Effect of cinacalcet cessation in renal transplant recipients with persistent hyperparathyroidism

BACKGROUND: Persistent hyperparathyroidism after renal transplantation affects bone and allografts. Cinacalcet, a calcimimetic, reduces serum calcium and PTH in renal transplant recipients with persistent hyperparathyroidism. Here, we address the question whether this effect of cinacalcet persists after withdrawal. METHODS: Therefore, cinacalcet was stopped after 12 months treatment in 10 stable renal transplant patients. Serum calcium, phosphate, PTH, creatinine and cystatin C were monitored for 3 months. RESULTS: Serum calcium, normalized in nine patients before cessation of cinacalcet (2.32 +/- 0.05mmol/l, mean +/- SEM), increased after 3 months of discontinuation by 0.17 +/- 0.04mmol/l, P < 0.05, but remained within the normal range in eight patients. Compared with the time point of cessation, PTH remained unchanged or decreased further after 3 months without therapy in six patients. Measurements of cystatin C suggested an improvement of the glomerular filtration rate after cessation in 9 out of 10 patients (1.55 +/- 0.09 vs 1.33 +/- 0.12 mg/l, P < 0.01). CONCLUSION: First, a beneficial effect of cinacalcet beyond the duration of a 12-month therapy appears to be present in some patients and second, the previously suspected influence of cinacalcet therapy on renal function is reversible. Thus, it is reasonable to consider a trial of cinacalcet cessation to identify these patients. The optimal time point for such a discontinuation is unknown. The present observations are preliminary. They clearly require a prospective randomized trial for definitive confirmation.

1,25-(OH)2-16ene-23yne-D3 reduces secondary hyperparathyroidism in uremic rats with little calcemic effect

To compare the effects of vitamin D analogs versus calcitriol on serum levels of Ca, P and parathyroid hormone (PTH). A compound better than calcitriol should increase the Ca x P product less than calcitriol for an equivalent decrease in PTH levels.

Effect of calcium-channel blockers on calcium-phosphate metabolism in patients with end-stage renal disease

After EDTA-induced hypocalcaemia, healthy volunteers treated with diltiazem display more severe hyperparathyroidism than subjects on felodipine studied under identical conditions. Therefore patients with end-stage renal disease (ESRD) and severe secondary hyperparathyroidism might be particularly sensitive to this side-effect.

Hiperparatiroidismo secundário e compromisso neurológico, que relação? : apresentação de um caso de osteodistrofia renal

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Secondary prevention of renal and cardiovascular disease: Results of a renal and cardiovascular treatment program in an Australian aboriginal community

Australian Aborigines are experiencing an epidemic of renal and cardiovascular disease. In late 1995 we introduced a treatment program into the Tiwi community, which has a three- to fivefold increase in death rates and a recent annual incidence of treated ESRD of 2760 per million. Eligible for treatment were people with hypertension, diabetics with micro or overt albuminuria, and all people with overt albuminuria. Treatment centered around use of perindopril (Coversyl, Servier), with other agents added to reach BP goals; attempts to control glucose and lipid levels; and health education. Thirty percent of the adult population, or 267 people, were enrolled, with a mean follow up of 3.39 yr. Clinical parameters were followed every 6 mo, and rates of terminal endpoints were compared with those of 327 historical controls matched for baseline disease severity, followed in the pretreatment program era. There was a dramatic reduction in BP in the treatment group, which was sustained through 3 yr of treatment. Albuminuria and GFR stabilized or improved. Rates of natural deaths were reduced by an estimated 50% (P = 0.012); renal deaths were reduced by 57% (P = 0.038); and nonrenal deaths by 46% (P = 0.085). Survival benefit was suggested at all levels of overt albuminuria, and regardless of diabetes status, baseline BP, or prior administration of angiotensin converting enzyme inhibitors (ACEI). No significant benefit was apparent among people without overt albuminuria, nor among those with GFR less than 60 ml/min. An estimated 13 renal deaths and 10 nonrenal deaths were prevented, with the number-needed-to-treat to avoid one terminal event of only 11.6. Falling deaths and renal failure in the whole community support these estimates. The program was extremely cost-effective. Programs like this should be introduced to all high-risk communities as a matter of urgency.

Efficacy and Safety of Ticagrelor for Long-term Secondary Prevention of Atherothrombotic Events in Relation to Renal Function: Insights from the PEGASUS TIMI-54 trial

Aims: We evaluated the relationship of renal function and ischaemic and bleeding risk as well as the efficacy and safety of the P2Y12 platelet receptor inhibitor ticagrelor in stable patients with prior myocardial infarction (MI). Methods & Results: Patients with a history of MI 1-3 years prior from the Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin (PEGASUS)-TIMI 54 were stratified based on estimated glomerular filtration rate (eGFR), with<60 ml/min/1.73m2 prespecified for analysis of the effect of ticagrelor on the primary efficacy composite of cardiovascular death, MI, or stroke (MACE) and the primary safety endpoint of TIMI major bleeding. Of 20,898 patients, those with eGFR<60 (N=4,849, 23.2%) had a greater risk of MACE at 3 years relative to those without, which remained significant after multivariable adjustment (HRadj 1.54, 95% CI 1.27–1.85, p<0.001). The relative risk reduction in MACE with ticagrelor was similar in those with eGFR<60 (ticagrelor pooled vs. placebo: HR 0.81; 95% CI 0.68–0.96) vs. ≥60 (HR 0.88; 95% CI 0.77–1.00, pinteraction=0.44). However, due to the greater absolute risk in the former group, the absolute risk reduction with ticagrelor was higher: 2.7% vs. 0.63%. Bleeding tended to occur more frequently in patients with renal dysfunction. The absolute increase in TIMI major bleeding with ticagrelor was similar in those with and without eGFR<60 (1.19% vs. 1.43%), whereas the excess of minor bleeding tended to be more pronounced (1.93% vs. 0.69%). Conclusion: In patients with a history of MI, patients with renal dysfunction are at increased risk of MACE and consequently experience a particularly robust absolute risk reduction with long-term treatment with ticagrelor.

Clinical outcomes of kidney transplants on patients with end-stage renal disease secondary to lupus nephritis, polycystic kidney disease and diabetic nephropathy

Background: Patients with lupus nephritis could progress to endstage renal disease (10-22%); hence, kidney transplants should be considered as the treatment of choice for these patients. Objective: To evaluate the clinical outcomes after kidney transplants in patients with chronic kidney diseases secondary to lupus nephritis, polycystic kidney disease and diabetes nephropathy at Pablo Tobon Uribe Hospital. Methods: A descriptive and retrospective study performed at one kidney transplant center between 2005 and 2013. Results: A total of 136 patients, 27 with lupus nephritis (19.9%), 31 with polycystic kidney disease (22.8%) and 78 with diabetes nephropathy (57.4%), were included in the study. The graft survivals after one, three and five years were 96.3%, 82.5% and 82.5% for lupus nephritis; 90%, 86% and 76.5% for polycystic kidney disease and 91.7%, 80.3% and 67.9% for diabetes nephropathy, respectively, with no significant differences (p= 0.488); the rate of lupus nephritis recurrence was 0.94%/person-year. The etiology of lupus vs diabetes vs polycystic disease was not a risk factor for a decreased time of graft survival (Hazard ratio: 1.43; 95% CI: 0.52-3.93). Conclusion: Kidney transplant patients with end stage renal disease secondary to lupus nephritis has similar graft and patient survival success rates to patients with other kidney diseases. The complication rate and risk of recurrence for lupus nephritis are low. Kidney transplants should be considered as the treatment of choice for patients with end stage renal disease secondary to lupus nephritis.

Urinary Tract Infection In Renal Transplant Recipients: Incidence, Risk Factors, And Impact On Graft Function.

Urinary tract infection (UTI) is the most common infection posttransplant. However, the risk factors for and the impact of UTIs remain controversial. The aim of this study was to identify the incidence of posttransplant UTIs in a series of renal transplant recipients from deceased donors. Secondary objectives were to identify: (1) the most frequent infectious agents; (2) risk factors related to donor; (3) risk factors related to recipients; and (4) impact of UTI on graft function. This was a retrospective analysis of medical records from renal transplant patients from January to December 2010. Local ethics committee approved the protocol. The incidence of UTI in this series was 34.2%. Risk factors for UTI were older age, (independent of gender), biopsy-proven acute rejection episodes, and kidneys from deceased donors (United Network for Organ Sharing criteria). For female patients, the number of pretransplant pregnancies was an additional risk factor. Recurrent UTI was observed in 44% of patients from the UTI group. The most common infectious agents were Escherichia coli and Klebsiella pneumoniae, for both isolated and recurrent UTI. No difference in renal graft function or immunosuppressive therapy was observed between groups after the 1-year follow-up. In this series, older age, previous pregnancy, kidneys from expanded criteria donors, and biopsy-proven acute rejection episodes were risk factors for posttransplant UTI. Recurrence of UTI was observed in 44%, with no negative impact on graft function or survival.

The secondary vascular system of Actinopterygii: interspecific variation in origins and investment

Vascular casts of 3 species of Chondrichthyes, 1 of Dipnoi, 1 of Chondrostei and 14 species of the Teleostei were examined by light and scanning electron microscopy in order to give a qualitative and quantitative analysis of interarterial anastomoses (iaas) that indicate the presence (or absence) of a secondary vascular system (SVS). Anastomoses were found to originate from a variety of different primary blood vessels, many of which have not been previously identified as giving rise to secondary vessels. Segmental arteries derived from the dorsal aorta and supplying body musculature were major sites of origin of the SVS, although there was considerable variation in where, in the hierarchy of arterial branching, the anastomoses occurred. The degree of investment in a SVS was species specific, with more active species having a higher degree of secondary vascularisation. This difference was quantified using an absolute count of iaas between Anguilla reinhardtii and Trachinotus baillonii. A range of general features of the SVS is also described. No evidence of iaas was found on the coeliac, mesenteric or renal circulation in any species. Evidence of iaas was lacking in the dipnoan and chondrichthyan species examined, suggesting that a SVS is restricted to Actinopterygii. The presence and distribution of a SVS does not appear to be exclusively linked to phylogenetic position, but rather to the physiological adaptation of the species.

K/DOQI-recommended intact PTH levels do not prevent low-turnover bone disease in hemodialysis patients

The guidelines proposed by the Kidney Disease Outcomes Quality Initiative (K/DOQI) suggested that intact parathyroid hormone (iPTH) should be maintained in a target range between 150 and 300 pg ml(-1) for patients with stage 5 chronic kidney disease. Our study sought to verify the effectiveness of that range in preventing bone remodeling problems in hemodialysis patients. We measured serum ionized calcium and phosphorus while iPTH was measured by a second-generation assay. Transiliac bone biopsies were performed at the onset of the study and after completing 1 year follow-up. The PTH levels decreased within the target range in about one-fourth of the patients at baseline and at the end of the study. The bone biopsies of two-thirds of the patients were classified as showing low turnover and a one-fourth showed high turnover, the remainder having normal turnover. In the group achieving the target levels of iPTH 88% had low turnover. Intact PTH levels less than 150 pg ml(-1) for identifying low turnover and greater than 300 pg ml(-1) for high turnover presented a positive predictive value of 83 and 62%, respectively. Our study suggests that the iPTH target recommended by the K/DOQI guidelines was associated with a high incidence of low-turnover bone disease, suggesting that other biochemical markers may be required to accurately measure bone-remodeling status in hemodialysis patients.

Worse renal outcome of lupus nephritis in male patients: a case-control study

Background: Progression and long-term renal outcome of lupus nephritis (LN) in male patients is a controversial subject in the literature. The aim of this study was to evaluate the influence of male gender on the renal outcome of LN. Methods: All male (M) LN patients who fulfilled American College of Rheumatology lupus criteria and who were referred for a kidney biopsy from 1999 to 2009 were enrolled in the study. Subjects with end-stage renal disease at baseline, or follow-up time below 6 months, were excluded. Cases were randomly matched to female (F) patients according to the class of LN, baseline estimated glomerular filtration rate (eGFR, Modification of Diet in Renal Disease simplified formula) and follow-up time. Treatment was decided by the clinical staff based on usual literature protocols. The primary endpoint was doubling of serum creatinine and/or end-stage renal disease. The secondary endpoint was defined as a variation of glomerular filtration rate (GFR) per year (Delta GFR/y index), calculated as the difference between final and initial eGFR adjusted by follow-up time for each patient. Results: We included 93 patients (31 M : 62 F). At baseline, M and F patients were not statistically different regarding WHO LN class (II 9.7%, IV 71%, V 19.3%), eGFR (M 62.4 +/- 36.4 ml/min/1.73 m(2) versus F 59.9 +/- 32.7 ml/min/1.73 m(2)), follow-up time (M 44.2 +/- 27.3 months versus F 39.9 +/- 27.9 months), and 24-hour proteinuria (M 5.3 +/- 4.6 g/day versus F 5.2 +/- 3.0 g/day), as well as age, albumin, C3, antinuclear antibody, anti-DNA antibody and haematuria. There was no difference in the primary outcome (M 19% versus F 13%, log-rank p = 0.62). However, male gender was significantly associated with a worse renal function progression, as measured by Delta GFR/y index (beta coefficient for male gender -12.4, 95% confidence interval -22.8 to -2.1, p = 0.02). The multivariate linear regression model showed that male gender remained statistically associated with a worse renal outcome even after adjustment for eGFR, proteinuria, albumin and C3 complement at baseline. Conclusion: In our study, male gender presented a worse evolution of LN (measured by an under GFR recovering) when compared with female patients with similar baseline features and treatment. Factors that influence the progression of LN in men and sex-specific treatment protocols should be further addressed in new studies. Lupus (2011) 20, 561-567.

The Bone Histology Spectrum in Experimental Renal Failure: Adverse Effects of Phosphate and Parathyroid Hormone Disturbances

Bone disease is a common disorder of bone remodeling and mineral metabolism, which affects patients with chronic kidney disease. Minor changes in the serum level of a given mineral can trigger compensatory mechanisms, making it difficult to evaluate the role of mineral disturbances in isolation. The objective of this study was to determine the isolated effects that phosphate and parathyroid hormone (PTH) have on bone tissue in rats. Male Wistar rats were subjected to parathyroidectomy and 5/6 nephrectomy or were sham-operated. Rats were fed diets in which the phosphate content was low, normal, or high. Some rats received infusion of PTH at a physiological rate, some received infusion of PTH at a supraphysiological rate, and some received infusion of vehicle only. All nephrectomized rats developed moderate renal failure. High phosphate intake decreased bone volume, and this effect was more pronounced in animals with dietary phosphate overload that received PTH infusion at a physiological rate. Phosphate overload induced hyperphosphatemia, hypocalcemia, and changes in bone microarchitecture. PTH at a supraphysiological rate minimized the phosphate-induced osteopenia. These data indicate that the management of uremia requires proper control of dietary phosphate, together with PTH adjustment, in order to ensure adequate bone remodeling.

Effects of bone remodelling on calcium mass transfer during haemodialysis

Background. During haemodialysis, calcium balance can affect, or be affected by, mineral metabolism. However, when dialysate calcium concentration (d[Ca]) is chosen or kinetic models are employed to calculate calcium balance, bone remodelling is rarely considered. In this study, we examined whether bone remodelling affects calcium mass transfer during haemodialysis. Methods. We dialysed 23 patients using a d[Ca] of 1.0, 1.25, 1.5 or 1.75 mmol/L. Calcium mass transfer was measured and associated with remodelling bone factors. Results. Calcium balance varied widely depending on the d[Ca]. Calcium removal was -578 +/- 389, -468 +/- 563, +46 +/- 400 and +405 +/- 413 mg when a d[Ca] of 1.0, 1.25, 1.5 or 1.75 mmol/L was used, respectively (1.0 and 1.25 VS 1.5 and 1.75 mmol/L, P<0.001; 1.5 vs 1.75 mmol/L, P<0.05). Univariate analysis showed that calcium balance correlated with calcium gradient, parathyroid hormone (PTH), osteocalcin and dialysis vintage. Multivariate analysis revealed that calcium balance was dependent on calcium gradient, PTH and osteocalcin. Conclusions. These results suggest that bone remodelling could affect calcium mass transfer during haemodialysis.

Dynamics of Parathyroid Hormone Secretion After Total Parathyroidectomy and Autotransplantation

Secondary hyperparathyroidism is a common complication in uremic patients. Total parathyroidectomy combined with partial autotransplantation into brachioradialis muscle has been the preference among the options for surgical treatment. This study was designed to evaluate the reserve and ability of suppression of autotransplanted parathyroid tissue using dynamics tests. We studied, prospectively, 12 patients in recent (RP) and late (LP) postoperative of total parathyroidectomy with autotransplantation. For analysis of the secretory reserve capacity, we induced hypocalcemia by ethylenediaminetetraacetic acid (EDTA) infusion. Furthermore, for analysis of the ability for parathyroid hormone (PTH) suppression, the hypercalcemia test was used, by intravenous administration of calcium in LP. In RP, there was a decrease in the average serum levels of PTH, phosphorus, and alkaline phosphatase, which ranged from 13 to 231 (87 +/- A 65) pg/ml, 2.3 to 6.2 (3.3 +/- A 1.1) mg/dl, and 77 to 504 (250 +/- A 135) U/L, respectively, similar to that observed in LP. The analysis of the average curve of variations in PTH during testing of the stimulus with EDTA showed lack of secretion in RP and partial response in LP. Impaired suppression ability of the graft in LP was observed in the test with intravenous calcium. Total parathyroidectomy followed by partial autotransplantation was effective in reducing PTH serum levels in patients with terminal kidney disease. The elevation of serum calcium during the suppression test was not able to inhibit the autograft gland secretion of PTH. The assessment of parathyroid graft function demonstrated an inability to respond to the stimulus of hypocalcemia induced by EDTA, although there was a partial recovery, in late postoperative period.

Orbital Involvement in Craniofacial Brown Tumors

Purpose: To describe the clinical and radiologic features of orbital involvement in craniofacial brown tumors and to compare the rate of brown tumors in primary and secondary hyperparathyroidism. Methods: A retrospective hospital-based study of 115 patients with chronic kidney disease and secondary hyperparathyroidism and 34 with primary hyperparathyroidism was conducted. Laboratory results such as serum levels of alkaline phosphatase, calcium, phosphorus, and parathyroid hormone were recorded. Demographic data (age, sex, duration of disease) and image findings (bone scan scintigraphy, skull and long bone x-rays, CT) were also obtained. The main outcome measures were analysis of clinical, biochemical, and radiologic findings of all patients. Results: Of the 115 patients with chronic kidney disease, 10 (8.7%) had brown tumors in different bones of the skeleton. Five patients had lesions in the craniofacial bones. The maxilla, mandible, maxillary sinus, and nasal cavity were the most affected sites. The orbit was involved in 2 patients with lesions arising in the maxillary and ethmoid sinuses. One patient had facial leontiasis. All patients with brown tumors had extremely high levels of parathyroid hormone (>1,000 pg/ml, normal values 10-69 pg/ml) and alkaline phosphatase (>400 U/l, normal values 65-300 U/l). The mean serum levels of phosphorus and calcium were not abnormal among the patients with brown tumors. Age and time of renal failure were similar for patients with and without brown tumors. Among the patients with primary hyperparathyroidism, only 2 (5.8%) had brown tumors, and in just 1, the lesion was localized in the craniofacial skeleton. A 2-tailed Z test applied to compare the proportion of occurrence of brown tumors in the 2 groups revealed that the difference at the 90% of confidence level was not significant. Conclusions: Brown tumors are equally found in secondary and primary hyperparathyroidism. Craniofacial brown tumors involve the orbit, usually because of the osteodystrophy process that involves the maxilla and paranasal sinuses. The lesions do not necessarily need to be excised and may regress spontaneously after the control of hyperparathyroidism.