Parathyroid hormone and clinical outcome in kidney transplant patients with optimal transplant function.

BACKGROUND: The aim of the study was to investigate whether serum levels of intact parathyroid hormone (iPTH) are associated with an increased risk of cardiovascular events, graft loss, or mortality in kidney transplant patients with optimal transplant function. METHODS: From the Norwegian Renal Registry, we identified 522 patients who received a first kidney transplant from 2001 to 2008 with optimal transplant function defined as an estimated glomerular filtration rate (eGFR)≥60 mL/min/1.73 m2, more than one yr after transplantation. Cox's proportional hazard models were used to assess the association between iPTH measured 10 wk after transplantation and the composite endpoint. The estimates were adjusted for age, gender, serum calcium, serum phosphate, diabetes mellitus, cardiovascular disease, and time on dialysis prior to transplantation. RESULTS: Median follow-up time was 3.9 yr (interquartile range, IQR: 2.0-6.0 yr). Patients in the third iPTH quartile (9.3-14.4 pM) had the lowest risk for reaching the composite endpoint. Patients in the fourth iPTH quartile (>14.4 pM) had an increased risk compared to those in the third quartile (HR: 2.60, 95% CI: 1.10-6.16, p=0.03). CONCLUSION: In patients with optimal transplant function, iPTH levels are associated with a clinical outcome consisting of cardiovascular events, graft loss, and all-cause mortality.

Fibroblast growth factor 23 and parathyroid hormone after treatment with active vitamin D and sevelamer carbonate in patients with chronic kidney disease stage 3b, a randomized crossover trial.

BACKGROUND: Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that is secreted from bone and serum level increases as renal function declines. Higher levels of FGF23 are associated with increased mortality in hemodialysis-patients and in patients with chronic kidney disease (CKD) stage 2-4. The use of active vitamin D and phosphate binders as recommended in international guidelines, may affect the level of FGF23 and thereby clinical outcome. We investigated the effects of a phosphate binder and active vitamin D on the serum levels of intact FGF23 (iFGF23) and intact parathyroid hormone (iPTH) in patients with CKD stage 3b (glomerular filtration rate (GFR) 30-44 ml/min/1.73 m(2)). METHODS: Seven women and 14 men were included, mean age 65.6 ± 12.2 years. They were randomized in a 1:1 ratio to receive one of two treatment sequences. Group-1 (the alphacalcidol-sevelamer carbonate group): alphacalcidol 0.25 µg once daily for two weeks followed by sevelamer carbonate 800 mg TID with meals for two weeks after a two-week washout period. Group-2 (the sevelamer carbonate-alphacalcidol group): vice versa. Nineteen patients completed the study. The 25-hydroxyvitamin D level at baseline was 97.6 ± 25.0 nmol/l. RESULTS: There were no treatment effects on the iFGF23 and iPTH levels overall. In group-1 the iFGF23 level was higher after treatment with alphacalcidol compared with sevelamer carbonate (mean 105.8 ± 41.6 vs. 79.1 ± 36.5 pg/ml, p = 0.047 (CI: 0.4-52.9), and the iPTH level was lower (median: 26.5, range: 14.6-55.2 vs. median 36.1, range 13.4-106.9 pg/ml, p = 0.011). In group-2 the iFGF23 level increased non-significantly after treatment with sevelamer carbonate and throughout the washout period. CONCLUSIONS: In this crossover trial with alphacalcidol and sevelamer carbonate in patients with CKD stage 3b, the levels of iFGF23 were not significantly different after the two treatments. However, in the group of patients initiating therapy with sevelamer carbonate the iFGF23 levels seemed to increase while this response was mitigated in the group of patients given alphacalcidol followed by sevelamer carbonate. This may have therapeutic implications on choice of first line therapy. The number of patients is small and this conclusion is in part based on subgroup analysis. It is therefore important that these results are confirmed in larger studies. TRIAL REGISTRATION NUMBER: European Clinical Trial Database (EudraCT) 2010-020415-36 and Clinical Trials.gov NCT01231438.

Intact parathyroid hormone levels in renal transplant patients with normal transplant function.

INTRODUCTION: Chronic kidney disease mineral and bone disorder (CKD-MBD) is common in patients who have undergone kidney transplantation. There is limited information on the extent to which patients with normal renal function after transplantation have persistent disturbances in their mineral metabolism. AIM: The aim of the study is to investigate the prevalence of elevated intact parathyroid hormone (iPTH) levels at least one yr after transplantation in patients living with a first renal transplant with normal transplant function. METHODS: A retrospective, observational study of 607 patients was collected from the Norwegian Renal Registry. Of these, iPTH was recorded for 360 patients. RESULTS: One hundred and eighty-eight patients (52%) had elevated iPTH levels. Twenty-six patients (7%) had iPTH levels >2.5 times the upper limit of normal (ULN). Patients with a pre-emptive transplant were significantly younger than the patients who had received treatment with dialysis (p < 0.0001). The prevalence of iPTH > ULN was significantly higher in patients with a pre-emptive transplant (p = 0.037). CONCLUSIONS: In post-transplant patients with normal transplant function, our data indicate that more than 50% have elevated levels of iPTH more than one yr after transplantation. If elevated iPTH level is associated with mortality in this patient population, it may have major impact on clinical treatment guidelines.

Glucose tolerance before and after renal transplantation.

BACKGROUND: Renal insufficiency predisposes to insulin resistance, hyperparathyroidism and derangements in calcium phosphate and nitrogenous compound balance, leading to pre-transplant hyperglycaemia. These metabolic risk factors are not fully corrected after renal transplantation. The present study aimed to assess the role of pre-transplant glycaemia and the named metabolic risk factors in post-transplant hyperglycaemia [PHYG; impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or diabetes mellitus (DM)]. METHODS: This is a retrospective cohort study involving 301 patients without pre-transplant DM. Measurements included a pre- and post-transplant oral glucose tolerance test (OGTT) as well as glomerular filtration rate (GFR), parathyroid hormone (PTH), phosphate, calcium and urea measured 10 weeks post-transplant. The risk of PHYG at 10 weeks post-transplant was analysed using multiple logistic regression. RESULTS: Ninety-three patients (31%) had PHYG (two IFG, 52 IGT, 39 DM). Variables associated with PHYG included pre-transplant 2-h glycaemia [OR 1.26, 95% CI (1.09, 1.46)] and post-transplant urea levels [OR 1.14, 95% CI (1.02, 1.27)]. Older age, non-Caucasian ethnicity, previous transplants, >or=3 HLA class 1 mismatches and high prednisolone doses were likewise associated with an increased PHYG risk (all P < 0.05). CONCLUSIONS: Pre-transplant glycaemia and high post-transplant levels of urea were associated with a greater risk of PHYG. This seemed to be independent of GFR, PTH, phosphate, calcium and traditional risk factors such as age and glucocorticoid load.

The Nephrocare project: referral, patient case-mix, follow-up and quality of renal care in Nordic renal centres.

OBJECTIVE: Few studies have focused on patients actually attending renal units for their follow-up over time. This study reports the type of prevalent patients (case-mix) with a renal condition being followed up by 19 renal units in the Nordic countries during 1998-99. MATERIAL AND METHODS: In a joint quality of care development project between the renal societies of the five Nordic countries and the unit for Quality of Health Systems, WHO (Europe), 19 renal units collected data on a random sample of their prevalent patients. RESULTS: At follow-up, 56% had chronic kidney disease (CKD) not in renal replacement therapy (RRT). Seventeen per cent had haemodialysis (HD), 6% peritoneal dialysis (PD) and 21% a functioning kidney transplant (Tx). In the CKD group, 5.9% were CKD stage 1, 17.6% stage 2, 35.2% stage 3, 25.6% stage 4 and 15.7% stage 5. One-third had known cardiovascular disease, 30% known diabetes, half had a blood pressure >140/90 mmHg and 75% > 130/80 mmHg. Twenty eight per cent had left ventricular hypertrophy, 20% were smokers and 17% were anaemic. One-third of those with known cardiovascular disease were prescribed lipid-lowering therapy and half of those with proteinuria were prescribed an angiotensin-inhibiting drug. CONCLUSIONS: The data, collected in 1998-99, indicate that there is room for improvement in the quality of care provided by renal units to patients with CKD. The data may serve as a basis for assessing possible change in nephrological practice after the introduction of K/DOQI guidelines and staging of chronic renal disease.

Role of prednisolone pharmacokinetics in postchallenge glycemia after renal transplantation.

Prednisolone may cause hyperglycemia after organ transplantation. Even at comparable weight-adjusted doses, prednisolone side effects vary considerably between individuals, suggesting between-patient pharmacokinetic differences. In renal transplant patients, assessment of glucocorticoid diabetogenicity is confounded by calcineurin inhibitors (CNIs). The present study aimed to investigate, in a CNI-free setting, the association between exposure to unbound prednisolone and glucose tolerance in stable nondiabetic long-term renal transplant patients. An oral glucose tolerance test and a 12-hour prednisolone pharmacokinetic study were performed in 108 nondiabetic CNI-naive subjects (41 women and 67 men) treated with prednisolone (median 0.15 mg kg d, interquartile range 0.14-0.18 mg kg d) and azathioprine. The area under the curve (AUC) of unbound prednisolone was analyzed in multiple linear regression analysis with 120-minute postchallenge glucose AUC as the dependent variable. A high AUC of unbound serum prednisolone was independently associated with a high glucose AUC (P = 0.030). A high glucose AUC was also associated with a high patient age and triglyceride level (both P < or = 0.001). No correlation was observed between the daily prednisolone dosage (mg/d or mg kg d) and glucose AUC. The association between exposure to unbound prednisolone and postchallenge glycemia is in line with current knowledge about mechanisms behind steroid-related side effects but has not previously been documented. The result may argue in favor of measuring unbound prednisolone in clinical settings. Increasing exposure to unbound prednisolone was independently associated with postchallenge glycemia. No such relationship was observed for prednisolone daily dose per se.

Soluble Klotho and intact fibroblast growth factor 23 in long-term kidney transplant patients.

BACKGROUND: Controversies exist whether disturbances in mineral and bone disorder (MBD) normalise or persist after kidney transplantation. We assessed markers of MBD in patients with well-functioning kidney transplants to minimise confounding by reduced transplant function. METHODS: In this cross-sectional study, 40 patients aged ≥18 years who received a first kidney transplant more than 10 years ago were included. A well-functioning transplant was defined as an estimated glomerular filtration rate (eGFR) ≥45 ml/min per 1.73 m(2). RESULTS: Median time since transplantation was 18.3 years (inter quartile range (IQR) 12.2-26.2). Albumin-corrected serum calcium levels were above upper limit of normal in 15% of the transplanted patients, and serum phosphate levels below lower limit of normal in 31%. The median levels of intact parathyroid hormone (iPTH) and intact fibroblast growth factor 23 (iFGF23) were significantly higher than that in a group of healthy volunteers (11.3 pmol/l (IQR: 8.7-16.2) vs 4.4 pmol/l (IQR: 3.8-5.9), P<0.001 and 75.0 pg/ml (IQR: 53.3-108.0) vs 51.3 pg/ml (IQR: 36.3-67.6), P=0.004 respectively). There was a non-significant reduction in soluble Klotho (sKlotho) levels (605 pg/ml (IQR: 506-784) vs 692 pg/ml (IQR: 618-866)). When compared with a control group matched for eGFR, levels of iPTH were significantly higher (P<0.001), iFGF23 had a non-significant trend towards higher levels and sKlotho towards lower levels. CONCLUSIONS: In long-term kidney transplant patients with well-functioning kidney transplants, we found inappropriately high levels of iPTH and iFGF23 consistent with a state of persistent hyperparathyroidism. We speculate that the primary defect, FGF23 resistance, has evolved in the parathyroid gland before transplantation, and persists due to long half-life of the parathyroid cells.

C2 monitoring in maintenance renal transplant recipients: is it worthwhile?

Presently, there is little knowledge regarding cyclosporine (CsA) concentration at 2 hr post-dose (C2) monitoring in maintenance patients. This study evaluates the actual C2 range in stable renal transplant recipients (who underwent transplantation >12 months ago). In addition, we investigated whether underexposure or overexposure to CsA (assessed by C2) affects graft function (as measured by serum [S]-creatinine). All renal transplant recipients in Norway receiving CsA were asked to participate; 1447 fulfilled the criteria. Valid C2 and CsA trough concentration (C0) measurements were performed in 1032 renal transplant recipients (71%) monitored by C0. Target C0 level was 75 to 125 mumol/L. CsA levels were measured using a Cloned Enzyme Donor Immunoassay method, and all analyses were performed in the same laboratory (overall mean [+/-standard deviation] CsA C0=112+/-31 mug/L, CsA C2=697+/-211 mug/L [range 81-1580 mug/L], CsA dose [mg/day]=208+/-61, CsA dose [mg/kg/day]=2.8+/-1.1, and S-creatinine=141+/-58 mumol/L). A univariate analysis of variance showed that patients with C2 levels between 700 and 800 mug/L (n=203, S-creatinine=136+/-49 mumol/L) had significantly lower S-creatinine levels compared with patients with C2 levels greater than 950 mug/L (n=94, S-creatinine=152+/-56 mumol/L) (P<0.02). The same was true for patients with C2 levels less than 450 mug/L (n=95, S-creatinine 141+/-72 mumol/L) (P<0.05) when compared with patients with C2 levels greater than 950 mug/L. There was no significant difference in S-creatinine between patients in the low and intermediate C2 group; 666 patients had C0 levels in the therapeutic range (75-125 mumol/L). A linear regression showed a significant relation between S-creatinine and C2 for these patients (P=0.03). The corresponding relation between S-creatinine and C0 was nonsignificant (P=0.3). Monitoring of C2 in maintenance patients is a valuable tool to detect overexposure to CsA. Until results from prospective studies are available, we recommend C0 in the therapeutic range and reduction in CsA in overexposed patients, aiming at a C2 value between 700 and 800 mug/L.

Health-related quality of life in kidney transplant patients and non-renal replacement therapy patients with chronic kidney disease stages 3b-4.

BACKGROUND: Patients with a functioning kidney transplant (Tx) and patients with chronic kidney disease (CKD) not in dialysis report better health-related quality of life (HRQoL) than patients requiring dialysis, but poorer than the general population. HRQoL is associated with kidney function, but it is unknown whether the kidney function per se is the main determinant of HRQoL. The aim of this study was to compare the HRQoL in 2 groups of patients with CKD: 1 group with native kidneys only (non-renal replacement therapy [non-RRT] group) and 1 group with a functioning kidney transplant (Tx group). MATERIAL/METHODS: The study was designed as a paired cross-sectional single-center study including 38 stable Tx patients age- and gender-matched with 38 non-RRT patients with the same kidney function, CKD stages 3b­4. HRQoL was evaluated using the short form-36 (SF-36) and a visual analogue scale (VAS). RESULTS: The multi-item scales and summary scores in SF-36 were not significantly different between the 2 groups of patients or the general Norwegian population. However, the non-RRT group scored significantly better than the Tx group when HRQoL was evaluated by VAS. The main determinants for HRQoL in both groups of patients were depression estimated by Beck depression inventory scores and comorbidity expressed by Davies comorbidity index scores. CONCLUSIONS: HRQoL evaluated by SF-36 in a group of stable Tx patients in CKD stages 3b­4 is comparable to that of a group of non-RRT patients. However, HRQoL VAS was better in the non-RRT group, suggesting that VAS and SF-36 may evaluate different aspects in HRQoL in the same group of patients.

Prevalence of diabetic retinopathy in Norway: report from a screening study.

PURPOSE: The purpose of the present study was to investigate the prevalence of diabetic retinopathy (DR) in Norway and adherence to the Norwegian Guidelines for screening for diabetic eye disease. METHODS: Two hundred and ninety-nine people with diabetes were randomly recruited from the patient lists of randomly selected general practitioners from three different regions in Norway. Retinopathy was evaluated from retinal photographs after dilation of the pupils using a red-free digital camera and visual acuity was measured using the Snellen chart. The patients were interviewed about their ophthalmological and general diabetes control, duration and type of diabetes and medical treatment. RESULTS: The prevalence of any DR was 28%, 66% for type 1 and 24% for type 2 diabetes. The prevalence of proliferative retinopathy was 38% in type 1 and 1.5% in type 2 diabetes. Two patients (one type 1 and one insulin-treated type 2) were visually impaired (visual acuity 0.3 or worse in the better eye) because of proliferative DR. Twenty-six per cent of the patients had never been to an eye examination, and only 69% attended routine eye examinations. Patients who did not attend regular eye screenings were mostly people with type 2 diabetes. CONCLUSION: The prevalence of DR was higher than previously reported in Norway. Screening for DR did not follow guidelines in a considerable proportion of the patients with type 2 diabetes. There is place for improvement in the implementation of guidelines for screening for DR for people with type 2 diabetes in Norway.

Undiagnosed diabetes in kidney transplant candidates: a case-finding strategy.

BACKGROUND AND OBJECTIVES: Guidelines recommend that candidates for kidney transplantation (KTx) who do not have diabetes perform a pretransplantation oral glucose tolerance test (OGTT) when fasting plasma glucose (FPG) is <110 mg/dl (<6.1 mmol/L); however, the OGTT is potentially costly and cumbersome. We studied the role of the OGTT for diagnosing diabetes and the accuracy of FPG and glycated hemoglobin (HbA(1c)) for predicting a diabetic OGTT before KTx. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this cross-sectional study, 889 first single-kidney transplant candidates without diabetes, mainly white, performed an OGTT during the transplantation workup. Results were studied using receiver operating characteristic analysis. RESULTS: Of 72 (8.1%) patients with undiagnosed diabetes, only 16 (22%) had a diabetic FPG (> or =126 mg/dl [> or =7.0 mmol/L]). In patients with a nondiabetic FPG, diabetes (2-hour plasma glucose [2h-PG] > or =200 mg/dl [> or =11.1 mmol/L]) was predicted by FPG but not by HbA(1c). Performing the OGTT in patients with FPG 92 to 125 mg/dl (5.1 to 6.9 mmol/L) identified 65 (90%) patients with diabetes (16 by FPG, 49 by 2h-PG) and required seven OGTTs per patient identified. Subjecting all patients with FPG <110 mg/dl (<6.1 mmol/L) to the OGTT identified 60 (83%) patients with diabetes (16 by FPG, 44 by 2h-PG) but required 14 OGTTs per patient. CONCLUSIONS: The OGTT was paramount in finding most cases of undiagnosed diabetes before KTx. FPG but not HbA(1c) predicted a diabetic OGTT. We suggest that white KTx candidates without diabetes perform a pretransplantation OGTT when FPG is 92 to 125 mg/dl (5.1 to 6.9 mmol/L).

Renal transplant and secondary hyperparathyroidism.

OBJECTIVE: To investigate the impact of mineral metabolism, renal function, months on dialysis and months since transplant for predicting intact parathyroid hormone (iPTH) levels in a cohort of patients who had undergone their first renal graft with estimated glomerular filtration rates (eGFRs) of 30-60 and >60 ml/min/1.73 m2. MATERIAL AND METHODS: One hundred and twenty-eight patients (mean age 56.0 +/- 14.6 years) with an eGFR of >30 ml/min/1.73 m2 were included. The median time since transplant was 88.6 months (range 2.8-403.2 months). Blood samples were collected for measurement of iPTH, 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3, calcium, albumin, phosphate and creatinine. The eGFR was calculated using the formula for the modification of diet in renal disease. RESULTS: One hundred and three patients (80%) had an elevated level of iPTH, 29 (23%) had hypercalcaemia and 42 (35%) had a 25-hydroxyvitamin D3 level of <40 nmol/L. In stepwise backward regression, eGFR and 25-hydroxyvitamin D3 were associated with iPTH, as follows: iPTH = 24.91 -(0.06 x 25-hydroxyvitamin D3) - (0.16 x eGFR) (R2 = 0.14). No associations with these two variables were, however, detected in patients with an eGFR of >60 ml/min/1.73 m2. Forty patients (31%) were transplanted pre-emptively, and the iPTH concentrations were significantly lower in these patients. CONCLUSIONS: Decreasing eGFR was the single most important variable predicting iPTH level in a cohort of renal transplant patients with an eGFR of 30-60 ml/min/1.73 m2, but not in patients with an eGFR of >60 ml/min/1.73 m2. Patients transplanted pre-emptively had a statistically significantly lower iPTH level compared with patients who had received dialysis.

Albumin-corrected or ionized calcium in renal failure? What to measure?

BACKGROUND: Secondary hyperparathyroidsm is frequently observed in patients with chronic renal failure, and clinical treatment guidelines have been published. Despite this, a large proportion of patients do not reach the target levels for calcium, phosphorus, calcium x phosphorus product, or intact parathyroid hormone. The use of albumin-corrected calcium is recommended as calcium measurement, but it is the concentration of ionized calcium that is biologically active. We hypothesized that in clinical practice, the use of ionized calcium rather than albumin-corrected calcium would influence the calcium classification of the individual patient. METHODS: Blood samples from 34 patients in chronic haemodialysis were analysed for evaluation of mineral metabolism according to K/DOQI guidelines. Blood for analysis of total and ionized calcium was drawn simultaneously. As ionized calcium is pH dependent, samples were analysed at the actual pH of the individual patient. RESULTS: For both methods, a similar number of patients were characterized as normocalcaemic. The use of albumin-corrected calcium caused one patient (3%) to be classified as hypocalcaemic, and 10 patients (26%) as hypercalcaemic whereas with ionized calcium, five (15%) and three patients (9%) were classified as hypo- and hypercalcaemic, respectively. CONCLUSIONS: According to present guidelines, the difference in calcium classification of patients might have clinical implications for the prescription of vitamin D, and on the choice of phosphate binders.