Zeynep Kendi Celebi

Urinary Angiotensinogen Level Is Correlated with Proteinuria in Renal Transplant Recipients

OBJECTIVE Along with immunologic mechanisms, intrarenal renin-angiotensin system (RAS) activation has been suggested to play a role in the development and progression of chronic allograft injury. In various glomerular diseases, urinary angiotensinogen (AGT) level is a good indicator for the activation of intrarenal RAS. In this study, we aimed to investigate the parameters associated with urinary AGT level in patients with kidney transplantation. METHODS Seventy renal transplant patients with stable graft function (≥ 6 months after transplantation, serum creatinine level <2 mg/dL) and 21 healthy volunteers were included in the study. Patients were taking standard triple immunosuppressive treatment. Demographic characteristics of patients and healthy volunteers, drug use, and 24-hour ambulatory blood pressure measurements were recorded. Morning second urine and fasting blood samples were taken from all participants. Serum biochemical markers and urine Na, K, uric acid, creatinine, and protein levels were measured. Urinary AGT levels were determined by enzyme-linked immunosorbent assay. RESULTS Mean systolic and diastolic blood pressures in patients with renal transplantation were higher than in healthy volunteers. Both urinary AGT-urinary creatinine ratio (UAGT/UCr) and urinary protein-urinary creatinine ratio (UPro/UCr) were higher in kidney transplant patients than in healthy volunteers (P < .01; P < .0001; respectively). In patients with renal transplantation, UAGT/UCr was positively correlated with UPro/UCr and negatively correlated with estimated glomerular filtration rate (eGFR) (r = 0.738; P = .01; and r = -0.397; P = .01; respectively). There was no correlation between UAGT/UCr and other study parameters, including bood pressure levels. CONCLUSIONS Our findings indicate that high urinary excretion of AGT is associated with proteinuria and lower eGFR in kidney transplant recipients without overt chronic allograft injury. These preliminary results encourage us to design a long-term longitudinal analysis using urinary AGT along with multiple markers to obtain early diagnosis and to predict the prognosis of chronic allograft dysfunction.

Pregnancy After Kidney Transplantation: Outcomes, Tacrolimus Doses, and Trough Levels.

Although pregnancy after kidney transplantation has been considered as high risk for maternal and fetal complications, it can be successful in properly selected patients. It is well known that pregnancy can induce changes in the plasma concentrations of some drugs; however, there has been very limited information about tacrolimus pharmacokinetics during pregnancy. In this study, we evaluated the tacrolimus doses, blood levels, and the outcomes of pregnancies in kidney allograft recipients. From 2004 to 2014, we found 16 pregnancies in 12 kidney allograft recipients at our center. We reviewed the files and data reports including fetal outcomes, graft function, complications, tacrolimus trough levels, and doses. We analyzed the tacrolimus trough levels and doses before pregnancy, during pregnancy (monthly), and in the postpartum period. Throughout the pregnancy, we aimed to achieve tacrolimus trough levels between 4 and 7 ng/mL. All patients were on triple immunosuppression, including tacrolimus, azathioprine, and prednisolone. In total, 11 of 16 (68.7%) pregnancies were successful, with a mean weight gain of 12.5 ± 1.66 kg. One patient developed gestational diabetes mellitus and 2 had preeclampsia. Although 5 of 11 babies were found to have low birth weight, 4 of these were premature. Two patients lost their grafts, 1 due to acute rejection and the second due to progression of chronic allograft dysfunction. We have shown that tacrolimus doses need to be significantly increased to keep appropriate trough levels during pregnancy (the doses: before, 3.20 ± 0.9 mg/day; first trimester, 5.03 ± 1.5; second trimester, 6.50 ± 1.8; third trimester, 7.30 ± 2.3; post-partum, 3.5 ± 0.9). In conclusion, the dose of tacrolimus needs to be increased to provide safe and stable tacrolimus trough levels during pregnancy. Although pregnancy can be successful in most cases, it should be kept in mind that there is an increased risk of maternal and fetal complications, including allograft loss, low birth weight, spontaneous abortus, and preeclampsia.

Evaluation of Infectious Complications in the First Year After Kidney Transplantation

Kidney transplantation (KT) is the best available therapy for patients with end-stage renal disease. Infectious complications are a common cause of morbidity and mortality. In this study, we evaluated the risk factors and outcomes of infectious complications in the first year after transplantation. This is a retrospective and observational study of kidney transplant recipients at Ankara Universitys Ibni Sina Hospital between January 2009 and August 2013. A total of 206 kidney transplant recipients were evaluated. In 129 patients, 298 infectious episodes occurred: 55 (26.7%) had 1; 33 (16%) 2; 19 (9.2%) 3; 7 (3.4%) 4; and 15 (7.3%) had 5 or more infectious episodes. The most common bacterial infection was urinary tract infection (128, 42.9%). Only 4 urinary tract infection episodes (3.1%) were associated with bacteriemia. Seventeen patients (5.7%) had bacteremia. Viral infections after transplantation were CMV infection (10.1%), BK virus infection (5.7%), and zona zoster (1.1%). Deceased donor kidney transplantation was the independent risk factor. Mean follow-up period was 66 months and was the same for the patients with and without infections. There was no significant difference in 5-year survival and creatinine levels at the last follow-up (logrank P = .409). Infections are the second most common cause of mortality in KT patients. The successful treatment of these complications and effective prophylaxis may decrease these complications.

Kidney Transplantation in Immunologically High-Risk Patients

An increased number of sensitized patients await kidney transplantation (KTx). Sensitization has a major impact on patient mortality and morbidity due to prolonged waiting time and may preclude live donor transplantation. However, recent reports have shown that KTx can be performed successfully using novel immunosuppressive protocols. This study presents our experience with patients displaying donor-specific antibody (DSA) (+). We enrolled 5 lymphocyte cross-match (LCM) negative (complement-dependent cytotoxicity) and panel-reactive antibody (PRA) plus DSA-positive patients mean fluorescein intensity [MFI] > 1000) who underwent living kidney donor procedures. All subjects were females and their mean age was 36.7 years. In our protocol, we started mycophenolate mofetil (2 g/d), tacrolimus (0.01 mg/kg) and prednisolone (0.5 mg/kg) on day -6. We performed 2 sessions of total plasma exchange (TPE) with albumin replacement and administered 2 doses of IVIG (5 g/d). On day -1, we added rituximab (200 mg). On the operation day and on day +4, the patients received doses of basiliximab. Serum samples were taken on days -6, 0, and 30 as well as at 1 year after transplantation. All patients displayed immediate graft function. Mean basal DSA titer was 5624 MFI. After desensitization, the MFI titers decreased at the time of transplantation to 2753 MFI, and were 2564 MFI at the 1st month and 802 MFI at 1st year. Three patients experienced acute rejection episodes (60%). After treatment for rejection, the average follow-up was 17 months and last creatinine levels were 0.6-0.8 mg/dL (minimum-maximum). In conclusion, KTx can be succesfully performed in sensitized patients displaying DSA. However, there seems to be a greater acute rejection risk. There is no consensus regarding adequate doses of IVIG or plasmapheresis treatments; furthermore, more studies are needed to clarify the safe MFI titer of the DSA.

Colchicine levels in chronic kidney diseases and kidney transplant recipients using tacrolimus.

Tacrolimus is a CYP3A4 inhibitor and can alter colchicine metabolism. In this study, we aimed to evaluate plasma colchicine levels in different stages of kidney disease as well as in kidney transplant (KTx) recipients using tacrolimus.

Urgency Priority in Kidney Transplantation: Experience in Turkey

BACKGROUND In Turkey, according to the directions of National Organ and Tissue Transplant Coordination System, a system has been established since 2008 of urgency priority for kidney transplantation in cases with imminent lack of access for either hemodialysis or peritoneal dialysis. In this study, we compared patient and graft outcomes between patients on the national waiting list having urgency priority for kidney transplantation (UKT) and those having the other kidney from the same deceased donor (control group). METHODS We examined retrospective data of patients, who underwent transplantation under urgency priority allocation in Turkey from 2010 to 2014 and compared that group with other patients receiving kidney transplants from the same deceased donors (control group). Then we compared these patients for early and long-term patient and graft outcomes. RESULTS Forty-seven patients had UKT, and 40 patients received transplants from the same deceased donors. Mean follow-up of patients after transplantation was 18 ± 12 months. Eight patients with UKT and 4 patients in the control group lost their grafts. At follow-up, 7 patients died in the UKT group, and 4 patients died in the control group. Patient survival in the UKT group was 90% at 1 year and 83% at 2 years, and in the control group was 93% at 1 year and 84% at 2 years (P = .384). Graft survival was 87% at 1 year and 81% at 2 years in UKT, and 91% at both 1 and 2 years in the control group (P = .260). CONCLUSIONS Although patients with UKT showed lower graft and patient survivals than the control group, the difference was statistically nonsignificant. UKT can be an obligatory treatment model for patients with lack of vascular or peritoneal access for dialysis.

Kidney Transplantation from Hepatitis B (HB)–Positive Donors to HB Negative Recipients: Anti–HB Core Immunoglobulin G Became Positive in All Recipients After the Transplantation

OBJECTIVE Hepatitis B surface antigen (HBsAg)-positive donors are not accepted by many transplant centers as a kidney source owing to risk of transmission of hepatitis B; however, some reports show that these donors can be used under a special protocol. Herein, we report our cases of kidney transplantation from HBsAg(+) donors to HbsAg(-) recipients. METHODS In the years 2010-2012, we transplanted 4 kidneys from 4 HBsAg(+) donors to HBsAg(-) recipients. They were all living related. All antiHBs(-) recipients were vaccinated before transplantation and became HBsAg(-), anti-HB core immunoglobulin G antibody negative [antiHBcIg(-)], and antiHBs(+). Pretransplantation antiHBs titers were targeted to be >100 IU. If lower, hepatitis B Ig was used at the time of transplantation. One patient received hepatitis B Ig at the time of transplantation (owing to titer of 62 IU/L antiHBs). Lamivudine was prescribed for all kidney allograft recipients after transplantation. RESULTS Two patients had special induction treatment including rituximab, intravenous immunoglobulin, and plasmapheresis owing to the presence of donor-specific antibody. CONCLUSIONS All patients became antiHBcIgG(+) at 1-6 months after the transplantation, despite the presence of antiHBs positivity, which might be explained by transmission of hepatitis B virus through the graft.

Colchicine-induced rhabdomyolysis following a concomitant use of clarithromycin in a haemodialysis patient with familial Mediterranean fever

Sir, Renal amyloidosis secondary to familial Mediterranean fever (FMF) is one of the common causes of nephrotic syndrome and chronic kidney disease in Turkey [1]. Colchicine is a microtubule-depolymerizing drug widely used for the treatment of gout which may prevent the development of secondary amyloidosis. In end-stage renal disease (ESRD), although the dose of colchicine is suggested to be reduced, there is limited information on efficacy and safety [2]. Inappropriately high doses or co-prescription of CYP3A4 or P-glycoprotein inhibitors have been reported to cause serious adverse effects, including death [3–7]. Herein, we present a case of colchicine-induced rhabdomyolysis after using clarithromycin, a macrolide antibiotic and a potent inhibitor of CYP3A4 and P-glycoprotein ABCB1. A 40-year old male patient on maintenance haemodialysis was admitted with recently developed fatigue, anorexia, headache, dizziness, diffuse myalgia and gastrointestinal symptoms including epigastric pain, diarrhoea and bloating. He presented with FMF in childhood (with frequent attacks of fever and abdominal pain with arthritis) and had developed secondary amyloidosis 10 years previously and ESRD 6 months previously. His long-term medication was colchicine 0.5 mg twice daily, doxazosin 4 mg once daily and 40 mg furosemide on non-dialysis days and sevelamer 1600 mg three times a day. A further history revealed that the patient had recently been diagnosed with acute sinusitis and was prescribed clarithromycin 500 mg twice daily in another hospital a week beofore. On his initial examination the patients blood pressure was 100/60 mmHg, he was in a euvolaemic state and had no significant finding except diffuse tenderness, but there was no rebound on abdominal palpation. In his biochemistry, his creatine kinase (CK)(5732 U/L- 9035 U/L) and transaminase levels (ALT:110 U/L, AST:309 U/L) were elevated and raised upon follow-up. Due to high CK and transaminases, colchicine-induced rhabdomyolysis was diagnosed and colchicine discontinued. The patients pain subsided 3 days after discontinuation of colchicine. An EMG was performed because of high levels of CK to exclude the diseases causing myopathie. During outpatient follow-up, the patients transaminases and CK returned to normal levels and his EMG was normal. After complete recovery, the patient started colchicine 0.5 mg/day again without recurrence of symptoms.

Effect of unilateral nephrectomy on urinary angiotensinogen levels in living kidney donors: 1 year follow-up study

Background: Urinary angiotensinogen (uAGT) has recently been proposed as a marker of kidney injury and activated intrarenal renin–angiotensin system. We investigated the effects of living donor nephrectomy on uAGT levels, blood pressure, estimated glomerular filtration rate, proteinuria and compensatory hypertrophy in the remaining kidney of living kidney donors. Methods: Twenty living kidney donors were included in the study and followed for 1 year. uAGT levels were measured with enzyme-linked immunosorbent assay preoperatively and postoperatively at the 15th day, 1, 6 and 12 months. Results: Four donors were excluded from the study due to lack of data. The mean baseline estimated glomerular filtration rate was 98 ± 15 ml/min/1.73 m². Serum creatinine, uAGT/creatinine, uAGT/protein levels were higher and estimated glomerular filtration rate was lower than baseline values at all time periods. Urinary protein/creatinine levels increased after donor nephrectomy, but after 6 months they returned to baseline values. Renal volume increased after nephrectomy, but these changes did not show any correlation with uAGT/creatinine, uAGT/protein, estimated glomerular filtration rate or systolic/diastolic blood pressures. uAGT/creatinine at 6 months and urinary protein/creatinine ratio at 12 months showed a positive correlation (P=0.008, r=0.639). Conclusion: After donor nephrectomy, increasing uAGT levels can be the result of activation of the intrarenal renin–angiotensin system affecting the compensatory changes in the remaining kidney. The long-term effects of increased uAGT levels on the remaining kidney should be examined more closely in future studies.

Kidney biopsy in AA amyloidosis: impact of histopathology on prognosis

Abstract In AA amyloidosis, while kidney biopsy is widely considered for diagnosis by clinicians, there is no evidence that the detailed investigation of renal histopathology can be utilized for the prognosis and clinical outcomes. In this study, we aimed to obtain whether histopathologic findings in kidney biopsy of AA amyloidosis might have prognostic and clinical value. This is a retrospective cohort study that included 38 patients who were diagnosed with AA amyloidosis by kidney biopsy between 2005 and 2013.The kidney biopsy specimens of patients were evaluated and graded for several characteristics of histopathological lesions and their relationship with renal outcomes. Segmental amyloid deposition in the kidney biopsy was seen in 29%, global amyloid deposition in 71, diffuse involvement of glomeruli in 84.2%, focal involvement in 7%, glomerular enlargement in 53%, tubular atrophy in 75% and interstitial fibrosis in 78% of patients. Histopathologically, glomerular enlargement, interstitial fibrosis, tubular atrophy, interstitial inflammation and global amyloid deposition were significantly associated with lower estimated glomerular filtration rate (eGFR) (p = .02, p < .001, p = .001, p = .009, p = .002, respectively) in univariate analysis. In multivariate analysis, tubular atrophy was the only predictor of eGFR (p = .019 B = −20.573). In the follow-up at an average of 27 months, 18 patients developed end-stage renal disease (ESRD). Among them, global amyloid deposition was the only risk factor for the development of ESRD (p = .01, OR = 18.750, %95 CI= 2.021–173.942). This is the first study showing that the histopathological findings in kidney biopsy of AA amyloidosis might have a prognostic and clinical value for renal outcomes.