The ELITE & the Rest in Kidney Transplantation

The ELITE-Symphony study enshrined standard triple therapy immunosuppression of tacrolimus, mycophenolic acid and prednisolone, for renal transplant recipients. We get familiar with these agents relatively quickly in our renal training, but what about the other less common agents that are used?  Why do we not use them as first line, when should we consider them and what side effects do we need to be aware of?

Sirolimus and everolimus are mTOR inhibitors (see previous RFN post), and prevent cell cycle progression and lymphocyte proliferation.  Their anti-proliferative effects mean they have a role in conditions such as tuberous sclerosis, psoriasis and certain cancers.  The antiproliferative and antiangiogenic effects pose issues post-surgery however with poor wound healing and lymphocele formation meaning they should not be used for around 6 months post-transplant.  Other side effects include pneumonitis, hyperlipidaemia, bone marrow suppression, thrombotic microangiopathy and proteinuria due to FSGS-type lesions. Alongside this relatively long list of side effects, the main concern with sirolimus is related to mortality. A meta-analysis of 21 studies with a total of 5876 patients showed sirolimus was  associated with increased mortality post-transplant, mainly from cardiovascular and infectious complications (adjusted hazard ratio 1.43, 95% CI 1.21-1.71). So why do some patients end up on sirolimus?  The same meta-analysis showed that sirolimus is associated with a 40% reduced risk of malignancy, particularly in non-melanoma skin cancers. The most common reasons for switching to mTORi are malignancy, often recurrent skin cancers, and for calcineurin-inhibitor (CNI) induced injury (although if eGFR<40mls/min or overt proteinuria outcomes are likely to be poor or no better with a switch). Moreover, as seen in ELITE-Symphony and other, acute rejection rates and patient dropouts are consistently higher with mTORi compared to CNIs.

Another agent we may be hearing more about in the future is belatacept: a co-stimulation pathway blocker. It is attractive as it is designed to replace the CNI in the treatment regime. It binds to CD80 and CD86 on antigen-presenting cells, thereby blocking CD28 mediated activation of T Cells. It is administered as an IV infusion every 4-6 weeks alongside steroid and an anti-metabolite.

The BENEFIT and BENEFIT-EXT (extended criteria donors) trials compared high and low intensity belatacept regimes with cyclosporine in non-sensitised recipients undergoing DBD or living donor renal transplants. Over 7 years of follow-up, they found improved patient and graft survival with belatacept in BENEFIT and better measured GFR and reduced formation of DSA with belatacept in both studies. There was an increased incidence of acute rejection in BENEFIT although this obviously didn’t translate into inferior outcomes. There were also initial concerns regarding a small increase in cases of PTLD in EBV seronegative recipients although longer term data was reassuring that the overall risk of this was very low.

A potential benefit of belatacept is it’s a directly observed therapy, so compliance will be known. Although it is expensive, if patients experience improved graft outcomes then any longer term savings need to be considered. However what about patients who are highly sensitised? Many patients we want to avoid CNIs in are sensitised but here is a dearth of data in using belatacept in this circumstance. Moreover, the studies compared belatacept to cyclosporine, not tacrolimus, the current standard of care. Currently belatacept is not available for new patients due to supply issues, another issue likely preventing its more widespread use.  

Post by Ailish Nimmo

mTOR Pathway in Anti-phospholipid Syndrome

Antiphospholipid syndrome (APS) is an autoimmune hypercoagulable disorder characterized by small-to-large vascular (both arterial and venous) thrombosis with end-organ damages, in presence of circulating antibodies against phospholipid binding proteins.

Kidney transplantation in patients with APS is challenging because  post-transplant thrombosis, vascular complications and requirement of anticoagulation during peripoperative period. Let’s start with a brief review of recent advances in transplantation in APS.

For post-transplant TMA due to recurrent APS nephropathy, Canaud et al. recently explored the use of eculizumab. Eculizumab, a humanized mAb that binds C5, prevents cleavage of C5 into C5a and C5b, thereby preventing generation of the membrane attack complex (MAC). At a molecular level, the pathogenesis of endothelial damage in APS is in part via complement activation; C5b-9 MAC deposition on endothelium, leading to cell lysis and/or activation of other proinflammatory pathways, so the use of eculizumab is reasonable. Three patients, maintained with steroids, CNI and MMF, were treated with eculizumab for posttransplant TMA with robust improvement of allograft functions after several doses, and all three patients were successfully withdrawn from maintenance eculizumab treatment after 3-12 months of initial dose. Interestingly, although biopsy showed improved TMA lesions, C5b-9 depositions were persistent for as long as 3 months as “foot prints”. The authors also noticed that eculizumab treatment did not prevent the chronic vascular lesions seen in 12-month protocol biopsies.

Preemptive use of eculizumab in kidney transplant in APS-related ESRD was also attempted in another case series. Three patients, two with CAPS (catastrophic APS), received 1,200 mg of Eculizumab on day 0, 900 mg on POD 1, and weekly thereafter until week 4. After week 5, they received 1200 mg every 2 week. Despite one  biopsy proven cellular rejection successfully treated with pulse steroid, graft function and survival was acceptable without recurrence of APS during follow-up of 6 months to 4 years. In the setting of no specific treatment other than systemic anticoagulation, eculizumab seems potentially promising treatment, however, the sufficient treatment length of this drug needs to be optimized, especially due to high cost. Also, there is no description of immunosuppressive regimen either for induction nor maintenance, and it is unclear these patients were on sirolimus or not.

 In a recent NEJM article, Canaud et al.  indicated the beneficial effect of sirolimus in proliferative vascular changes associated with APS and CAPS, which were not reversed by eculizumab in their previous study. They demonstrated that the chronic vascular changes in APS patients were induced by activation of mTORC via phosphorylation of Akt-S6K pathway, using immunohistochemistry of renal biopsy samples and in vitro signaling studies with HIMEC-1, a human microvascular endothelial cell line, as well as autopsy samples of CAPS. Furthermore, using a cohort of kidney transplant patients with APS (10 treated with steroids+sirolimus+purine inhibitor and 27 with steroids+CNI+purine inhibitor), their nested-case-control study demonstrated that posttransplant allograft functions were better preserved at 144 months post transplant in the sirolimus group compared with CNI group (7 of 10 vs 3 of 27 patients with functioning grafts) and this effect was observed only in patients with APS and not in patients without APS. Other variables including cold ischemia time and immunologic risk profile were comparable between sirolimus and CNI groups. Although this is a relatively small case-controlled study, the use of mTOR inhibitors for the prevention of APS post-transplant seems very promising.

Naoka Murakami

Rapamycin and PCKD

A couple of years ago, it was noted that mTOR inhibitors slowed the growth of cysts in animal models of Polycystic Kidney Disease. Although the activity of mTOR is minimal in normal renal epithelial cells, in cyst epithelial cells, expression is markedly increased. At the time, there was understandably a lot of excitement about this and the potential for a role for rapamycin for treating patients with PCKD. (We got in on this ourselves and had two posts from Nate and Conall about this possible therapeutic pathway) Unfortunately, the clinical studies were not very impressive and the excitement has since faded somewhat. One of the reasons put forward for why it was ineffective was that the doses were inadequate. The dose of rapamycin needed to suppress cyst growth in mice was far higher than was tolerable for humans. Anyone who has used rapamycin in transplant recipients knows about the side-effect profile which prevents many people from taking the drug,

An article was just published in JASN which raises the possibility that rapamycin could be used in higher doses than previously thought possible. The folate receptor is selectively expressed on cancer cells and renal epithelial cells. As a result, there has been some work done on combining drugs with folate to increase the specificity of drug delivery, particularly chemotherapeutic agents and thus limiting toxicity. The beauty of this is that folic acid is taken up into most cells by an alternative pathway and this pathway is not available to conjugated folate. In this study, the authors conjugated rapamycin to folate and gave it to mice with PKD. They showed that it was effective both at reducing expression of downstream targets of mTOR and slowing cyst growth. This suggests that the combined compound could be given in large doses to humans with PKD and offer targeted therapy with less chance of significant extra-renal side effects.

Photo from the University of Indiana website

Miracle drug?

A 72 year-old man who received a kidney transplant 5 years ago comes for a routine follow up. He is a quite active guy who recently traveled to Asia. His only major issue after transplant has been repetitive skin cancers requiring frequent resections. Today he complains of increased dyspnea. With the history of travel to Asia, I started to think of all the possible atypical bugs he might have caught in the setting of his immunosuppressed state. However, one aspect of his history was interesting. He had been recently switched to sirolimus in attempt to decrease his skin cancers. Sirolimus is a macrolide antibiotic, produced by Streptomyces hygroscopicus. Its discovery is quite interesting so let me diverge here for a second.

Let’s head to the Pacific Ocean, more specifically Easter Island or Rapa Nui, a volcanic island and a World Heritage Site. This island became famous for its 887 extant monumental statues, called moai (Figure), created by the early Rapanui people. Its original population was completely devastated by the introduction of diseases carried by European colonizers in 1860. A Canadian Medical Expedition in 1964 isolated from its soil a compound that was shown to have antifungal properties. They brought the compound back home and were excited by its potential antimicrobial properties. The compound failed as an antibiotic, however it demonstrated potent immunosuppressant properties. They called the compound Rapamycin.

When it was first introduced in the market, Rapamycin had the promise to decrease CNI toxicity and improve allograft outcomes. However, side effects limited its use and the promised improve in graft survival did not prevail in clinical trials.

The main side effects of sirolimus therapy are thrombocytopenia, hyperlipidemia, edema, and rash. Rapamycin may also cause lung toxicity in up to 5% of patients and it doesn’t seem to be dose-dependent. The exact mechanism is unknown but it usually completely resolves after stopping the drug. Risk factors include late switch from tacrolimus, poor renal function and older age; initial presentation varies between 3-14 months. Finally, rapamycin can also cause increased proteinuria in some patients. The latter is possibly related to podocyte toxicity via inhibition of VEGF and/or via decrease expression of nephrin.

Going back to the case, infectious workup was negative. We decided to stop his sirolimus with the presumed dx of lung toxicity from Rapa. Repeat imaging 2 weeks later showed complete resolution of symptoms. In general, sirolimus should not be used if creatinine is above 2mg/dl or proteinuria is above 500mg/dl. After a switch in transplant recipients, it is necessary to carefully monitor the creatinine since it is a weaker immunosuppressive drug than FK and it has showed an increased incidence of angioedema when combined to ACEI.

Despite all that, rapamycin has shown great promise in multiple fields, including reducing malignancies, decreasing vascular smooth muscle proliferation after stenting, decreasing LVH in patients with CKD, decreasing cysts in PKD and prolonging life!!!

Similar to the Rapa Nui people when the colonizers arrived, progress come with a cost and sometimes it might be greater than we can tolerate.

Polycystic Kidney Disease, mTOR and Sirolimus

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the gradual enlargement of multiple fluid filled cysts in both kidneys, which compress and destroy normal adjacent nephrons, typically resulting in ESRD by the fifth decade of life. Management has traditionally been limited to the treatment of the complications of hypertension and renal failure; however, several promising new therapies are on the horizon, such as nonpeptide vasopressin 2 receptor antagonists, inhibitors of the receptors for EGF and vascular endothelial growth factor (VEGF), and inhibitors of cmyc expression. All of which have been shown to inhibit disease progression in experimental models of PKD.

The mTOR inhibitor Sirolimus (Rapamycin) is another promising potential therapy, having also been shown to slow cyst development in rat models. Interestingly, it also slows the increase in size of native polycystic kidneys in human renal transplant recipients. It is currently the subject of three clinical trails underway in the US and Europe. Mechanistically, the cytoplasmic tail of wild-type Polycystin 1 normally interacts with, and inhibits, mTOR; loss of function of Polycystin 1, as seen in ADPKD, results in marked activation of mTOR within the epithelial cells of renal cysts. Sirolimus is believed to exert its effect via this mechanism. As mutations in PKD1, which encodes PC1, account for 85% of cases of ADPKD, Sirolimus has the potential to ameriorate the condition of the vast majority of APCKD patients.