Vitamin D metabolite profiles in moderate renal insufficiency of childhood

In a prior study, we reported vitamin D metabolite profiles in the plasma of healthy children. In view of these findings, we investigated these same profiles in children with moderate renal insufficiency. Specimens were obtained in boty summer and winter in untreated patients, and before and after treatment for up to 1 year, with either 25(OH)D₃ or 1,25(OH)₂D₃. Mean pretreatment 1,25(OH)₂D levels were normal. Levels of 25(OH)D₃ were also normal and continued to vary with season. Mean pretreatment 24,25(OH)₂D₃ levels were significantly lower in patients and, interestingly, did not show the normal seasonal variation. Treatment with 25(OH)D₃ resulted in consistent and sustained rises in 25(OH)D₃ and 24,25(OH)₂D₃ levels, but no increase in 1,25(OH)D₃ levels. After 1,25(OH)₂D₃ treatment, 25(OH)D₃ levels were unchanged but still showed seasonal variation in some patients, suggesting a lack of feedback control by 1,25(OH)₂D₃. Levels of 24,25(OH)₂D₃ were not significantly different from baseline values. Levels of 1,25(OH)₂D increased initially then dropped to pretreatment levels or lower. Normal 1,25(OH)₂D levels and reduced 24,25(OH)₂D₃ levels with the loss of seasonal variation suggests in our patients that the kidney was able to maintain 1,25(OH)₂D levels at the expense of 24,25(OH)₂D₃ levels, presumably to preserve calcium homeostasis.     

Vitamin D deficiency is associated with short stature and may influence blood pressure control in paediatric renal transplant recipients

Vitamin D deficiency is common in adult renal transplant recipients, but data in children are scarce. Vitamin D is shown to have multiple effects on the cardiovascular system, renal function, and maintenance of bone health. We hypothesized that 25(OH)D deficiency is common in pediatric renal transplant recipients, and may be associated with hyperparathyroidism, short stature, renal function, and blood pressure control. We recruited 106 children during the winter/spring season who had a functioning renal transplant for at least 3 months. Twenty-five hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)₂D] were measured and correlated with clinical and biochemical parameters. Of the renal transplant patients, 38% were 25(OH)D deficient, 54% had insufficient levels, and only 8% had adequate 25(OH)D levels. Despite alfacalcidol supplementation in 59 (56%) patients, parathyroid hormone was increased in 58 (55%) and showed an inverse correlation with 25(OH)D (p = 0.0003, r = 0.61) but not with 1,25(OH)₂D levels. Height standard deviation score (SDS) correlated with 25(OH)D (p = 0.007, r = 0.42) and time post transplantation (p = 0.02, r = 0.23); both were significant and independent predictors of height SDS. 25(OH)D inversely correlated with systolic BP SDS (p = 0.02, r =−0.26); this association was lost on multiple regression analysis, but 25(OH)D was the only modifiable risk factor for hypertension. There was no correlation with estimated GFR or proteinuria. In conclusion, 25(OH)D deficiency is common in pediatric renal transplant recipients and correlates with hyperparathyroidism and short stature. 25(OH)D deficiency may be a modifiable risk factor for hypertension in transplant recipients. Further studies are required to test if routine supplementation with ergo or cholecalciferol is safe and effective in children after renal transplantation.     

Prevalence of 25(OH) vitamin D (calcidiol) deficiency at time of renal transplantation: a prospective study

25(OH) Vitamin D (calcidiol) is the major circulating form of vitamin D and is considered the most reliable measure of vitamin D status. Adequate vitamin D status is important for bone health but there is increasing evidence that low serum concentrations of calcidiol (<30 ng/mL) are associated with many adverse health outcomes in the general population. Little is known about calcidiol status at the time of renal transplantation, a period when bone loss is greatest and immunosuppression is highest. We prospectively measured serum calcidiol and parathyroid hormone immediately after transplant from March 2005 onwards. Of 112 patients studied, 29% had calcidiol deficiency (<10 ng/mL), 59% had calcidiol insufficiency (10-29 ng/mL) and only 12% of patients had a normal calcidiol concentration (>30 ng/mL). The prevalence of calcidiol deficiency in black recipients was extremely high at 41%. Serum calcidiol tended to be lower in winter than other seasons. In conclusion, the prevalence of 25(OH) vitamin D (calcidiol) deficiency/insufficiency at the time of renal transplant is very high. The clinical effects of this deficiency/insufficiency deserve further study.     

Cholecalciferol supplements improve vitamin D deficiency in renal transplant recipients

Most renal transplant recipients display vitamin D deficiency or insufficiency. The KDIGO guidelines suggest that this deficit should be treated as in the general population. Since there are few studies about the effects of cholecalciferol in de novo renal transplant recipients, we sought to assess these effects in long-term kidney graft recipients. Among 37 renal transplant recipients (19 males, 18 females) at a mean of 105 ± 82 months posttransplantation, vitamin D insufficiency or deficiency was treated with cholecalciferol (400-800 IU/d) plus calcium supplements (600-1200 mg/d of elemental calcium). These subjects were compared with 37 untreated recipients for a period between 6 and 12 months. At baseline, there were no differences between the groups in age at transplantation, sex, length of follow-up after grafting, function measured by estimated glomerular filtration rate (44.4 ± 16.8 treated vs 42.0 ± 15.0 mL/min/1.73 m² untreated; P = .527); iPTH (157 ± 103 treated vs 176 ± 118 pg/mL untreated; P = .461); 25OHD (14.7 ± 4.7 treated vs 15.7 ± 9.7 ng/mL untreated; P = .584); or 1.25OHD (34.1 ± 26.0 treated vs 34.0 ± 13.0 pg/mL untreated; P = .950). When compared with baseline values, iPTH (157 ± 103 vs 144 ± 89 pg/mL; P = .11) and 1.25OHD levels at 6 months (34.1 ± 26.0 vs 35.9 ± 26.3 pg/mL; P = .282) showed no change but 25OHD levels (14.7 ± 4.7 vs 22.6 ± 7.4 ng/mL; P = .000) and phosphate tubular reabsorption (64% ± 17% baseline vs 69% ± 14% at 6 months; P = .030) were increased in the treated patients. There were no differences in the parameters studied in untreated patients. Among the 27 recipients followed at 12 months, iPTH was decreased compared with baseline values (157 ± 103 vs 124 ± 62 pg/mL; P = .024) and 25OHD remained stable with respect to the values at 6 months (21.1 ± 5.3 ng/mL). No adverse effects of cholecalciferol were observed such as those to increase urinary calcium excretion. Low doses of cholecalciferol improved vitamin D status and decreased iPTH levels at 12 months. Higher doses than those used in our study are needed to increase serum 25OHD concentrations above 30 ng/mL.     

Magnesium repletion therapy improved lipid metabolism in hypomagnesemic renal transplant recipients: a pilot study.

BACKGROUND: Hypomagnesemia has been associated with hypertension, abnormal glucose and lipid metabolism, and accelerated atherosclerosis in nontransplant patients. METHODS: In this prospective short-term pilot study, 14 hypomagnesemic renal transplant recipients with stable renal function were evaluated monthly over a 6-month interval. The first 3 months was the baseline observation period. During the second 3 months, MgO2 was administered to normalize the serum Mg level. Glucose tolerance, lipid levels, blood pressure, weight, and routine chemistries were assessed before and after Mg replacement. All others medications were held constant during the 6-month study. RESULTS: Serum Mg levels increased to normal range after MgO2 therapy, which was well tolerated. There were significant decreases in total cholesterol, low density lipoprotein, and total cholesterol/high density lipoprotein ratio after 3 months of MgO2 therapy. Only three patients had abnormal baseline glucose tolerance tests. All three patients showed improved glucose tolerance after MgO2, but this was not statistically significant. CONCLUSIONS: Mg repletion may be an important ancillary therapy in hypomagnesemic renal transplant patients with hyperlipidemia.     

Audit of diabetes in a renal transplant population

AIMS: To determine the prevalence of diabetes and its glycemic control in the renal transplant population of northeast England (Newcastle, Sunderland, Middlesborough, and Carlisle). METHODS: All renal transplant notes in northeast England were reviewed. Data on patient details, type of diabetes, time of onset of diabetes, diabetes medications, time of insulin commencement, date of renal transplant, immunosuppressive medications, and HbA(1C) were recorded. RESULTS: Living renal transplant patients (n = 1073) transplanted between March 1982 and November 5, 2003 were identified. One hundred and nine (10.2%) patients had diabetes, of whom 39 were type 1 and 70 were type 2. Median HBA(1C) in patients with type 1 diabetes on tacrolimus was 10.1% +/- 1.94% (SD) versus 7.8% +/- 1.98% (SD) for patients not on tacrolimus. Among patients with type 2 diabetes, 25 had diabetes prior to transplant and 45 (4.5%) developed posttransplant diabetes (PTDM). Those who developed PTDM and were taking tacrolimus were more likely to require insulin for blood glucose control (0.39 U/kg/24 hours vs 0 U/kg/24 hours; P = .05) compared to those not on tacrolimus. Both type 1 and type 2 diabetics on tacrolimus showed better preservation of renal function as measured by mean serum creatinine (type 1: 145 +/- 53 vs 196 +/- 74, P = .02; type 2 pretransplant: 159 +/- 73 vs 172 +/- 59, P = .35; type 2 posttransplant: 123 +/- 35 vs 167 +/- 63, P = .01). CONCLUSIONS: Tacrolimus use in renal transplant patients with diabetes appeared to be associated with more problematic blood glucose control; however, it seemed to be better at preserving renal function. Intensive blood glucose monitoring is recommended for this group.     

Vitamin D deficiency and parathyroid hormone levels following renal transplantation in children

The objectives were to determine the prevalence of vitamin D deficiency [25(OH)D < 10 ng/ml] in pediatric renal transplant (RTx) recipients, compared with controls and identify correlates of changes in 25(OH)D and intact parathyroid hormone (iPTH) levels following transplantation. Serum 25(OH)D, 1,25(OH)₂D, and iPTH were measured once in 275 healthy controls and at transplantation, and 3 and 12 months posttransplantation in 58 RTx recipients. Multivariate logistic regression models determined the odds ratio (OR) of vitamin D deficiency in RTx recipients vs. controls adjusted for age, sex, race, and season. Generalized estimating equations were used to assess changes following transplantation. At transplantation, 22% of nonblack and 27% of black RTx recipients were vitamin D deficient. The adjusted OR of vitamin D deficiency was greater in RTx recipients (p < 0.001) compared with controls; however, the transplant association was greater in nonblack vs. black individuals (interaction p = 0.02). Overall, 25(OH)D levels did not change significantly following transplantation. Younger age (p < 0.01), nonblack race (p < 0.001), visits in nonwinter months (p < 0.001), and supplementation with ≥400 IU/day ergo/cholecalciferol (p < 0.001) were associated with increases (or lesser declines) in 25(OH)D following transplantation. Increases in 25(OH)D levels (p < 0.001) and vitamin D supplementation (p < 0.01) were associated with greater reductions in iPTH levels following transplantation, independent of 1,25(OH)₂D levels.     

Skeletal disorders in a pediatric renal transplant population

Relatively little is known about the incidence of musculoskeletal disorders in patients with chronic renal failure, the conditions that give rise to particular types of deformities, and indications for operative management. Two selected patient pools were evaluated for the presence of disorders commonly seen in these patients: bony deformity, epiphysiolysis, and osteonecrosis. Relationships were noted between the occurrence of these abnormalities and age at diagnosis of renal failure, the patient's age at the appearance of the disorder, and age at time of renal transplantation. Recognition of such patterns and relationships should be helpful in earlier identification and management of these disorders.     

Vitamin D deficiency is common in kidney transplant recipients,but is not associated with infections after transplantation

The relevance of vitamin D for infections after kidney transplantation is poorly defined. 25-OH vitamin D (25-OHD) levels of 135 kidney transplant recipients, enrolled in the Swiss Transplant Cohort Study, were determined peri-transplant and 6 months post-transplant. Logistic regression was used to address the associations of 25-OHD and overall infections and bacterial infections, respectively. For the first 6 months post-transplant, 25-OHD peri-transplant, and for the second period (after 6 to 30 months post-transplant), 25-OHD at 6 months post-transplant was considered. Vitamin D deficiency was common peri-transplant and remained highly prevalent 6 months after transplantation despite frequent supplementation. Median 25-OHD levels increased from 12.0 ng/mL (IQR 5.3-19.5) peri-transplant to 16.5 ng/mL (IQR 10.6-22.6) 6 months post-transplant (P = .005). We did not detect a significant association between 25-OHD and overall infections (adjusted odds ratio (aOR) 1.05, 95% confidence interval (95%CI) 0.44-2.51; aOR 0.67, 95%CI 0.31-1.43) or bacterial infections (aOR 0.79, 95%CI 0.32-1.96; aOR 0.79, 95%CI 0.35-1.75) for the first and second period. To conclude, at both time points, vitamin D deficiency was observed in more than 50% of kidney recipients, albeit an increase in 25-OHD in the longitudinal course was observed. No significant association between 25-OHD and infections was detected.     

Nonhepatitis B-associated liver disease in a renal transplant population

The spectrum of liver disease in a population of 293 patients receiving 353 renal transplants (1971-1984) was reviewed. This study looked retrospectively at the histological features of liver disease in this population, and prospectively at the clinical and biochemical features of liver disease associated with renal transplantation. In all patients, infection with hepatitis B was excluded. Six deaths, primarily attributable to hepatic failure have occurred: one, acute herpes simplex infection; one, subacute massive hepatic necrosis of uncertain etiology; two, pretransplant liver disease; and two, posttransplantation cirrhosis of uncertain etiology. Review of the hepatic histology of 26 patients with known liver disease following transplantation revealed a wide range of pathologies with few specific correlations with their clinical status or biochemical tests of liver function. The prevalence of hepatic dysfunction following transplantation in our patient population was assessed by prospective biochemical screening of 111 transplant recipients over a 6-month interval. During this time period, 27 patients (24%) displayed biochemical evidence of hepatic dysfunction. Liver disease was known to have predated transplantation in only three of 27. Episodes of abnormal liver function occasionally occurred during an identifiable acute illness (six of 27), although the majority (21 of 27) had chronic hepatic dysfunction. Transplant recipients with abnormal liver function could not be differentiated from a cohort with normal liver function on the basis of age, sex, duration of graft function, or alcohol/drug intake. The possible etiologies of nonhepatitis B liver dysfunction following renal transplantation are discussed, and the high prevalence of biochemical evidence of hepatic dysfunction in this population free of hepatitis B infection is emphasized.     

Early experience with conversion to sirolimus in a pediatric renal transplant population

Sirolimus is an immunosuppressive agent that offers potentially significant benefits for young transplant patients facing life-long treatment. Its action of reducing cell proliferation may reduce the risk of chronic allograft nephropathy and posttransplant neoplasia. Twenty-nine children were converted from calcineurin inhibitors to sirolimus after renal transplantation and followed for a minimum of 12 months. Glomerular filtration increased transiently in those converted before 12 months after transplantation but not in those converted later, when chronic histological changes had developed. Mild acute rejection occurred after conversion in 10%, and side effects led to cessation of sirolimus in 31%. Anemia occurred in 55% of patients and responded well to darbepoetin. Most side effects (anemia, hypercholesterolemia, mouth ulcers, and myalgias) became less severe with time. The number of antihypertensive drugs required decreased significantly on sirolimus. Although side effects are frequent on sirolimus, in the majority of children, they are mild enough to allow the patient to continue taking the drug, and for these children the long-term benefits are potentially valuable.     

Low-dose simvastatin is safe in hyperlipidaemic renal transplant patients

Hyperlipidaemia is common after renal transplantation, and becauseof its association with atherosclerosis, interest has increasedin the use of lipid-lowering drugs in transplant patients. Dietaryapproaches have not been consistently successful, and multiplepharmacotherapy and drug interactions have led to difficultiesin establishing lipid-lowering drug regimes. The statins reduceplasma cholesterol by inhibiting the rate-limiting step in cholesterolsynthesis, and although some side-effects have been reportedin their use after transplantation, the efficacy and safetyof low doses has not been formally established. A randomized single-blind placebo crossover study designed todetermine the safety and effectiveness of simvastatin in a singledaily 5-mg evening dose was therefore conducted in 26 stablerenal transplant patients, 14 of whom were receiving cyclosporinA. The results demonstrated no difference between total cholesterollevels in the baseline simvastatin and placebo periods: 7.97± 1.2 and 7.59±1.5 mmol/l respectively. After8 weeks of simvastatin, the total cholesterol declined significantlyto 6.72±0.87 mmol/l (P<0.001). A significant differencewas found when the placebo and simvastatin cholesterol levelswere compared at 4 and 8 weeks (P<0.01). LDL cholesterol decreased from 4.74 ± 0.87 to 3.78 ±0.78 mmol/l after 8 weeks on simvastatin (P<0.001), and apoB fell from 142 ± 31 to 112 ± 22 mg/dl (P<0.001).The difference in LDL cholesterol and apo B after 8 weeks ofsimvastatin when compared with the corresponding values on placebowas also significant (P<0.01). A slight but not significantincrement in HDL cholesterol from 1.10 ± 0.47 to 1.13± 55 mmol/l (NS) was seen after 8 weeks on simvastatin. Triglycerides and serum creatinine did not change during thestudy in any of the groups. Creatine kinase (CK.) remained inthe normal range (0–200 U/l), except for one patient nottaking cyclosporin who had a CK value slightly above the upperlimit of normal during the simvastatin period, without abnormalclinical signs. Repeated cyclosporin measurements remained withinthe therapeutic range (50–150 ng/ml). These results suggestthat low-dose simvastatin is effective and safe in reducingtotal cholesterol and LDL cholesterol in renal transplant patients.     

Investigation of HTLV-3 serology in a renal transplant population

From June 1977 to March 1985, 572 renal transplants were performed at The University of Texas Medical School at Houston. This represented 220 patients (151 cadaveric [CAD] and 69 living-related donor [LRD] recipients) treated with azathioprine and prednisone (Aza-Pred) and 352 patients (250 CAD and 102 LRD) treated with cyclosporine (CsA) and Pred. Sera from each recipient before and after transplant (Tx) as well as from each of their 436 donors (265 CAD and 171 LRD) were retrospectively tested for the presence of antibody to the human T cell lymphotrophic virus type III (HTLV-3) by enzyme immunoassay (EIA) and Western Blot analysis. Of the 436 donors tested, only 1/265 (0.38%) CAD donors were both EIA repeatedly reactive and Western Blot positive, whereas none of the 171 LRD were reactive. Pre-Tx, 4/401 (1.0%) CAD and 1/171 (0.6%) LRD recipient sera were EIA repeatedly reactive, however, all 5 were to be Western Blot negative. Post-Tx, 4.2% of the sera (24/572, 4 LRD and 20 CAD recipients) were EIA-reactive. All 20 CAD recipient sera were subsequently found to be negative with Western Blot testing. However, 2 LRD sera (2/572, 0.35%) displayed EIA reactivity as well as Western Blot positivity. One LRD, Western-Blot-positive recipient is alive and well with a functioning allograft 39 months post-Tx, whereas the second LRD, Western Blot positive recipient died of septic complications 16 months post-Tx. Finally, the recipient of the Western-Blot-positive CAD allograft is alive with a well-functioning graft and remains EIA and Western-Blot-negative 36 months post-Tx.