Post-Kidney Transplant Cancer: A Real-World Retrospective Analysis From a Single Italian Center.

We describe the epidemiology of cancer after kidney transplantation (KTx), investigating its risk factors and impact on therapeutic management and survival in KTx recipients (KTRs). The association between modification of immunosuppressive (IS) therapy after cancer and survival outcomes was analyzed. We collected data from 930 KTRs followed for 7 [1-19] years. The majority of KTRs received KTx from a deceased donor (84%). In total, 74% of patients received induction therapy with basiliximab and 26% with ATG. Maintenance therapy included steroids, calcineurin inhibitors, and mycophenolate. Patients with at least one cancer (CA+) amounted to 19%. NMSC was the most common tumor (55%). CA+ were older and had a higher BMI. Vasculitis and ADPKD were more prevalent in CA+. ATG was independently associated with CA+ and was related to earlier cancer development in survival and competing risk analyses (p = 0.01 and <0.0001; basiliximab 89 ± 4 vs. ATG 40 ± 4 months). After cancer diagnosis, a significant prognostic impact was derived from the shift to mTOR inhibitors compared to a definitive IS drug suspension (p = 0.004). Our data confirm the relevance of cancer as a complication in KTRs with ATG as an independent risk factor. An individualized choice of IS to be proposed at the time of KTx is crucial in the prevention of neoplastic risk. Finally, switching to mTORi could represent an important strategy to improve patient survival.

Osimertinib in a patient with end-stage kidney disease not on hemodialysis.

Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) effective in non- small cell lung cancer (NSCLC) with EGFR mutations. Since the drug is primally eliminated by the fecal route no dose adjustment is needed in patient with chronic-kidney disease (CKD); despite this there is limited data about its safety in cancer patients with end-stage renal disease (ESRD). Herein, we reported a case report of a 77-year-old woman, diagnosed in 2018 with lung adenocarcinoma EGFR mutated with lymph nodal and cerebral metastasis, who started Osimertinib 80 mg/day. She under- went 41 cycles of therapy with no Osimertinib interruptions, no severe toxicities and obtaining complete radiological response. We conclude that Osimertinib has an acceptable safety profile also in cancer patients with ESRD not undergoing hemodialysis (HD).

How to deal with renal toxicities from immune-based combination treatments in metastatic renal cell carcinoma. A nephrological consultation for Oncologists.

We are witnessing a revolution in the treatment of metastatic renal cell carcinoma (mRCC). Indeed, several immune-based combinations (ICI [immune checkpoint inhibitor] + ICI, or ICI + antiangiogenic agents) have been approved as first-line therapy for mRCC after demonstrating superior efficacy over the previous standard. Despite all the improvements made, safety remains a critical issue, adverse events (AEs) being the main reason for drug discontinuations or dose reductions, ultimately resulting in an increased risk of losing efficacy. Thus, a good understanding of the AEs associated with the use of immune-based combinations, their prevention, and management, are key in order to maximize therapeutic effectiveness. Among these AEs, renal ones are relatively frequent, but always difficult to be diagnosed, not to take into account that it is often difficult to determine which drug is to blame for such toxicities. Chronic kidney disease (CKD) is a common finding in patients with RCC, either as a pre-existing condition and/or as a consequence of cancer and its treatment; furthermore, CKD, especially in advanced stages and in patients undergoing dialysis, may influence the pharmacokinetics and pharmacodynamics properties of anticancer agents. Finally, managing cancer therapy in kidney transplanted patients is another challenge. In this review, we discuss the therapy management of immune-based combinations in patients with CKD, on dialysis, or transplanted, as well as their renal toxicities, with a focus on their prevention, detection and practical management, taking into account the crucial role of the consulting nephrologist within the multidisciplinary care of these patients.

[Biomarkers and Bone Turnover Markers in Chronic Kidney Disease - Mineral and Bone Disorders (CKD-MBD): Recent Advances].

Chronic Kidney Disease (CKD) provokes biochemical and systemic alterations, causing bone fragility with an increase in bone fracture risk, extraskeletal calcifications, increased morbidity, and cardiovascular mortality. The complex pathophysiological mechanism causes a syndrome called CKD-MBD (Chronic Kidney Disease - Mineral and Bone Disorders), which includes mineral and bone alterations leading to renal osteodystrophy (ROD). An early diagnosis is therefore essential to prevent the onset of more severe complications. A precise diagnosis of bone disorders and the subsequent administration of the best therapy is difficult without performing a bone biopsy. However, lately, the diagnostic focus is shifting to a series of molecules, the bone turnover markers (BTM), generated by the same bone tissue during the remodeling process, which is proving to be a useful diagnostic tool in the definition of ROD. BTMs are divided into bone formation molecules (amino-terminal propeptide of type 1 procollagen, P1NP; osteocalcin, OC; bone alkaline phosphatase, bALP) and bone resorption molecules (carboxy-terminal cross-linked telopeptide of type 1 collagen, CTX; isoform 5b tartrate-resistant acid phosphatase, TRAP-5b). There are also biomarkers of bone metabolism such as parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and sclerostin. Although PTH is one of the most used molecules, P1NP, bALP, CTX, and TRAP-5b have proven to be superior in the discrimination of low turnover pathologies. The diagnostic capability of these molecules and their potential still require further studies, but clinicians must include BTMs in the diagnostic process of CKD-MBD.

Real-world usage of Chronic Kidney Disease - Mineral Bone Disorder (CKD-MBD) biomarkers in nephrology practices.

Background: Chronic kidney disease mineral bone disorder (CKD-MBD) is a condition characterized by alterations of calcium, phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF-23) metabolism that in turn promote bone disorders, vascular calcifications, and increase cardiovascular (CV) risk. Nephrologists' awareness of diagnostic, prognostic, and therapeutic tools to manage CKD-MBD plays a primary role in adequately preventing and managing this condition in clinical practice. Methods: A national survey (composed of 15 closed questions) was launched to inquire about the use of bone biomarkers in the management of CKD-MBD patients by nephrologists and to gain knowledge about the implementation of guideline recommendations in clinical practice. Results: One hundred and six Italian nephrologists participated in the survey for an overall response rate of about 10%. Nephrologists indicated that the laboratories of their hospitals were able to satisfy request of ionized calcium levels, 105 (99.1%) of both PTH and alkaline phosphatase (ALP), 100 (94.3%) of 25(OH)D, and 61 (57.5%) of 1.25(OH)2D; while most laboratories did not support the requests of biomarkers such as FGF-23 (intact: 88.7% and c-terminal: 93.4%), Klotho (95.3%; soluble form: 97.2%), tartrate-resistant acid phosphatase 5b (TRAP-5b) (92.5%), C-terminal telopeptide (CTX) (71.7%), and pro-collagen type 1 N-terminal pro-peptide (P1NP) (88.7%). As interesting data regarding Italian nephrologists' behavior to start treatment of secondary hyperparathyroidism (sHPT), the majority of clinicians used KDOQI guidelines (n = 55, 51.9%). In contrast, only 40 nephrologists (37.7%) relied on KDIGO guidelines, which recommended referring to values of PTH between two and nine times the upper limit of the normal range. Conclusion: Results point out a marked heterogeneity in the management of CKD-MBD by clinicians as well as a suboptimal implementation of guidelines in Italian clinical practice.

[Management of Chemotherapy in Patients Subjected in Chronic Dialysis Treatment].

The incidence of tumors is increased in patients with chronic renal failure and even more in patients on dialysis. Dialysis can affect both therapy and prognosis of oncological patients. It increases both cancer-related and non-cancer-related mortality rates and is the main cause of a suboptimal use of therapies. In patients with renal impairment, the dosage of many chemotherapies should be reduced but, due to the lack of real knowledge of the pharmacokinetic and pharmacodynamic properties of these drugs in dialysis, dosage adjustments are often done empirically and most often avoided. Although many papers are available in the literature regarding chemotherapy in dialysis, there is a lack of consensus regarding drug dosages and administration schedules. Furthermore, guidelines are absent due to the lack of "evidence" for most of these patients, usually excluded from experimental treatments. Specific onconephrologic trials are therefore mandatory to decide how much, how, and when to use chemotherapy in patients on dialysis and thereby ensure adequate treatment for these patients.

[The Treatment of Metastatic Renal Cell Carcinoma: An Update].

The therapeutic landscape for renal cell carcinoma (RCC) has undergone significant changes in recent years. In this Literature review, we offer a synopsis of the latest scientific evidence in this field. The introduction of a standard of care in the adjuvant setting, based on immune checkpoint inhibitors (ICI), was a breakthrough. The efficacy of this treatment, calculated as the relapse risk reduction, can vary depending on multiple factors, whose knowledge is important for the clinician in the therapeutic choice. Another innovation concerns the first-line therapy for metastatic RCC. In this setting, the new standard is represented by an immune combination, a therapy based either on a doublet of ICIs or on a combination between an ICI and one VEGFR-TKI. Making the best choice between the available options requires careful evaluation, in order to tailor the most appropriate treatment for each patient. The critical analysis of the most recent clinical trials is a fundamental tool to tailor the correct clinical management of localized and advanced RCC. Finally, this review focuses on the role of the nephrologist in the management of RCC patients, across different disease settings.

Ultrasound elastography in chronic kidney disease: a systematic review and meta-analysis.

Ultrasound elastography (USE) is a noninvasive technique for assessing tissue elasticity, and its application in nephrology has aroused growing interest in recent years. The purpose of this article is to systematically review the clinical application of USE in patients with chronic kidney disease (CKD), including native and transplanted kidneys, and quantitatively investigate differences in elasticity values between healthy individuals and CKD patients. Furthermore, we provide a qualitative analysis of the studies included, discussing the potential interplay between renal stiffness, estimated glomerular filtration rate, and fibrosis. In January 2022, a systematic search was carried out on the MEDLINE (PubMed) database, concerning studies on the application of USE in patients with CKD, including patients with transplanted kidneys. The results of the included studies were extracted by two independent researchers and presented mainly through a formal narrative summary. A meta-analysis of nine study parts from six studies was performed. A total of 647 studies were screened for eligibility and, after applying the exclusion and inclusion criteria, 69 studies were included, for a total of 6728 patients. The studies proved very heterogeneous in terms of design and results. The shear wave velocity difference of - 0.82 m/s (95% CI: - 1.72-0.07) between CKD patients and controls was not significant. This result agrees with the qualitative evaluation of included studies that found controversial results for the relationship between renal stiffness and glomerular filtration rate. On the contrary, a clear relationship seems to emerge between USE values and the degree of fibrosis. At present, due to the heterogeneity of results and technical challenges, large-scale application in the monitoring of CKD patients remains controversial.

Time for Revival of Bone Biopsy with Histomorphometric Analysis in Chronic Kidney Disease (CKD): Moving from Skepticism to Pragmatism.

Bone Biopsy (BB) with histomorphometric analysis still represents the gold standard for the diagnosis and classification of different forms of renal osteodystrophy. Bone biopsy is the only technique able to provide comprehensive information on all bone parameters, measuring static and dynamic parameters of turnover, cortical and trabecular microarchitecture, and mineralization defects. In nephrological practice, bone biopsy yields relevant indications to support therapeutic choices in CKD, heavily impacting the management and prognosis of uremic patients. Unfortunately, the use of bone biopsy has decreased; a lack of expertise in performing and interpreting, perceived procedure invasiveness and pain, and reimbursement issues have all contributed to this decline. Nevertheless, both bone biomarkers and instrumental images cannot be considered reliable surrogates for histological findings, being insufficiently accurate to properly evaluate underlying mineral and bone disorders. This is a multidisciplinary position paper from the Nephrology and Osteoporosis Italian Scientific Societies with the purpose of restating the role of bone biopsy in CKD patient management and of providing strong solutions to allow diffusion of this technique in Italy, but potentially also in other countries. The Italian approach through the optimization and standardization of bone biopsy procedure, the construction of the Italian Hub and Spoke network, and a request for adjustment and national homogenization of reimbursement to the Italian Health Ministry has led the way to implement bone biopsy and to improve CKD patient management and prognosis.

[Immunotherapy in kidney cancer: how it has changed and what are the challenges for the nephrologist - focus on pembrolizumab].

Kidney cancer accounts for about 3.5% of all malignant neoplasms; in 85% of cases the tumor arises from cells of the renal parenchyma, with an incidence of 70% of the clear cells subtype. Surgery, at present, is the treatment of choice for most renal cancers; medical therapy, on the other hand, has only palliative purposes and is used only in the relapsed or metastatic patients. The therapeutic toolbox available in the fight against renal cancer is continuously renewed due to the approval of new drugs. In particular, in the 2000s, antiangiogenic drugs were introduced and showed good efficacy in terms of increased survival in patients with advanced renal carcinoma. Immunotherapy was a treatment strategy for renal cancer in the 1980s, when cytokines such as Interleukin-2 and Interferon were administered. The advent of antiangiogenic drugs had bound immunotherapy to a secondary role until the discovery of immune check-point inhibitors (ICIs), which have been approved in the various lines of treatment, in monotherapy or in combination with other drugs, as they have shown to increase the oncological outcome. In this review we analyze the evolution of immunotherapy for the treatment of kidney tumor from the viewpoint of nephrologists, with a special focus on renal adverse events, pembrolizumab and its recent approval as first line therapy in association with axitinib.