Mustafa Balal

Uncommon side effect of MMF in renal transplant recipients

Mycophenolate mofetil (MMF) is a potent immunosuppressive agent used in renal transplantation. Gastrointestinal and hematological side effects are commonly observed, but hepatotoxicity has not been reported. In this study, we assessed MMF-related hepatotoxicity in renal transplant recipients. A total of 124 renal transplantation recipients (RTRs) were evaluated for elevated liver enzymes associated with MMF, and 79 patients were enrolled to the study. Patients used MMF 2 g/day. The patients who had progressive increase in liver enzymes after renal transplantation and their AST, ALT, GGT, ALP, bilirubin levels, hepatitis, cytomegalovirus (CMV), abdominal ultrasonography, duration of hepatotoxicity, and decreased dosage or withdrawal of MMF were recorded. Also, we evaluated their liver enzymes while the patients were on the waiting list. Of the 79 patients, 11 patients (13.9%) had a progressive increase in liver enzymes. The median (min–max) age of the patients with MMF-hepatotoxicity was 29 (19–54) and 72.7% of them were male. None of the patients had hepatitis B or C, CMV infection, or other possible causes for elevated liver enzymes and their abdominal ultrasonography were normal. High liver enzyme levels regressed after the withdrawal (n = 6) or reduce dosage (n = 5) of MMF. The median time of the increase in liver enzymes was 28 (4–70) days and after 50% reduction or withdrawal of MMF, returned to normal values in 16 (4–210) days. The median levels of ALT in waiting list (I), before (II), and after (III) reduction dosage or withdrawal of MMF were 22.0 (3–22), 222.0 (51–508), and 33.0 (21–64) U/L, respectively (p I–II = 0.004, p I–II = 0.013, and p II–III = 0.005). There were no differences for ALP, GGT, total bilirubin, and direct bilirubin levels. Also, the correlation between recovery time of ALT and persistence time of ALT elevation before adjustment of MMF was significant (r = 0.739, p = 0.009). Consequently, after renal transplantation, hepatotoxicity can occur due to a lot of reason including MMF usage. If hepatotoxicity related to MMF is not considered, especially in the early period of renal transplantation, resolution of hepatotoxicity can be required long term.

Is there any relationship between serum levels of interleukin-10 and atherosclerosis in hemodialysis patients?

Objective. Cardiovascular complications due to atherosclerosis (AS) are the major cause of mortality in hemodialysis (HD) patients. Inflammation may play an important role in the development of AS. Several studies have demonstrated an association between AS and acute-phase proteins and cytokines in the general population and in HD patients. Interleukin-10 (IL-10) is an anti-inflammatory cytokine. The aim of this study was to compare serum levels of inflammatory and anti-inflammatory indicators in HD patients according to the presence or absence of AS. Material and methods. A total of 33 HD patients were studied. AS was defined as the presence of plaques as detected by Doppler ultrasonography. The patients were subgrouped according to the presence or absence of plaques. Serum levels of IL-1, -2, -6 and -10, C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α) were measured. Risk factors for AS, such as age, gender, hypertension, hyperlipidemia and duration of HD, were also evaluated. Results. Patients with AS had significantly higher high sensitivity (hs)-CRP and lower IL-10 levels. Blood pressure was also elevated in patients with AS. There was an inverse correlation between CRP and IL-10 levels in patients with AS. Conclusion. Patients with AS undergoing HD had low serum levels of the anti-inflammatory cytokine IL-10 and high serum levels of hs-CRP. These results may suggest that limitation of the anti-inflammatory response in atherosclerotic uremic patients is a triggering or contributory factor for AS.

Which Parameter Is More Influential on the Development of Arteriosclerosis in Hemodialysis Patients

Arteriosclerosis is characterized by stiffening of arteries. The incremental elastic modulus (Einc) measurement is a good marker of arterial wall stiffness. Metabolic, inflammatory and hemodynamic alterations cause structural changes and vascular complications in end stage renal disease. The aim of the present study was to evaluate the factors that may affect the development of arteriosclerosis by measurement of Einc in hemodialysis (HD) patients. Thirty-two patients (16 men; 16 female) on chronic HD with a mean age of 42.2 ± 19.3 (range: 15–80) were included in the study. The carotid Einc was measured to determine arteriosclerosis by high-resolution echo-tracking system (Acuson Aspen, Acuson Corp., Mountain View, California, USA). Einc measurement was calculated from transcutaneous measurements of common carotid arterial (CCA) internal diameter and wall thickness and carotid pulse pressure. Common carotid compliance and distensibility were determined from changes in carotid artery diameter during systole and simultaneously measured carotid pulse pressure. Common carotid artery stuffiness (Einc) was influenced by age, systolic blood pressure (SBP), pulse pressure (PP), calcium (Ca) and alkaline phosphatase (ALP). The distensibility of CCA was correlated with age, SBP, diastolic blood pressure (DBP), PP, Ca, ALP, and parathormone (PTH). The inflammatory parameter, hs-CRP, was increased with Einc. The mean Einc measurement was found significantly increased in patient receiving vitamin D. In conclusion, the stiffening of carotid artery in HD patients is related not only to hemodynamic changes (increased SBP, PP) but also to metabolic (increased Ca) and to inflammation (increased hs-CRP). Carotid Einc is accepted independent risk factor for cardiovascular mortality. Because of the positive correlation between Einc and serum Ca, vitamin D and Ca containing phosphorus (P) binders should be used carefully.

Heart Rate Variability, Left Ventricular Functions, and Cardiac Autonomic Neuropathy in Patients Undergoing Chronic Hemodialysis

Objective. Autonomic neuropathy and impairment of left ventricular functions (LVF) have been frequently encountered in chronic renal failure (CRF). The aim of the present study was to evaluate the relationship of cardiac autonomic modulation impairments, as assessed by means of heart rate variability (HRV), with clinical characteristics, and left ventricular function in the patients with CRF undergoing hemodialysis (HD). Methods. Twenty control subjects (Group I) and 22 comparable by age and gender patients with CRF undergoing hemodialysis (Group II) were enrolled in the study. After routine clinical and biochemical evaluations, electrocardiography, and 2 Dimensional, M Mode echocardiography were performed in all participants. Frequency domain HRV analysis was studied by using Kardiosis System. The powers (P1 and P2) and the central frequencies (F1 and F2) of low and of high frequency spectral bands were recorded. Results. End systolic (ESV) and end diastolic volumes (EDV) were significantly higher in Group II (59.3 ± 21.1 mL vs. 34.0 ± 14.3 mL and 131.5 ± 37.3 mL vs. 96.9 ± 18.9 mL, p<0.01, p<0.05, respectively) when compared to those of Group I. Ejection fraction (EF) and fractional shortening (FS) were significantly lower in Group II than in control subjects (52.3 ± 2.4% vs. 63.7 ± 10.1% and 0.29 ± 0.01 vs. 0.34 ± 0.07, p<0.001, p<0.05, respectively). P1 and P2 were decreased in Group II than in Group I (136.2 ± 173.9 m s2 vs. 911.0 ± 685.5 and 96.5 ± 149.6 vs. 499.7 ± 679.5, p<0.001, p<0.01, respectively). Significant correlations were found between high frequency spectral power and dialysis duration (DD), ESV, EDV, EF, FS (r = 0.52 p<0.01, r = 0.68 p<0.001, r = 0.65 p<0.002, r = 0.66 p<0.02, and r = 0.69 p<0.01). Conclusion. As a result, the dependence of cardiac autonomic neuropathy on the disease duration and degree of left ventricular function impairment was shown in the patients undergoing chronic hemodialysis.

Tissue Doppler is a More Reliable Method in Early Detection of Cardiac Dysfunction in Patients with AA Amyloidosis

Objective. Cardiac deposition of AA amyloidosis may result in increasing left ventricular mass and systolic and diastolic dysfunction (DD). The aim of this study was to investigate the left ventricular systolic and diastolic functions by both tissue Doppler imaging (TDI) and pulsed wave Doppler echocardiography (PWD) in patients with AA amyloidosis without congestive heart failure symptoms or arrthymia. Methods and Results. Twenty-four patients with AA amyloidosis without congestive heart failure symptoms or arrthymia (15 men and nine women; mean age 44.3 ± 16.7 years) and 25 healthy subjects (19 men and six women; mean age 43.1 ± 9.2 years) as controls were included in the study. M-mode, two-dimensional, PWD, and TDI were performed. Peak transmitral filling velocity (E wave), peak transmitral atrial filling velocity (A wave), deceleration time, and isovolumic relaxation time were measured by PWD recordings. Peak myocardial systolic velocity (Sm), peak myocardial early (Em), and late diastolic velocities (Am) were also recorded by TDI. E/A ratio less than one was accepted as DD for both methods. Ejection fraction (EF) was calculated by Teicholtz method. The subjects were divided into three groups as follows: healthy controls (group 1), patients without DD (group 2), and patients with DD (group 3) according to the PWD findings. PWD echocardiography showed that DD was present in 50% of the patients, whereas TDI showed DD in 66% of such cases. In subgroup analysis, Sm wave as a systolic function index was lower in group 3 than in groups 1 and 2, whereas mean EF values were similar in all groups. Conclusion. Although AA amyloidosis uncommonly causes cardiac symptoms and findings, according to our results, patients with AA amyloidosis may have systolic and diastolic dysfunction eventhough they are asymptomatic. Also, tissue Doppler imaging is a more reliable method in the early detection of cardiac dysfunction in such patients.

Outcomes of Total Parathyroidectomy with Autotransplantation versus Subtotal Parathyroidectomy with Routine Addition of Thymectomy to both Groups: Single Center Experience of Secondary Hyperparathyroidism

BACKGROUND Secondary hyperparathyroidism is a common acquired disorder seen in chronic renal failure. It may result in potentially serious complications including metabolic bone diseases, severe atherosclerosis and undesirable cardiovascular events. Parathyroidectomy is required in about 20% of patients after 3-10 years of dialysis and in up to 40% after 20 years. AIMS The aim of the current study was to evaluate the short-term and long-term outcomes of patients with secondary hyperparathyroidism who had undergone total parathyroidectomy with autotransplantation and thymectomy or subtotal parathyroidectomy with thymectomy by the same surgical team during the study period. STUDY DESIGN Retrospective comparative study. METHODS Clinical data of 50 patients who underwent parathyroid surgery for secondary hyperparathyroidism between 2003 and 2011 were reviewed retrospectively. Patients were divided into two subgroups of total parathyroidectomy with autotransplantation or subtotal parathyroidectomy. Thymectomy was routinely performed for both groups. Short term outcome parameters included intact parathyroid hormone, ionized calcium and alkaline phosphatase levels. Bone pain, bone fractures, persistent or recurrent disease were included in long term outcome parameters. RESULTS The mean duration of dialysis was eight years. The mean ionized calcium levels dropped significantly in the total parathyroidectomy with autotransplantation group (p=0.016). No serious postoperative complications were observed. Postoperative intravenous calcium supplementation was required in four patients in the total parathyroidectomy with autotransplantation group (total PTX+AT) and in three patients in the subtotal parathyroidectomy group (subtotal PTX). Postoperatively, all patients received oral calcium carbonate and calcitriol. The length of average hospital stay was 5 (3-10) days. Including nine patients who underwent successful renal transplantation pre-operative bone symptoms, hypercalcemia, hyperphosphatemia, and an increased alkaline phosphatase levels were improved or resolved in all patients. After a mean follow-up of 65 months, three patients (6%) had persistent and one (2%) had recurrent disease. CONCLUSION Total parathroidectomy with autotransplantation is a beneficial and safe surgical procedure for patients on chronic dialysis with otherwise uncontrollable secondary hyperparathroidism and even in patients who have undergone renal transplantation after parathyroidectomy. Careful cervical exploration and routine thymectomy should be considered as a routine part of the surgical approach regardless of the preferred technique.

Bone Disease in Renal Transplantation and Pleotropic Effects of Vitamin D Therapy

Osteoporosis, osteopenia, and osteonecrosis are common in renal transplant recipients. In this study, we evaluated relationship between bone mineral density (BMD) and posttransplant duration; creatinine clearance; serum levels of glucose, calcium, phosphorus, alkaline phosphatase, vitamin D (vitD), parathormone, magnesium, C telopeptide, osteocalcin, lipids, and vit D therapy. Eighty five subjects included in this study had a mean age of 36.25 ± 10.5 years. At least at 6-month intervals we measured femoral neck (FN) and lumbar vertebra (LV) by DEXA and biochemical parameters. VitD was prescribed in 57 patients (vitDG). The mean duration of posttransplantation follow-up was 9.82 ± 2.72 months. T scores (TS) of FN and LV were normal in 29.4% and 21.2%; osteopenia in 56.5% and 49.4%; and osteoporosis in 12.1% and 29.4% of patients, respectively. Upon follow-up, TS improved significantly from -1.58 to -1.46 in FN and from -1.88 to -1.70 in LV (P < .05 for both). In patients receiving vitDG, TS improved significantly from -1.74 to -1.61 on FN and from -2.16 to -1.97 on LV (P < .05 for both). Osteocalcin and vitDG levels decreased in all patients (P < .05 for all). Blood urea nitrogen and serum creatinine increased (P < .05). In VitDG cohort, triglyceride levels decreased (P < .05) with unchanged blood glucose values; but among the other patients, triglycerides were unchanged but glucose levels had increased (P < .05). Bone disease including osteopenia or osteoporosis was observed among 70%. During the follow-up period, BMD increased significantly from baseline at 9.82 ± 2.72 months. VitD therapy caused more prominent improvements in BMD and decreases in serum triglycerides as well as mutigated the increase in blood glucose.

The Relationship between the VEGF Levels and VEGF mRNA Expression and Clinical Course in Different Glomerulonephritis

In this study, serum and urinary VEGF levels and VEGF expression in PBMNC were correlated with daily proteinuria, renal function tests, and renal histopathologic findings in untreated patients with different glomerulonephritis and with the course of renal function and proteinuria for one year. Forty-five untreated patients with different glomerulonephritis and 11 healthy persons comprised the study and control groups, respectively. VEGF mRNA expression was detected by RT- PCR in peripheral blood mononuclear cells (PBMNC), and VEGF levels were measured by ELISA in serum and urine samples simultaneously. Male/female ratio was 24/21 and mean ages were 34.49 ± 14.98. Serum and urinary VEGF levels, VEGF expressions in PBMNC, and the ratios of urine VEGF/urine creatinine were found to be similar in patients and controls. There were important correlations between urinary VEGF levels and baseline serum Cr (p = 0.035) and ESR (p = 0.022). There was also a marginal correlation between urinary VEGF levels and baseline CCr (p = 0.072). There was no correlation between serum and urinary VEGF levels and PBMNC mRNA expression and pathological findings such as with or without glomerular sclerosis, tubulointerstitial fibrosis (TIF), periglomerular fibrosis, and mesangial cell proliferation in renal biopsy. Serum and urinary VEGF levels or VEGF expression in PBMNC in patients with renal amyloidosis or proliferative or nonproliferative glomerulonephritis were similar with that of healthy controls and each other. Serum and urinary VEGF levels and PBMNC VEGF mRNA expression in untreated patients with different glomerulonephritis and controls were similar. We found only one important correlation, that between urinary VEGF levels and baseline serum creatinine levels in patients with different glomerulonephritis. Urinary VEGF can be an important pathogenesis of glomerular disease or a simple proteinuria. Serum and urinary VEGF levels and PBMNC VEGFmRNA did not change by periglomerular sclerosis, periglomerular fibrosis, or tubulointerstitial fibrosis on renal biopsy. PBMNC VEGF mRNA expression decreased in patients undergoing remission. In addition to the important correlation between urinary VEGF and serum creatinine, we also found an important correlation between erythrocyte sedimentation rate and urinary VEGF. This finding was interesting because we could not find a similar conclusion in other studies.

Severe acute renal failure due to tubulointerstitial nephritis, pancreatitis, and hyperthyroidism in a patient during rifampicin therapy

It is well known that rifampicin can cause nephrotoxicity. Rifampicin-related pancreatitis and hyperthyroidism are rarely reported in the same patient in the presence of tubulointerstitial nephritis. Reported herein is the medical management of a patient with hemolytic anemia, acute renal failure, pancreatitis, and hyperthyroidism during with rifampicin therapy. A 50-year-old man was admitted to the hospital owing to abdominal colic and acute renal failure. He was treated with 2 courses of tetracycline-rifampicin for brucellosis 3 weeks and 4 months prior to admission. Physical examination showed blood pressure of 130/70 mm Hg, pulmonary crackles, and edema. Laboratory findings are detailed in the case report. Findings of abdominal ultrasonography suggested edematose pancreatitis and thyroid ultrasonography showed several solid nodules. Renal biopsy showed tubu-lointerstitial nephritis. Although rifampicin-related tubulointerstitial nephritis and acute renal failure are not uncommon during rifampicin therapy, the convergence of hyperthyroidism, pancreatitis, tubulointerstitial nephritis, and acute renal failure rarely presents in the same patient. Although pancreatitis, tubulointerstitial nephritis, and acute renal failure were ameliorated with corticoid therapy within 2 months, hyperthyroidism continued and required antithyroid therapy. In conclusion, rifampicin may trigger hyperthyroidism in patients with goiter.

Avascular Osteonecrosis and Accompanying Anemia, Leucocytosis, and Decreased Bone Mineral Density in Renal Transplant Recipients

BACKGROUND Avascular osteonecrosis (AVN) is a complication of renal transplantation. In this study, we present 12 cases of AVN associated with renal transplantation. METHODS Renal transplant recipients (RTRs) with AVN (group I [GI]) were evaluated by using magnetic resonance imaging and blood urea nitrogen, creatinine, glucose, calcium, phosphorus, magnesium, alkaline phosphatase, parathyroid hormone, and urine analysis. We evaluated bone mineral density (BMD) of the femoral neck and lumbar vertebrae. All patients were treated with steroids, cyclosporine, or tacrolimus plus mycophenolate mofetil. Twenty-six RTRs (GII) without AVN were randomly selected as control subjects. RESULTS The mean ages of GI and GII, were 33.81 ± 6.72 and 34.00 ± 7.65 years respectively (P > .05). The mean interval between transplantation and development of AVN was 12.08 ± 6.48 months. Although levels of blood urea nitrogen, creatinine, calcium, magnesium, and parathyroidhormone, as well as glucocorticoid doses in the first 12 months were similar in GI and GII, there were significant differences in serum alkaline phosphatase, hemoglobin levels, and white blood cell count between GI and GII (P < .05 for each). BMD T score <-1.5 was observed in 8/9 GI and 15/26 patients in GII. All of the patients with AVN except 1, were followed with conservative measures including calcium, magnesium, and vitamin D replacement therapies, bisphosphonate, and reduced or ceased glucocorticoid treatment. Although T scores of the femoral head were similar in GI and GII, the lumbar vertebral T score was significantly lower in GI than in GII (P < .052). CONCLUSION AVN developed within the first year after transplantation. Decreased lumbar vertebral BMD, which can be an indicator of glucocorticoid effect, accompanied AVN in nearly all patients. Despite the absence of renal dysfunction, increased bone destruction, anemia, and leucocytosis were coincidental or accompanying findings in our patients with AVN.