Comparing Plasmapheresis plus IVIg with Plasmapheresis plus IVIg plus Rituximab on the Management of Suspicious Antibody-Mediated Acute Rejection in Kidney Transplant Recipients.

BACKGROUND: There is no treatment of choice for the management of acute antibody-mediated rejection (ABMR) in kidney transplant recipients. Plasmapheresis ± intravenous immunoglobulin (IVIg) ± rituximab has been used in different regimens with contradictory results. OBJECTIVE: To compare three regimens of acute ABMR management including plasmapheresis + IVIg ± rituximab in two different rituximab regimens. METHODS: In this prospective, observational study kidney transplant recipients with suspicious ABMR were categorized into three groups. Group 1 patients were treated with plasmapheresis + IVIg. Groups 2 and 3 received weekly rituximab at a dosage of 375 mg/m2 for either 4 doses (group 2 or high dose) or 2 doses (group 3 or low dose) in addition to plasmapheresis + IVIg. RESULTS: 8, 15, and 9 patients were categorized in groups 1, 2, and 3, respectively. There was no difference among the groups in terms of demographic and clinical characteristics of recipients and donors. Although, 1-year graft (37.5%, 60.0%, and 66.7% for groups 1, 2, and 3, respectively; p=0.308) and patients survival (75.0%, 86.7%, and 77.8% for groups 1, 2, and 3, respectively; p=0.730) were not significantly different among studied groups, graft survival was 22%-30% higher in rituximab-treated groups. Estimated glomerular filtration rate at 12th month of follow-up did not differ among groups (56.3±19.6, 57.3±20.6, 48.7±16.1 mL/min/1.73 m2 for groups 1, 2, and 3, respectively; p=0.683). However, kidney function steadily improved over time in rituximab-treated patients. CONCLUSION: Adding high or low doses of rituximab to plasmapheresis + IVIg comparably increased graft survival in suspicious acute ABMR kidney recipients and steadily improved kidney function among survived allografts over time.

Tacrolimus interaction with oral oestrogen in kidney transplant recipients: A case-control study.

WHAT IS KNOWN AND OBJECTIVE: Oestrogens could inhibit the metabolism of drugs, such as calcineurin inhibitors, that are substrates for cytochrome P-450 microsomal enzymes. This study assessed the potential tacrolimus interaction with oral conjugated oestrogen in kidney transplant recipients who received conjugated oestrogen as prophylaxis against bleeding, before kidney biopsy. METHODS: In this case-control study, 13 kidney transplant recipients who received oral conjugated oestrogen as prophylaxis against uraemic bleeding before allograft biopsy were considered as cases. Thirteen matched kidney transplant recipients with similar immunosuppressive regimen served as controls. In this study, comparisons were made between the groups regarding daily dose, blood trough concentrations and calculated concentration corrected for dose of tacrolimus at three time points of the study. RESULTS AND DISCUSSION: All patients in the case group received conjugated oestrogen at a dose of 3.75 mg/day for 4.78 ± 0.83 days. Without any change in tacrolimus dose, the blood concentration of tacrolimus increased during concomitant administration of conjugated oestrogen (from 8.10 ± 2.85 to 12.35 ± 4.62 ng/mL; P = .11) and decreased after cessation of conjugated oestrogen (6.07 ± 2.18 ng/mL; P = .015). The calculated concentration corrected for dose of tacrolimus increased from 127.04 ± 79.23 to 211.40 ± 146.38 ngmLmgkg/d after conjugated oestrogen administration (P = .036). Thereafter, it decreased to 108.55 ± 78.61 ngmLmgkg/d after cessation of oestrogen (P = .003). Only one patient experienced nausea while taking oestrogen without any change in her liver enzymes. WHAT IS NEW AND CONCLUSION: Concomitant administration of oral oestrogen increased tacrolimus blood concentration. Hence, it is necessary to monitor tacrolimus blood levels during concomitant oestrogen therapy and for several days after oestrogen withdrawal.

Plasma Neutrophil Gelatinase-Associated Lipocalin as a Marker for Prediction of 3-Month Graft Survival after Kidney Transplantation.

BACKGROUND: Ischemic injury during organ transplantation increases the risk of acute and chronic rejections by promoting alloimmune responses. Measurement of neutrophil gelatinase-associated lipocalin (NGAL) immediately after kidney transplantation may be promising for early detection of ischemic injuries to allograft. OBJECTIVE: This study assessed possible predictive values of plasma NGAL levels during first hours after kidney transplantation for graft loss within the first 3 months after transplantation. METHODS: 45 kidney transplant recipients were classified into those without graft loss or with graft loss during 3 months after transplantation. Plasma NGAL levels were measured before and at 2, 6, 12, 24 and 96 hours after transplantation. Serum creatinine concentration was assessed daily during hospitalization and at 1, 2, and 3 months post-transplantation. RESULTS: Serum creatinine and plasma NGAL levels were consistently higher in patients with graft loss compared with those without graft loss. At 2, 24, and 96 hours after transplantation, plasma NGAL concentration was significantly higher in patients who developed allograft loss within 3 months post-transplantation. The cutoff point of plasma NGAL at 2, 24, and 96 hours after transplantation for prediction of graft loss was 304.5 ng/mL (sensitivity of 71.4%, and specificity of 73.7%), 207.8 ng/mL(sensitivity of 85.7%, and specificity of 60.5%), and 184 ng/mL (sensitivity of 85.7%, and specificity of 71.1%), respectively. CONCLUSION: Plasma NGAL levels at 2, 24, and 96 hours after transplantation can predict 3-month graft loss with fair sensitivity and specificity.

Tacrolimus Dose Requirement in Iranian Kidney Transplant Recipients within the First Three Weeks after Transplantation.

BACKGROUND: Tacrolimus is the main immunosuppressive agent in many kidney transplant protocols with an initial recommended daily dose of 0.2 mg/kg of ideal body weight (IBW). However, due to the high inter- and intra-patient variability in its pharmacokinetics, the required tacrolimus doses may differ markedly from patient to patient. OBJECTIVE: To assess the required tacrolimus dose to achieve the desired whole blood concentration within the first three weeks after kidney transplantation among Iranian patients. METHODS: This cross-sectional study was performed at kidney transplantation ward of Imam Khomeini Hospital Complex where almost all patients receive thymoglobulin induction therapy and a calcineurin inhibitor, mainly tacrolimus, plus mycophenolate, and prednisolone as maintenance immnosuppressive drugs with the target tacrolimus whole blood concentration of 8-12 ng/mL for the first month after transplantation. RESULTS: The mean±SD administered daily dose of tacrolimus during the first three weeks after transplantation was 0.085±0.024 mg/kg of IBW that resulted in a mean±SD whole blood concentration of 10.34±5.44 ng/mL. The required mean±SD dose of the drug to achieve the desired whole blood level of 8-10 ng/mL was 0.08±0.02 mg/kg. Only 27.4% of the assessed tacrolimus blood levels were within the desired range. Compared with males, females needed 19% more daily dose of tacrolimus to reach similar whole blood levels. Tacrolimus blood levels were significantly correlated with daily tacrolimus doses (r=0.307, p=0.001) and patients' age (r=0.283, p=0.003). CONCLUSION: It seems that Iranian kidney transplant recipients need lower daily doses of tacrolimus to achieve the desired whole blood levels; compared with males, females need a higher dose.

Carotid intima-media thickness as a marker of atherosclerosis in hemodialysis patients.

Atherosclerotic changes in carotid arteries of hemodialysis (HD) patients reflect global atherosclerotic changes in vasculature. Carotid intima-media thickness (CIMT) can be used for atherosclerosis prediction and assessment of cardiovascular risks in HD patients, and thus screening high-risk patients. In this cross-sectional study, CIMT was measured using ultrasonography (B-mode with 5-10-MHz multifrequency linear probe) in HD patients in our hospitals. Additionally, we assessed the relationship between their CIMT and some cardiovascular risk factors. A total of 62 HD patients (64.5% male) were included. Age, body mass index, low-density lipoprotein, fasting blood sugar, history of diabetes mellitus and cardiovascular disease, serum albumin, and duration and adequacy of HD in study patients had significant association with their CIMT. There were no significant relationships between CIMT and patient's gender, smoking, serum calcium, phosphate, calcium x phosphate product, hemoglobin, and uric acid level. More diagnostic modalities must be performed for detecting the impact of atherosclerosis on HD patients with high CIMT.

Genetic analysis of Iranian autosomal dominant polycystic kidney disease: new insight to haplotype analysis.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) caused by mutations in two PKD1 and PKD2 genes. Due to the complexity of the PKD1 gene, its direct mutation screening is an expensive and time-consuming procedure. Pedigree-based haplotype analysis is a useful indirect approach to identify the responsible gene in families with multiple affected individuals, before direct mutation analysis. Here, we applied this approach to investigate 15 appropriate unrelated ADPKD families, selected from 25 families, who referred for genetic counseling. Four polymorphic microsatellite markers were selected around each PKD1 and PKD2 loci. In addition, by investigating the genomic regions, two novel flanking tetranucleotide STR markers were identified. Haplotype analysis and calculating Lod score confirmed linkage to PKD1 in 9 families (60%) and to PKD2 in 2 families (13%). Linkage to both loci was excluded in one family (6.6%). In 2 families (13%) the Lod scores were inconclusive. Causative mutation was identified successfully by direct analysis in two families with confirmed linkage, one to PKD1 and another to PKD2 locus. The study showed that determining the causative locus prior to direct mutation analysis is an efficient strategy to reduce the resources required for genetic analysis of ADPKD families. This is more prominent in PKD2-linked families. Selection of suitable markers, and appropriate PCR multiplexing strategy, using fluorescent labeled primers and 3 primer system, will also add value to this approach.

The role of neutrophil-gelatinase-associated lipocalin in early diagnosis of contrast nephropathy.

Neutrophil-gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury. The aim of this study was to define a cut-off for NGAL in the early diagnosis of contrast-induced nephropathy (CIN) in patients with normal kidney function. We enrolled 121 patients with normal serum creatinine who underwent coronary angiography. NGAL was measured in urine before the procedure and 12 and 24 h afterward. CIN was defined as a 0.3 mg/dl increase in serum creatinine within 48 h after the procedure. Seven of 121 patients had CIN (5.8%). The NGAL levels in the 12- and 24-h urine samples of these patients were 30 (5-45) and 20 (15-40) ng/ml, respectively, whereas those in patients without CIN were 15 (5-45) and 15 (10-51) ng/ml, respectively (P = 0.8). In patients with CIN, the sensitivity and specificity of NGAL with a cut-off of 22.5 ng/ml were 71.4% and 57.9% in 12-h urine samples, with the negative predictive values (NPV) and positive predictive values (PPV) of 97.1% and 9.4%, respectively. In conclusion, we suggest that urine NGAL with cut-off point of 22.5 ng/ml has acceptable sensitivity and specificity for early diagnosis of CIN in patients with normal serum creatinine, but regarding NPV and PPV the best performance of this value is to rule out the CIN in patients at risk who received contrast media.

Quality and Quantity of Health Evaluation and the Follow-up of Iranian Living Donors.

BACKGROUND: Shortage of donors is the main obstacle in organ transplantation. In renal transplantation living donation is the key solution for removing this barrier. The Iranian model of kidney transplantation has been faced with many challenges, but there are limited reports about the depth of evaluation and outcome of donors. This study was conducted to assess the quality and quantity of donors' health evaluation before donation and their follow-up afterward. METHODS: With assistance of the Iranian Kidney Foundation, we accessed the contact information of living donors through the years 2001-2012. We tried to contact donors who have donated at least 2 years before the survey. We interviewed these donors according to a questionnaire that was approved by the ethics committee of the research deputy of Tehran University of Medical Sciences. The collected data were analyzed using the SPSS software version 20. RESULTS: The contact data of 388 donors were available but we were able to contact only 60 donors. We found that 40% of donors had been informed about the risks and benefits of donation. Also, 11% of donors had not had a full physical examination and in 5% even blood pressure was not measured before donation by the transplantation team. The donors reported that 34% of them had not been educated on how they should follow up their health status and 50% of the donors did not have any follow-up after donation. CONCLUSION: In the Iranian model of transplantation the donors are the neglected victims of renal transplantation and this model should be revised immediately, concerning both the medical and ethical issues.

Comparison of Serum Neutrophil Gelatinase-associated Lipocalin (NGAL) with Serum Creatinine in Prediction of Kidney Recovery after Renal Transplantation.

BACKGROUND: Because of some insult to kidney during transplantation, assessment of kidney function after the procedure is essential. It would be ideal to find a marker better than creatinine to early predict the acute kidney injury. OBJECTIVE: To compare with creatinine the predictive value of serum neutrophil gelatinase-associated lipocalin (NGAL) in detecting kidney recovery after renal transplantation. METHODS: We studied 33 patients who received kidney transplantation (deceased [n=20] and live [n=13]) during a 6-month period in 2010. Serum NGAL and creatinine, hemoglobin, and blood glucose were measured at 0, 12, 24, 48, and 72 hours after transplantation. The need for dialysis and kidney function in one week were studied. RESULTS: There were 16 men and 17 women with the mean±SD age of 36.3±12.2 (range: 14-58) years. Of the studied patients, 6 had delayed graft function (DGF; hemodialysis within the first week of transplant); 9 had slow graft function (SGF; serum creatinine reduction from transplantation to day 7 <70%), and 23 had immediate graft function (IGF; reduction in serum creatinine ≥70%). At any time, serum NGAL, and creatinine levels were significantly higher among patients with DGF (p=0.024) and SGF (p=0.026) compared with those with IGF. However, in those who got IGF vs non-IGF, serum creatinine levels were not significantly different (p=0.59) but serum NGAL levels differed significantly(p=0.020). Receiver-operating characteristic (ROC) curve and area under curves (AUCs) of serum NGAL and serum creatinine levels on the first post-transplantation day had similar significance in predicting the patient's need to dialysis in the first week. However, using AUC of serum creatinine was not helpful in predicting non-IGF, compared to serum NGAL. The AUCs of the serum NGAL were 0.70 (95% CI: 0.52-0.89) and 0.76 (95% CI: 0.59-0.93) after 12 and 24 hours, respectively (p<0.05). The highest AUC (0.82) was attributed to serum NGAL of 24 hour (p=0.002). CONCLUSION: Serum NGAL level especially 24 hours post-transplantation, seems to be an early accurate predictor of both the need to dialysis and slow graft function within the first week of kidney transplantation.

Posttransplant diabetes mellitus: incidence and risk factors.

OBJECTIVE: Posttransplant diabetes mellitus (PTDM) is a common and serious complication of renal transplantation. Estimates of the incidence of PTDM after renal transplantation vary between 2% and 54%. The aim of the present study was to evaluate the incidence and risk factors for PTDM among our renal transplant patients. PATIENTS AND METHODS: In this study we evaluated 121 nondiabetic patients with end-stage renal disease (ESRD) who underwent kidney transplantation for the first time at our centers since 2005. All patients received the same protocol of immunosuppressive therapy. PTDM was defined according to the clinical practice recommendations of the American Diabetes Association. RESULTS: At 12 months following renal transplantation, 9.9% of patients developed PTDM. Patients with PTDM were significantly older (P = .013) and had higher body mass index (P = .001). There were significant differences (P

Infertility among female renal transplant recipients.

We studied 122 women with renal allograft transplantation to evaluate their reproductive systems. The patients were recruited from the three main kidney transplant surgery centers in Tehran, from September to October 2005. Fifteen (12%) patients were either in the menopausal stage or had hysterectomies, and the other 33(27%) were unmarried. Of the 76(62%) married women at the reproductive age, 10 (13.1%) had infertility that was defined as the failure of a married woman to conceive after 12 months of frequent intercourse without contraception. Three patients had male factor infertility, three others had ovulatory problems, and four cases were undefined. Only six cases were actively treated by ovulation induction +/- an intrauterine inducer (IUI); two patients became pregnant, while the other four refused infertility treatment. The reasons of unwillingness for infertility treatment included old age (40 years) in one patient, positive HBsAg in one, renal retransplantation in one, and previous clomiphene therapy failure in another. We conclude that the prevalence of infertility among female renal transplant recipients is the same as the general population, and the causes are mostly treatable. However, many are less motivated to be treated for this problem.

Renal allograft accumulation of technetium-99m sulfur colloid as a predictor of graft rejection.

Differentiation between rejection (the most common cause) and many other possibilities for detrimental effects on graft function represents a difficult issue to diagnose the cause of renal allograft dysfunction. This study was designed to determine whether technetium-99m sulfur colloid (TSC) accumulation predicted graft rejection. We prospectively studied 54 episodes of allograft dysfunction in 53 kidney transplant recipients who underwent TSC scintiscanning and graft biopsy. Visual analysis of TSC uptake compared uptake, in the allograft with that in the marrow of the fifth lumbar vertebra (L5). A 3+ result meant that allograft uptake was greater than L5 marrow uptake; 2+, the same; 1+, less and finally 0, no allograft uptake. Transplant accumulation of 2+ or more was considered consistent with rejection (P = .01). Allograft biopsies interpreted based on the Banff Working Classification showed rejection in 45 of 54 renal biopsies with 42 the biopsy-proven rejection episodes showing at least 2+ graft uptake. Furthermore, this nuclear medicine technique had a sensitivity of 93.3%, a specificity of 44.4%, a positive predictive value of 89.3%, a negative value of 57.1% and an efficiency of 83.3% for the diagnosis of renal allograft rejection.

Value of pretransplantation cytokine profiles for predicting acute rejection in renal transplant recipients.

Episodes of acute rejection may represent an important risk factor for the development of chronic allograft nephropathy. Various studies have shown that pretransplant cytokine profiles in recipient blood are associated with transplant outcome. Serum samples were collected 24 hours before transplantation from 57 patients (38 men and 19 women of age 36 +/- 5 years) receiving kidneys from unrelated living donors. Additional samples were collected at 1 and 2 weeks after transplantation, as well as during every rejection episode. The immunosuppression consisted of a cyclosporine, prednisolone, and mycophenolate mofetil. Among the transplanted patients, 19 (33.3%) individuals experienced an acute rejection episode based on an increased level of serum creatinine and blood urea nitrogen during the first 14 days after transplantation. TGF-beta, IL-2 and IFN-gamma serum levels were determined by an ELISA method using Bindermed system kits. The mean concentration of TGF-beta before transplantation tended to be lower among patients with acute rejection episodes compared to those with stable graft (75,265 versus 85,394 pg/mL; P = .34) and at 1 week after transplantation (77,558 versus 84,390 pg/mL), although the differences were not significant. Among patients with rejection the mean IL-2 concentration was significantly higher before, at 1 week, and at 2 weeks after transplantation (15.0 versus 6.8 pg/mL, P = .005; 19.0 versus 4.9 pg/mL, P = .001; and 21.1 versus 4.7 pg/mL, P = .0001). The mean concentration of IFN-gamma was significantly higher pre- and at 1 and 2 weeks posttransplantation in patients with acute rejection episodes (161.1 versus 65.2, 175.6 versus 66.5 and 173.7 versus 77.1 pg/mL, all P < .001). In conclusion, evaluation of Th1 cytokines before transplantation may represent valuable predictive marker for an acute rejection episode.

Impact of Ramadan fasting on renal allograft function.

Fasting during the holy month of Ramadan is a religious duty for all healthy adult Muslims. They are only allowed to eat and drink between sunset and dawn. This study was designed to find the effect of Ramadan fasting on allograft function. We prospectively studied 19 kidney transplant recipients who voluntarily chose to fast during Ramadan versus 20 matched recipients, who had not fasted for 3 consecutive years. Data were recorded before, during, and after the fasting month. The mean posttransplant periods in the fasting and control groups were 52.6 +/- 30.3 and 56.6 +/- 30.0 months, respectively. A statistical analysis showed no significant changes in serum creatinine concentrations before and after Ramadan 1.07 +/- 0.24 versus 1.08 +/- 0.22 mg/dL (P > .05) and 1.00 +/- 0.24 versus 1.03 +/- 0.28 mg/dL (P > .05) in fasting and control groups, respectively. The results did not show any adverse effects of fasting in recipients with stable renal function. In conclusion, our study suggests that fasting during the month of Ramadan is safe and has no significant harmful effects on kidney transplant recipients with normal renal function.

Fertility and contraceptive issues after kidney transplantation in women.

PURPOSE: Our purpose was to investigate reproductive performance among kidney transplant recipients. MATERIALS AND METHODS: We studied 126 kidney transplanted women 15 to 68 years of age including 33 who were single and 93 who were married. RESULTS: Infertility was seen in 10.4% of those who desired pregnancy, a rate similar to the general population. The most common method of contraception was coitus interruptus (56%), 22% of patients had tubal ligation, 6% had husbands who had vasectomies, 14% were using condoms, and only 2% used oral contraceptives. Among 33 pregnancies, 16 were unintended (48.5%). Most of the patients with unwanted pregnancy were using coitus interruptus (93.7%). In the group with unintended pregnancy, abortion was induced in three, spontaneous abortion or intrauterine fetal death occurred in six, and only seven pregnancies resulted in a live birth (43.7%). CONCLUSION: Kidney transplantation greatly improves fertility, so those who do not desire pregnancy should be protected by an effective method of contraception.