Long-Term Bone Mineral Density Changes in Kidney Transplant Recipients Treated with Denosumab: A Retrospective Study with Nonequivalent Control Group.

Data on the effectiveness of denosumab on osteoporosis after kidney transplantation are limited. We investigated the long-term bone mineral density (BMD) changes in kidney transplant recipients (KTRs) treated with denosumab compared to untreated KTRs. We enrolled KTRs treated with denosumab 60 mg/6 months for 4 years. An untreated group of sex and age-matched KTRs with a 1:1 ratio was included. The primary outcome was BMD changes assessed by Dual-energy X-ray Absorptiometry over 4 years. Data on serum creatinine, alkaline phosphatase (ALP), parathyroid hormone, and 25-hydroxyvitamin D were collected. All patients received oral cholecalciferol and calcium supplementation. 23 denosumab-treated KTRs were enrolled, and 23 untreated KTRs. The median time from transplant to the start of denosumab was 4 years (range 0:24). The denosumab group showed a significant increase from baseline in BMD at the lumbar spine (LS) (9.0 ± 10.7%, p < 0.001), and total hip (TH) (3.8 ± 7.9%, p = 0.041). The untreated group showed a significant decrease at all sites (- 3.0 ± 7%, p = 0.041 at the LS; - 6.3 ± 9.2%, p = 0.003 at the TH; - 6.7 ± 9.3%, p = 0.003 at the FN). The between-group differences in percent BMD changes were statistically significant at all sites. Similar results were found for the respective Z-scores. The ALP serum levels significantly decreased from baseline only in the denosumab group, with a significant between-group difference (p = 0.032). No significant differences in serum creatinine, hypocalcaemic events or acute graft rejection rates were observed. Four years of denosumab therapy were associated with increased BMD in KTRs, while untreated KTRs showed significant BMD losses at all sites.

Diagnostic policies on nephrolithiasis/nephrocalcinosis of possible genetic origin by Italian nephrologists: a survey by the Italian Society of Nephrology with an emphasis on primary hyperoxaluria.

BACKGROUND: Primary hyperoxaluria is a genetic disorder of the metabolism of glyoxylate, the precursor of oxalate. It is characterized by high endogenous production and excessive urinary excretion of oxalate, resulting in the development of calcium oxalate nephrolithiasis, nephrocalcinosis, and, in severe cases, end-stage kidney disease and systemic oxalosis. Three different forms of primary hyperoxaluria are currently known, each characterized by a specific enzymatic defect: type 1 (PH1), type 2 (PH2), and type 3 (PH3). According to currently available epidemiological data, PH1 is by far the most common form (about 80% of cases), and is caused by a deficiency of the hepatic enzyme alanine:glyoxylate aminotransferase. METHODS: A survey on rare forms of nephrolithiasis and nephrocalcinosis with a focus on primary hyperoxaluria in the setting of Italian Nephrology and Dialysis Centers, using an online questionnaire, was recently conducted by the Project Group "Rare Forms of Nephrolithiasis and Nephrocalcinosis" of the Italian Society of Nephrology, with the aim of assessing the impact and management of this disorder in clinical practice in Italy. RESULTS: Forty-five public and private Italian Centers participated in the survey, and responses to the questionnaire were provided by 54 medical professionals. The survey results indicate that 21 out of the 45 participating Centers are managing or have managed primary hyperoxaluria patients, most of whom are on dialysis, or are recipients of kidney transplants. CONCLUSIONS: The data of this survey indicate the need to implement genetic testing in suspected cases of primary hyperoxaluria, not only in the setting of dialysis or transplantation, but also with the aim of encouraging early diagnosis of PH1, which is the only type of primary hyperoxaluria for which specific drug therapy is currently available.

Nephrolithiasis: A Red Flag for Cardiovascular Risk.

Epidemiological evidence shows that nephrolithiasis is associated with cardiovascular (CV) morbidities. The association between nephrolithiasis and CV disease is not surprising because both diseases share conditions that facilitate their development. Metabolic conditions, encompassed in the definition of metabolic syndrome (MS), and habits that promote nephrolithiasis by altering urine composition also promote clinical manifestations of CV disease. By inducing oxidative stress, these conditions cause endothelial dysfunction and increased arterial stiffness, which are both well-known predictors of CV disease. Furthermore, the subtle systemic metabolic acidosis observed in stone formers with CV disease may have a pathogenic role by increasing bone turnover and leading to reduced mineral content and osteoporosis/osteopenia. Heart valves and/or coronary artery and aortic calcifications are frequently associated with reduced mineral density. This is known as the 'calcification paradox' in osteoporosis and has also been observed in subjects with calcium nephrolithiasis. Evidence supports the hypothesis that osteoporosis/osteopenia is an independent risk factor for the development of CV calcifications. In the long term, episodes of renal stones may occur from the onset of metabolic derangements/MS to arterial stiffness/atherosclerosis and CV morbidities. These episodes should be considered a warning sign of an ongoing and silent atherosclerotic process. The evaluation of cardiometabolic risk factors and MS components should be routine in the assessment of renal stone formers. This would allow for treatment and prevention of the development of CV complications, which are much more severe for the patient and for public health.

Outcomes in AB0 Incompatible Living Donor Kidney Transplantation: A Case - Control Study.

Background: Patients waiting for a kidney transplant by far exceed available organs. AB0 incompatible living donor kidney transplantation (AB0i LDKT) represents an additional therapeutic strategy, but with higher risk for complications. We aimed at evaluating outcomes of AB0i LDKTs compared to compatible (AB0c) controls at our Institution. Methods: Retrospective matched case - control study (1:2) comparing AB0i vs. AB0c LDKTs from March 2012 to September 2021. Considered outcomes: graft function, acute rejection, sepsis, CMV infection, BK virus reactivation, death-censored graft survival, patient survival. Results: Seventeen AB0i LDKTs matched to 34 AB0c controls. We found excellent graft function, comparable in the two groups, at all considered intervals, with an eGFR (ml/min/1.73 m2) of 67 vs. 66 at 1 year (p = 0.41), 63 vs. 64 at 3 years (p = 0.53). AB0i recipients had a statistically significant higher incidence of acute rejection, acute antibody-mediated rejection and sepsis within 30 days (p = 0.016; p = 0.02; p = 0.001), 1 year (p = 0.012; p = 0.02; p = 0.0004) and 3 years (p = 0.004; p = 0.006; p = 0.012) after surgery. There was no difference in CMV infection, BK virus reactivation, death-censored graft survival between the two groups. Patient survival was inferior in AB0i group at 1 and 3 years (88.2 vs. 100%; log-rank p = 0.03) due to early death for opportunistic infections. AB0i LDKTs spent longer time on dialysis (p = 0.04) and 82.3 vs. 38.3% controls had blood group 0 (p = 0.003). Conclusions: AB0i LDKT is an effective therapeutic strategy with graft function and survival comparable to AB0c LDKTs, despite higher rates of acute rejection and sepsis. It is an additional opportunity for patients with less chances of being transplanted, as blood group 0 individuals.

Hypomethylation of NLRP3 gene promoter discriminates glucocorticoid-resistant from glucocorticoid-sensitive idiopathic nephrotic syndrome patients.

To assess whether NLRP3 gene promoter methylation was able to discriminate glucocorticoid (GC)-resistant from GC-sensitive idiopathic nephrotic syndrome (INS), patients with minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS), we measured the methylation level of NLRP3 promoter in DNA from peripheral blood cells of 10 adult patients with GC-resistant FSGS already in hemodialysis and 18 patients with GC-sensitive INS (13 MCD/5 FSGS) and in 21 pediatric patients with INS with MCD/FSGS before starting any treatment. Association of NLRP3 inflammasome with GC resistance was recapitulated in vitro in monocytic cell lines (THP-1 and U937). In both adults and pediatric patients, NLRP3 promoter methylation was significantly reduced in GC-resistant compared with GC-sensitive patients. Indeed, NLRP3 methylation distinguished GC-resistant and GC-sensitive patients (area under the receiver operating characteristic curve [AUROC] 86.7% in adults, p = 0.00019, and 73.5% in children, p = 0.00097). NLRP3 knock-down augmented sensitivity to GCs in THP-1 cells, whereas NLRP3 inflammasome activation lowered GC receptor concentration, increasing GC resistance in U937 cells. Our results uncovered a new biological mechanism by which patients with INS may acquire GC resistance, that could be used in future as a novel noninvasive diagnostic tool. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? ☑ Approximately 80% of patients with idiopathic nephrotic syndrome (INS) respond to glucocorticoids, with the remaining 20% being steroid-resistant. WHAT QUESTION DID THIS STUDY ADDRESS? ☑ Whether NLRP3 gene promoter methylation was able to discriminate glucocorticoid-resistant from glucocorticoid (GC)-sensitive INS. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? ☑ In both adults and children, NLRP3 promoter methylation was significantly reduced in leukocytes of patients with GC-resistant compared with GC-sensitive INS. NLRP3 inflammasome activation lowered GC receptor concentration and augmented GC resistance, whereas NLRP3 knockdown increased sensitivity to GCs in cell lines representative of monocytes (U937 and THP1). HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? ☑ Our findings uncovered a new biological mechanism whereby patients with INS may develop resistance to GCs that could be used in the future as a novel noninvasive diagnostic tool.

Assessment of physical performance and body composition in male renal transplant patients.

BACKGROUND: Renal transplant (RTX) recipients seem to experience a better quality of life compared to dialysis patients. However, the factors responsible for this positive effect are not completely defined. Conceivably, a change in the physical performance of these patients could play a role. METHODS: To assess this, we measured: (1) waist circumference, fat mass and appendicular fat-free mass (aFFM) by dual-energy X-ray densitometry, (2) physical performance with the Short Physical Performance Battery, and (3) muscle strength with the handgrip test, in 59 male RTX, 11 chronic kidney disease in conservative treatment (CKD) and 10 peritoneal dialysis (PD) patients. RESULTS: Surprisingly, anthropometric characteristics and body composition were similar among the three groups. However, despite a low aFFM, muscle strength was higher in stable RTX recipients > 5 years after transplantation than in dialyzed patients. Instead, CKD (wait-listed for RTX) had similar muscle strength to RTX patients. Waist circumference in RTX recipients showed a redistribution of body fat with increased central adipose tissue allocation compared to PD. At linear regression analysis, age, weight, height, aFFM, hemoglobin and transplant age were independent predictors of handgrip strength, explaining about 37% of the variance. Age and transplant age accounted for 18 and 12% of variance, respectively. CONCLUSIONS: Our study demonstrates, for the first time, that clinically stable RTX recipients have greater muscle strength than dialyzed patients and suggests that the handgrip test could be an effective and easy-to-perform tool to assess changes in physical performance in this large patient population.

mTOR Inhibition Role in Cellular Mechanisms.

The mammalian target of rapamycin inhibitors (mTOR-I), drugs widely used in transplant medicine and oncology, exert their function by inhibiting a serine/threonine kinase with a pivotal role in cellular metabolism and in a wide range of eukaryotic biological/cellular functions and signaling networks. Additionally, as largely described, the inhibition of mTOR has a major impact on cellular metabolism by stimulating synthesis of proteins and lipids, inhibiting catabolic processes, such as lysosome biogenesis and autophagy, and controlling cell survival, cytoskeleton organization, lipogenesis, and gluconeogenesis. All these biological functions are essential to guarantee body homeostasis and survival. Therefore, it is necessary for clinicians and researchers to better understand this complex pathway to ameliorate patients' treatment empathizing therapeutic effects to minimize/avoid toxicities and to propose new valuable research strategies.The aim of this article has been to underline the complexity of the mTOR pathway and to review the recent literature describing the consequences of its inhibition on several cellular functions including (a) protein synthesis, (b) cell cycle,

[Pharmacogenetics: a promising tool to personalize immunosuppressive therapy in renal transplantation]. / Farmacogenetica: un possibile strumento per la personalizzazione della terapia immunosoppressiva nel trapianto renale.

Renal transplantation is the gold standard therapy for patients affected by end stage renal disease. It is a clinical condition characterized by severe biological/biochemical alterations that requires renal replacement therapy to ensure patients survival. In most cases, it is followed by a significant improvement of patients quality of life, reduction in medical expenses and prolongation of life. However, to reach these positive clinical effects, patients need to take several immunosuppressive medications (calcineurin inhibitors, mTOR inhibitors and antimetabolites) characterized by a narrow therapeutic index, that, in some cases, could cause important adverse effects. To avoid toxicities and adverse drug reactions, immunosuppressors should be correctly administered, according to the blood trough levels. Nevertheless, in most of the times, this methodology to adjust drug doses gives inadequate and non-reproducible results. Additionally, as largely described, inherited differences in drug metabolism and disposition and genetic variability in therapeutic targets (e.g. receptors) need to be taken into account because of their role in modulating drug effects and toxicities. Therefore, worldwide researchers are working together to identify biomarkers, useful to personalize therapy based on genetic characteristics of patients. In this context, we believe that the omics techniques could represent a future powerful instruments that, whether employed routinely, could help to reach this objective.

The relationship between calcium kidney stones, arterial stiffness and bone density: unraveling the stone-bone-vessel liaison.

BACKGROUND AND OBJECTIVES: Kidney stone disease is associated with a higher incidence of cardio-vascular (CV) events for still unclear reasons. Reduced bone density is also a frequent finding in calcium kidney stones. The association of reduced bone density with increased vascular stiffness and calcification has been discovered in a number of conditions. We investigated the hypothesis that patients with calcium kidney stones have increased arterial stiffness, which would be associated with reduced bone density and higher CV risk. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: We compared measures of arterial stiffness [carotid-radial pulse-wave velocity (CR-PWV), carotid-femoral pulse-wave velocity (CF-PWV) and augmentation index (AI)] and of bone density (T-scores determined at lumbar spine, neck and hip) among 42 idiopathic calcium stone formers compared with 42 age- and sex-matched healthy volunteers. RESULTS: Stone formers had higher values of CR-PWV, CF-PWV and AI, and lower values of all T-scores. Furthermore, the prevalence of abnormal arterial stiffness and reduced bone density was significantly higher among stone formers. Statistical adjustment for age, sex, body mass index and other covariates did not change the results. CONCLUSIONS: Our study confirms that stone formers have increased arterial stiffness and reduced bone density. Abnormal arterial stiffness appears to be independent of reduced bone density and may explain the higher CV risk observed in stone formers.

[Extra-renal adverse effects of mTOR inhibitors: know them to optimize their use in renal transplantation]. / Effetti avversi extra-renali degli inibitori di mTOR: conoscerli per ottimizzare l'utilizzo di questi farmaci nel trapianto renale.

The mammalian target of rapamycin inhibitors (mTOR-I) sirolimus and everolimus represents a class of immunosuppressive drugs largely used in renal transplantation. The main mechanism of action of these drugs is the inhibition of the mammalian target of rapamycin (mTOR), a regulatory protein kinase involved in lymphocyte proliferation. Additionally, the inhibition of the crosstalk among mTORC1, mTORC2 and PI3K confers the anti-neoplastic activities of these drugs. Because of their specific pharmacological characteristics and their relative lack of nephrotoxicity, these inhibitors are a valid option to calcineurine inhibitors (CNIs) for maintenance immunosuppression in renal transplant recipients with chronic allograft damage. However, as other immunosuppressive drugs, mTOR-I may induce the development of several adverse effects (e.g., pulmonary toxicity, hematological disorders, dismetabolism, lymphedema) that need to be early diagnosed and treated to avoid severe illness in renal transplant patients. All these side effects are most of the time reversible and dose related. Therefore, it is unquestionable that these particular drugs should be administered at the lowest dose able to maintain relatively low trough levels, in order to increase their importance and specific therapeutic effects minimizing or avoiding drug toxicities. Utilization of low dosages of mTOR-I should be encouraged not only in CNI-combined schemas, but also when administered alone in CNI-free immunosuppressive protocol.