Sirolimus: A Switch Option for Mycophenolate Mofetil–Induced Leukopenia in Renal Transplant Recipients

Mycophenolate mofetil (MMF) is a potent immunosuppressive agent used to prevent acute and chronic rejection in kidney transplantation or for rescue therapy. One side effect of MMF is bone marrow toxicity, including leukopenia, which may necessitate drug withdrawal. We report 2 patients who underwent kidney transplantation and developed leukopenia while receiving MMF and safely switched to sirolimus. A 35-year-old woman underwent deceased donor kidney transplantation. She received basiliximab, tacrolimus, MMF, and a corticosteroid. On postoperative day (POD) 75, her white blood cell (WBC) count was 1800/μL. A 44-year-old women underwent deceased donor kidney transplantation and received basiliximab, tacrolimus, MMF, valganciclovir, and a corticosteroid. On POD 88, her WBC count was 1320/μL. MMF was switched to sirolimus, resulting in recovery of WBC count without rejection. Switch from MMF to sirolimus is safe and favorable in MMF-induced leukopenia in renal transplant recipient.     

Do Antithymocyte Globulin-Free Acute Rejection Therapies Increase the Risk of Polyoma Nephropathy in Renal Transplant Recipients?

IntroductionBK virus nephropathy is a serious complication that can lead to allograft kidney loss. Excessive immunosuppression increases the risk. We aimed to evaluate whether there is an increased risk of BK viremia and nephropathy in patients who underwent high-dose immunosuppression because of the development of acute rejection in the early period after kidney transplantation.MethodsThis retrospective cohort study was performed between April 2015 and March 2016. Twenty-nine patients who had biopsy-proven acute rejection in the first 3 months were evaluated for BK viremia and nephropathy. Thirty patients who had transplantations at the same period were the control group. Plasma BK-DNA values were examined at 1, 2, 3, 6, 9, and 12 months after the rejection treatment and at 3, 6, 9, and 12 months in the control group. Presence of polyoma nephropathy was examined with surveillance biopsies at the 6 and 12 months.ResultsAcute rejection treatment was started on the 12th day after transplantation (2–37 days). Seventeen cellular rejections and 12 humoral rejections were reported by biopsy. Two of the 12 humoral rejections were suspicious. Only pulse steroid (PS) (n = 18); PS, plasmapheresis, and intravenous immunoglobulin (n = 8); PS and intravenous immunoglobulin (n = 2); and PS and plasmapheresis (n = 1) treatments were performed. In 21 patients in the rejection group and 25 patients in the control group, BK-DNA was not positive at all. Two patients had graft loss at 11 and 36 months in the rejection group. Graft losses were secondary to rejection.ConclusionsTreatment with antithymocyte globulin-free regimens after acute rejection episodes did not lead to an increase in BK viremia.     

Cytomegalovirus Infectıon in Renal Transplant Recipients: One Center's Experience

BackgroundCytomegalovirus (CMV) is the most common opportunistic viral infection that causes morbidity, graft loss, and mortality among renal transplant recipients (RTRs). The aim of this study was to evaluate the impact of CMV infection on allograft function, graft/patient survival, and the possible asssociations between CMV infection and HLA typing.MethodThis retrospective study included 162 RTRs who had at least 1 year regular post-transplantatioin follow-up between January 2007 and December 2011. Recipients who had positive quantative CMV–polymerase chain reaction (PCR) were assigned to the study group (n = 17) and PCR-negative patients were assigned to the control group (n = 145). To determine whether CMV infection was related to HLA specificities, the incidence of CMV infection was analyzed in relation to HLA-A, -B, and -DR typing.ResultsStudy groups were similar in terms of demographic, clinical, and basal laboratory findings. Duration of dialysis before transplantation was significantly longer in this study group (P = .018). Although the total HLA mismatches of both groups were similar, we found that HLA-B51–positive recipients had a lower risk for CMV infection (P = .018). CMV infection was more frequent in patients with a double-J stent (P = .001). Although basal creatinine levels of the two groups were similar, the study group patients' creatinine levels were significantly increased during the 1-year post-transplantation period compared to controls (P = .0001). Frequency of acute rejection was significantly higher in the study group (41.2% vs 11%, P = .001). Graft loss due to any cause was also significantly higher in the study group (29.4% vs 6.9%, P = .01). Patients who had preoperative induction therapy and post-transplantatioin tacrolimus-based regimens were prone to CMV infection (P = .0001, .006).ConclusionsDespite recent advances in prophylaxis, CMV infection is still a risk factor for RTRs. According to our data, long pretransplantation dialysis duration, being HLA-B51–negative, having a double-J stent, preoperative induction therapy, and post-transplantation tacrolimus-based regimens might induce development of CMV infection by 1-year post-transplantation follow-up.     

Visceral Leishmaniasis in Renal Transplant Recipients: Report of 2 Cases

Visceral leishmaniasis is a disease caused by the protozoan Leishmania and is transmitted by Lutzomyia longipalpis (sand fly). It is an endemic parasitic infection in numerous areas around the Mediterranean basin. Though immunocompetent patients may not develop the disease, in transplant recipients the use of corticoids and intensified immunosuppressants to prevent graft rejection may accelerate the disease, causing severe damage to the liver, spleen, and hematopoietic system. We report 2 cases of visceral leishmaniasis with an atypical presentation in transplant recipients. The first patient, who had a kidney transplant, was treated successfully with liposomal amphotericin B, and the second patient, a combined kidney-pancreas transplant recipient, suffered a relapse 3 years after treatment. Visceral leishmaniasis should be considered in the differential diagnosis of pancytopenia or unexplained fever occurring after organ transplantation in patients living in endemic areas or returning from endemic countries.     

CARDIOVASCULAR AND SURVIVAL PARADOXES IN DIALYSIS PATIENTS: Is There a Reversal of Reverse Epidemiology in Renal Transplant Recipients?

Similar to the general population, cardiovascular disease is the leading cause of death in patients with a functioning renal graft. Recent studies have shown an inverse relationship between cardiovascular risk factors and outcomes in dialysis patients. Low blood pressure, low body mass index (BMI) and low serum cholesterol levels are correlated with a higher risk of adverse cardiovascular outcomes in dialysis patients. The explanation for these observations is unclear. In renal transplant recipients (RTR), these parameters are correlated with a lower risk of cardiovascular adverse outcomes, a phenomenon labeled as "reversal of reverse epidemiology." The aims of this review are: (1) to explore the association between cardiovascular risk factors and outcomes in RTR; (2) to assess whether these effects are reversal of the reverse epidemiology in dialysis predecessors; and (3) to determine the strategies for minimizing cardiovascular risk in RTR. This article also compares the determinants of cardiovascular risk factors among the general population, maintenance dialysis patients and RTR. Because definitive evidence on optimal intervention is lacking, population-specific clinical trials are needed to define optimum targets for treatment of these risk factors in maintenance dialysis patients and RTR separately.     

Transforming Growth Factor-β1 Gene Polymorphism in Renal Transplant Recipients

Background. Cytokine transforming growth factor (TGF) is involved in regulation of tissue repair after injury. More recently, TGF–β1 codon 10 gene polymorphism has been shown to be associated with circulating TGF-β levels. We tested whether TGF-β1 genotype polymorphism was predictive of renal allograft function decline. Patients and Methods. The study population consisted of 129 consecutive cadaveric or living related renal transplant recipients at our center between 1985 and 2001. The recipient TGF-β1 genotype polymorphism was determined from peripheral blood leucocytes DNA. The primary endpoint was rate of glomerular filtration rate decline between the first year and the third year of transplant. Results. Baseline glomerular filtration rate as estimated by MDRD study equation at 1 year measured 50 ± 17 mL/min/1.73 m². At the end of the 3-year follow-up period, 52 patients (40%) experienced biopsy-confirmed acute rejections. Frequency and severity of allograft rejection did not differ with TGF-β genotypes. However, the decline in glomerular filtration rate was significantly greater in Leu/Leu (TT) than Leu/Pro (CT) recipients, 6.3 ± 16.9 mL/min/1.73 m² versus 0.1±10.2 mL/min/1.73 m², p = 0.04. Conclusion. Our results demonstrate that recipient TGF-β1 codon 10 Leu/Leu homozygosity is a potential risk factor of kidney allograft function decline.     

Hepatic Metastasectomy for Soft-Tissue Sarcomas: Is It Justified?

Background   Except for patients with gastrointestinal stromal tumors (GIST), systemic chemotherapy in patients with liver metastasis of soft-tissue sarcoma (STS) is not effective. Therefore, all patients with resectable liver metastases underwent surgical therapy. We present our experience with this approach during the last 13 years. Methods   All patients (n = 45) with liver metastasis of STS undergoing surgical therapy were prospectively analyzed. Clinical and histopathological parameters as well as the postoperative course were recorded. Survival data were analyzed by using the Kaplan-Meier method and the log-rank test. Results   Twenty-seven of 45 patients with liver metastasis underwent hepatic resection; 59% of these patients had a solitary metastasis, 22% had two metastases, and 18% had three or more metastatic nodules. The surgical perioperative mortality was 7%. The median survival was 44 (range, 1–123) months, and the 5-year survival was 49%. Repeated resection for recurrent tumor was performed in eight patients, which yielded a median survival of 76 months. Conclusions   Patients who have hepatic metastases that are functionally and technically resectable should be considered for surgery because this treatment offers the chance for long-term survival (>5 years). Supported by the Günther-Haenisch Forschungs- und Studienstiftung der Vereinigung Nordwestdeutscher Chirurgen (MP).     

Endovascular Therapy: Is It Effective in the Diabetic Limb?

Reducing the risk of lower extremity amputation in diabetics is a top priority. To make progress in this area, we must bring all options to bear in the treatment of diabetic peripheral vascular disease. The "endovascular promise" of lower morbidity, while attaining the primary clinical goal (in this case, limb salvage), was late to arrive in the treatment of the ischemic diabetic lower extremity. This is due to complex and severe lesion morphologies requiring treatment, as well as the complexity of the vascular disease and the clinical scenario in diabetic critical limb ischemia. Although not without remaining challenges, significant strides have been made in the last 5 years that have increased the role of endovascular therapy in this setting.     

Is Neutrophil Gelatinase–Associated Lipocalin an Optimal Marker of Renal Function and Injury in Liver Transplant Recipients?

Background

Recently, research has focused on the association of neutrophil gelatinase–associated lipocalin (NGAL) with acute and/or active kidney injury. However, it should be remembered that NGAL is involved in iron metabolism and antimicrobial defense mechanisms.

Methods

One hundred seven consecutive liver transplant recipients were included in this study. Plasma and urine NGAL levels were measured with the use of enzyme-linked immunosorbent assay. NGAL levels were studied as plasma concentrations (pNGAL), urine concentrations (uNGAL), urinary NGAL to creatinine ratio (uNGAL/Cr), and fractional NGAL secretion (fNGAL).

Results

pNGAL was found to be inversely correlated with estimated glomerular filtration rate (eGFR) and plasma cystatine C (pCysC) (r = −0.26 and P = .007, r = −0.38 and P = .00006, respectively). uNGAL was positively correlated with urinary cystatine C to creatinine ratio (uCysC/Cr) and fractional cystatine C excretion (fCysC) (r = 0.43 and P = .000004; r = 0.4 and P = .1; respectively). uNGAL/Cr was inversely correlated with hematocrit (Htc) and hemoglobin (Hb) (r = −0.35 and P = .0002; r = −0.39 and P = .00004; respectively), and positively correlated with uCysC/Cr (r = 0.5 and P < .0000001). fNGAL was directly correlated with uCysC/Cr and fCysC (r = 0.53 and P < .0000001; r = 0.39 and P = .00005; respectively) and inversely correlated with red blood cell count (RBC; r = −0.31 and P = .001). We observed significant differences of pNGAL, uNGAL/Cr, and fNGAL between sexes, with highest values of uNGAL, uNGAL/Cr, and fNGAL in women and pNGAL in men. In multivariate regression analysis, pNGAL was positively correlated with time elapsed from liver transplantation, neutrophil count, pCysC, and sex (β = 0.36 and P = .00001; β = 0.32 and P = .0001; β = 0.58 and P < .0000001; β = 0.17 and P = .025; respectively) and inversely correlated with patient's age (β = −0.18 and P = .02) with R = 0.67 and R² = 0.45, independently from blood glucose, eGFR, RBC, white blood cell count, Hb, uCysC, uCysC/Cr, and fCysC.

Conclusions

Plasma and urine NGAL levels are strongly correlated not only with kidney function parameters, but also with red and white blood cell parameters and patient's age and sex.     

N-Terminal Pro–B-type Natriuretic Peptide Is Inversely Related to Bone Mineral Density in Renal Transplant Recipients

IntroductionBone mineral density (BMD) was significantly lower in heart failure patients. Our aim was to evaluate the relationship between BMD and fasting serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration in renal transplant recipients.MethodsFasting blood samples were obtained from 69 renal transplant recipients. BMD was measured by dual energy x-ray absorptiometry in lumbar vertebrae (L2–L4). Serum NT-proBNP levels were measured by electrochemiluminescence immunoassay.ResultsAmong the renal transplant recipients, 8 patients (11.6%) had osteoporosis and 28 (40.6%) had osteopenia; 33 had a normal BMD. Increased serum NT-proBNP (P < .001) and decreased body mass index (P = .033) and body weight (P = .010) were significantly correlated with low lumbar T-score cutoff points between groups (normal, osteopenia, and osteoporosis). Women had lower lumbar BMD than did men (P = .013). Menopause in women (P = .005), use of tacrolimus (P = .020), and use of cyclosporine (P = .046) among renal transplant recipients were associated with lower lumbar BMD. Multivariate forward stepwise linear regression analysis of the significant variables revealed that log-transformed NT-proBNP (β, ?0.545; R² = 0.331; P < .001), and body weight (β, 0.273, R² = 0.104; P = .005) were independent predictors of lumbar BMD values among the renal transplant recipients.ConclusionsSerum NT-proBNP concentrations correlate negatively with lumbar BMD values among renal transplant recipients and may be an alternative to energy x-ray absorptiometry for identifying at risk of osteoporosis in renal transplant recipients.     

Low Body Mass Index in Kidney Transplant Recipients: Risk or Advantage for Long-Term Graft Function?

OBJECTIVES: Nutritional status is known to be a marker of overall health status and a strong predictor of patient survival in several diseases. Whereas obesity is suspected to have a negative influence on general renal transplantation outcomes, the relationship between impaired nutritional status and long-term kidney graft survival is not yet clear. METHODS: We retrospectively analyzed graft survival with a follow-up time of 5 to 12.5 years among 224 kidney transplantations. A Cox proportional hazards model was applied to estimate risk factors for loss of graft function. RESULTS: The Cox model initially showed no significant influence of the body mass index (BMI) at 1 year after transplantation on the risk of transplant failure (relative risk 0.97 per BMI unit, P = .34). When the patients were divided into two groups according to BMI, a clear disadvantage was shown in terms of long-term graft survival for the groups with a low BMI. The risk of loss of transplant function increased by a factor of 1.85 (relative risk) if the BMI 1 year after kidney transplantation was less than 23 (P = .035). CONCLUSIONS: These findings suggested impaired long-term kidney graft survival among patients with reduced nutritional status. This result is assumed to reflect improved immune function due to reduced nutrient availability, thus leading to reinforcement of chronic rejection processes. This assumption is consistent with the already known immunomodulatory effect of caloric restriction to mitigate T-cell activation.     

Donors With Immune Thrombocytopenia: Do They Pose a Risk to Transplant Recipients?

Transplant‐mediated alloimmune thrombocytopenia (TMAT) from donors with immune thrombocytopenia (ITP) can result in significant bleeding complications in the recipient. The risk to a recipient of TMAT if they receive an organ from a donor with ITP is unknown. The outcomes of recipients of organs from deceased donors with ITP recorded in the UK Transplant Registry between 2000 and 2015 were reviewed. Twenty‐one deceased organ donors had a predonation diagnosis of ITP. These donors were significantly more likely to have died from intracranial hemorrhage than were all other deceased organ donors (85% vs. 57%, p < 0.001). Organs from donors with ITP resulted in 49 organ transplants (31 kidney, 14 liver, four heart), with only one case of TMAT, which occurred in a liver transplant recipient and resulted in death from bleeding complications 18 days posttransplantation. The recipient of a kidney from the same organ donor was not affected. Unadjusted 5‐year patient and graft survival was significantly worse for liver transplant recipients from donors with ITP compared with liver transplant recipients from donors without ITP (64% vs. 85%, p = 0.012). Organs from donors with ITP may be considered for transplantation, but livers should be used with caution.     

Is Screening for IgG Antibody to Cytomegalovirus and Epstein-Barr Virus Infections Mandatory in Potential Renal Transplant Recipients and Donors in Iran?

Objective

Cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV) infections in renal transplant recipients may cause significant morbidity and mortality. To manage these infections, established guidelines suggest that both the recipient and the donor be routinely tested for anti-CMV and anti-EBV antibodies prior to renal transplantation. The aim of this study was to assess the value of screening among people living in Iran.

Patients and Methods

We retrospectively analyzed the incidences of CMV and EBV infections among 925 and 710 potential renal allograft donors and recipients, respectively, between 2005 and 2008. All cases were first transplantations. Enzyme-linked immunosorbent assays (ELISA) were performed to determine whether there were antibodies to CMV (IgG) or EBV viral capsid antigen (VCAIgG). Finally, we analyzed the seroprevalence and demographic factors.

Results

Five hundred sixty-eight (61.40%) potential renal transplant donors and 483 (68.02%) potential renal transplant recipients were men. Donor ages ranged from 18 to 50 years (mean ± SD, 34.7 ± 8.1 years) and recipient ages ranged from 18 to 60 years (mean ± SD, 45.9 ± 7.3 years). Pretransplant CMV (IgG) and EBV (VCAIgG) seroprevalence was 100% among all donor, and recipient ages and sexes.

Conclusion

Our findings suggested that kidney transplant centers in Iran do not need to perform routine screening for IgG antibodies to CMV and EBV among renal transplant recipients and donors of ages ≥18 years.     

Improvement of Blood Pressure Control in Renal Transplant Recipients—Retrospective Longitudinal Study

Background

Hypertension is a very common complication in renal transplant recipients (RTRs). It has been identified as a potent cardiovascular risk factor associated with impaired patient and graft survival.

Is Early COVID-19 in Kidney Transplant Recipients Concerning Enough to Halt Transplantation? A Multicenter Comparative Analysis from India

BackgroundLimited data exist on the incidence and outcome of early coronavirus disease 2019 (COVID-19) in kidney transplantation recipients (KTR).MethodsA retrospective multicenter research study was conducted across 12 centers in India. We explored the symptomatology, demographic, laboratory findings, and outcome of COVID-19 within 30 days of transplantation. The outcome was compared with the overall KTR and waitlisted patients acquiring COVID-19.ResultsThe incidence of early COVID-19 was 2.6% (n = 22) for the cumulative 838 renal transplants performed since nationwide lockdown in March 2020 until May 2021. Overall, 1049 KTR were diagnosed with COVID-19 and 2% of those had early COVID-19. The median age of the early COVID-19 cohort was 43 (31-46) years. COVID-19 severity ranged from asymptomatic (18.2%), mild (59.1%), moderate (9.1%), and severe (13.6%). Among clinical symptoms, dyspnea and anosmia were frequent, and in laboratory parameters, neutrophil lymphocyte ratio, high-sensitivity C-reactive protein, and D-dimer were higher in patients requiring oxygen. The mortality in early COVID-19 was not higher than overall KTR (4.5% vs 8.5%; P = 1). COVID-19 severity (23.9% vs 15.7%; P = .0001) and mortality (15.5% vs 8.5%; P = .001) among waitlisted patients (n = 1703) were higher compared with overall KTR.ConclusionsWe report higher burden of COVID-19 in waitlisted patients compared with KTR and a favorable outcome in early COVID-19 in KTR. Our report will help the transplant physicians in dealing with the ongoing dilemma of halting or resuming transplantation in the COVID-19 era.     

Long-Term Outcomes of Pancreas After Kidney Transplantation in Small Centers: Is It Justified?

Background

Currently, the long-term advantages of having a pancreas transplantation (PT) are debated, particularly in patients receiving pancreas after kidney (PAK) allografts. The United Network for Organ Sharing (UNOS) requires that a transplant center perform a minimum number of PT per year to remain an active PT center. The long-term outcomes and challenges of PAK in small pancreas transplant centers are not well studied.

Methods

In this retrospective analysis, we report short- and long-term outcomes in a small center performing 2–9 PT annually.

Results

Forty-eight PT (25 simultaneous pancreas and kidney transplantation [SPK], 23 PAK) were performed in our center. Donor and recipient demographics were similar in both groups. All suitable local donors were used for SPK. All organs for PAK transplantation were imported from other UNOS regions. Mean follow-up was 61 ± 46 and 74 ± 46 months for SPK and PAK, respectively. Patient and graft survival rates were similar in SPK and PAK groups and better than the reported national average. Four patients (11%) died (1 due to trauma, 1 brain lymphoma, 1 ruptured aneurysm; and 1 unknown cause). Two patients (4%; 1 SPK, 1 PAK) lost their grafts because of thrombosis on postoperative days 3 and 5 in 2002. No graft thrombosis occurred since 2002. Seven patients (15%) required reoperation (4 for bleeding, 2 anastomotic leaks, 1 small bowel perforation). Two patients (4%) developed post-transplantation lymphoproliferative disease. Five patients (11%) experienced cytomegalovirus antigenemia which responded well to antiviral therapy.

Conclusions

Compared with outcomes for diabetic patients on dialysis, current SPK and PAK short- and long-term results are favorable even in a small PT center. Therefore, unless there is a contraindication, PT should be offered to all type 1 diabetic patients with end-stage renal disease at the time of kidney transplantation or afterward.     

Axillary Node Staging for Microinvasive Breast Cancer: Is It Justified?

Background

The natural history and role of axillary staging in microinvasive breast cancer (DCISM) remains controversial. We report clinical characteristics and outcome in patients with DCISM, focusing on the role of sentinel lymph node (SLN) biopsy.

Methods

From our prospective database we retrospectively identified 112 patients with DCISM who underwent SLN biopsy between 1996 and 2004 at our institution. Median follow-up was 6?years.

Results

We found positive SLN in 12?% of patients (14 of 112): macrometastasis in 2.7?% (3 of 112) and micrometastases or isolated tumor cells (ITC) in 10?% (11 of 112). We performed axillary dissection (ALND) in all patients with macrometastasis (3 of 3), finding additional positive nodes in 66?% (2 of 3), and in 27?% of those with micrometastases/ITCs (3 of 11), finding no additional positive nodes. Among 98 patients with negative SLN (38?% of whom received systemic therapy), there were 5 locoregional recurrences (1 in the ipsilateral axilla, 4 in the ipsilateral breast, all DCIS) and 4 contralateral second primary cancers. Among 14 patients with positive SLN (82?% of whom received systemic adjuvant therapy), there were no locoregional or distant recurrences.

Conclusions

Our results suggest that SLN biopsy may be justified for DCISM, but is clearly most beneficial to identify a very small subset of DCISM patients (2.7?%, with SLN macrometastasis) who could benefit from systemic adjuvant therapy. The benefit of SLN biopsy for patients with SLN micrometastases/ITCs (pN0mi or pN0(i+)) is uncertain, and in these cases ALND does not appear to be warranted. We suggest a wider reappraisal of routine SLN biopsy for DCISM.