may also decrease intestinal phosphate absorption by inhibiting NaPi cotransporter activity.
In addition, it reduces the synthesis of 1,25-dihydroxyvitamin D [1,25(OH)2D3] by down-regulating the activity of 1α-hydroxylase and accentuating the activity of 24-hydroxylase.
In the early stages of CKD, high levels of FGF23 attenuate hyperphosphatemia at the expense of 1,25(OH)2vitamin D suppression, thus initiating the development of secondary hyperparathyroidism.
The decrease in serum 1,25(OH)2D3 leads to decreased intestinal calcium absorption. The triad of low levels of calcium, calcitriol and hyperphosphatemia further enhances excessive PTH secretion.
This excess PTH leads to mobilization of calcium from the bone and osteitis fibrosa.
Other consequences of progressive worsening of kidney function include hypo-responsiveness of the vitamin D receptor (VDR) on the parathyroid gland with further enhancement of production of PTH and reduced expression of the calcium-sensing receptor on the parathyroid gland leading to parathyroid gland hyperplasia.
In some subsets of patients, the parathyroid gland undergoes hypertrophy and becomes autonomous.
Great Dr. Alaa
FGF23, Klotho, and renal mass decreases may be the first events in CKD-MBD pathophysiology. These modifications limit kidney 1–hydroxylase, which lowers calcitriol, the most potent natural activator of VDR, which decreases intestinal calcium absorption and serum calcium, which stimulates PTH production and release. PTH increases bone turnover and 1–hydroxylase production.
These pathways cause compensatory calcium increases. FGF23 and PTH stimulate urinary phosphate excretion, preserving normal serum phosphate levels until CKD stages 3–4. In CKD, PTH hyporesponsiveness restricts its activity despite compensatory increases.
FGF23 and PTH synergistically excrete phosphate, although they oppose calcitriol production. PTH increases calcitriol synthesis, whereas FGF23 inhibits it. PTH binds to its receptor, whereas FGF23 binds to its Klotho co-receptor and activates its FGFR-1 and FGFR-3 receptors. Both reduce the sodium cotransporters NaPi2a and NaPi2c via Protein Kinase A and C-dependent pathways to promote phosphate excretion.
Calcium and calcitriol act on para-thyroid cells through their receptors, the CaSR and VDR, respectively. VDR is a nuclear receptor that operates as a transcription factor when attached to any active form of vitamin D (VDRA). CaSR is a G protein-coupled membrane receptor. VDRAs and receptors may operate differently and synergistically on parathyroid cells.
The CaSR detects minor drops in extracellular calcium concentrations and releases stored PTH within seconds or minutes. If the stimulus is reversed, it suppresses hormone release.
PTH production rises post-transcriptionally if calcium decreases for hours or days, affecting mRNA stability. The reduction in serum calcium increases PTH mRNA stability and half-life, whereas the rise decreases it. PTH mRNA stability and half-life increase with phosphate and vice versa. Phosphate affects the CaSR. Calcitriol, unlike calcium and phosphate, binds to VDR and reduces PTH gene transcription and production.
Thanks Dr. Weam
Increase in FGF23, Decrease of Klotho, Reduction of renal mass. These changes favor the low levels of calcitriol due to reduction of 1-α-hydroxylase in the kidney. This results in reduction of intestinal calcium absorption and so the decrease in serum calcium. Hypocalcemia leads to stimulation of the synthesis and release of PTH. The increase in PTH stimulates the production of 1-α-hydroxylase. All of these mechanisms translate into compensatory increases to normalize serum calcium. Furthermore, the increase in FGF23 and PTH increase phosphaturia, thus serum phosphate levels are maintained normal until stages 3–4. When GFR progressively reduces, these complex and tightly interrelated mechanisms fail to adequately control the mineral metabolism, and despite increases in FGF23 and PTH, serum phosphate increase, and serum calcitriol decrease.
In advanced stages of CKD-MBD, this situation worsens, and as a consequence of the decrease in calcium and calcitriol and the increase in phosphate, the parathyroid gland is subjected to a permanent proliferative stimulus that triggers severe forms of secondary hyperparathyroidism with hyperplasia of the gland, first diffuse and then nodular, with a significant reduction in the CaSR, VDR and FGFR/Klotho expression which ends in a poor response of the parathyroid glands to calcium, VDR activators (VDRA) and FGF23.
The pathogenesis of CKD-MBD:
the pathogenesis of CKD-MBD implies the mechanisms of calcium and phosphorus homeostasis, which depends on the action of calcitrophic hormones;
All are modulated and regulated via absorption, elimination, and deposition of calcium and phosphate, to maintain the birth elements of sustained level.
Kidneys, intestines, parathyroid glands, and bones all maintain this balanced level.
At the early stage of CKD with an increase in phosphate level as a consequence of phosphate retention, FGF23 increase, and Klotho expression level decreases, and decrease the level of 1-alpha-hydroxylase level and the resultants hyperphosphatemia and hypocalcemia.
Hyperphosphatemia and hypocalcemia with decreased viD level lead to activation of PTH via activation of CaSR by hypocalcemia and hyperphosphatemia and increase PTH expression by vitD deficiency via VDR in the parathyroid gland.
The increase in PTH serum level leads to bone calcium resorption to keep normcalcemia.
In advanced stages of CKD 3-5, with reduced levels of GFR, and increase PTH resistance, in the bone, lead to continuing deteriorating imbalance and persistently defective homeostasis, this will lead to persistently activated parathyroid gland proliferation and diffuse enlargement and nodular formation with reduced CaSR and VDR in the new parathyroid glandular tissue.
The persistent imbalance and defective homeostasis lead to clinical and laboratory evidence of CKD-MBD.
The timing of follow-up and management should be individualized and according to the CKd stage by KDIGO recommendation, and keeping all elements within the targeted level.
Assessment of CKD should be started as early as stage 2-3a.
Pathology of CKD metabolic disorder not only implies the ROD but should include all associated metabolic and systemic effects such as;
Good Dr. Kamal