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Biomedical subjects

Kathleen Claes

Publications and source records attributed to Kathleen Claes.

At least 19 recordsLinked to original sources
PubMed2006

TGFbeta1 polymorphisms and late clinical radiosensitivity in patients treated for gynecologic tumors.

PURPOSE: To investigate the association between six transforming growth factor beta1 gene (TGFbeta1) polymorphisms (-1.552delAGG, -800G>A, -509C>T, Leu10Pro, Arg25Pro, Thr263Ile) and the occurrence of late normal tissue reactions after gynecologic radiotherapy (RT). METHODS AND MATERIALS: Seventy-eight women with cervical or endometrial cancer and 140 control individuals were included in the study. According to the Common Terminology Criteria for Adverse Events version 3.0 (CTCAEv3.0) scale, 25 patients showed late adverse RT reactions (CTC2+), of whom 11 had severe complications (CTC3+). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), single base extension and genotyping assays were performed to examine the polymorphic sites in TGFbeta1. RESULTS: Homozygous variant -1.552delAGG, -509TT, and 10Pro genotypes were associated with the risk of developing late severe RT reactions. Triple (variant) homozygous patients had a 3.6 times increased risk to develop severe RT reactions (p=0.26). Neither the -800A allele, nor the 25Pro allele or the 263Ile allele were associated with clinical radiosensitivity. There was perfect linkage disequilibrium (LD) between the -1.552delAGG and the -509C>T polymorphisms, and tight LD between the -1.552/-509 and the Leu10Pro polymorphisms. Haplotype analysis revealed two major haplotypes but could not distinguish radiosensitive from nonradiosensitive patients. CONCLUSIONS: The present study shows that homozygous variant TGFbeta1 -1.552delAGG, -509TT, and 10Pro genotypes may be associated with severe clinical radiosensitivity after gynecologic RT.

Adult↗
PubMed2006

Prometheus versus molecular adsorbents recirculating system: comparison of efficiency in two different liver detoxification devices.

Albumin dialysis by the molecular adsorbents recirculating system (MARS) and by fractionated plasma separation, adsorption, and dialysis (Prometheus[PROM]) represent novel nonbiological liver support systems specifically designed to remove albumin-bound substances. Preliminary evidence suggests a favorable impact of MARS on the course and outcome of liver failure. This study aimed at comparing the detoxification capacity of both devices. For this purpose, we performed a retrospective analysis on data prospectively collected in patients with acute-on-chronic liver failure treated with either the MARS (n = 9) or the PROM (n = 9) device on 2-5 consecutive days. Each treatment was performed for at least 5 h at identical blood and dialysate flows. Blood clearances were calculated during the first treatment session for urea nitrogen, creatinine, total bilirubin, and bile acids from paired arterial and venous line samples after 1, 4, and 6 h of treatment. Reduction ratios for all single-treatment sessions, and the overall treatment phase, were calculated from pretreatment and post-treatment values. For all markers but bile acids, the single-treatment as well as the overall treatment phase reduction ratios obtained with PROM were significantly higher compared with those obtained with MARS. PROM led at all time points to higher clearances for all evaluated solutes. Blood clearances of protein-bound substances declined over time with MARS, but not with PROM. In conclusion, a significant decline in the serum level of water-soluble and protein-bound toxins was achieved with both devices. PROM produces higher blood clearances for most toxins, which results in higher delivered treatment doses compared with a matching treatment with MARS.

Adult↗
PubMed2005

Radiation-induced damage to normal tissues after radiotherapy in patients treated for gynecologic tumors: association with single nucleotide polymorphisms in XRCC1, XRCC3, and OGG1 genes and in vitro chromosomal radiosensitivity in lymphocytes.

PURPOSE: To examine the association of polymorphisms in XRCC1 (194Arg/Trp, 280Arg/His, 399Arg/Gln, 632Gln/Gln), XRCC3 (5' UTR 4.541A>G, IVS5-14 17.893A>G, 241Thr/Met), and OGG1 (326Ser/Cys) with the development of late radiotherapy (RT) reactions and to assess the correlation between in vitro chromosomal radiosensitivity and clinical radiosensitivity. METHODS AND MATERIALS: Sixty-two women with cervical or endometrial cancer treated with RT were included in the study. According to the Common Terminology Criteria for Adverse Events, version 3.0, scale, 22 patients showed late adverse RT reactions. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays were performed to examine polymorphic sites, the G2 assay was used to measure chromosomal radiosensitivity, and patient groups were compared using actuarial methods. RESULTS: The XRCC3 IVS5-14 polymorphic allele was significantly associated with the risk of developing late RT reactions (odds ratio 3.98, p = 0.025), and the XRCC1 codon 194 variant showed a significant protective effect (p = 0.028). Patients with three or more risk alleles in XRCC1 and XRCC3 had a significantly increased risk of developing normal tissue reactions (odds ratio 10.10, p = 0.001). The mean number of chromatid breaks per cell was significantly greater in patients with normal tissue reactions than in patients with no reactions (1.16 and 1.34, respectively; p = 0.002). Patients with high chromosomal radiosensitivity showed a 9.2-fold greater annual risk of complications than patients with intermediate chromosomal radiosensitivity. Combining the G2 analysis with the risk allele model allowed us to identify 23% of the patients with late normal tissue reactions, without false-positive results. CONCLUSION: The results of the present study showed that clinical radiosensitivity is associated with an enhanced G2 chromosomal radiosensitivity and is significantly associated with a combination of different polymorphisms in DNA repair genes.

Adult↗
PubMed2005

Detoxifying capacity and kinetics of prometheus--a new extracorporeal system for the treatment of liver failure.

BACKGROUND/AIMS: Extracorporeal liver support therapies have been used for several decades as a bridging therapy prior to liver transplantation or as an addendum to standard medical therapy. The Prometheus system represents a cell-free, extracorporeal, liver assist method for the removal of both albumin-bound and water-soluble endogenous toxins. The aim of the present study was to evaluate the removal capacity and selectivity of the different inbuilt dialyzers and adsorption columns during a single 6-hour treatment. METHODS: Nine patients with acute on chronic liver failure were included (6 females, age 49+/- 4 years). Levels of endogenous toxins (urea nitrogen [UN, mg/dl], creatinine [Cr, mg/dl], total bilirubin [tB, mg/dl], and bile acids [BA, mumol/l]) and albumin [Alb, g/l] were monitored in blood sampled at different sites (arterial line, venous line and between the absorbers and the high-flux dialyzer) and at various time points (time 0, 30, 60, 120, 240, and 360 min). RESULTS: A significant decrease of the serum level of all toxins was observed (UN 108.7+/- 23.2 vs. 38.1+/- 14.9, Cr 2.4+/- 0.7 vs. 1.2+/- 0.3, tB 31.1+/- 4.1 vs. 17.0+/- 1.6, BA 155.7+/- 32.5 vs. 66.0+/- 15.4; mean+/- SEM, time 0 vs. time 360, signed rank rest, all p< 0.005). The reduction rate of UN, Cr, tB and BA amounted to 68.1+/- 5.1, 45.9+/- 6.2, 41.2+/- 5.1, and 58.2+/- 5.0%, respectively. Blood clearances [Cl, ml/min] of all, but especially of the protein-bound toxins declined over time (Cl UN 171.5+/- 4.3 vs. 142.9+/- 16.8; Cl Cr 135.7+/- 10.0 vs. 111.8+/- 9.1; Cl tB 29.3+/- 5.1 vs. 13.7+/- 3.7; Cl BA 84.9+/- 4.8 vs. 45.1+/- 13.3; time 30 vs. time 360; linear mixed models, all p< 0.005). Serum albumin levels decreased by 2.9+/- 0.9 g/l (signed rank test, p=0.055). Not unexpectedly, tB was almost uniquely cleared by the adsorbers (UN 0.2+/-1.1, Cr 6.9+/- 5.7, tB 92.3+/- 4.2, BA 62.9+/- 3.9% of total Cl). CONCLUSION: Both albumin-bound and water-soluble toxins are adequately removed by the Prometheus system. Our data suggest that the rate and efficacy of removal of albumin-bound toxins is related to both the strength of the albumin binding and the saturation of the adsorption columns. Limited losses of albumin occur during treatment with the Prometheus system.

Bile Acids and Salts↗
PubMed2005

Impact of parathyroidectomy on renal graft function, blood pressure and serum lipids in kidney transplant recipients: a single centre study.

BACKGROUND: Successful kidney transplantation is believed to reverse secondary hyperparathyroidism, but persistent disease has emerged in a significant number of allograft recipients. Parathyroid hormone (PTH) is not only involved in the aetiology of calcium/phosphate abnormalities and osteitis fibrosa, but it is also a permissive factor in the occurrence of hypertension, cardiovascular damage and dyslipidaemia. In experimental renal failure, abrogation of hyperparathyroidism by administration of a calcimimetic or parathyroidectomy (PTX) attenuates progression of renal failure. To evaluate the impact of PTX on blood pressure (BP), renal graft function and serum lipids, we performed a retrospective case-controlled study in renal graft recipients. METHODS: Charts of 1647 kidney allograft recipients, transplanted between 1989 and 2004, were reviewed. Thirty-two patients with a functioning graft and a history of a successful PTX performed at least 9 months after transplantation were identified. Biochemical and clinical data available 6 months pre- and post-PTX were registered. Changes in BP, renal function and serum lipids were assessed. The data were compared with those obtained in a similar time frame in a control group closely matched for date of transplantation. RESULTS: Systolic BP (149.9 vs 141.7 mmHg), diastolic BP (85.6 vs 81.9 mmHg), pulse pressure (64.3 vs 58.8 mmHg), total cholesterol concentration (221.4 vs 211.1 mg/dl) and low-density lipoprotein cholesterol concentration (123.9 vs 106.7 mg/dl) improved significantly after successful PTX. Serum creatinine, conversely, significantly increased after PTX (1.75 vs 2.13 mg/dl, P<0.0001). No significant changes were observed in the control group in the same time period. CONCLUSION: In patients with a functioning renal graft, BP and dyslipidaemia improve, whereas serum creatinine worsens following successful PTX. Our data are in agreement with a stimulatory effect of PTH on plasma renin activity and an inhibitory effect on lipase activity, as previously demonstrated by others. To what extent the increased serum creatinine following PTX reflects a true deterioration of the glomerular filtration rate and/or is the consequence of vitamin D-induced reduction of the renal tubular secretion of creatinine needs to be elucidated by further research.

Blood Pressure↗
PubMed2005

A simplified strategy for clinical management of late cytomegalovirus infection after oral ganciclovir prophylaxis in renal recipients.

OBJECTIVES: Late cytomegalovirus disease after completion of prophylactic therapy occurs in 5-21% of renal allograft recipients within the first year post-transplantation. Identifying patients at risk for late infection is clinically difficult; prolonged cytomegalovirus (CMV) monitoring is costly and cumbersome as follow-up intervals lengthen. PATIENTS AND METHODS: We performed a prospective 1 year study in 54 de novo renal recipients to assess the minimum CMV monitoring frequency for identifying patients at risk. RESULTS AND CONCLUSIONS: CMV DNA PCR monitoring on the last day, and again 2 weeks after conclusion of oral ganciclovir prophylaxis, seemed sufficient for identifying recipients at risk for developing clinically relevant late CMV disease and for whom closer clinical follow-up is warranted.

Administration, Oral↗
PubMed2005

A prospective, randomized, double-blind crossover study on the use of 5% citrate lock versus 10% citrate lock in permanent hemodialysis catheters.

Central venous catheters are used as permanent vascular access for chronic hemodialysis when construction of an arteriovenous fistula is not possible or contraindicated. We prospectively evaluated the efficacy and safety of a 5% citrate versus 10% citrate catheter lock for permanent single-lumen dialysis catheters in a double-blind, crossover study of 28 patients during 1,876 dialysis sessions. There was a slightly higher number of dialysis sessions with clot formation in the 5% citrate group; entirely attributable to the formation of small clots. There was no statistically significant difference in the formation of large clots, complete obstruction of the catheter or the need for urokinase between the 2 study groups. In view of the ongoing debate on the safety of high-concentration citrate catheter locks, we conclude that a 5% citrate lock is equally efficient in preventing catheter dysfunction compared with a 10% citrate lock and is therefore the preferred citrate catheter-locking solution.

Aged↗
PubMed2005

Chromosomal radiosensitivity of breast cancer with a CHEK2 mutation.

Recently, multiple studies have shown that a sequence variant in CHEK2 (CHEK2 1100delC) plays a role in the susceptibility to breast cancer. This mutation should confer about a twofold increased breast cancer risk in women and a 10-fold increased risk in men. Because the CHEK2 gene plays a critical role in DNA damage repair and the CHEK2 1100delC variant confers susceptibility to breast cancer, we investigated if patients carrying the CHEK2 1100delC mutation are characterized by an enhanced chromosomal radiosensitivity. To this end, familial breast cancer patients, sporadic breast cancer patients, and healthy women, considered in our previously studied to determine their chromosomal radiosensitivity with the G2 and G0-MN assay, were all tested in present study for the presence of the CHEK2 1100delC variant. The 1100delC variant was detected in none of the 100 healthy individuals, in 1 of 100 (1%) unselected breast cancer patients and in 3 of 78 (3.8%) breast cancer patients with a family history of breast cancer. The breast cancer patients with the CHEK2 1100delC genotype had a mean radiation-induced yield of chromatid breaks that was not significantly different from that of the healthy control group. Although the mean yield of micronuclei (MN) was significantly higher compared to the healthy control group, this higher mean MN yield was due to a single patient who had a very high number of MN compared to the parallel control. Our data suggest that breast cancer patients with a CHEK2 1100delC mutation are in general not characterized by a distinct enhanced chromosomal radiosensitivity. These conclusions are, however, very preliminary, because of the small numbers of CHEK2 1100delC breast cancer patients studied.

Base Sequence↗
PubMed2005

Rapid detection of VHL exon deletions using real-time quantitative PCR.

Various types of mutations exist that exert an effect on the normal function of a gene. Among these, exon/gene deletions often remain unnoticed in initial mutation screening. Until recently, no fast and efficient methods were available to detect this type of mutation. Molecular detection methods for gene copy number changes included Southern blot (SB) and fluorescence in situ hybridisation, both with their own intrinsic limitations. In this paper, we report the development and application of a fast, sensitive and high-resolution method for the detection of single exon or larger deletions in the VHL gene based on real-time quantitative PCR (Q-PCR). These deletions account for approximately one-fifth of all patients with the von Hippel-Lindau syndrome, a dominantly inherited highly penetrant familial cancer syndrome predisposing to specific malignancies including phaeochromocytomas and haemangioblastomas. Our VHL exon quantification strategy is based on SYBR Green I detection and normalisation using two reference genes with a normal copy number, that is, ZNF80 (3q13.31) and GPR15 (3q12.1). Choice of primer sequences and the use of two reference genes appears to be critical for accurate discrimination between 1 and 2 exon copies. In a blind Q-PCR study of 29 samples, all 14 deletions were detected, which is in perfect agreement with previously determined SB results. We propose Q-PCR as the method of choice for fast (within 3.5 h), accurate and sensitive (ng amount of input DNA) exon deletion screening in routine DNA diagnosis of VHL disease. Similar assays can be designed for deletion screening in other genetic disorders.

Benzothiazoles↗
PubMed2005

Acute-onset, steroid-sensitive, encapsulating peritoneal sclerosis in a renal transplant recipient.

Encapsulating peritoneal sclerosis is a severe complication of peritoneal dialysis. Immunosuppressive drugs have been claimed to be helpful in the treatment of this disease, although the pathophysiological background is poorly understood. In this report, we present a patient with encapsulating peritoneal sclerosis after successful renal transplantation. Maintenance immunosuppressive therapy consisted of mycophenolate mofetil, tacrolimus, and low-dose corticosteroids. The patient was treated successfully with high doses of corticosteroids. A subsequent relapse of the encapsulating peritoneal sclerosis, probably resulting from fast tapering of the corticosteroid dose, responded well to an increase in corticosteroid dose. Our case strongly supports a therapeutic role for high-dose steroids in the treatment of encapsulating peritoneal sclerosis during its initial inflammatory stage.

Acute Disease↗
PubMed2005

Secondary effects of immunosuppressive drugs after simultaneous pancreas-kidney transplantation.

BACKGROUND: This report examines the early and late secondary effects of tacrolimus, cyclosporin microemulsion (ME), mycophenolate mofetil (MMF) and rabbit anti-thymocyte globulin (rATG) in simultaneous pancreas-kidney (SPK) recipients. METHODS: Of the 205 patients participating in the Euro-SPK 001 study, 103 were randomized to tacrolimus (0.2 mg/kg) and 102 to cyclosporin-ME (7 mg/kg). All patients received rATG for 4 days [ATG-Fresenius (ATG-F) 4 mg/kg/day or Thymoglobulin (Thymo-S) 1.25 mg/kg/day] plus MMF and short-term corticosteroids. RESULTS: Thymo-S induction therapy was associated with a lower white cell count in the first 3 months than was seen with ATG-F, while ATG-F caused a lower initial nadir in platelet count. Both polyclonal preparations were well tolerated and no clinically relevant differences were observed with respect to side effects such as infections and malignancies. High cyclosporin-ME trough levels were associated with pancreas graft thrombosis, and concentrations >150 ng/ml were associated with poor renal allograft function. Treatment discontinuation was higher with cyclosporin-ME (57.8%) than with tacrolimus-based therapy (36.9%) due to more frequent toxicity, graft loss and lack of efficacy requiring a switch to tacrolimus. The main reason for withdrawal in the tacrolimus group was MMF discontinuation; MMF-related side effects resulted in more frequent dose reductions to <2 g/day and discontinuations in the tacrolimus group, and indirectly indicate a higher dose-corrected exposure to mycophenolic acid, as previously observed in kidney transplant patients. CONCLUSIONS: Short-term induction therapy is effective and well tolerated in patients undergoing SPK transplantation. Tacrolimus was the preferred immunosuppressive agent, resulting in fewer cases of pancreas graft loss and drug discontinuation compared with cyclosporin-ME.

Antilymphocyte Serum↗
PubMed2005

Adjuvant low-dose cidofovir therapy for BK polyomavirus interstitial nephritis in renal transplant recipients.

BK virus interstitial nephritis (BKVIN) is a serious complication after kidney grafting, necessitating drastic reduction of immunosuppressive therapy in order to enable viral clearance. Despite these measures, progressive graft dysfunction and graft loss occur in the majority of recipients. We diagnosed BKVIN in 21 recipients grafted between 1998 and 2004. Eight of 21 patients were treated with weekly, adjuvant low-dose cidofovir in addition to reduction of immunosuppressive therapy. BKVIN caused irreversible deterioration of graft function in all patients but renal function stabilized after antiviral treatment (creatinine clearance: 51.8-32 mL/min; p=0.001) and no graft loss occurred in cidofovir-treated recipients during 24.8 (8-41) months follow-up. Peak serum cidofovir concentrations were dose-dependent and attained approximately one-tenth of thein vitroEC50 for cidofovir against BK-virus, while pre-treatment with probenecid did not alter peak serum concentrations nor affected the incidence of nephrotoxicity. In fact, no cidofovir-related renal toxicity occurred; few patients had minor transient side effects (nausea, skin rash). In contrast, 9 of 13 patient who received no adjuvant cidofovir therapy lost their graft after median 8 (4-40) months. In this selected group of recipients with BKVIN, the use of adjuvant low-dose cidofovir therapy resulted in prolonged graft survival and stabilized graft function.

Adult↗
PubMed2004

The rate of gastric emptying determines the timing but not the extent of oral tacrolimus absorption: simultaneous measurement of drug exposure and gastric emptying by carbon-14-octanoic acid breath test in stable renal allograft recipients.

Tacrolimus is characterized by a highly variable oral bioavailability and narrow therapeutic window. Tacrolimus absorption from the gastrointestinal tract is to a large extent determined by the genotypic, phenotypic, and functional expression of P-glycoprotein and CYP3A in the gut wall and liver. It is disputed whether the gastric emptying rate per se is important for determining oral bioavailability of tacrolimus and whether delayed gastric emptying is clinically relevant for therapeutic drug dosing. We conducted a pharmacokinetic study in 50 renal recipients, measuring simultaneously the rate of gastric emptying using a carbon-14-octanoic acid breath test and quantifying drug exposure by area under the concentration-time curve sampling. Gastric half emptying time (t1/2) significantly correlated with time to reach maximum blood tacrolimus (tmax) concentration (r2 = 0.30; p < 0.0001), whereas the gastric emptying coefficient, reflecting the overall gastric emptying rate, showed a weak inverse correlation with tmax (r2 = 0.14; p = 0.007). The time-dependent rate of gastric emptying strongly correlated with the simultaneously measured blood tacrolimus concentration over the first 4 h after oral drug administration (r2 = 0.96; p < 0.0001). Comparison between patients with and without delayed gastric emptying confirmed that maximum blood tacrolimus concentration was reached significantly more slowly in the former group (tmax, 2 +/- 1 h versus 1.48 +/- 0.68 h; p = 0.04), whereas the extent of tacrolimus absorption was not different. Despite a strong association between gastric emptying rate and the timing of tacrolimus absorption from the gut in stable recipients, gastric emptying rate does not affect the total extent of drug absorption and is not responsible for significant alterations in drug exposure, even in situations of delayed gastric emptying.

Administration, Oral↗
PubMed2004

A prospective proof of concept study of the efficacy of tacrolimus ointment on uraemic pruritus (UP) in patients on chronic dialysis therapy.

BACKGROUND: Uraemic pruritus (UP) is a serious symptom of chronic dialysis patients and patients with end-stage renal disease. UP causes skin damage, discomfort, sleeping disorders and diminished quality of life. Since UP is considered to be in part an immune-mediated inflammatory process, immunosuppressive drugs like tacrolimus may be beneficial. METHODS: We conducted a prospective study on the effect of 6 weeks treatment with two sequential concentrations of tacrolimus ointment on the severity of UP in chronic dialysis patients and again after 2 weeks wash-out. Twenty-five patients with UP were enrolled in the study; 21 patients completed the study. UP was measured using a validated modified pruritus assessment score and a Visual Analogue Scale (VAS). RESULTS: The modified pruritus assessment score decreased significantly by 81.8% after 6 weeks treatment from [median score 11 (interquartile range: IQR 6-16) on day 0 to median score 2 (IQR 0-5.25) at week 6: P<0.0001]. After 2 weeks wash-out, the median score returned to 72.7% of baseline levels [8 (IQR 2-16)]. Using the VAS score an identical evolution could be demonstrated. Tacrolimus ointment was well tolerated and no serious adverse events were noted. Transient stinging and burning sensation was reported by four patients in the first weeks of the trial, one patient suffered a mild skin rash. No systemic exposure to tacrolimus was detected. CONCLUSION: This prospective study has shown that 6 weeks treatment with tacrolimus ointment significantly reduces the severity of UP in chronic dialysis patients and is well tolerated. Randomized placebo-controlled studies are necessary to confirm these encouraging preliminary results.

Female↗
PubMed2004

Natural history of parathyroid function and calcium metabolism after kidney transplantation: a single-centre study.

BACKGROUND: The natural history of parathyroid function after successful renal transplantation (RT) and the factors predisposing to persistent hyperparathyroidism (HPT) are not well established. A better knowledge of these data may be helpful in the development of algorithms for optimal surveillance and treatment of HPT after successful RT. Our aim was to evaluate the post-transplant natural history of parathyroid function and calcium metabolism in patients with a functional renal graft and to identify risk factors for persistent HPT. METHODS: Charts of 1165 allograft kidney recipients transplanted between 1989 and 2000 were reviewed. Patients with an intact parathyroid hormone (iPTH) level available at the time of transplantation were identified. The charts of the latter patients were checked for a variety of demographic and clinical data, and all determinations of the iPTH concentration available since transplantation were recorded. Serum levels of calcium, phosphorus, alkaline phosphatases and creatinine, concurrently determined, were also registered. RESULTS: After an initial fall, iPTH levels showed a slow but steady decline towards the upper normal limit. The prevalence of persistent HPT, defined as an iPTH level > or =2.5 times the upper normal limit or the need for parathyroidectomy following transplantation, remained stable at approximately 17% up to 4 years after transplantation. Patients with persistent HPT had significantly elevated serum levels of iPTH, calcium and phosphorus at the time of RT, and had spent a longer time on dialysis. Post-transplant iPTH levels correlated significantly with transplant kidney function. CONCLUSION: Kidney transplant recipients with a high iPTH and calcium x phosphate product at the time of transplantation are at risk for persistent HPT especially when renal function is suboptimal. Therapy for persistent HPT, if considered, should be initiated 3 months post-transplantation since further spontaneous improvement of parathyroid function thereafter is limited.

Calcium↗