[The Outpatient Activity of the Onconephrology Clinic of Cremona in the First Semester of 2023].

Despite the rapidly growing area of onconephrology in the last decade, nephropathic patients have been rarely involved in clinical trials of cancer therapy, particularly in the case of chronic kidney disease (CKD) stage 4 (CKD4) or stage 5 (CKD5). We could offer better therapeutic opportunities to our patients thanks to the Onconephrology Clinic and the Multidisciplinary group, in which a dedicated team of specialists guarantees the highest level of possible care. In this paper, we analysed the activity of the first Italian OnconephrologyClinic, twelve years after its foundation. We studied retrospectively a cohort of 174 patients referred to our center in the last six months (from 11/01/2023 to 12/07/2023), with a total of 262 visits (40 first visits). We highlight a prevalence of moderated or advanced kidney disease, in contrast with the literature, which is probably the result of a transversal II level clinic with different specialists involved. Furthermore, in patients with a prolonged follow-up, we observed a progressive better attention to every kidney involvement, particularly in patients in active cancer therapy, by the oncologist colleagues. We observed a reduction of treatment withdrawals due to kidney toxicity, thanks to a multidisciplinary approach and experienced-based management. On the other side, we highlight also a delayed addressing of patients with acute kidney injury (AKI), which often results in chronic kidney damage. This could be related to a delayed identification of the reduced renal function, which is difficult to correctly value in patients with cancer.

Preventive strategies for acute kidney injury in cancer patients.

Acute kidney injury (AKI) is a common complication of cancer that occurs in up to 50% of neoplastic patients during the natural history of their disease; furthermore, it has a huge impact on key outcomes such as overall prognosis, length of hospitalization and costs. AKI in cancer patients has different causes, either patient-, tumour- or treatment-related. Patient-related risk factors for AKI are the same as in the general population, whereas tumour-related risk factors are represented by compression, obstruction, direct kidney infiltration from the tumour as well by precipitation, aggregation, crystallization or misfolding of paraprotein (as in the case of multiple myeloma). Finally, treatment-related risk factors are the most common observed in clinical practice and may present also with the feature of tumour lysis syndrome or thrombotic microangiopathies. In the absence of validated biomarkers, a multidisciplinary clinical approach that incorporates adequate assessment, use of appropriate preventive measures and early intervention is essential to reduce the incidence of this life-threatening condition in cancer patients.

Canakinumab as treatment for COVID-19-related pneumonia: A prospective case-control study.

OBJECTIVES: Canakinumab is an IL-1ß antibody that neutralises the activity of IL-1ß. This study examined the efficacy and safety of canakinumab in patients with moderate COVID-19-related pneumonia. DESIGN: This study aimed to evaluate the reduction in duration of hospitalisation with adequate oxygen status. Forty-eight patients with moderate COVID-19-related pneumonia were asked to participate in the prospective case-control study: 33 patients (cases) signed informed consent and received canakinumab (Cohort 1) and 15 patients (Controls) refused to receive the experimental drug and received institutional standard of care (Cohort 2). RESULTS: Hospital discharge within 21 days was seen in 63% of patients in Cohort 1 vs. 0% in Cohort 2 (median 14 vs. 26 days, respectively; p < 0.001). There was significant clinical improvement in ventilation regimes following administration of canakinumab compared with Cohort 2 (Stuart-Maxwell test for paired data, p < 0.001). Patients treated with canakinumab experienced a significant increase in PaO2:FiO2 (p < 0.001) and reduction in lung damage by CT (p = 0.01), along with significant decreases in immune/inflammation markers that were not observed in Cohort 2. Only mild side-effects were seen in patients treated with canakinumab; survival at 60 days was 90.0% (95% CI 71.9-96.7) in patients treated with canakinumab and 73.3% (95% CI 43.6-89.1) for Cohort 2. CONCLUSIONS: Treatment with canakinumab in patients with COVID-19-related pneumonia rapidly restored normal oxygen status, decreased the need for invasive mechanical ventilation, and was associated with earlier hospital discharge and favourable prognosis versus standard of care.

Overweight-obesity is associated with decreased vitamin K2 levels in hemodialysis patients.

OBJECTIVES: Obesity is an important risk factor for morbidity and mortality. Vitamin K2 is involved in the production of bone and matrix amino acid g-carboxy-glutamic acid (Gla) proteins (vitamin K-dependent proteins [VKDPs]), regulating bone and vascular calcification (VC). Bone Gla protein (BGP) is involved both in bone mineralization and VCs. We assessed the relationships between vitamin K levels and body mass index (BMI) according to the hypothesis that the impact of BMI on mortality is partly driven by low vitamin K levels. METHODS: The Vitamin K Italian (VIKI) study included 387 hemodialysis patients from 18 dialysis centers in Italy. We determined plasma levels of bone markers: vitamin K levels, VKDPs, vitamin 25(OH)D, alkaline phosphatase (ALP), parathyroid hormone (PTH), calcium (Ca), phosphorus (P) and routine biochemistry. BMI was classified into the following categories: underweight (BMI < 18.5 kg/m2), normal weight (18.5 ≤ BMI < 25 kg/m2), overweight (25 ≤ BMI < 30 kg/m2) and obese (BMI ≥ 30 kg/m2). RESULTS: 45.2% of patients were overweight or obese. Stratification by BMI demonstrated lower median menaquinone-7 (MK7)/triglycerides levels in obese patients (0.42 ng/mg [0.19, 0.87], p = 0.005). BGP levels were lower in overweight and obese patients (152 mcg/L [83.2, 251] and 104 mcg/L [62.7, 230], p = <0.001). Furthermore, there was an inverse correlation between MK7/triglycerides levels and BMI (regression coefficient ß = -0.159; p = 0.003). In multiple linear regression, there was an inverse relationship between BGP levels and BMI (ß = - 0.119; p = 0.012). CONCLUSIONS: These data are the first to report an inverse relationship between Vitamin K2 levels and BMI in hemodialysis patients. Further studies are needed to confirm these findings and to determine if lower levels of Vitamin K are related to greater morbidity and mortality in this at-risk population.

The basics of onco-nephrology in the renal clinic.

Onconephrology is a rapidly evolving subspecialty that covers all areas of renal involvement in cancer patients. The complexity of the field may benefit from well-defined multidisciplinary management by a dedicated team. Patients with cancer frequently suffer from concurrent chronic kidney disease (CKD), with a prevalence ranging from 12% to 53% at the time of cancer diagnosis. Taking into account the incidence of cancer and the prevalence of CKD in the Italian population, we estimate that about 44,000 patients suffered from both diseases in 2020. Since there is an increasing necessity to address the needs of this population in dedicated outpatient clinics, it is critical to highlight some basic characteristics and to suggest areas of development. Our experience in the nephrological management of cancer patients clearly suggests the need to implement dedicated multidisciplinary teams and to create onconephrology clinics (at least within larger, referral, hospitals). Furthermore, it must be kept in mind that not only is CKD common in cancer patients, but also that the concomitant presence of these two conditions too often excludes cancer patients from clinical trials, thus limiting their access to therapies that could potentially improve their outcomes. Indeed, the Renal Insufficiency and Cancer Medications (IRMA) study found that cancer patients with CKD or on dialysis are often undertreated, or are exposed to either ineffective or toxic anticancer agents. Finally, the aim of this article is to initiate a debate about what an onconephrology outpatient clinic might look like, in order to ensure the highest quality of care for this growing patient population.

Vitamin K and Kidney Transplantation.

The assessment of the vitamin K status and its effects on clinical outcomes in kidney transplantation (KT) patients has sparked interest, but it is still largely unfulfilled. In part, this is due to difficulties in laboratory measurements of vitamin K, especially K2 vitamers. Vitamin K status is currently best assessed by measuring undercarboxylated vitamin-K-dependent proteins. The relative contribution of vitamin K1 and K2 to the health status of the general population and CKD (chronic kidney disease) patients, including KT patients, is also poorly studied. Through a complete and first review of the existing literature, we summarize the current knowledge of vitamin K pathophysiology and its potential role in preventing KT complications and improving organ survival. A specific focus is placed on cardiovascular complications, bone fractures, and the relationship between vitamin K and cancer. Vitamin K deficiency could determine adverse outcomes, and KT patients should be better studied for vitamin K assessment and modalities of effective therapeutic approaches.

Genetic variant of C1GalT1 contributes to the susceptibility to IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is a common form of primary glomerulonephritis characterized by diffuse glomerular mesangial IgA1 deposition that leads to mesangial proliferation and chronic glomerular inflammation. Analyses of serum IgA1 from IgAN patients revealed an abnormal galactosylation of the O-linked carbohydrate moieties of IgA that may be a result of altered activity of core 1 beta1,3-galactosyltransferase (C1GalT1). To evaluate the association between C1GalT1 single nucleotide polymorphisms (SNPs) and IgAN, we performed a case control study on cohorts from the Italian population. METHODS: We sequenced C1GalT1 coding and promoter regions in 284 IgAN patients and 210 healthy controls. The functional role of 3' untranslated region (3'UTR) SNPs was studied using electrophoretic mobility shift assays and real-time quantitative PCR. RESULTS: We analyzed 8 SNPs in the C1GalT1 gene: 5 SNPs were in the promoter region and 3 SNPs in the 3'UTR. The allele 1365G in the 3'UTR was significantly more frequent in IgAN patients than in healthy controls. CONCLUSION: The 1365G allele and 1365G/G genotype seem to confer susceptibility to IgAN.

Genetic heterogeneity in Italian families with IgA nephropathy: suggestive linkage for two novel IgA nephropathy loci.

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide, but its etiologic mechanisms are still poorly understood. Different prevalences among ethnic groups and familial aggregation, together with an increased familial risk, suggest important genetic influences on its pathogenesis. A locus for familial IgAN, called "IGAN1," on chromosome 6q22-23 has been described, without the identification of any responsible gene. The partners of the European IgAN Consortium organized a second genomewide scan in 22 new informative Italian multiplex families. A total of 186 subjects (59 affected and 127 unaffected) were genotyped and were included in a two-stage genomewide linkage analysis. The regions 4q26-31 and 17q12-22 exhibited the strongest evidence of linkage by nonparametric analysis (best P=.0025 and .0045, respectively). These localizations were also supported by multipoint parametric analysis, in which peak LOD scores of 1.83 ( alpha =0.50) and 2.56 ( alpha =0.65) were obtained using the affected-only dominant model, and by allowance for the presence of genetic heterogeneity. Our results provide further evidence for genetic heterogeneity among families with IgAN. Evidence of linkage to multiple chromosomal regions is consistent with both an oligo/polygenic and a multiple-susceptibility-gene model for familial IgAN, with small or moderate effects in determining the pathological phenotype. Although we identified new candidate regions, replication studies are required to confirm the genetic contribution to familial IgAN.

IgA nephropathy: the presence of familial disease does not confer an increased risk for progression.

BACKGROUND: Immunoglobulin A (IgA) nephropathy is the most common form of glomerulonephritis worldwide. Familial and sporadic cases are recognized, and a locus associated with the familial form of the disease was mapped to chromosome 6. Recent data suggest the familial IgA nephropathy form may have a poorer outcome than the sporadic form. METHODS: We tested the hypothesis of unequal survival rates between the 2 forms of disease by analyzing time from biopsy to end-stage renal disease in patients of Italian ancestry; 589 patients with sporadic and 96 patients with familial IgA nephropathy. RESULTS: Overall 10- and 20-year renal survival probabilities of the cohort as a whole were 71% and 50%, respectively. Macroscopic hematuria was the modality of clinical presentation in 51% of patients with familial IgA nephropathy and 39% of patients with sporadic IgA nephropathy. At univariable analysis, the sporadic form of IgA nephropathy was associated significantly with increased risk for renal death. However, patients with the sporadic form tended to be more hypertensive and diagnosed later, with signs of more advanced renal disease than those with familial disease at baseline. In the regression model, form of disease lost any independent effect. Only male sex, lower baseline glomerular filtration rate, greater proteinuria, and histopathologic score proved to be independent predictors of disease progression. Treatment with steroids or angiotensin-converting enzyme inhibitors was associated with improved outcomes. CONCLUSION: Our study does not confirm that familial IgA nephropathy has a worse prognosis than the sporadic form. The similar renal phenotype may support a common pathogenic mechanism underlying familial and sporadic IgA nephropathy.

Role of interferon-gamma gene polymorphisms in susceptibility to IgA nephropathy: a family-based association study.

T helper (h) lymphocytes in pathogenic immune response at mucosal effector site play a key role in IgA nephropathy (IgAN). We evaluated the impact of some Th1/Th2/Th3/T(R)-type, and of monocyte/macrophage cytokines on IgAN susceptibility with a family-based association study including 53 patients, 45 complete trios, 4 incomplete trios and 36 discordant siblings. Cytokine gene polymorphisms with a potential regulatory role on their production were investigated using the family-based association test (FBAT): IFNgamma intron-1 CA repeat at position 1349-1373; IL-13 -1055C/T; TGFbeta +915G/C; IL-10 5'-proximal and distal microsatellites; TNFalpha -308G/A, -238G/A. The FBAT multi-allelic analysis showed an association between IFNgamma polymorphism and susceptibility to IgAN (P=0.03). The bi-allelic analysis evidenced that the 13-CA repeat allele was preferentially transmitted to the affected individuals (P=0.006; Bonferroni P-value=0.04). The direct sequencing of IFNgamma amplicons showed a strict association between the 13-CA repeat allele and the A variant of the +874T/A single nucleotide polymorphism (SNP rs2430561) directly adjacent to the 5' end of the microsatellite. The in vitro production of IFNgamma evaluated in peripheral blood mononuclear cells from 10 genotyped patients demonstrated a correlation between the +874A allele and a lower production of IFNgamma (P=0.028 Mann-Whitney test). This SNP affects IFNgamma production lying within a binding site for the transcription factor NF-kappaB. No significant difference was observed in the 15 years renal survival between IgAN patients carrying different IFNgamma gene polymorphisms. This first family-based association study demonstrates that the +874A allele, strictly associated with IFNgamma 13-CA repeat allele, confers susceptibility to IgAN, without influencing renal survival.

The IgA nephropathy Biobank. An important starting point for the genetic dissection of a complex trait.

BACKGROUND: IgA nephropathy (IgAN) or Berger's disease, is the most common glomerulonephritis in the world diagnosed in renal biopsied patients. The involvement of genetic factors in the pathogenesis of the IgAN is evidenced by ethnic and geographic variations in prevalence, familial clustering in isolated populations, familial aggregation and by the identification of a genetic linkage to locus IGAN1 mapped on 6q22-23. This study seems to imply a single major locus, but the hypothesis of multiple interacting loci or genetic heterogeneity cannot be ruled out. The organization of a multi-centre Biobank for the collection of biological samples and clinical data from IgAN patients and relatives is an important starting point for the identification of the disease susceptibility genes. DESCRIPTION: The IgAN Consortium organized a Biobank, recruiting IgAN patients and relatives following a common protocol. A website was constructed to allow scientific information to be shared between partners and to divulge obtained data (URL: http://www.igan.net). The electronic database, the core of the website includes data concerning the subjects enrolled. A search page gives open access to the database and allows groups of patients to be selected according to their clinical characteristics. DNA samples of IgAN patients and relatives belonging to 72 multiplex extended pedigrees were collected. Moreover, 159 trios (sons/daughters affected and healthy parents), 1068 patients with biopsy-proven IgAN and 1040 healthy subjects were included in the IgAN Consortium Biobank. Some valuable and statistically productive genetic studies have been launched within the 5th Framework Programme 1998-2002 of the European project No. QLG1-2000-00464 and preliminary data have been published in "Technology Marketplace" website: http://www.cordis.lu/marketplace. CONCLUSION: The first world IgAN Biobank with a readily accessible database has been constituted. The knowledge gained from the study of Mendelian diseases has shown that the genetic dissection of a complex trait is more powerful when combined linkage-based, association-based, and sequence-based approaches are performed. This Biobank continuously expanded contains a sample size of adequately matched IgAN patients and healthy subjects, extended multiplex pedigrees, parent-child trios, thus permitting the combined genetic approaches with collaborative studies.