Michele Battista

Kidney transplant recipients receiving mTOR inhibitors experienced twice as many thrombotic events: A single cohort observational study

Thrombotic events are ominous complications in patients undergoing kidney transplant (Kidney Transplant Recipients – KTR) [1] and different immunosuppressive (IS) medications have been involved [2]. Recently, Baas et al have shown that KTRs receiving everolimus have higher levels of circulating von Willebrand factor, prothrombin fragment 1 + 2, thrombin-activable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1, leading eventually to a pro-thrombotic state, which may be associated with more thrombotic events [3]. The mammalian target of rapamycin inhibitors (mTOR-I) sirolimus and everolimus are immunosuppressive agents used in renal transplantation for the prevention of acute rejection: their main mechanism of action is the inhibition of the mTOR, a regulatory protein kinase involved in lymphocyte proliferation [4]. Moreover they inhibit the crosstalk among mTORC1, mTORC2, and PI3K with a potential antineoplastic activity, so some mTOR-I (ie: temsirolimus) are being used at higher doses as chemotherapy in renal clear cell carcinoma. Even if a high dosemTOR-I therapy is associatedwith renal toxicity [5], in kidney transplantation mTOR-I based regimens have been shown to have similar or lower nephrotoxicity when compared to standard cyclosporineor tacrolimus-based regimens [6]. In lung transplant recipients, significantlymore venous thromboembolisms (VTE)were observed in patients treatedwith sirolimus and low dose tacrolimus, as comparedwith patients treatedwith tacrolimus and azathioprine (17,2% vs 3,2%) [7]. Moreover, some case reports described devastating thrombotic events in solid organ transplant recipients treated with mTOR-I [8,9], but randomized controlled trials on mTOR-I in KTR did not describe vascular complications as common adverse events [10,11]. This could reflect differences between different solid organ transplants and possibly drug dosing and associations, or it may be due to a different subtype of cardiovascular (CV) events: for instance in patients treatedwithmTOR-I the incidence of coronary artery disease was reported as significantly higher unlike overall CV adverse events [12]. Therefore we retrospectively studied the incidence of major thrombotic events (MTE) in a cohort of unselected KTRs to evaluate if patients experienced more MTE while on mTOR-I.

Autosomal dominant tubulointerstitial kidney disease (ADTKD)

Autosomal Dominant Tubulointerstitial Kidney Diseases (ADTKD) are a group of autosomal dominant hereditary nephropathies which share a rather aspecific pathological picture of interstitial fibrosis and tubular atrophy (IFTA) and a slowly progressing tubulointerstitial clinical profile: end-stage renal disease (ESRD) generally occurs between 30 and 50 years. Four types of ADTKD have been described so far, each showing some peculiarities: hepatocyte nuclear factor-1 β (HNF1β) ADTKD, in which ADTKD can be associated with renal cysts and a wide spectrum of congenital abnormalities of kidney and urinary tract (CAKUT) and extra-renal manifestations (diabetes, liver enzyme alterations, genital malformations), uromodulin (UMOD) ADTKD, characterised by early onset of hyperuricemia and gout, mucin-1 (MUC-1) ADTKD, a recently discovered form which appears to be an isolated tubulointerstitial nephropathy, and renin (REN) ADTKD, which appears in childhood and is characterised by anemia and mild signs of hyporeninism. A better awareness is needed in order to perform genetic analysis whenever clinical setting is compatible with this nephropathy. A timely diagnosis can have an important impact on both the patient and his family members in terms of therapy and prognosis, also at the prospect of renal transplant.

Comment on: Think to prevent before than to treat renal impairment in multiple myeloma: do not forget tubular damage mimicking Fanconi syndrome

In a recent paper, renal impairment is correctly described as a common complication of symptomatic myeloma (20 -40%) needing dialysis. Significant improvement has been attributed to novel therapeutic chemotherapy regimens coupled with extrarenal free light chain removal obtained by plasma exchange or dialysis [1]. As nephrologists, we would like to stress the importance of recognizing early symptoms of renal impairment other than by measuring renal function as glomerular filtration rate (GFR) [2]. An increase in serum creatinine and/or a decrease in GFR are not the only markers of renal impairment in patients with multiple myeloma. Although a serum creatinine > 2 mg/dl is one of the hypercalcemia, renal impairment, anemia, bone disease (CRAB) diagnostic criteria for symptomatic myeloma requiring therapy, it has been stated that “a variety of other types of end-organ dysfunctions can occur and lead to a need for therapy. Such a dysfunction is sufficient to support classifications of myeloma if proven to be myeloma-related” [3]. Tubular dysfunctions, and mainly proximal tubular dysfunctions with the picture of complete or incomplete Fanconi syndrome, constitute such “other end-organ dysfunctions” [1-3]. As far as the kidney is concerned, it is important to have early indicators of tubular dysfunction. This includes hypophosphatemia, hypouricemia, hypokalemia and metabolic acidosis coupled with urine loss of phosphate, urate, potassium, bicarbonate, low-molecular-weight proteins and glycosuria (in the presence of normal blood glucose levels). Therefore, even if free light chains detected in the urine (Bence Jones proteinuria) is not a sign of renal damage by itself, its transcellular “traffic” may cause tubular damage, eventually leading to tubular crystal-storing histiocytosis and Fanconi syndrome. Subsequently, tubular casts precipitating in the distal tubule may cause acute renal failure of the classical ‘myeloma kidney’ [4,5]. Therefore, a delay in diagnosis could allow irreversible kidney damage to occur and might shorten patient survival.