T. Colak

Percutaneous Therapy of Ureteral Obstructions and Leak After Renal Transplantation: Long-Term Results

The purpose of this study was to evaluate the long-term outcome of percutaneous therapy of ureteral complications after renal transplantation. Between January 2000 and June 2006 we percutaneously treated 26 renal transplant patients with ureteral obstruction (n=19) and leak (n=7). Obstructions were classified as early (<2 months after transplantation) or late (>2 months). Patients with leak were treated with nephro-ureteral catheter placement and subsequent double-J stenting. Balloon dilatation, stent placement, and basket extraction were used to treat ureteral obstructions. Patients were followed with ultrasonography. No major procedure-related complication occurred. The mean follow-up time was 34.3 months (range: 6 to 74 months). Initial clinical success was achieved in all 19 patients with obstruction and 6 of 7 patients with leak. Four of 9 early obstructions and 4 of 10 late obstructions recurred during the follow-up. All recurrences were initially managed again with percutaneous methods, including cutting balloon technique and metallic stent placement. Although there was no recurrence in patients with successfully treated leak, stricture was seen at the previous leak site in two patients. These strictures were also successfully managed percutaneously. We conclude that in the treatment of ureteral obstruction and leak following renal transplantation, percutaneous therapy is an effective alternative to surgery. However, further interventions are usually needed to maintain long-term patency.

Conversion to Sirolimus for Chronic Allograft Nephropathy and Calcineurin Inhibitor Toxicity and the Adverse Effects of Sirolimus After Conversion

BACKGROUND Chronic allograft nephropathy and calcineurin inhibitor toxicity may cause graft loss. After kidney transplantation, especially among those patients with chronic allograft nephropathy, sirolimus may be a good alternative to calcineurin inhibitors. Unlike calcineurin inhibitors, sirolimus is devoid of significant nephrotoxicity, but approximately 30% to 50% of patients on sirolimus therapy display mild or severe adverse effects. We sought to report our experience with sirolimus conversion among patients with chronic allograft nephropathy as well as the mild versus severe adverse effects that limit the drugs use. MATERIALS AND METHODS We analyzed the outcomes of 88 patients (64 men and 24 women) of overall mean age of 35.9 +/- 9.9 years (range, 21-59 years) who had undergone kidney transplantation. Immunosuppressive therapy had been converted from a calcineurin inhibitor to sirolimus because of biopsy-proven chronic allograft nephropathy, calcineurin inhibitor toxicity, or presence of malignancy. We excluded patients with prior acute rejection episodes. Subjects were divided into two groups with respect to their creatinine levels: Group A < 2 mg/dL and Group B >or= 2 mg/dL. After conversion to sirolimus, possible adverse effects of sirolimus were evaluated at the follow-up inset. Each patient underwent a physical examination, and estimation of serum lipid and electrolyte levels as well as hemoglobin concentration. RESULTS At the time of conversion of the 88 renal transplant patients, their mean duration after grafting was 48 +/- 15 months (range, 4-296). The prior treatment consisted of a calcineurin inhibitor, prednisolone, and mycophenolate mofetil. After conversion, the calcineurin inhibitor was stopped and sirolimus was begun. The 48 Group 2 patients (34 men, 14 women) of overall mean posttransplant time of 22.7 +/- 14.6 months who underwent conversion displayed a mean serum creatinine increase to 3.2 +/- 1.4 mg/dL, including 17 subjects who underwent rejection. The 40 Group 1 patients (30 men, 10 women) with a mean overall posttransplant period of 67.6 +/- 49.9 months showed an fall in serum creatinine level to 1.4 +/- 0.5 mg/dL among only 3 patients. While 5/88 patients showed no increase in proteinuria (5.6%); 83 (94.4%) did experience it. Proteinuria increased from a mean of 192 +/- 316 to 449 +/- 422 mg/d. Only three patients displayed heavy proteinuria (>3 g/d); sirolimus was discontinued for this reason. Proteinuria was well controlled in the other patients with angiotensin-converting enzyme and/or angiotensin II receptor inhibitor agents. After sirolimus conversion, serum cholesterol levels increased from 187 +/- 42 to 214 +/- 52 mg/dL, and serum triglyceride levels increased from 161 +/- 61 to 194 +/- 102 mg/dL. All but four patients responded to statin therapy, with serum lipid levels falling to acceptable levels. Another four patients developed unilateral lower extremity edema with sirolimus discontinued for this reason. One patient displayed generalized arthralgia. CONCLUSION Chronic allograft nephropathy or calcineurin inhibitor toxicity can lead to loss of graft kidney function. Calcineurin inhibitor toxicity can lead to chronic allograft nephropathy. Patients with a low baseline serum creatinine level who undergo sirolimus conversion showed stabilized kidney function. Late conversion of patients with a serum creatinine above 2 mg/dL face a risk of graft failure. Sirolimus displayed a limited incidence of serious adverse effects; mild or moderate adverse effects, such as hyperlipidemia and proteinuria, were easily controlled with countermeasure therapy.

Memokath Metallic Stent in the Treatment of Transplant Kidney Ureter Stenosis or Occlusion

PurposeTo determine the efficacy of the Memokath 051 stent (Engineers & Doctors, Hornbaek, Denmark) in the treatment of recurrent ureteral stenosis or occlusion in transplant kidneys.MethodsFrom October 1985 through January 2004, 1,131 renal transplantations were performed at our center. Four patients who developed recurrent renal transplant ureter obstruction had nephrostomy catheters placed. Antegrade pyelography showed ureteral stenosis in three cases and complete occlusion in one patient. In each case, a Memokath 051 stent was inserted via an antegrade approach. Mean follow-up was 20 months (range 18–21 months). Creatinine levels were measured and ultrasonography was performed during follow-up.ResultsAll stent procedures were technically successful. During follow-up, one stent migrated within 10 days after stent insertion and was removed cystoscopically. Another stent had to be removed in the 14th month due to resistant infection, and was replaced with a new Memokath 051 stent which remained patent for another 8 months. The other two stents were fully patent at the 18th and 21st month of follow-up, respectively.ConclusionPlacement of a Memokath 051 stent appears to be a promising treatment alternative to balloon dilation, double-J stents and open surgical intervention for ureteral stenosis or occlusion in kidney transplant recipients. Further study of larger series is necessary.

Influence of 1,25-Dihydroxyvitamin D3 on Human Leukocyte Antigen-DR Expression, Macrophage Infiltration, and Graft Survival in Renal Allografts

Vitamin D plays an important role in the regulation of cellular growth and cell proliferation as well as exerting immunoregulatory activities. We sought to show the influence of vitamin D on renal graft survival. Among 102 patients, 40 were treated with vitamin D (group D) and the remaining 62 cases were not, forming a control group (group C). We studied human leukocyte antigen (HLA)-DR expression on tubules, interstitial cells, peritubular capillaries (PTCs), and evaluated macrophage infiltration of the interstitium and the PTCs. Compared to group C, group D patients showed fewer acute rejection episodes. Compared to group C patients group D patients showed significantly lower degrees of tubular and interstitial HLA-DR expression as well as interstitial and PTC macrophage infiltration. In addition in the PTC, HLA-DR expression was greater and therefore PTC destruction less in group D patients (P<.001). Twenty-seven (43.5%) of 62 group C patients lost their grafts at 29.2±15 months, whereas only 7/40 (17.5%) group D patients lost their grafts at 43.2±13 months. A significant difference was noted between the two groups in regard to the time of graft loss (P<.01). Testing vitamin D therapy along with several other covariates showed an independent effect on 5-year graft survival (P<.001). These data confirmed that vitamin D therapy shows an independent positive impact on long-term graft survival, which may be explained by its immunosuppressive effects of to reduce renal HLA-DR expression and renal macrophage infiltration and in turn mitigate PTC destruction. In conclusion, these results highlighted the potential use of vitamin D in renal allograft patients.

Effect of Amyloidosis on Long-Term Survival in Kidney Transplantation

Amyloidosis is characterized by the accumulation of an amorphous material in various organs and tissues secondary to a variety of inflammatory, immune, infectious, and hereditary diseases. Since 1975, our transplantation team has performed 1470 renal transplantations. Between 1985 and July 2004, among 1159 kidney transplantations, 953 (82.3%) were from living donors and 206 (17.7%) from cadaveric donors. There were 32 recipients (28 men, 4 women; mean age, 31.4 +/- 1.7 years; range, 21 to 48 years) with amyloidosis, including, 28 (87.5%) who received grafts from living donors and 4 (12.5%) from cadaveric donors. Amyloidosis was secondary to familial Mediterranean fever in 22 (68.7%) patients and rheumatoid arthritis in 1 (3.1%). The remaining 9 (28.1%) patients had primary amyloidosis. The mean follow-up time was 51.2 +/- 5.7 months (range, 2-124 months). Mean HLA mismatch rate was 2.2 +/- 1. Twenty-six (81.2%) patients are alive at this time with functioning grafts, and a mean serum creatinine value of 2.1 +/- 1.5 ng/dL. The 1- and 5-year patient and graft survival rates were 90.6% and 84.3%, and 81.2% and 68.7%, respectively. We conclude that patients with amyloidosis may undergo kidney transplantation safely expecting outcomes similar to those patients who receive transplantations for other reasons.

Pulmonary complications in renal recipients after transplantation.

BACKGROUND Renal transplantation is the most common type of solid organ transplantation. Recipients are susceptible to a variety of pulmonary complications, in particular during intense immunosuppression therapy. OBJECTIVE To evaluate pulmonary complications during the first year after renal transplantation. MATERIALS AND METHODS Medical records were reviewed retrospectively for all patients who underwent renal transplantation between 2007 and 2010. Data pertinent to pulmonary complications were obtained including patient demographics, findings at chest radiography and pulmonary function testing, concentrations of C-reactive protein and albumin, and white blood cell count. RESULTS The study included 136 patients (71.3% men), with mean (SD) age of 36.3 (12.2) years. The most frequently prescribed immunosuppression therapy included prednisolone plus cyclosporine, tacrolimus, or rapamycin. Fifteen patients developed complications during the first year after surgery including respiratory infections in 12 (80%), namely, bacterial pneumonia in 10 (66.6%), and tuberculosis (caused by Mycobacterium tuberculosis) in 2 (33.3%). Pneumonia developed within the first 5 months after transplantation in 6 patients, and tuberculosis after the third month. Microbiologic agents were detected in 3 of the 6 patients (20%), and empyema, postoperative atelectasis, and pulmonary embolism, respectively, in the other 3 patients. No association was observed between complications and baseline pulmonary function test results. C-reactive protein concentration was significantly increased in patients with pulmonary complications. No invasive procedures were performed to diagnose complications, all of which resolved with appropriate treatment. CONCLUSION Pulmonary infections are a primary complication in renal transplant recipients, and are observed most frequently in the first 6 months after surgery. Immunosuppression therapy is the most likely cause of these complications, and rigorous monitoring of drug concentrations is essential. An invasive diagnostic approach may not always be necessary to determine the early specific therapy.

Hepatitis B virus reactivation after renal transplantation: report of two cases

Recovery from acute hepatitis B virus (HBV) infection is associated with the loss of HBV DNA and hepatits B surface antigen (HBsAg) together with the development of antibodies against HBsAg (anti-HBs), HB ‘e’ antigen (anti-HBe) and HBcore antigen (anti-HBc). Individuals with serological markers implying past exposure to HBV are generally believed to have cleared the virus and also to have acquired protective immunity. However, clinical observation has shown that individuals with such a constellation may nevertheless develop the reactivation of HBV infection spontaneously or under immunosuppression. We describe two recipients of a renal transplant who exhibited prior serologic resolution of HBV infection and in whom HBsAg reappeared 10 and 9 months after renal transplantation, respectively. A 35-year-old woman presented with chronic renal failure of unknown etiology requiring dialysis for 2 years. Serologic test results revealed a prior HBV infection that had apparently resolved (HbsAg-negative, anti-HBcIgG and anti-HBs-positive) on admission. The patient’s antiHBs titer was 12 IU/ml, and serum HBV DNA level was not assessed at the time of transplantation. She underwent kidney transplantation from her brother, whose serologic testing was negative for HBV. Ten months after transplantation, she demonstrated the elevated levels of aspartate-aminotransferase (AST) 87 IU/ml and alanineaminotransferase (ALT) 133 IU/ml. Viral markers became positive for HBsAg, HBeAg and HBV DNA (by hybridization) but became negative for anti-HBe and anti-HBs. Liver biopsy revealed a mild degree of active hepatitis without fibrosis and immunohistochemical staining indicated the presence of HBsAg in hepatocytes. Lamivudine treatment was initiated. After 2 months of lamivudine treatment, AST and ALT levels were increased to 105, 193 IU/ml respectively, HBeAg became negative, anti-HBe became positive. Two months later, AST and ALT levels returned to normal and serum HBV DNA became negative with hybridization (Fig. 1). A 24-year-old man exhibited renal failure that had been treated with hemodialysis for 4 years. On admission and also at the time of renal transplantation, the test results for HBsAg were negative and that for anti-HBs, and antiHBcIgG were positive. The patient’s anti-HBs titer was 33 IU/ml at the time of transplantation. Serum HBV DNA levels were not assessed before and at the time of transplantation. He underwent a kidney transplantation from his father, whose serologic results were negative for HBsAg, anti-HBs, and anti-HBcIgG. Early rejection of the transplant (detected by renal biopsy) was treated with pulse steroid treatment. On follow-up 9 months later, liver function and serologic test results were as follows: AST, 54 IU/ml and ALT, 58 IU/ml, HBsAg positive, antiHBs and HBV DNA negative. Thirteen months after transplantation, AST and ALT levels were increased to 60 and 105 IU/ml, respectively and serum HBV DNA level became positive with hybridization (quantitatively > 0.5 pg/ml was accepted as positive). Liver biopsy revealed a mild degree of chronic active hepatitis without fibrosis, and immunohistochemical staining revealed HBsAg in all hepatocytes. Lamivudine treatment was initiated. After 6 months of lamivudine treatment, serum testing for HBV DNA yielded a negative result, and liver function tests returned to normal range (Fig. 2). In our report, both patients had experienced the HBV infection in past silently and they were not treated for HBV infection before the transplantation. For both patients, immunosuppression was not tapered after the diagnosis of hepatitis B reactivation. The possibility of occult HBV infection after complete clinical recovery from acute hepatitis is a known entitity, which suggests possible viral reactivation from occult HBV infection in the presence of anti-HBc and anti-HBs during long-term immunosuppressive therapy after renal transplantation [1,2]. The re-emergence of HBV infection in our cases might have been caused by reactivation of a latent infection or by a new HBV infection. If we had performed HBV DNA measurements at the time of transplantation and if we had got positive HBV DNA levels with low titers, the problem with our cases would be easier with being occult HBV infection. But as we did not perform serum HBV DNA level measurements for both patients at the time of the transplantation, and we were not able to compare the HBV strain identified in each patient’s initial infection with the strain detected after

Posttransplant proteinuria is associated with higher risk of cardiovascular disease and graft failure in renal transplant patients.

In this study, we sought to determine whether proteinuria after renal transplantation was associated with cardiovascular disease (CVD), patient survival, and long-term allograft survival. One hundred twenty-six patients included 102 males and 24 females of mean age 30.7 +/- 8.9 years. Their mean follow-up was 63.21 +/- 19.9 months. All patients were evaluated for CVD, namely, ischemic heart disease, cerebrovascular disease, and peripheral vascular disease. Proteinuria was defined as urinary protein >or=500 mg/d which persisted for >6 months after transplantation. We retrospectively examined pre- and posttransplant data, including sex, age at transplantation, smoking, pretransplant dialysis duration, donor status, number of acute rejection episodes, body mass index, systolic and diastolic blood pressure levels, lipid profile and other biochemical parameters, immunosuppressive regimens, as well as pulse steroid dose. Proteinuria was significantly associated with CVD (P = .001; RR = 6.43; confidence interval [CI] 2.15-19.22). Patients with proteinuria showed significantly lower graft survival rates than those without proteinuria (58.62% vs 80.41%; P = .02). The mean time to appearance of proteinuria was 14.1 +/- 11.4 months (range, 1-36 months). There was no significant association between proteinuria and patient survival. Patients with persistent proteinuria displayed a greater number of acute rejection episodes (1.20 +/- 1.17 vs 0.62 +/- 0.85; P = .004) and higher pulse steroid dosages (4380.0 +/- 3123.4 vs 2800.0 +/- 2766.7; P = .022). In conclusion, persistent proteinuria is a strong risk factor for CVD among renal transplant patients. Therefore, an etiologic search and antiproteinuric strategy should be considered routinely to improve patient and graft outcomes.

Relationship of Renal Resistive Index and Cardiovascular Disease in Renal Transplant Recipients

BACKGROUND Cardiovascular disease is the primary cause of death in renal transplant recipients, and elevated renal allograft resistive index (RI) has been associated with patient survival. OBJECTIVE To evaluate the predictive value of intrarenal RI on atherosclerotic disease. PATIENTS AND METHODS Ninety-seven patients who had undergone renal transplantation between 1999 and 2001 and had stable renal function were included in the study. Patients with renal artery stenosis, urinary tract obstruction, clinical symptoms of acute rejection, or chronic allograft nephropathy were excluded. Clinical and laboratory information was obtained from the medical records and included demographic data, medications used, body mass index, blood pressure, and laboratory values. Intrarenal RI and carotid intima-media thickness (IMT) were determined using Doppler ultrasonography. RESULTS At linear regression analysis, RI was significantly correlated with recipient age, C-reactive protein concentration, systolic blood pressure, pulse pressure, body mass index, smoking, and carotid IMT. At multivariate linear regression analysis, only pulse pressure was an independent predictor of intrarenal RI. CONCLUSION Intrarenal RI is associated with traditional cardiovascular risk factors and carotid IMT. Elevated intrarenal graft RI may be predictive of cardiovascular disease in renal transplant recipients without complications.

Comparison of Basiliximab and Daclizumab With Triple Immunosuppression in Renal Transplantation

PURPOSE Graft rejection is a serious problem despite immunosuppressive agents. Immunosuppression has been achieved with monoclonal antibodies (mAb) that bind specifically to the α subunit of the interleukin (IL)-2 receptor present on activated T lymphocytes. We explored the effects of two of the mAbs-daclizumab and basiliximab-on graft function. MATERIALS AND METHODS Our 1543 renal transplant recipients received baseline therapy with cyclosporine or tacrolimus plus corticosteroids and mycophenolate mofetil. In addition standard dosages intravenously of daclizumab (n=156) or basiliximab (n=45) in were administered intravenously to 201 renal transplant patients who included 122 men and 79 women of overall mean age of 30±13.7 years. RESULTS Patient and donor characteristics including age, sex, causes of renal failure, presence of comorbidities, panel-reactive antibodies, and numbers of human leukocyte antigen-mismatched were similar between the groups. During a mean follow-up of 27±20 months, biopsy-proven acute rejection was observed in three patients in the basiliximab group and 23 in the daclizumab group. Cytomegalovirus infection occurred in 13 patients. There was no case of posttransplant lymphoproliferative disorder. Three polyoma BK nephropathies were detected in the daclizumab group. No hypersensitivity reaction occurred in either group. One-year patient survival was 100% in the basiliximab group and 99% in the daclizumab group, with graft survivals of 95% versus 94%, respectively. The mean creatinine levels at discharge were 2 mg/dL versus 2.3 mg/dL and at 12 months, 1.3 mg/dL versus 1.2 mg/dL, respectively. CONCLUSIONS Acute rejection episodes remain a significant risk factor for the development of graft dysfunction and poor long-term graft survival. IL-2R antagonists were effective antibody therapies. There was no apparent difference between basiliximab and daclizumab treatment.