Biblio Cluj

1- Joy S, Karagiannis P, Peyerl F , Outcomes of Secondary Hyperparathyroidism in Chronic Kidney Disease and the Direct Costs of Treatment. JMPC, 5:397-407, 2007

2- Zadeh K, Kovesdy C, Clinical Outcomes with Active versus Nutritional Vitamin D Compunds in Chronic Kidney Disease. Clin J AM Soc Nephrol , 4:1529-1539, 2009

???3-Verstuyf A, Carmeliet G, Bouillon R, Mathieu C, Vitamin D- a pleiotropic hormone. Kidney International, 2010

???4- KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and

Treatment of Chronic Kidney Disease-Mineral and Bone Disorder, 9: Kidney International 76 (Suppl 113): S3S8, 2009

5- Cozzolino M, Bover J, Vervloet M, Brandenburg V, A multidisciplinary review of the science of vitamin D receptor activation, Kidney International Supplements. 2011:107-109

6 (din 5)- National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003; 42 (4 Suppl 3): s1-s201

7- Melamed ML, Michas ED, Post W et al. cited by Cozzolino (5)

8- Kovesdy C, Lu J, Malakauskas S, Andress D, Zadeh K, Ahmadzadeh S, Paricalcitol Versus Ergocalciferol for Secondary Hyperparathyroidism in CKD Stages 3 and 4: A Randomized Controlled Trial. Am J Kidney Dis, 59(1): 58-66, 2012

9- http://www.nlm.nih.gov/medlineplus/ency/article/003690.htm

???10- Chandra P, Binongo JN, Ziegler T et al, Cholecalciferol (Vitamin D3) Therapy and Vitamin D Insufficiency in Patients with Chronic Kidney Disease: A Randomized Controlled Pilot Study. Endocr Pract, 14(1):10-7,2008 (gasit pe NCBI-revista si anul???)

BACKGROUND

One of the most common complications in chronic kidney disease, arising early and really influencing clinical outcome and mortality, is the disorder of mineral metabolism (citat KDIGO).

The pathophysiologic process that leads to this is mainly related to abnormal regulation of serum PTH, using the negative feedback information offered by serum 1,25OHD. SHPT represents the combined effect between the decrease in renal 1 hydroxylation, the deficit in serum calcidiol and the non-response of hyperplastic cells in parathyroids to serum elevated calcium levels.

This is how the vitamin D-PTH loop is altered, causing poor control of metabolic functions: biochemical- increase in calcium and phosphorus levels (1), increase in alkaline phosphatase levels (2)- and metabolic- deficitary/insufficient vitamin D . Main complications in SHPT are cardiovascular (visceral and vascular calcifications, LVH, PAD, CHF) and bone-related (osteitis fibrosa, osteomalacia, adynamic bone disease (1)).

Normally, PTH is secreted secondary to low serum Ca levels, and acts mainly through the activation of 25OHD (obtained via renal and peripheral, paracrine (8) 1 hydroxylation). Also, its secretion is stimulated by ??? high plasmatic levels of vitamin D and PO4 and inhibited by increased levels of FGF23 (3). 1,25(OH)D stimulates intestinal absorbtion of Ca and PO4, Ca reabsorbtion in kidney and releasing Ca from bone, hence primarily regulating serum levels of calcium and phosphorus, but also regulates other functions, such as cell differentiation and cell growth inhibition, immune modulation and cardiovascular actions (3).

In order to correct CKD-associated mineral and bone disorders, vitamin D supplementation is currently used, but this strategy has its lacks: there is only observational data suggesting an association between the level of active vitamin D and survival rates in NDD-CKD patients (1) and also, there are no large well designated randomized studies which can correlate active or nutritional vitamin D replacement therapy with specific clinical outcomes in CKD patients (2). Not graded and level 2C indications exist in guidelines (4) to start medication in SHPT CKD vitamin D deficient/insufficient patients with native vitamin D as a first step and active vitamin D (alternative VDRA) respectively, if the first approach fails (4,9).

Nutritional vit D provides the substrate for both paracrine and systemic functions, while active vit D compounds substitute only endocrine, calcium-phosphate effects. This is why they have different effects on what seem to be the most important efficacity indicators in substitutive Vit D therapy: serum levels of PTH, 25OHD, calcium, phosforus and alkaline phosphatase.

STUDY AIM and DESIGN

Randomized studies so far evaluate the efficiency of native vitamin D versus placebo (10) proving optimal vitamin D status and a trend in decreasing PTH levels, the efficiency of paricalcitol versus placebo suggesting marked decrease in iPTH and also a marked decrease in ALP levels levels in the paricalcitol groups (1, 2) *ALP high levels are negatively associated with both all-cause and cardiovascular mortality, independent of SHPT and its control (2). Targeted value of ALP seems to be under 120 U/L.

Also proven is the reduced incidence of HCa as adverse effects in paricalcitol groups, compared with calcitriol (1) . Mainly epidemiologic studies and relatively few randomized studies compare head-to-head effictiveness between nutritional and VDRA therapy (1), making uncertain which therapy is superior and which compound is to be chosen from various agents available on both categories.

In our one-to-one randomized stratified, controlled, open-label study, we aimed to investigat the cholecalciferol and paracalcitol effects on biochemical parameters of mineral metabolism in non-dialysis CKD patients, with vitamin D defficiency.

Established inclusion criteria were: age (minimum 18 years old), eFGR30 mg/g creatinin, serum 25OHDnormal value for CKD stage.

Exclusion criteria: existing/ soon to be implemented (in 6-12 months) SRT, immunosupressive and biphosphonate therapy in the last 6 months, existing corticotherapy or corticotherapy in the last 6 months, neoplasia in the last 6 months, malabsorbtion-maldigestion syndromes, active hepatopathies or hepatic insufficiency ( starting Child B class), active infections, renal acute injuries, previous treatment with VDRA or Cinacalcet (6 months), hypercalemia (>10,5mg/dL) and hyperphosphatemia (4,6mg/dL).

METHODS

There are no clearly established superior or inferior limits in serum 25OHD levels (5), but are considered a minimum level of 30 ng/mL (6) and a maximum level of 50 ng/mL (7). Normal levels of PTH are 10 to 55 pg/mL (9).

In our study, the laboratory parameters limits were established to: 12-75 pg/mL for PTH, >30ng/mL for 25OHD, 8,5-10,5 mg/dL for calcemia and 2-5mg/dL for serum phosphate.

Our primary endpoint was defined by:

a iPTH median change in each group from baseline and

25OHD median change in each group from baseline(reaching a targeted level of minimum 30 ng/mL)

Secondary endpoints were:

iPTH decrease by at least 30% from baseline in each group

absolute change and variations in iPTH serum levels in each group

bone specific alkaline-phosphatase (ALP) absolute (median??) change in each group, from baseline.

Safety parametres were:

incidence of hypercalcemia, hyperphosphatemia (defined above) and a??? decline in eGFR

SUBJECTS

Continuous data are presented as median, while categorical data, as number (percentage). Baseline values were the values measured after screening phase, before the initiation of therapies. There were no statistical significant differences between C group and P group, except the measured variables of plasma PTH and ALP (both being more elevated in P group).

RESULTS

CONCLUSIONS

CLINICAL APPLICABILITY

The importance of correct prevention and/or treatment of this condition is one of improving clinical outcomes and reducing the main cause of morbidity and mortality (including costs), but also one of financial interest (new alternative therapies- VDRA or active therapies are far more expensive than the old gold standards-nutritional vitamin D) (1).

On might speculate that combined native and active vitamin D therapy could be useful in the setting of non-dialysis chronic kidey disease, given the fact that the net superiority of one or another strategy is yet to be proven.

!!!!!proportia pacientilor care au concomitent 3 si 4 parametri ai metabolismului fosfocalcic (iPTH, Ca, PO4 +/- 25OHD) in limitele de referinta ale laboratorului la baseline si la 6 luni in cele 2 loturi.