Guillaume Canaud

Factors influencing long‐term outcome after kidney transplantation

Many factors influence the long‐term outcome of kidney transplantation, which is defined very schematically by patient death or renal dysfunction leading to graft loss. The most important of these factors is most likely the quality of the transplant itself, with kidneys from living donors showing a positive impact, while kidneys from expanded criteria donors show deleterious impacts. Various clinicopathological scores exist to predict mid‐ to long‐term outcomes and avoid the transplantation of kidneys displaying inferior results. The key factors related to the recipient include their age as well as disease recurrence, HLA matching, HLA immunization, ethnic background, time on dialysis, and cardiovascular comorbidities. Renal function, defined based on estimated GFR and/or proteinuria values, is a result of all these factors. Delayed graft function has a detrimental long‐term impact, as does the level of renal function impairment either in stable condition or in case of progressing dysfunction. Finally, although current immunosuppression regimes are highly efficient in preventing acute rejection, the burden of specific (diabetes, nephrotoxicity) and nonspecific (infection and cancer) side effects has significant negative long‐term consequences that may well be worse in the future because of the increasing ages of both donors and recipients. The development of safer immunosuppression strategies is therefore crucial to improve long‐term outcomes.

Eculizumab Improves Posttransplant Thrombotic Microangiopathy Due to Antiphospholipid Syndrome Recurrence but Fails to Prevent Chronic Vascular Changes

Thrombotic microangiopathy (TMA) is one of the hallmark vascular lesions of antiphospholipid syndrome nephropathy (APSN). These lesions are at high risk of recurrence after kidney transplantation. The complement pathway is thought to be active in this process. We used eculizumab to treat three consecutive kidney transplant recipients with posttransplant TMA due to APSN recurrence that was resistant to plasmapheresis and explored the complement deposition and apoptotic and vascular cell markers on the sequential transplant biopsies. Treatment with eculizumab resulted in a rapid and dramatic improvement of the graft function in all three patients and in improvement of the TMA lesions within the graft. None of these patients had TMA flares after eculizumab was withdrawn. At the time of TMA diagnosis, immunofluorescence studies revealed intense C5b‐9 and C4d depositions at the endothelial cell surface of the injured vessels. Moreover, C5b‐9 colocalized with vessels exhibiting a high rate of apoptotic cells. Examination of sequential biopsies during eculizumab therapy showed that TMA lesions, C4d and apoptotic markers were rapidly cleared but the C5b‐9 deposits persisted for several months as a footprint of the TMA. Finally, we noticed that complement inhibition did not prevent the development of the chronic vascular changes associated with APSN. Eculizumab seems to be an efficient method for treating severe forms of posttransplant TMA due to APSN recurrence. Terminal complement inhibition does not prevent the development of chronic APSN.

Vitamin D Status and Outcomes After Renal Transplantation

Kidney transplant recipients usually have low vitamin D levels, especially in the early posttransplantation period, but the association between vitamin D status with renal outcomes is not well described in this population. Here, we studied a prospective cohort of 634 kidney recipients who underwent transplantation at a single institution between January 2005 and June 2010. In this cohort, low 25-hydroxyvitamin D concentrations 3 months after transplantation did not predict early death or graft loss but were independently associated with lower measured GFR at 12 months (P=0.001) and higher risk for interstitial fibrosis and tubular atrophy (P=0.01). In contrast, levels of calcium, phosphorus, calcitriol, parathyroid hormone, or fibroblast growth factor-23 were not consistently associated with any of the studied outcomes. In conclusion, low 25-hydroxyvitamin D concentration measured 3 months after transplantation is an independent risk factor for interstitial fibrosis progression and is associated with a lower GFR 1 year after transplantation.

Therapeutic mTOR inhibition in autosomal dominant polycystic kidney disease: What is the appropriate serum level?

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease, and sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been shown to significantly retard cyst expansion in animal models. The optimal therapeutic dose of sirolimus is not yet defined. Here, we report the history of a previously unknown ADPKD deceased donor whose kidneys were engrafted in two different recipients. One of the two received an immunosuppressive regimen based on sirolimus for 5 years while the other did not. After transplantation, both patients developed severe transplant cystic disease. Donor DNA sequence identified a new hypomorphic mutation in PKD1. The rate of cyst growth was identical in the two patients regardless of the treatment. While sirolimus treatment reduced the activation of mTOR in peripheral blood mononuclear cells, it failed to prevent mTOR activation in kidney tubular cells, this could account for the inefficiency of treatment on cyst growth. Together, our results suggest that the dose of sirolimus required to inhibit mTOR varies according to the tissue.

V-ATPase/mTOR Signaling Regulates Megalin-Mediated Apical Endocytosis

mTOR kinase is a master growth regulator that can be stimulated by multiple signals, including amino acids and the lysosomal small GTPase Rheb. Recent studies have proposed an important role for the V-ATPase in the sensing of amino acids in the lysosomal lumen. Using the Drosophila wing as a model epithelium, we show here that the V-ATPase is required for Rheb-dependent epithelial growth. We further uncover a positive feedback loop for the control of apical protein uptake that depends on V-ATPase/mTOR signaling. This feedback loop includes Rheb-dependent transcriptional regulation of the multiligand receptor Megalin, which itself is required for Rheb-induced endocytosis. In addition, we provide evidence that long-term mTOR inhibition with rapamycin in mice causes reduction of Megalin levels and proteinuria in the proximal tubular epithelium of the kidney. Thus, our findings unravel a homeostatic mechanism that allows epithelial cells to promote protein uptake under normal conditions and to prevent uptake in lysosomal stress conditions.

Therapeutic approach to focal and segmental glomerulosclerosis recurrence in kidney transplant recipients

Primary focal segmental glomerulosclerosis (FSGS) leads to end-stage renal disease in a high proportion of cases. The recurrence of FSGS after kidney transplantation is frequent (20%-40%) and associated with poor graft survival. The pathophysiology of primary FSGS remains uncertain, but secretion of a circulating factor is suspected to play a key role in excessive glomerular permeability. The treatment of recurrence is still controversial, and most reports related to use of plasma exchange have been uncontrolled trials with relatively small groups of patients and conflicting results. Plasma exchange and protein immunoadsorption can markedly reduce urinary protein excretion and induce complete remission in some cases but usually fail to achieve sustained remission. Steroids and high-dose cyclosporine can reduce proteinuria based on their immunosuppressive properties and through stabilization of the podocyte actin cytoskeleton. Recent advances in our understanding of primary FSGS and podocyte function open the way to more targeted therapies. This review summarizes the therapeutic approach to FSGS recurrence.

Glomerular Collapse Associated With Subtotal Renal Infarction in Kidney Transplant Recipients With Multiple Renal Arteries

Collapsing glomerulopathy is an aggressive kidney disease with rapid progression toward end-stage renal disease. Rare cases of de novo collapsing glomerulopathy have been reported during the post-transplant course and, in some instances, have been associated with renal graft vascular lesions. This finding raises the important question of whether ischemia could induce podocyte transdifferentiation, a hypothesis supported by evidence of hypoxia-inducible factor-dependent podocyte proliferation in HIV-associated nephropathy. We describe here 3 HIV-negative kidney transplant recipients in whom early graft biopsy performed in the vicinity of segmental graft infarction disclosed the typical features of glomerular collapse. Podocyte transdifferentiation was characterized by hallmark lesions, such as loss of mature podocyte phenotype, podocyte proliferation, and acquisition of a macrophage-like phenotype. Together, these data suggest that acute glomerular ischemia may lead to glomerular collapse in kidney transplants.

AKT/mTORC pathway in antiphospholipid-related vasculopathy: a new player in the game

Since the early 1990s, it has become clear that the antiphospholipid syndrome (APS) is not only associated with vascular thrombosis but also with a severe intimal hyperplasia called ‘antiphospholipid arterial vasculopathy’. Such vasculopathy has been recognized as a major contributor to large artery occlusion rather than thrombosis or vasculitis. These lesions are described in many vascular territories, including the coronary, carotid or mesenteric arteries. However, their best morphological characterization was conducted in the kidneys, where these lesions have been called APS nephropathy (APSN). These lesions have been associated with a progressive decline of kidney function leading to end-stage renal failure. Interestingly, APSN recurs after kidney transplantation, sometimes quickly, and reduces the allograft survival rate. The molecular pathways that were involved in the development of such lesions were unknown, and therefore no specific treatment was offered to these patients.

Antiphospholipid syndrome and kidney disease

The antiphospholipid syndrome is a common autoimmune disease caused by pathogenic antiphospholipid antibodies, leading to recurrent thrombosis and/or obstetrical complications. Importantly for nephrologists, antiphospholipid antibodies are associated with various renal manifestations including large renal vessel thrombosis, renal artery stenosis, and a constellation of intrarenal lesions that has been termed antiphospholipid nephropathy. This last condition associates various degrees of acute thrombotic microangiopathy, proliferative and fibrotic lesions of the intrarenal vessels, and ischemic modifications of the renal parenchyma. The course of the disease can range from indolent nephropathy to devastating acute renal failure. The pejorative impact of antiphospholipid antibody-related renal complication is well established in the context of systemic lupus erythematous or after renal transplantation. In contrast, the exact significance of isolated antiphospholipid nephropathy remains uncertain. The evidence to guide management of the renal complications of antiphospholipid syndrome is limited. However, the recent recognition of the heterogeneous molecular mechanisms underlying the progression of intrarenal vascular lesions in antiphospholipid syndrome have opened promising tracks for patient monitoring and targeted therapeutic intervention.

The costimulatory receptor B7-1 is not induced in injured podocytes

Recent research on podocytes has proposed B7-1 as an important player in podocyte biology and as a potential new therapeutic target. B7-1 was upregulated in injured podocytes and described as a biomarker to identify patients who may benefit from abatacept, a B7-1 blocker. However, after this initial enthusiasm, several reports have not confirmed the efficiency of abatacept at inducing proteinuria remission in patients. In order to resolve these discrepancies, we explored the role of B7-1 in the injured podocyte. Both primary cultured and immortalized podocytes were exposed to lipopolysaccharides, but this failed to induce B7-1 expression at the mRNA and protein levels. Importantly, TLR-4 engagement confirmed lipopolysaccharide efficacy. We then evaluated B7-1 expression in several mouse models of podocyte injury including treatment with lipopolysaccharide or Adriamycin, a lupus prone model (NZB/W F1) and subtotal nephrectomy. Using 3 commercially available anti-B7-1 antibodies and appropriate controls, we could not find B7-1 expression in podocytes, whereas some infiltrating cells were positive. Thus, our findings do not support a role for B7-1 in podocyte biology. Hence, further studies are mandatory before treating proteinuric patients with B7-1 blockers.