A szekunder hyperparathyreosis modern szemlélete Dr. Deák György egyetemi adjunktus Semmelweis Egyetem ÁOK I. sz. Belgyógyászati Klinika, Budapest

A szekunder hyperparathyreosis modern szemlélete Deák György I.sz. Belgyógyászati Klinika Semmelweis Egyetem Tisztelt hallgatók, Előadásomban a k

A Ca/P anyagcsere feedback szabályozása + _ PTH _ _ + _ FGF23 levels increase early in CKD before the development of serum mineral abnormalities and are independently associated with serum Pi, Pi excretion, and 1,25(OH)2D deficiency.50 It was suggested that increased FGF23 may contribute to maintaining normal serum Pi levels in the face of advancing CKD but may worsen 1,25(OH)2D deficiency and thus contribute to the development of2HPT.50 FGF23 did not increase postprandially in patients with CKD or in health FGF23

Krónikus vesebetegség / csont- ásványi-anyagcsere zavar: Szisztémás betegség Ca, P, PTH, D vitamin metabolizmus zavara Renális osteodystrophia: Csont átépülés, mineralizáció, volumen, lineáris növekedés, erősség zava - SHPTH - Osteomalacia - Adynámiás - Kevert Lágyrész- és vaszkuláris kalcifikáció

A fibroblaszt növekedési faktor (FGF-23) hatásai Osteocyta, osteoblast Foszfát retenció FGF-23 Klotho-FGFR 1α-hidroxiláz NaPi-2a NaPi-2c 24-hidroxiláz CaSR VDR PTH Hyperplasia Foszfát ürítés Kalcitriol szint

_ _ _ + PTH PTH Foszfát mellékpajzsmirigy dogs with experimental CKD that dietary Pi restriction prevented 2HPT Pi restriction corrected the 2HPT of CKD independent of changes in serum calcium and 1,25(OH)2 vitamin D levels. low levels of 1,25(OH)2 vitamin D occur earlier in the course of estimated glomerular filtration rate (GFR) decline than do elevations in serum PTH levels. The increased serum PTH preceded the changes in serum Ca2ţ or Pi. low levels of serum 1,25(OH)2 vitamin D may reflect a response to a direct effect of Pi on the renal synthesis of 1,25(OH)2 vitamin D. Pi directly regulated the production of 1,25(OH)2 vitamin D by kidney In vitro studies have shown that the effect of serum Pi on the parathyroid was direct. A high Pi concentration stimulated PTH secretion. parathyroid responds to changes in serum Pi at the level of secretion, gene expression, and cell proliferation, Arachidonic acid and its metabolites inhibit PTH secretion. It was suggested that Pi decreases the production of arachidonic acid activation of the CaR by calcimimetics is able to potently decrease parathyroid cell proliferation despite CKD and hyperphosphatemia. Inhibition of signaling by endothelin 67,68 or EGFR antagonists69 was also able to inhibit parathyroid cell proliferation. Therefore, there is a common downstream signaling node that may be a shared target for the effects of Pi depletion, high extracellular Ca2ţ, calcimimetics, or 1,25(OH)2 vitamin D to decrease PTH gene expression, parathyroid cell proliferation, and PTH secretion. _ + Foszfát PTH PTH

A SHPT patogenezise: tradicionális szemlélet Vesefunkció csökkenés Ca felszívódás Szérum Ca PTH szekréció 1. + 1,25(OH)2D3 + Key Points The traditional view of SHPT is that it is develops from a deficiency of vitamin D/1,25(OH2)D3 (calcitriol) owing to reduced kidney mass (yellow arrow) The reduced kidney mass has several effects on renal function, including: Reduced production of active vitamin D (1,25[OH]2D3; calcitriol) Reduced tubular reabsorption of calcium Reduced tubular excretion of phosphorous (increased reabsorption of P) Low Ca and vitamin D/1,25(OH2)D3 lead to increased PTH secretion from the parathyroid gland (PTG) Low vitamin D/1,25(OH2)D3 also leads to reduced absorption of Ca and P in the gut PTH stimulates resorption of bone and the efflux of Ca and P into the serum: in healthy kidney, this would correct the mineral imbalance The kidney with reduced mass (CKD), cannot respond to PTH to produce sufficient vitamin D/1,25(OH2)D3, such that the levels of vitamin D/1,25(OH2)D3 and Ca remain low and PTH remains unsuppressed (dotted red arrow) Early stages of CKD are marked by low Ca (hypocalcaemia) as the kidney and gut cannot reabsorb enough Ca to maintain homeostasis With worsening CKD, glomerular filtration drops with resultant uraemia: Ca released from bone leads to hypercalcaemia Reduced P excretion and increased efflux from bone lead to hyperphosphataemia References Wetmore J and Quarles D. Nat Clin Pract Nephrol. 2009;5(1):24-33. Ca kiáramlás P kiárámlás - Foszfát retenció Szérum P Wetmore J and Quarles D. Nat Clin Pract Nephrol. 2009;5(1):24-33.

Slatopolsky E, Bricker NS Slatopolsky E, Bricker NS. The role of phosphorus restriction in the prevention of secondary hyperparathyroidism in chronic renal disease. Kidney Int 1973; 4: 141-146 Foszfát diéta < 100 mg/nap 1200 mg/nap Foszfát PTH (U) GFR ml/min

A foszfát, FGF-23, PTH és kalcitriol szintek a GFR függvényében a vesebetegség korai stádiumaiban Foszfát (mg/dl) PTH (ng/l) p<0,0001 p<0,0001 Kalcitriol (ng/l) FGF23 (ng/ml) Evenepoel P.Clin J Am Soc Nephrol 2010;5:

Frakcionális foszfát exkréció és foszfát ürítés veseelégtelenségben FGF-23 Kalcitriol PTH Frakcionális foszfát exkréció p<0,05 p<0,05 p<0,05 Frakcionális foszfát exkréció 24 h vizelet foszfát (mg) p<0,05 p<0,05 KVB 1. 2. 3. 4. 5. stádium KVB 1. 2. 3. 4. 5. stádium Craver L. Nephrol Dial Transplant 2007;22:1171–1176

A SHPT patogenezise: modern szemlélet Vesefunkció csökkenés Foszfát retenció FGF-23 szekréció _ _ PTH szekréció 1. + 1,25(OH)2D3 Szérum Ca Key Points The alternative model of SHPT development by Wetmore and Quarles proposes that the disease is driven by hyperphosphataemia caused by reduced kidney mass (yellow arrow)1 In normal conditions, the system provides an adaptive mechanism that normalises serum phosphorus in early kidney disease mediated by fibroblast growth factor (FGF-23).1 FGF-23 is a bone-derived hormone that inhibits phosphorus reabsorption, thereby increasing phosphorus excretion in the kidney.2 An increase in serum phosphorus levels also leads to a decrease in the conversion of vitamin D to active vitamin [1,25(OH)2D3] by the kidneys via FGF-23, causing a decrease in serum 1,25(OH)2D3 levels.2,3 An increase in serum phosphate stimulates the secretion of FGF-23 by bone osteocytes. The kidney is the major target organ for FGF-23.2 FGF-23 inhibits phosphate reabsorption in the proximal tubule, leading to phosphaturia.1 Inhibition of 1α-hydroxylase by FGF-23 leads to decreased levels of 1,25(OH)2D3.1 The phosphaturic effects of FGF-23 along with suppression of 1,25(OH)2D3 formation provide a means to lower serum phosphate levels.3 In CKD, the reduction in kidney function leads to diminished response to FGF-23 such that serum P remains high Reduced kidney function also leads to low serum calcium and calcitriol (activated vitamin D), both of which increase PTH secretion from the parathyroid gland CKD-derived hyperphosphataemia thus drives SHPT development through FGF-23 and hypocalcaemia References Wetmore J and Quarles D. Nat Clin Pract Nephrol. 2009;5(1):24-33. Urena Torres P, et al. Kidney Int. 2008;73:102-107. National Kidney Foundation. Am J Kidney Dis. 2003;42(suppl 3):S1-S201. P ürítés Ca felszívódás P felszívódás P reabszorpció Wetmore J and Quarles D. Nat Clin Pract Nephrol. 2009;5(1):24-33.

Foszfát retenció Direkt parathyreoidea sejt hatás PTH szintézis: pre-pro-PTH mRNS stabilizálás PTH szekréció Hyperplasia FGF-23 termelődés fokozódása Vese: 1-alfa hidroxiláz gátlása Klotho expresszió gátlása

A receptorok szerepe a szekunder hyperparathyreosis patogenezisében

Klotho expresszió szekunder hyperparathyreosisban normál diffúz hyperplasia noduláris hyperplasia p<0,001 p<0,01 Klotho score normál diffúz noduláris hyperplasia

D vitamin receptor expresszió szekunder hyperparathyreosisban kontroll Noduláris hyperplázia Kidney Int. 2002;62:1196

Kálcium érzékelő receptor expresszió szekunder hyperparathyreosisban CaSR pozitív sejtek (%) normál sec HPT sec HPT noduláris diffúz h y p e r p l a s i a Gogusev J. Kidney Int1997;51:328

Vitamin D receptor (VDR) és kálcium érzékelő receptor (CaSR) Veseelégtelenségben Csökkent VDR expresszió Csökkent kalcitriol-VDR kötődés Lassult sejtmagba történő kalcitriol-VDR migráció Kisebb VDR hatékonyság a pre-pro-PTH génre Csökkent CaSR expresszió Metabolikus acidosis: csökkent CaSR érzékenység Normális CaSR működés és normokalcemia esetén a PTH normalizálódik VDR működés hiányában is, míg CaSR hiányában a kalcitriol nem normalizálja a PTH-t. A CaSR működése domináns Li Y. Endocrinology 1998;139:4391, Drüeke T. Nephrol Dial Transplant 2007;22:1828

Kalcimimetikum hatása a PTH szekrécióra maxPTH %-a iPTH ng/l ionizált Ca mmol/l ionizált Ca mmol/l Kalcimimetikum Ca érzékenység CaSR expresszió VDR expresszió PTH maximum Hyperplasia deFrancisco A. Nephrol Dial Transplant 2008;23: 2895

A szekunder hyperparathyreosis patogenezise alapján levonható klinikai következtetések Jelentősen emelkedett FGF23 rezisztens SHPTH-t tükrözhet. A foszfát restrikció (diéta, foszfát kötők) az elsődleges terápiás cél. Foszfát restrikció mellett csökken a PTH szekréció, fokozódik a Klotho expresszió. A seCa szint a normál tartomány alsó felében legyen. Az acidosis korrekciója fokozza a CaSR Ca++ érzékenységét. Kalcimimetikumok: PTH, Ca, P, hyperplasia prevenció Aktív D vitamin: PTH, hyperplasia prevenció, DE: Ca, P Kalcimimetikum és kis adagú aktív D vit. kezelés nagyon hatékony. DE: Hypokalcemia esetén a kalcitriol nem gátolja a PTH szekréciót! (A calreticulin gátolja a VDR hatást)

A terápiás lépések hierarchiája Foszfát /kálcium kontroll Natív D vitamin D vitamin hiány esetén ? Kis adag aktív D vitamin Kalcimimetikum Kis adag aktív D vitamin + Kalcimimetikum Kalcimimetikum + Kis adag aktív D vitamin

A se Foszfát szint változás a 60 ml/min feletti GFR tartományban normál tartomány Cirillo M. Nephrol Dial Transplant 2009;24:2123–2131

Az FGF-23 szint a GFR tükrében (Heart and Soul Study) N=792 Ix J. Nephrol Dial Transplant 2010;25:993

A mortalitás és FGF-23 szint kapcsolata hemodializáltakban logFGF23 RU/ml seP mmol/l napok FGF-23 Quartilisek (RU/ml) 1. Quartilis: <1100; 2. Quartilis: 1100–2700; 3. Quartilis: 2701–8400; 4. Quartlis >8400 Jean G. NDT 2009;24:2792

PTH és 1,25(OH)2D3 szintek a GFR függvényében iPTH (pg/mL) 1,25(OH)2D3 (pg/mL) GFR (mL/min) iPTH 1,25(OH)2D3 CKD 2 CKD 3 CKD 4 & 5 Key Points Mineral metabolism disturbances start early in the course of CKD, and changes in serum levels of PTH, and 1,25(OH)2D3 are observed with decline in kidney function. The top figure shows the median values of 1,25(OH)2D3 and PTH by level of eGFR in the Study for the Evaluation of Early Kidney Disease (SEEK). These data show an early rise in PTH measured as iPTH accompanied by a decrease in serum 1,25(OH)2D3. Hyperparathyroidism (iPTH > 65 pg/mL) began to occur at eGFR levels of approximately 45 mL/min/1.73 m2. 1,25(OH)2D3 began to approach levels deemed deficient (22 pg/mL) at this GFR also. Background SEEK was a cross-sectional, prospective, community-based, noninterventional cohort study, which was designed to examine the abnormalities in serum PTH, vitamin D, calcium, and phosphorous in patients with CKD. Patients were screened between June and October 2004 across 153 centers. Out of 5,255 patients screened, 1,814 (866 male and 948 female) met the entry criteria (eGFR values calculated using the most recent serum creatinine as documented in the chart of < 60 mL/min/1.73 m2).1 Based on discrepancies between the chart-documented serum creatinine and the baseline creatinine measured at study entry, 23%, or 405 patients included in this study, had an eGFR > 60 mL/min/1.73 m2. Exclusion criteria included renal replacement therapy, a history of primary parathyroid disease, or use of any prescription-based vitamin D therapy in the 12 months before screening. Study limitations include age-weighting of the study population (71% of the sample was over 65 years old) and kidney function (eGFR) was defined by a single creatinine measure. In addition, no longitudinal data were provided, reported here, thus relationships between the variables and different eGFR levels may change over time. The CKD population was from outpatient nephrology clinics in Massachusetts General Hospital, University of Maryland, Baltimore. References Levin A, et al. Kidney Int. 2007;71:31-38. N = 1,814 1. Levin A, et al. Kidney Int. 2007;71:31-38.

Hemodializált betegek 2 éves mortalitása aktív D vitamin kezelés mellett D vitamin kezelés: N = 37173, D vitamint nem kapók: N = 13864 mort. N % Teng M. J Am Soc Nephrol 16: 1115-1125, 2005.