Serum bone markers in ROD patients across the spectrum of decreases in GFR: Activin A increases before all other markers
.

INTRODUCTION: Renal osteodystrophy (ROD) develops early in chronic kidney disease (CKD) and progresses with loss of kidney function. While intact parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3 (1,25D), and fibroblast growth factor-23 (FGF-23) levels are usually considered the primary abnormalities in ROD development, the role of serum activin A elevations in CKD and its relationships to ROD have not been explored. The aims of this study were to evaluate serum activin A at different CKD stages, and to establish the relationships between activin A, bone biomarkers, and bone histomorphometric parameters. MATERIALS AND METHODS: 104 patients with CKD stages 2 - 5D underwent bone biopsies. We measured in the serum activin A, BSAP, DKK1, FGF-23, α-Klotho, intact PTH, sclerostin, TRAP-5b, and 1,25D. Biochemical results were compared across CKD stages and with 19 age-matched controls with normal kidney function. RESULTS: Median activin A levels were increased in all stages of CKD compared to controls from 544 pg/mL in CKD 2 (431 - 628) to 1,135 pg/mL in CKD 5D (816 - 1,456), compared to 369 pg/mL in controls (316 - 453, p < 0.01). The increase of activin A in CKD 2 (p = 0.016) occurred before changes in the other measured biomarkers. Activin A correlated with intact PTH and FGF-23 (r = 0.65 and 0.61; p < 0.01) and with histomorphometric parameters of bone turnover (BFR/BS, Acf, ObS/BS and OcS/BS; r = 0.47 - 0.52; p < 0.01). These correlations were comparable to those found with intact PTH and FGF-23. CONCLUSION: Serum activin A levels increase starting at CKD 2 before elevations in intact PTH and FGF-23. Activin A correlates with bone turnover similar to intact PTH and FGF-23. These findings suggest a role for activin A in early development of ROD.

Complications of pediatric live-donor kidney transplantation: a single center's experience in Egypt.

Our objective was to study the complications of chronic renal failure (CRF) among pediatric live-donor kidney transplant recipients. Between March 1976 and December 2005, 1,785 live-donor kidney transplantations were carried out at our center. Of the recipients, 292 were 20 years old or younger (mean age 12.8 years, ranging from 4 years to 20 years). Clinical and laboratory parameters of these 292 patients were analyzed retrospectively. They were 182 boys and 110 girls. Patients who had received transplants before 1988 were treated with prednisolone and azathioprine as combined therapy. From 1988 to 1998, a triple regimen comprising prednisolone, azathioprine and cyclosporine A (CsA) was administered. Tacrolimus and mycophenolate mofetil (MMF) were introduced as primary therapy in 1998. Growth, anemia, infections, and surgical, cardiac, neurologic, bone and other medical complications were assessed. Triple-drug immunosuppression (prednisone + CsA + azathioprine) was used in 68.2% of transplants. Acute rejection rate was 47.6%; chronic rejection rate was 31%. Hypertension (62%) was the commonest complication. Anemia was diagnosed in 61%. A substantial proportion of patients (48%) were short, with height standard deviation scores (SDSs) of less than -1.88. The overall infection rate was high, and the majority (54%) was bacterial. Malignancy was diagnosed in eight (3%) patients. The incidence of urological complications was 14%, and that of vascular complications was 1%. Cardiac complications included left ventricular hypertrophy (LVH) in 47.9% of patients, left atrial enlargement (31.5%) and left ventricular dilatation and systolic dysfunction (13.7% for each). Neuropathic changes were found in 19% of our cases, with the distal muscles of lower limbs more affected. Other complications included avascular bone necrosis in 8% (all of them in the hip joint) and bone loss in 60% of patients. We concluded that, despite the long-term success of pediatric renal transplantation in a developing country, there is a risk of significant morbidity.

Growth in children with chronic renal failure and after renal transplantation.

Growth retardation is a major problem for many children with chronic renal failure (CRF) and transplantation. The aim of this study is to assess the relation between height, glomerular filtration rate (GFR), hormonal alterations in children with CRF on regular haemodialysis (HD), and the impact of functioning graft after kidney transplantation.Thirty-six hemodialysed children were included in the study beside 32 pediatric transplants. Mean duration on HD was 14.72 +/- 7.73 months for the CRF group, while the mean interval after transplantation was 1.97 +/- 0.9 years for the second group. Moreover, twenty healthy children of matched age and sex served as controls. Assessment of growth parameters included height, expressed as standard deviation scores (Ht SDS) for chronological age, serum levels of growth hormone (hGH), and parathormone (PTH). Growth performance was evaluated twice: at the start of the study and one year later. Children with CRF and transplantation had significantly higher levels of both serum hGH and PTH compared to their controls, while CRF children experienced significantly higher serum levels of both hGH and PTH compared to those with functioning graft. Furthermore, analysis of our results by non-parametric Kendall's correlation at the start and one year later revealed negative correlation concerning dialysis duration, serum creatinine, and PTH. On the other hand, positive correlation was achieved for serum calcium and GFR.

Pediatric live-donor kidney transplantation in Mansoura Urology & Nephrology Center: a 28-year perspective.

Our objective was to evaluate our overall experience in pediatric renal transplantation. Between March 1976 and March 2004, 1,600 live-donor kidney transplantations were carried out in our center; 216 of the patients were 18 years old or younger (mean age 12.9 years). There were 136 male patients and 80 female patients. The commonest causes of end-stage renal disease (ESRD) were renal dysplasia (22%), nephrotic syndrome (20%), hereditary nephritis (16%), and obstructive uropathy (16%). Of the donors, 94% were one-haplotype matched and the rest were identical. Pre-emptive transplantation was performed in 51 (23%) patients. Triple-therapy immunosuppression (prednisone + cyclosporine + azathioprine) was used in 78.2% of transplants. Rejection-free recipients constituted 47.7%. Hypertension (62%) was the commonest complication. A substantial proportion of patients (48%) were short, with height standard deviation score (SDS) less than -1.88. The overall infection rate was high, and the majority (53%) of infections were bacterial. The graft survival at 1 year, 5 years and 10 years were 93.4%, 73.3% and 48.2%, respectively, while the patients' survival at 1, 5 and 10 years were 97.6%, 87.8% and 75.3%, respectively. Despite long-term success results of pediatric renal transplantation in a developing country, there is a risk of significant morbidity.

Characteristics of long-term live-donor pediatric renal transplant survivors: a single-center experience.

OBJECTIVES: To study the characteristics and the predictors of survival observed in our pediatric live-donor renal transplant recipients with an allograft that functioned for more than 10 yr. METHODS: One hundred fifteen children underwent renal transplantation between 1976 and 1995. Of these, 30 had functioning allografts for more than 10 yr (range, 11-18). The patients included 18 males and 12 females, with a mean age at transplantation of 13 yr (range, 5-18). Characteristics of the patients, data on graft survival, and determinants of outcome were obtained by reviewing all medical charts. RESULTS: At most recent follow-up (January 2005), the mean daily dose of azathioprine was 1.2 mg/kg (range, 1-2) and that of prednisone was 0.16 mg/kg (range, 0.1-0.2). Mean creatinine clearance was 72 mL/min per 1.73 m(2) (range, 45-112). Acute rejection occurred in 14 (47%) patients. Seven patients had one episode, five had two episodes, and two had three episodes of acute rejection. Three patients (10%) developed malignancy. A substantial proportion of patients (44%) were short, with a height standard deviation score (SDS) less than -1.88, which is below the third percentile for age and gender. One quarter of the patients, more commonly the females, were obese. Other complications included osteoporosis in 16 (53%) patients, avascular bone necrosis in four (13%), post-transplantation diabetes mellitus in three (10%), and hypertension in 18 (60%). Twelve (40%) patients were married and 27% had children post-transplantation. The independent determinants of long-term graft survival were acute rejection and post-transplant hypertension. CONCLUSION: Despite good renal function, long-term pediatric renal transplant survivors are at risk of significant morbidity. The determinants of long-term graft survival are acute rejection and post-transplant hypertension.

Determinants of graft survival in pediatric and adolescent live donor kidney transplant recipients: a single center experience.

To study the independent determinants of graft survival among pediatric and adolescent live donor kidney transplant recipients. Between March 1976 and March 2004, 1600 live donor kidney transplants were carried out in our center. Of them 284 were 20 yr old or younger (mean age 13.1 yr, ranging from 5 to 20 yr). Evaluation of the possible variables that may affect graft survival were carried out using univariate and multivariate analyses. Studied factors included age, gender, relation between donor and recipient, original kidney disease, ABO blood group, pretransplant blood transfusion, human leukocyte antigen (HLA) matching, pretransplant dialysis, height standard deviation score (SDS), pretransplant hypertension, cold ischemia time, number of renal arteries, ureteral anastomosis, time to diuresis, time of transplantation, occurrence of acute tubular necrosis (ATN), primary and secondary immunosuppression, total dose of steroids in the first 3 months, development of acute rejection and post-transplant hypertension. Using univariate analysis, the significant predictors for graft survival were HLA matching, type of primary urinary recontinuity, time to diuresis, ATN, acute rejection and post-transplant hypertension. The multivariate analysis restricted the significance to acute rejection and post-transplant hypertension. The independent determinants of graft survival in live-donor pediatric and adolescent renal transplant recipients are acute rejection and post-transplant hypertension.

Acute postinfectious crescentic glomerulonephritis: clinicopathologic presentation and risk factors.

BACKGROUND: Glomerular crescent formation is a feature of the most severe forms of human glomerulonephritis. The postinfectious form of rapidly progressive glomerulonephritis with crescents is a form of immune complex glomerulonephritis which seem to have a better prognosis. A relatively poorer prognosis for crescentic postinfectious glomerulonephritis in South Africa has been reported. In the present study, we have tried to determine the mode of presentation, and the prognostic factors for renal and patient outcome for cases with postinfectious crescentic glomerulonephritis (CGN). METHODS: Between 1990 and 2000 a total number of 128 patients with CGN were managed at our center, among them 23 cases were diagnosed as postinfectious CGN. They were followed-up for a mean period of 40.1 +/- 28.9 months. Among them 12 were males and 11 were females. The median age was 12.35 years (range 4-55 years). The median serum creatinine at presentation was 7.24 mg/dl (range 1.3-14.5 mg/dl). We studied the clinical, laboratory and histopathological data .of our cases and their impact on the renal and patient outcome. RESULTS: By univariate study the risk factors for renal dysfunction were the age, hypertension, and nephrotic range proteinuria during the follow-up period. By multivariate analysis only the, hypertension, and presence of nephrotic range proteinuria during the follow-up period were the significant risk factors. The risk factors that significantly affected patient mortality were hypertension and serum creatinine at last follow-up. CONCLUSION: postinfectious CGN is a severe form of glomerulonephritis that usually presents with rapidly progressive renal failure. The persistence of hypertension and nephrotic range proteinuria during the follow-up are major bad prognostic predictors for renal dysfunction.

Neurophysiologic changes in live related kidney transplant children and adolescents.

Uremic neuropathy is one of the most debilitating symptoms associated with end stage renal disease. In adults the only potential cure for uremic neuropathy is renal transplantation. No studies have investigated the neurophysiologic abnormalities among pediatric renal transplant recipients. The objective of this study is to describe the incidence, nature and factors affecting neurophysiologic abnormalities in young renal transplant recipients. Neurophysiologic study was performed for 31 of our live related pediatric renal transplant recipients; they were 21 males and 10 females. The mean age at transplantation was 13.2 +/- 3.1 yr. The neurophysiologic studies were performed at different time points after transplantation (range 12-60 months), with a mean period of follow-up after transplantation 3.2 +/- 1.1 yr. Electromyography of the following muscles was tested: abductor pollicis brevis of the thenar eminence, biceps brachii, extensor digitorum brevis and rectus femoris. The median and lateral popliteal nerves were tested for estimating the motor conduction velocity. Neuropathic changes were found in 19% of our cases with more affection of the distal muscles of lower limbs. Motor conduction velocities were reduced, distal latencies were lengthened, and motor unit action potentials were reduced or dispersed. The predictors for development of neuropathy by multivariate analysis were the cumulative steroid dose and graft dysfunction. These results suggest that neuropathy is prevalent among young pediatric renal transplants. The independent predictors for development of neuropathy are graft dysfunction and anemia. It is unclear how significant these findings are in view of absent clinical signs and symptoms. This may represent an early stage of a disease that is still silent.

A prospective randomized study for prevention of postrenal transplantation bone loss.

BACKGROUND: We aimed to investigate different treatment drugs for the prevention of post-transplant bone loss. METHODS: Sixty adult male recent renal transplant recipients were enrolled into the study. Patients were randomized into 4 groups: group I received daily alfacalcidol 0.5 microg PO; group II received oral alendronate 5 mg/day; group III received intranasal salmon calcitonin 200 IU every other day; and group IV was considered a control group. Every patient was supplemented with daily 500 mg oral calcium carbonate. Parameters of bone metabolism were measured before and at 12 months after starting treatment. Bone mineral density (BMD) was measured by (DEXA) at lumber spine, femoral neck, and forearm before and after treatment period. RESULTS: BMD was increased at lumber spine by 2.1%, 0.8%, 1.7%, by 1.8%, 0.6%, 1.6% at femoral neck, and by 3.2%, 1.9%, 2.6% at forearm in groups I, II, and III, respectively, while it decreased by 3.2%, 3.8%, and 1.8% at the same sites, respectively, in control group (P= <0.05). iPTH level decreased significantly in group I, while the decrease was insignificant in other groups (P= 0.003). All other parameters were not statistically significant between treatment groups. Apart from transient hypocalcaemia in 3 patients in group II, and 2 patients in group III, no other significant adverse effects were noted. CONCLUSION: This study proves that early bone loss that occurs during the first 12 months after renal transplantation could be prevented by alfacalcidol, calcitonin, or alendronate. Among the treatment groups, alfacalcidol significantly improved the hyperparathyroidism. All treatment drugs are safe and tolerable.

A prospective randomized study for the treatment of bone loss with vitamin d during kidney transplantation in children and adolescents.

The effect of treatment with alfacalcidol on post-transplantation bone loss in children and adolescents was investigated. Of the 63 young patients who received renal transplant and were subjected to dual-energy x-ray absorptiometry (DEXA), 30 patients had low-bone mineral density (BMD) (z-score < or = -1) and were enrolled into the study. Their mean age at the time of transplantation was 14.5 +/- 4.0 years and the mean duration after transplantation was 48 +/- 34 months. Patients with low BMD were randomized into two equal homogeneous groups: group 1 (control) received placebo and group 2 received daily alfacalcidol 0.25 microg by mouth. Parameters of bone metabolism (intact parathyroid hormone, serum osteocalcin and urinary deoxypyridinoline) and BMD were assessed before and after the study period. After 12 months of treatment BMD at the lumber spine decreased from -2.2 to -2.5 in group 1 while it increased from -2.1 to -0.6 in group 2 (p < 0.001). Serum intact parathyroid hormone level decreased significantly in group 2 (p = 0.042). Apart from transient hypercalcemia in 1 patient in group 2, no other significant adverse effects were noted. This study suggested the value of alfacalcidol in the treatment of bone loss in young renal transplant recipients.

Bone mineral density in live related kidney transplant children and adolescents.

Successful kidney transplantation corrects many of the metabolic abnormalities associated with development of renal osteodystrophy, but despite a well-functioning graft, osteopenia, remains prevalent in adult and pediatric kidney recipients. The factors that affect the bone mineral density (BMD) and the long term course of BMD after transplantation in children is still unknown. We performed a cross sectional study to determine BMD in 83 recipients who received living renal allotransplants in Mansoura Urology & Nephrology Center between 1981 and 2002 (mean age at transplantation 13.2 +/- 3.1 years) by dual energy x-ray absorptiometry at various time intervals up to 16 years after transplantation (mean duration after transplantation was 48 +/- 34 months, range 12-192 months). The mean +/- SD for BMD was -2.28 +/- 2.06 for lumbar 2-4 spine and -1.44 +/- 1.44 for the total body BMD as corrected for body surface area. Osteopenia/osteoporosis were present in about two thirds of our kidney transplant recipients. The significant risk factors for osteopenia/osteoprosis using univariate analysis were the cyclosporine based immunosuppressive regimen, cumulative dose of steroids/m2 surface area, graft dysfunction and the urinary deoxypyridinoline. Using logistic regression analysis the cumulative steroid dose/m2 surface area and the urinary deoxypyridinoline were the major significant predictors for bone loss. In conclusion, osteopenia and osteoprosis are common in pediatric and adolescent renal transplant patients. The cumulative steroid dose and the urinary deoxypyridinoline were the major predictors for bone loss.

Treatment of osteopenia and osteoporosis in renal transplant children and adolescents.

Successful renal transplantation corrects many of the metabolic abnormalities associated with the development of renal osteodystrophy, but despite a well-functioning graft osteopenia, growth failure, spontaneous fractures, and avascular necrosis remain prevalent in adult and pediatric kidney recipients. A paucity of information exists regarding the effects of different therapies to prevent and treat bone loss in the renal transplant recipients. We constructed a design to study the effect of different modalities of treatment on bone mass in our renal transplant children. Among 93 patients who underwent renal transplantation at the age of 17 yr or less and were subjected to dual-energy X-ray absorptiometry (DEXA), we blindly randomized 60 patients who had osteopenia or osteoporosis (T-score = -1 by DEXA) in a prospective study. Their mean age at time of transplantation was 13.4 +/- 4.3 yr. The mean duration after transplantation was 48 +/- 34 months. The patients were classified randomly into four groups. Each group consisted of 15 patients: group 1 was the control group, group 2 received oral alfacalcidol 0.25 microg daily, group 3 received oral alendronate 5 mg daily, and group 4 received 200 IU/day nasal spray calcitonin. Parameters of bone turnover, calcium metabolism, and DEXA were measured before and after 12 months of treatment duration. The characteristics of all groups were comparable at the beginning of the study. At the lumber spine, bone mass density decreased from -2.4 to -2.8 in group 1, increased from -2.3 to -0.5 in group 2, from -2.3 to -1.9 in group 3, and from -2.3 to -1.0 in group 4. The four groups had similar patient profiles, serum creatinine, intact parathyroid hormone, osteocalcin, and deoxypyridinoline. This study confirmed the value of alfacalcidol and antiresorptive agents in the treatment of osteopenia and osteoporosis in young renal transplant recipients.These therapies were safe, tolerable, simple to administer and potentially applicable to other renal transplant patients.

Echocardiographic changes and risk factors for left ventricular hypertrophy in children and adolescents after renal transplantation.

Long-term consequences of cardiac alteration in children with chronic renal failure and after renal transplantation are largely unknown. In chronic uremia, cardiomyopathy manifests itself as systolic dysfunction, concentric left ventricular hypertrophy (LVH) or left ventricular dilatation. The correction of uremic state by renal transplantation leads to normalization of left ventricular contractility, regression of LVH and improvement of cavity volume and so dialysis patients with uremic cardiomyopathy would benefit from renal transplantation. We studied 73 patients, aged 17 yr or less, who underwent renal transplantation in our center. This cross-sectional study was performed 4.6 yr (median) after transplantation. Of the total, 48 were males and 25 were females. Transthoracic echocardiographic examination was performed for all cases. The effects of clinical, demographic, biochemical and therapeutic data on echocardiographic parameters were assessed. Multivariate analysis was used to assess the relation between the risk factors and the left ventricular muscle mass index. The most common echocardiographic abnormalities were the LVH (47.9%), left atrial enlargement (31.5%) and left ventricular dilatation and systolic dysfunction (13.7% for each). The pretransplant dialysis, arteriovenous fistula, acute rejection, cumulative steroid dose per square meter surface area, post-transplant hypertension, anemia and graft dysfunction were significant risk factors for LVH by univariate analysis. The significant factors by multivariate analysis were pretransplant dialysis, post-transplant hypertension and anemia. From this study we may conclude that LVH is a common problem among renal transplant children and adolescents. Early transplantation, control of hypertension and correction of anemia may be beneficial regarding left ventricular function and structure.

The impact of hepatitis C virus viremia on renal graft and patient survival: a 9-year prospective study.

BACKGROUND: The impact of hepatitis C virus (HCV) infection on long-term patient and renal graft survival is controversial. METHODS: We prospectively followed up for approximately 9 years 133 hepatitis B surface antigen (HBsAg)-negative successive renal transplant recipients for whom HCV RNA polymerase chain reaction (PCR) results were available before transplantation. We compared graft and patient survival rates and causes of death and graft failure in PCR-positive and PCR-negative transplant recipients. Cox proportional hazards models were used to detect the impact of HCV infection on patient and graft survival. We also studied posttransplantation hepatic function and graft performance. RESULTS: HCV RNA was detected in sera of 87 patients (65%). Univariate and multivariate analyses did not show an increased risk for death or graft failure in viremic compared with nonviremic transplant recipients. However, HCV-infected transplant recipients with chronic alanine aminotransferase level elevations had increased risks for death (odds ratio, 3.7; 95% confidence interval [CI], 1 to 13.7) and graft failure (odds ratio, 3; 95% CI, 1.4 to 6.7) compared with viremic transplant recipients with persistently normal liver function test results and noninfected patients. Five viremic and no nonviremic transplant recipients died of liver disease. HCV viremic transplant recipients had significantly greater frequencies of biochemical chronic liver disease, proteinuria, and biopsy-proven chronic allograft nephropathy (CAN) compared with noninfected transplant recipients. CONCLUSION: HCV infection per se has no adverse effect on long-term renal graft and patient survival. However, HCV-infected transplant recipients with abnormal liver function have inferior survival rates. HCV infection in renal transplants is associated with greater rates of proteinuria and CAN.

Preventing bone loss in renal transplant recipients with vitamin D.

Very rapid bone loss, osteopenia, and osteoporosis have been documented in the first 6 to 12 mo after renal transplantation. Investigated was the effect of treatment with active vitamin D on the prevention of posttransplantation bone loss. Forty adult men who were recent renal transplant recipients were enrolled onto the study. Patients were randomized into two groups: group 1 received daily alfacalcidol 0.5 micro g by mouth, and group 2 (control) received placebo. Every patient in both groups received daily 500-mg calcium carbonate supplements. Parameters of bone metabolism and bone mineral density measured at three sites were assessed before and after the study period. Bone mineral density was increased by 2.1%, 1.8%, and 3.2% at lumbar spine, femoral neck, and forearm, respectively, in group 1, whereas it decreased by 3.2%, 3.8%, and 1.8% at the same sites in the control group (P < 0.05). Serum intact parathyroid hormone level decreased significantly in group 1 compared with the control group (P = 0.003). Early bone loss that occurs during the first 1 yr after renal transplantation could be prevented by alfacalcidol. Use of alfacalcidol early after transplantation is safe and well tolerated.

Crescentic glomerulonephritis in Egypt: clinical and histopathological risk factors.

We followed up 128 patients with crescentic glomerulonephritis (CGN), having sufficient clinical and histopathological data for a mean period of 34 +/- 28 months. There were 49 males and 79 females, mean age 22.7 +/- 14 years. We studied the effects of clinical, laboratory and histopathological parameters on kidney function and survival at the end point of the study. Multivariate analysis indicated that serum creatinine at presentation, nephrotic range proteinuria during the follow-up period, percentage of glomeruli with crescents, percentage of fibrous crescents and absence of cellular infiltration were significant risk factors affecting kidney function at the end of the study. The only risk factor significantly correlated with mortality was serum creatinine at last follow-up.