The place of sirolimus in kidney transplantation: can we reduce calcineurin inhibitor renal toxicity?

Sirolimus, a macrocylic lactone, blocks T-cell activation by a mechanism of action distinct from calcineurin inhibitors (CNIs). Therefore, it may be expected that sirolimus would display a safety profile without the vasomotor form of nephrotoxicity characteristic of CNIs. Initial studies in rodent models and in psoriasis patients showed that sirolimus alone did not impair renal function. Subsequently, two pivotal, randomized double dummy, phase III trials in human renal transplantation demonstrated that sirolimus exacerbated the nephrotoxicity of full doses of CNIs. Both pharmacokinetic and pharmacodynamic mechanisms have been implicated in the pathogenesis of this disorder. Subsequent experience has shown that cyclosporin A dose reduction, elimination, or avoidance mitigates these effects, particularly in patients distant from the transplant procedure. However, there is concern about recovery from ischemia-reperfusion injury. Animal models suggesting that sirolimus may delay recovery in this setting have been supported by non-randomized experiences at single centers, which have observed an increased incidence of delayed graft function among sirolimus-treated recipients. In contrast, large single- and multi-center studies have not confirmed this finding; impaired renal recovery has been observed in only occasional instances. Thus, present data indicate that sirolimus does not impair the function of an uninjured kidney, but whether the drug acts alone or potentiates conditions that delay recovery after ischemic injury remains to be established by large randomized trials specifically targeted to recipients at high risk for this complication.     

Does the calcineurin inhibitor have influence on cytomegalovirus infection in heart transplantation?

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality in heart transplant (HTx). Our aim was to analyze the rate of CMV infection in HTx patients receiving treatment with cyclosporine (CsA) or tacrolimus (Tac). Ninety‐five patients were randomized to receive either CsA (53.7%) or Tac (46.3%). We performed prophylaxis with valganciclovir in patients with the highest risk of CMV infection. We considered CMV infection as an increased viral load or the presence of CMV in histological samples. We analyzed baseline characteristics, CMV infection, and other complications. Event‐free rates were calculated using the Kaplan‐Meier method. There were no significant differences in baseline characteristics between both groups. CMV infection was detected in 31.6% of patients (in 66.7% due to asymptomatic replication). The group treated with Tac had a lower rate of CMV infection (15.9% vs. 45.1%, p = 0.002) and longer CMV infection‐free survival time (1440 vs. 899 d, p = 0.001). No differences were observed in the complications analyzed in both groups. The independent risk factors for infection identified in the multivariate analysis were treatment with CsA and bacterial infections. This was the first study to demonstrate a lower rate of CMV infection in patients treated with Tac vs. those treated with CsA after HTx.     

Which calcineurin inhibitor is preferred in renal transplantation: tacrolimus or cyclosporine?

Cyclosporine and tacrolimus are potent inhibitors of the calcineurin-dependent cytokine synthesis in activated lymphocytes. In renal transplant patients tacrolimus is more powerful in preventing severe and refractory rejections, even when compared with the new cyclosporine microemulsion formulation. Both drugs are equally nephrotoxic, but tacrolimus induces less hypertension and less pronounced hyperlipidaemia. Especially in some categories of patients, a higher incidence of de-novo diabetes mellitus is seen with tacrolimus therapy.     

Prevention: can we stop problems before they arise?

It is estimated that 50% of diabetic ulcerations and amputations can be prevented by identifying the at-risk foot and implementing preventative strategies. Patients with diabetes mellitus (DM) should be screened and placed in the appropriate risk category. Risk factors for the development of ulcer in several prospective studies include neuropathy, deformity, limited joint mobility, vascular disease, and history of previous ulceration or amputation. Early identification of the at-risk foot and placing the patient in the appropriate risk category is essential to prevention. Once the at-risk foot is identified, abnormal foot pressures should be reduced or eliminated using several treatment options. Repetitive, moderate mechanical stress (the pressure time integral) is often the initial mechanism of injury in the formation and/or recurrence of diabetic foot ulcers. Once conservative treatment options to off load the foot have failed, surgery should be considered. There are patients with diabetic foot ulcers for whom a combination of surgery (intrinsic off loading) and extrinsic off loading is better than either method alone. These difficult wounds are characterized by a combination of variables acting singularly or together, such as neuropathy, rigid deformity, limited joint mobility, and activity level. Our experience dictates, patients with rigid deformity and limited joint mobility get caught in the cycle of repetitive stress and cannot break the cycle until the etiology of the structural deformity is addressed surgically and preventative strategies for off loading, temperature monitoring, and activity level are implemented. If a structural deformity exists, the deformity will delay or prevent healing of the ulcer. Once the ulcer is healed, the likelihood for recurrence is high unless the deformity is corrected. When a structural deformity exists, the patient should be referred for evaluation and possible prophylactic surgery.     

TB and HIV: how can we reduce mortality?

Despite ART scale‐up, tuberculosis (TB) remains a leading cause of HIV‐related deaths worldwide and much of this disease may remain unascertained. In patients receiving ART, TB incidence is highest during the first few months of treatment (many cases of which were prevalent disease missed by baseline screening) and long‐term rates remain several‐fold higher than background. We identify three groups of patients starting ART for which different interventions are required to reduce TB‐related deaths. First, diagnostic screening is needed in patients who have undiagnosed active TB so that timely anti‐tuberculosis treatment can be started. This may be greatly facilitated by new diagnostic assays such as the Xpert MTB/RIF assay and a novel point‐of‐care urine test for lipoarabinomannan (LAM). Second, patients with a diagnosis of active TB need optimised case management, which includes early initiation of ART (with early timing now defined by randomised controlled trials), trimethoprim‐sulphamethoxazole prophylaxis and treatment of co‐morbidity. Third, in high TB burden settings, all remaining patients who are TB‐free at enrolment have high ongoing risk of developing TB and require optimised immune recovery (with ART ideally started early in the course of HIV infection), isoniazid preventive therapy and infection control to reduce infection risk. Further specific measures are needed to address multi‐drug resistant TB (MDR‐TB) and there are now new promising developments in antimycobacterial agents. Finally, in high burden settings, scale‐up of all these interventions requires nationally and locally tailored models of care that are patient‐centred and provide integrated health care delivery for TB, HIV and other co‐morbidities.     

Domino liver transplantation: how far can we push the paradigm?

Domino liver transplantation (DLT) has emerged as a strategy for increasing the number of liver grafts available: morphologically normal livers from donors with metabolic diseases can be used for select recipients with hepatocellular carcinoma (usually outside the Milan criteria). Familial amyloidotic polyneuropathy (FAP) is the most common indication for DLT. When FAP patients are involved in DLT, the indications and outcomes are clear and good, although de novo FAP development within various periods of time has been described in DLT recipients of FAP livers. With the increasing need for organs, livers explanted from patients with rare metabolic diseases, such as primary hyperoxaluria (PH), acute intermittent porphyria (AIP), maple syrup urine disease (MSUD), and homozygous familial hypercholesterolemia (HFHC), are being used for DLT. However, insufficient data about the use of livers from patients with these rare metabolic diseases are available. In this review, we focus on the latter disorders. PH is not a good indication for DLT because recipients of PH livers develop hyperoxaluria and early acute renal failure. AIP also seems to be a debatable indication for DLT because of the rapid development of neurotoxicity in AIP liver recipients. However, the outcomes of DLT with HFHC and MSUD liver grafts (which include the risk of the de novo development of these genetic diseases) are promising. For rare metabolic liver diseases to be established as indications for DLT, more reports and studies are needed.     

Renal cancer: what can we expect from emerging new technologies: radiofrequency and cryoablation?

Radiofrequency and cryoablation are both minimally invasive techniques applied to the treatment of renal cell carcinoma. These techniques allow in situ destruction of neoplasm. Although cryotherapy is the most studied, radiofrequency is the most currently used technique. Indications mostly accepted as elective indication are the less than 4 cm in diameter exophytic tumors. Radiofrequency and cryoablation can also be proposed in patients with solitary kidney, multiple bilateral tumors and patients with contraindication for surgical resection. The radiofrequency parietal tract can be coagulated at the time of radiofrequency electrode withdrawal reducing the rare risk of parietal tumor dissemination. Preliminary oncological results in exophytic small renal tumors are promising with only few complications. A longer follow-up is however mandatory to better define the place of these two new technologies in the treatment of renal cancer.     

Pegfilgrastim vs. filgrastim for supportive care after autologous stem cell transplantation: can we decide?

Granulocyte-colony-stimulating factors are helpful for the support of patients receiving autologous hematopoietic stem cell transplantation, resulting in faster neutrophil recovery and lower incidence of febrile neutropenia (FN). Our aim was to evaluate the use of pegfilgrastim vs. filgrastim with regard to absolute neutrophil count (ANC) recovery, risk, and duration of FN and length of hospital stay. Mean difference was the summary effect for continuous data, and odds ratio for binary data, using random-effects modeling. MEDLINE, EMBASE, and the Cochrane Registry of Randomized Controlled Trials were included in the search. Randomized controlled trials (RCTs), case-control studies, and studies with historical control group for filgrastim were eligible. Of the initial 114 studies screened, 12 studies were analyzed (four were RCTs, including one phase III trial). The use of pegfilgrastim resulted in a one d gain in ANC recovery (mean difference -0.82, 95% CI -1.07 to -0.57, p < 0.001) and duration of FN (-0.67, 95% CI -1.28 to -0.06, p < 0.001) but had no effect on the risk of FN or length of stay. Pegfilgrastim was more expensive (baseline marginal cost €116.97, p < 0.001), which was largely determined by the treatment duration and pegfilgrastim cost. Non-randomized setting attenuated the effect on duration of FN whereas delayed onset of filgrastim injections (to pegfilgrastim) overestimated the protective effect on the risk of FN. Both drugs are at least equally effective, though methodology and disease stratification in published trials warrant further improvement.