secondary hyperparathyroidism ( shpt ) is often underdiagnosed or insufficiently treated in patients not yet receiving dialysis , when therapy would have greater short- and long - term benefits .
hyperparathyroidism also frequently persists after successful renal transplantation   and is present in up to 50% of patients 1 year after renal transplant surgery .
thus , early diagnosis and management of shpt in chronic kidney disease ( ckd ) patients and recognition and treatment of persistent hyperparathyroidism in post - transplant patients is important and might reduce morbidity from cardiovascular and bone disease . the efficacy of the calcimimetic cinacalcet was recently explored in these two distinct patient populations . in this article , the manifestations of hyperparathyroidism in stage 3 and 4 ckd and in kidney transplant patients will be discussed , and data regarding the efficacy of cinacalcet in these two groups of patients will be presented .
patients with stage 3 and 4 ckd are more likely to die than to progress to end - stage renal disease . among patients with stage 3 ckd , 24.3% of patients died within 5 years versus 1.3% who progressed to renal replacement therapy . among patients with stage 4 ckd
, 45.7% died within 5 years , compared with 19.9% who progressed to dialysis or transplantation ( figure 1 ) .
accordingly , the national kidney foundation kidney disease outcomes quality initiative guidelines recommend treatment of shpt in stage 3 and 4 ckd patients to reduce disease severity and associated morbidity .
the underrecognition and undertreatment of shpt in these patients   has serious consequences , including vascular calcifications and bone disease .
thus , in the context of shpt , elevated serum phosphorus has been associated with increased mortality risk and with acute myocardial infarction in ckd patients not receiving dialysis .
the hypercalcaemia , hyperphosphataemia and increased calcium  phosphorus product ( ca  p ) associated with shpt contribute to the development of vascular calcifications that are commonly observed in chronic dialysis patients .
the process of vascular calcification begins early in the progression of ckd and continues as kidney function declines .
the incidence of vascular calcifications among ckd patients not receiving dialysis is 40% ; this value increases to 64% in patients who are starting dialysis   and to 83% in patients established on dialysis .
shpt also contributes to renal bone disease , which may cause additional morbidity in haemodialysis patients .
once again , the development of renal bone disease occurs early in the progression of ckd .
manipulation of the calcium - sensing receptor ( car ) impacts the synthesis and secretion of parathyroid hormone ( pth ) and parathyroid gland hyperplasia .
calcimimetics , by modulating the car , can directly address the pathophysiology of shpt early in ckd .
charytan et al .   reported the results of a double - blind , placebo - controlled trial to determine the safety and efficacy of cinacalcet in 54 patients with stage 3 and 4 ckd .
all patients included in the study had a serum intact pth ( ipth ) concentration of > 130 pg / ml and a serum calcium concentration of > 9.0 mg / dl .
doses of vitamin d could be adjusted appropriately : decreased if hypercalcaemia ( calcium > 11 mg / dl ) or hyperphosphataemia ( phosphorus > 5.5 mg / dl ) occurred , or increased if serum calcium was < 8.4 mg / dl or ipth concentrations were at least 50% greater than baseline on three consecutive visits .
the study design consisted of a 12-week titration phase during which the cinacalcet dose was adjusted between 30 and 180 mg / day according to the ipth and calcium concentrations .
efficacy was assessed during the following 6 weeks of treatment by measuring weekly ipth concentrations .
more patients treated with cinacalcet achieved the primary endpoint of at least a 30% reduction in ipth from baseline compared with placebo - treated patients ( 56% versus 19% , p = 0.006 ; figure 2 ) .
after 2 weeks , mean ipth decreased by approximately 33% in the cinacalcet group and remained approximately 30% to 40% below baseline for the duration of the study .
in contrast , mean ipth in the placebo group remained near baseline levels throughout the study ( figure 3 ) .
percentage of stage 3 and stage 4 ckd patients achieving primary endpoint of 30% reduction from baseline in ipth with cinacalcet ( n = 27 ) or placebo ( n = 27 ) therapy .
reduction of ipth from baseline ( week 0 ) during treatment with cinacalcet ( n = 27 ) or placebo ( n = 27 ) in stage 3 and 4 ckd patients .
b , baseline ; se , standard error . adapted with permission from charytan et al .   mean serum calcium concentrations were decreased by 7% in the cinacalcet treatment group but were unchanged ( 0.1% ) in the placebo group .
patients with ckd not on dialysis receiving cinacalcet were more likely to experience low serum calcium levels compared with those on dialysis [ 1720 ] .
in most instances , low serum calcium concentrations ( < 8.4 mg / dl ) were successfully treated by increasing the dose of vitamin d sterols , phosphate binders and/or calcium supplements .
four patients discontinued treatment because of low serum calcium while receiving the lowest dose of cinacalcet , and serum calcium levels returned to normal after stopping therapy .
the increased likelihood of hypocalcaemia appeared to be associated with lower calcium concentrations before the commencement of cinacalcet therapy in stage 3 and 4 ckd patients .
urinary calcium excretion was more elevated in the cinacalcet group compared with the placebo group ( p < 0.05 ; table 1 ) but remained below the upper limit of normal ( 300 mg/24 h ) in both treatment groups .
effect of cinacalcet on kidney function in patients with stage 3 and 4 ckd gfr , glomerular filtration rate ; se , standard error .
mean serum phosphorus concentrations were increased in the cinacalcet treatment group but were unchanged in the placebo group ( p < 0.05 , cinacalcet versus placebo ) .
this effect of cinacalcet was most likely due to reduced pth secretion , resulting in reduced urinary excretion of phosphorus .
consistent with this hypothesis , 24-h urine phosphorus excretion was decreased by 13.3% in the cinacalcet group and was unchanged in the placebo group ( 1.5% ; p = 0.19 ) . in the cinacalcet group , ca  p increased 6.7% from baseline , whereas in the placebo group , ca  p increased 3.2% from baseline .
importantly , in both the cinacalcet- and placebo - treated groups , the mean values of serum calcium and phosphorus remained within normal limits at each visit .
the glomerular filtration rate was not significantly changed from baseline in either treatment group ( table 1 ) .
in addition , cinacalcet was well tolerated in this population of stage 3 and stage 4 ckd patients .
the most common adverse events were nausea , myalgia and diarrhoea ( table 2 ) .
these side effects were of mild to moderate severity and of short duration . in summary ,
the results of this study demonstrate , for the first time , the efficacy and safety of cinacalcet in the treatment of shpt in stage 3 and 4 ckd patients .
these findings need to be confirmed , and in particular the determination of an appropriate dosing strategy for this patient population requires further investigation in a phase 3 clinical trial .
most common adverse events in stage 3 and 4 ckd patients treated with placebo or cinacalcet data from charytan et al . .
hyperparathyroidism frequently persists after successful renal transplantation . in a study by lobo et al .
, ipth levels were measured over a 0.5- to > 4-year period in 52 patients with intact graft function after renal transplantation .
one year after transplantation , ipth remained elevated ( 65 pg / ml ) in more than 50% of patients . in a similar study ,
ipth values were measured in the month preceding kidney transplant and over a mean 69-month follow - up period after transplant in 62 patients with stable graft function .
after > 2.5 years following transplantation , only 23% of transplant patients with good renal function had normal ipth levels , and 27% of patients had ipth values more than twice the upper normal limit ( > 130 pg / ml ) .
persistent hyperparathyroidism causes hypercalcaemia , which is commonly observed following renal transplantation . in a study of 129 transplant patients , reinhardt et al
.   found that 52% were hypercalcaemic ( > 10 mg / dl ) 3 months after kidney transplantation , and 15% were still hypercalcaemic at 24 months .
post - transplant hypercalcaemia may pose a significant risk for renal and vascular calcifications following transplantation and a subsequent increased risk of cardiovascular death [ relative risk ( rr ) = 2.6 ; p = 0.033 ] and overall mortality ( rr = 1.8 ; p = 0.015 ) . in the study by gwinner et al .
, calcifications in the kidneys were present in 26% of renal transplant patients , and those patients with calcifications had both elevated ipth and calcium . interestingly , even though there was no association between serum phosphorus and vascular calcification , post - transplant phosphorus supplementation occurred more frequently in those with vascular calcification .
persistent hyperparathyroidism is also associated with high bone turnover and may contribute to bone disease following transplantation . of interest
pretransplant ipth level was significantly correlated ( r = 0.58 ; p = 0.0001 ) with post - transplant ipth level in patients with normal transplant function > 2.5 years after transplantation . a similar relationship between pre- and post - transplant ipth levels
correlations between pretransplant and post - transplant ipth levels have been shown to persist for up to 4 years after transplantation .
these studies suggest that treatment of hyperparathyroidism and hypercalcaemia before transplant surgery might help reduce the severity of hyperparathyroidism after transplantation .
the current treatment strategies for hyperparathyroidism after renal transplantation are limited and have important side effects . as mentioned above , phosphorus supplementation has been associated with the occurrence of interstitial calcifications in the graft .
bisphosphonates generally do not reduce pth levels significantly and may promote low turnover bone disease .
parathyroidectomy is effective to lower pth and to correct hypercalcaemia ; however , several studies have suggested that renal allograft function may deteriorate , and cases of graft loss have been described after parathyroidectomy [ 2932 ] .
based on these data , more suitable and safer therapies that correct persistent hyperparathyroidism and hypercalcaemia and the consequent morbidity would be beneficial to this group of patients .
given that hyperparathyroidism remains a problem for many patients after successful renal transplantation [ 24 ] , and because there are few effective therapeutic options , there has been interest in novel treatments for the control of hyperparathyroidism in this group of patients . the effect of cinacalcet in patients with persistent hyperparathyroidism after
renal transplant has been reported in a number of small prospective and retrospective open - label studies in transplant patients with stable allograft function [ 3441 ] . in general ,
patients in these studies had stable renal function with mean creatinine clearances in the range of 30 75 ml / min .
the primary objective of cinacalcet therapy was control of post - transplant hypercalcaemia , and cinacalcet was titrated to achieve this endpoint .
avoided the use of vitamin d , whereas apostolou et al .   allowed its use once calcium levels were normalized
in general , the cinacalcet dosage needed to control hypercalcaemia was relatively low ( average , 3040 mg / day ) . baseline characteristics of the studies are summarized in table 3 .
overall , efficacy results across the studies were consistent ( table 4 ) . within 2 to 4 weeks of cinacalcet treatment , serum ipth
was significantly reduced and maintained over the treatment duration ( 10 weeks to 14 months ) . in the study by kruse et al . , the sustained reduction in ipth levels after cinacalcet treatment was not significant because of large ipth differences among patients and the small sample size .
reported that cinacalcet reduced serum ipth from baseline by an average of 40% during the first month of treatment ; ipth levels remained 4050% lower than baseline for the duration of the 6-month follow - up .
similarly , serra et al .   observed a maximal reduction in ipth following 8 weeks of cinacalcet treatment , with reduced ipth being maintained for 26 weeks ( figure 4 ) . 

( n = 12)(n = 14)(n = 9)(n = 10)(n = 11)(n = 7)(n = 2)(n = 18)age ( years)meannrnr52nrnrnr6245range49702365nrnr2264387252711966sex ( n)men679nr6428women670nr53010dialysis duration before study entry ( months)mean32nrnr65nrnrnr84time from renal transplant to study entry ( months)mean28nr59nrnrnrnrnrrange63847168nrnr26043510161276pth at study entry ( pg / ml)mean190nr171605nr424nr627rangenr801295nrnr99723nr256407nrnr , not reported . 

table 4.summary of results from cinacalcet studies in post - transplant patientsgraft functionstudycinacalcetimmuno-(creatinine clearance orstudyreferencedurationpatients ( n)pthcapca  psuppressantsserum creatinine)serra et al .  6 months12kruse et al . 
.  6 months10nsnrnrnrsrinivas et al.18 months11nsnrapostolou et al.18 months  7nrapostolou et al.14 months  2nsnsnsnrel - amm et al . 
4.reduction in ipth during treatment with cinacalcet in renal transplant recipients ( n = 12 ) .
baseline demographics in renal transplant patients with persistent hyperparathyroidism summary of results from cinacalcet studies in post - transplant patients nr , not reported ; ns , not significant .
reduction in ipth during treatment with cinacalcet in renal transplant recipients ( n = 12 ) .
cinacalcet significantly reduced calcium levels within days of treatment , and calcium levels overall were maintained in the normal range over the treatment periods [ 3341 ] .
serra et al .   reported that serum calcium was maintained within normal limits in all patients for 6 months , with serum - ionized calcium being reduced by 17.7% .
kruse et al .   reported normalization of serum calcium in 12 of 14 patients . in the case report by apostolou et al .
, calcium levels declined rapidly after just 1 day of cinacalcet treatment . in general , serum phosphorus remained unchanged or was increased towards the normal range [ 3441 ] . in one study , after 6 months of treatment with cinacalcet , 90% of patients had serum phosphorus levels within the normal range .
when it was measured , serum ca  p remained unchanged ( table 4 ) .
graft function was measured in seven studies of renal transplant patients treated with cinacalcet , and renal function remained stable in five of the studies ( table 4 ) [ 3336,3841 ] . in one study , the glomerular filtration rate , measured by serum creatinine prediction equations ,
declined over the observation period of cinacalcet treatment ; however , the observation period was only 3 months , precluding conclusions regarding long - term graft function . in another study ,
the decline in the glomerular filtration rate after cinacalcet therapy was consistent with the rate of decline before treatment , and therefore , this may not have been a result of cinacalcet therapy .
there was no reported interference of cinacalcet with immunosuppressants , and no increase in rejection episodes was reported in these studies . in summary ,
the results of these small studies show that treatment with cinacalcet effectively normalized hypercalcaemia and significantly reduced ipth levels in renal transplant recipients , without adversely affecting graft function .
larger studies are required to confirm these findings and to obtain long - term data regarding safety and efficacy .
in patients undergoing chronic dialysis , cinacalcet has been demonstrated to substantially improve the control of shpt compared with standard care [ 1719,42,43 ] .
the role of calcimimetics in the treatment of shpt in stage 3 and 4 ckd patients and in the treatment of persistent hyperparathyroidism in post - transplant patients is less well characterized . nonetheless , the car is a promising target for these two distinct patient populations . in the early studies reported here ,
cinacalcet significantly reduced ipth concentrations by more than 30% in most patients with stage 3 and 4 ckd . in kidney transplant patients , cinacalcet therapy significantly reduced calcium and ipth levels and placed phosphorus into the normal range .
these early clinical studies suggest that cinacalcet is effective in controlling mineral metabolism in patients with stage 3 and 4 ckd and post - renal transplantation . because these studies were of short duration and included only small numbers of patients , long - term studies in larger groups of patients
 cinacalcet has proven effective in the treatment of secondary hyperparathyroidism ( shpt ) in dialysis patients , and it may also have benefits in stage 3 and 4 chronic kidney disease ( ckd ) . 
 the efficacy of cinacalcet in the treatment of shpt was investigated in a study of 54 patients with stage 3 and 4 ckd not receiving dialysis . 
 a significant number of these patients achieved at least a 30% reduction in parathyroid hormone ( pth ) from baseline with cinacalcet therapy compared with placebo ( 56% versus 19% ; p = 0.006 ) . 
 another potential use of cinacalcet is in the treatment of persistent hyperparathyroidism ( hpt ) after kidney transplantation . 
 the pathophysiologic considerations for persistent hpt in patients who have undergone renal transplantation are different from those in stage 3 and 4 ckd . 
 post - transplant patients with normal graft function often present with hypercalcaemia , low serum phosphorus and persistently elevated levels of pth . in eight small open - label studies including a total of 83 patients with persistent hpt after successful kidney transplantation , cinacalcet treatment effectively corrected hypercalcaemia and significantly reduced elevated pth levels . 
 these studies suggest that cinacalcet therapy is an effective therapy in controlling hyperparathyroidism in patients with stage 3 and 4 ckd and in post - transplant patients with persistent hyperparathyroidism . 
Introduction
Manifestations of stage 3 and 4 CKD
Cinacalcet treatment in stage 3 and 4 CKD
Kidney transplant patients
Cinacalcet treatment in renal transplant patients
Summary and conclusions