Cristina Izzo

Unexpectedly high prevalence of rare genetic disorders in kidney transplant recipients with an unknown causal nephropathy

Patients with a rare genetic disease may receive renal transplantation (KTx) without a correct diagnosis of causal nephropathy and therefore develop unexpected and even severe complications. The aim of the study was to describe the cases of rare genetic disorders diagnosed after KTx, in order to draw clinical lessons for the transplant physician.

Calcium-sensing-related gene mutations in hypercalcaemic hypocalciuric patients as differential diagnosis from primary hyperparathyroidism: detection of two novel inactivating mutations in an Italian population

BACKGROUND Inactivating mutations of the calcium-sensing receptor (CaSR), of the G-protein subunit α11 (GNA11) and of the adaptor-related protein complex 2, sigma 1 subunit (AP2S1) genes are responsible for familial hypocalciuric hypercalcaemia (FHH). The aim of this study was to analyse prevalence and pathogenicity of CaSR, GNA11 and AP2S1 mutations in patients with an FHH phenotype and to compare them with a sample of patients with primary hyperparathyroidism (PHPT) in order to identify the most useful laboratory parameter for a differential diagnosis. METHODS Patients with an FHH phenotype were studied with polymerase chain reaction amplification and direct sequencing of the entire CaSR, GNA11 and AP2S1 coding sequences. Novel mutations were introduced in a Myc-tagged human wild-type (WT) CaSR cDNA-expressing vector, and functional assay was performed on human embryonic kidney cells evaluating expression and function of mutated proteins. RESULTS Among 16 FHH patients, none had an inactivating GNA11 or AP2S1 mutation while 3 (18.8%) carried a CaSR mutation and 10 (62.5%) at least one CaSR polymorphism. Within the latter group, 7 of 10 patients had more than one polymorphism (4.1 ± 2.1 per patient). Two novel CaSR mutations [c.2120A>T (E707V) and c.2320G>A (G774S)] were identified: the E707V mutation prevented CaSR expression (western blot), whereas the G774S mutation determined a reduced receptor sensitivity to calcium (IP3 assay). PHPT patients showed significantly (P < 0.001) higher serum calcium, parathyroid hormone, urinary calcium and calcium-creatinine clearance ratio (CCCR) and significantly lower serum phosphate than FHH ones. CONCLUSIONS FHH should be clearly differentiated by PHPT to avoid unnecessary surgery: CCCR could be a useful screening tool while genetic analysis should include the two novel CaSR mutations herein described. The role of multiple polymorphisms deserves further investigation in patients with an FHH phenotype.

Cumulative radiation dose from medical imaging in kidney transplant patients

BACKGROUND Although many patients undergoing kidney transplant are exposed to multiple examinations that increase cumulative effective doses (CEDs) of ionizing radiation, no data are available characterizing their total longitudinal radiation burden and relating radiation burden with risk factors for more exposure. METHODS We did a retrospective cohort study of 92 patients (mean age 52 years; range: 20-75 years) who underwent kidney transplant at University Hospital, Novara, Italy, that evaluated all following medical imaging procedures involving ionizing radiation undergone beginning June 2007, and all subsequent procedures through August 2011, at the centre. RESULTS The mean and median annual CED were 17.2 and 4.9 millisieverts (mSv) per patient-year. The mean and median total CED per patient over the study period were 46.1 and 17.3 mSv, respectively. Twenty-eight and 12% of patients had total CED >50 and 100 mSv, values which are associated with a good or strong evidence of an increased cancer mortality risk, respectively. Computed tomography scanning accounted for 73% of the total CED. The annual CED was significantly higher in incident patients and in patients with ischaemic heart disease and cancer. CONCLUSION In this institution, multiple testing of kidney transplant patients was common in many patients associated with high cumulative estimated doses of ionizing radiation.

Letter to the Editor re: Are intravenous injections of contrast media really less nephrotoxic than intra-arterial injections?

AbstractIn a recent paper, the authors oppose the opinion that “ intra-arterial administration of iodinated-based contrast media (CM) appears to pose a greater risk of contrast-induced nephropathy (CIN) than intravenous administration” . As nephrologists, we are happy to have the opportunity to offer our expertise in the setting of renal disease aimed at optimizing diagnostic algorithm and preventive strategies. Our comment relies on the fact that, from a nephrologist’s point of view, there is no doubt that renal damage following CM intra-venous administration in patients not in intensive care or emergency department and treated with conventional preventive strategies not only occurs with low frequency, but also appears of negligible clinical impact; it is confined to an asymptomatic increase of serum creatinine of 25% or 0.5 mg/dL lacking any prognostic negative impact, and in some case not significantly different from controls.True CIN, just related to intravenous CM injection for diagnostic purpose, has to be differentiated from all the other cause of renal involvement in people stricken with sudden and acute illness also receiving intra-arterial CM injection, in order to avoid patients being denied necessary radiological examinations due to an inappropriate fear of risk. Key Points • Contrast induced nephropathy (CIN) is not any nephropathy following contrast medium(CM). • CIN should only refer to renal damage strictly due to CM infusion. • True CIN following CM intravenous infusion is a clinically insignificant event. • Renal damage following intra-arterial CM infusion in compromised patients is not CIN. • Patients should not forego necessary radiological examinations for inappropriate understanding about risk.

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.

Very high frequency of TMPRSS6 gene variations in iron deficiency anaemia of patients with polyendocrine autoimmune syndromes: more than a casual association?

Sophie Gandrille R egis Peffault de Latour Emeline Levionnois Paula Rodriguez-Otero Isabelle Galy–Fauroux Laurence Zemori Sarah Abbes Anna D. Petropoulou G erard Soci e Anne-Marie Fischer Dominique Helley INSERM U765, Paris, France, Univ Paris Descartes, Sorbonne Paris Cit e, Paris, France, AP-HP, Biological Haematology, Georges Pompidou European Hospital, Paris, France, AP-HP, Haematology Bone Marrow Transplantation, Hospital Saint-Louis, Paris, France, Univ Paris Diderot, Sorbonne Paris Cit e, Paris, France, and INSERM U728 Paris, France E-mail: dominique.helley@egp.aphp.fr

Type iv renal tubular acidosis: an emerging type of nephropathy

Type IV renal tubular acidosis (RTA IV) is a form of hyperchloremic RTA caused by an absolute or functional hypoaldosteronism that determines a distal acidification defect by inhibiting ammoniagenesis and H+ excretion by the collecting duct. Etiology is often multifactorial and includes disorders causing a reduction in aldosterone levels or in the sensitivity of the collecting duct to the hormone. Several drugs block the renin-angiotensin system (RAS) at different steps, thus increasing the risk of developing RTA IV especially when used in association in elderly patients with diabetes, congestive heart failure, chronic renal failure, or in renal transplant recipients. Diagnosis is based on the presence of hyperkaliemia disproportionate to the degree of renal function, associated with a metabolic acidosis with normal serum anion gap and a positive urinary anion gap; urinary pH can be lower than 5.5. Some laboratory features allow differential diagnosis with distal type I RTA. The clinical impact of RTA IV is becoming progressively heavier due to the widespread use of RAS-blocking drugs in elderly patients already at risk for this complication because of their comorbidities; this situation is inducing a critical revision of the indications to association therapies with these agents. The onset of hyperkalemia in this setting poses a therapeutic dilemma, as the patients at highest risk for RTA IV are also those who can derive the strongest cardiovascular benefits from RAS pharmacological blockade. It is therefore necessary to find a balance between risks and benefits in each patient, adopting preventive measures against RTA IV.

Membranous material in the urine: A diagnosis of cystic echinococcosis at first glance.

We herein report the case of a 19-year old woman who was referred to our unit for a large pale white-yellow, balloon-like, grape-sized “membranous material” measuring around 7 cm, with an uneven internal surface and a smooth external surface, which was expelled with urine. In the previous 3months she had a few episodes of urinary discharge of such “membranous material” associated with mild dysuria. Her previous medical history was uneventful and physical examination was normal. No major laboratory abnormalities were detectable: creatinine was 51.3mmol/L, wihte blood cells 9.6 ×10/L (neutrophils 68%), C-reactive protein 11mg/L, and urinalysis showed microscopic haematuria (++) and leukocyte esterase (+) without nitrites. Abdomen ultrasound showed multiple uncomplicated cysts in the left kidney, completely distorting the renal profile, which were confirmed by a contrast-enhanced CT scan and an MRI; these exams also excluded other abdominal lesions (Fig. 1). The gross characteristics of this material and the imaging are highly suggestive for cystic echinococcosis (CyEc). Indeed, the patient used to have a dog livingwith her formany years before the onset of symptoms. Microscopic examination of the material confirmed the diagnosis (laminated structure consistent with a hydatid cyst), and a chest and head CT excluded other metastatic lesions. She was treated with albendazole (4weeks) followed by left nephroureterectomy; right before surgery she was given one-shot of i.v. steroids to prevent allergic reaction. Serum creatinine has been stable thereafter (52.2mmol/L). CyEc occurs in humans as accidental intermediate hosts from direct contact with dogs or consumption of contaminated vegetables or water containing eggs of Echinococcus granulosus or multilocularis. The larval stage emerging from the eggs produces CyEc by haematogenous dissemination through the portal system mainly in liver and lungs. Renal CyEc is rare (2%)

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.