Pemetrexed (PEM) is a new-generation multitargeted antifolate agent with a demonstrated broad-spectrum activity in several types of human cancers, including non-small cell lung cancer (NSCLC) and ...mesothelioma. Major side effects include dose-limiting hematologic toxicities. PEM nephrotoxicity is well known; however, its frequency is considered to be low.
Here we report two cases of acute kidney injury (AKI) related to PEM administration (500 mg/m2) in patients with NSCLC. The first patient required hemodialysis treatment and was submitted to renal biopsy which showed acute tubular damage and interstitial edema without acute tubular necrosis. No other potential nephrotoxic agents were identified. The second patient developed AKI, not proven by biopsy and did not require renal replacement therapy. Both patients, on regular supplementation with folic acid and vitamin B12, concomitantly developed myelosuppression and even several months after PEM withdrawal, showed only a modest improvement of renal function.
PEM is an antifolate antineoplastic agent with a broad-spectrum activity in locally advanced or metastatic NSCLC. It has been shown that PEM allows longer survival. The risk of acute or chronic kidney disease may be one of the prices to be paid for this success.
Hyperphosphatemia is associated with morbidity and mortality in hemodialysis patients. The use of calcium chelators is restricted by the risk of hypercalcemia and vascular calcifications. Sevelamer, ...a non-calcium chelator, is associated with risks of metabolic acidosis and poor compliance. Lanthanum carbonate is a non-calcium chelator not associated with these issues. However, accumulation in liver and bone has been a reason for concern.
Adult patients (n=112) from 9 hemodialysis centers, with serum phosphorus >5.5 mg/dL and on hemodialysis for >1 year, were selected to switch to lanthanum carbonate (mean dosage: 2,189 ± 491 mg/day); 103 completed the study. Laboratory assays for serum phosphate, calcium, parathyroid hormone, alkaline phosphatase, gamma-glutamyl transpeptidase (gammaGT), aspartate transaminase, alanine transaminase and plasma bicarbonate were performed monthly. Seven patients underwent a bone biopsy for evaluation of lanthanum bone content.
Switching to lanthanum carbonate led to a reduction in mean serum phosphate levels (-18.2%; p<0.001) and calcium × phosphorus product (-17.6%; p<0.0001). There were no important changes in other variables, except for an increase in transaminases in 2 patients with preexisting liver disease, who discontinued therapy. An increase in plasma bicarbonate concentration was observed (p=0.001). Although some lanthanum was detected in bone, its distribution did not follow the mineralization front.
Lanthanum carbonate is effective and well tolerated, provided that recipients do not have preexisting liver disease. After 8 months of treatment, lanthanum was not detected in the mineralization front of bone. In hemodialysis patients, lanthanum carbonate does not seem to be involved in metabolic bone disease.
Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) are a major cause of morbidity in children. We measured the risk of progression to end-stage renal disease in 312 patients with CAKUT ...preselected for the presence of anomalies in kidney number or size. A model of dialysis-free survival from birth was established as a function of the renal CAKUT categories of solitary kidney; unilateral and bilateral hypodysplasia; renal hypodysplasia associated with posterior urethral valves; and multicystic and horseshoe kidney. Cox regression analysis took into account the concomitant presence of vesicoureteral reflux, year of diagnosis, and time-varying values of serum creatinine, proteinuria, and hypertension. By 30 years of age, 58 patients had started dialysis, giving a yearly incidence of 0.023 over a combined 2474 patient risk years. The risk for dialysis was significantly higher for patients with a solitary kidney or with renal hypodysplasia associated with posterior urethral valves (hazard ratios of 2.43 and 5.1, respectively) compared to patients with unilateral or bilateral renal hypodysplasia, or multicystic or horseshoe kidney, and was independent of other prognostic factors. Our study shows that sub-clinical defects of the solitary kidney may be responsible for a poorer prognosis compared to more benign forms of CAKUT. Prospective studies are needed to validate these results.
We examined the burden of large, rare, copy-number variants (CNVs) in 192 individuals with renal hypodysplasia (RHD) and replicated findings in 330 RHD cases from two independent cohorts. CNV ...distribution was significantly skewed toward larger gene-disrupting events in RHD cases compared to 4,733 ethnicity-matched controls (p = 4.8 × 10−11). This excess was attributable to known and novel (i.e., not present in any database or in the literature) genomic disorders. All together, 55/522 (10.5%) RHD cases harbored 34 distinct known genomic disorders, which were detected in only 0.2% of 13,839 population controls (p = 1.2 × 10−58). Another 32 (6.1%) RHD cases harbored large gene-disrupting CNVs that were absent from or extremely rare in the 13,839 population controls, identifying 38 potential novel or rare genomic disorders for this trait. Deletions at the HNF1B locus and the DiGeorge/velocardiofacial locus were most frequent. However, the majority of disorders were detected in a single individual. Genomic disorders were detected in 22.5% of individuals with multiple malformations and 14.5% of individuals with isolated urinary-tract defects; 14 individuals harbored two or more diagnostic or rare CNVs. Strikingly, the majority of the known CNV disorders detected in the RHD cohort have previous associations with developmental delay or neuropsychiatric diseases. Up to 16.6% of individuals with kidney malformations had a molecular diagnosis attributable to a copy-number disorder, suggesting kidney malformations as a sentinel manifestation of pathogenic genomic imbalances. A search for pathogenic CNVs should be considered in this population for the diagnosis of their specific genomic disorders and for the evaluation of the potential for developmental delay.
We report a case of acute interstitial nephritis (AIN), most likely induced by rosuvastatin, in an 83-year-old male patient. The patient underwent angioplasty of the left internal carotid artery, ...after which he began a regimen of rosuvastatin (20 mg/day). After 3 weeks the patient was admitted to our unit for acute renal failure with mild proteinuria with negligible urinary sediment. A left kidney biopsy showed dense interstitial infiltrates, mainly composed of lymphocytes with evident tubulitis. Rosuvastatin withdrawal plus prednisolone (1 mg/kg/day) treatment, which was slowly tapered over a period of 4 weeks, allowed for a complete recovery of renal function. To our knowledge, this is the first case report of rosuvastatin-induced AIN. Acute renal failure is associated with a clear increase in morbidity, length of hospital stay and mortality. Moreover, since statins are among the most widely prescribed drugs in Western countries, we think that the risk of AIN should be taken into account as a possible side effect of rosuvastatin.
Oocytes isolated from cows of reproductive age with reduced antral follicle counts (AFC) have a diminished capacity of embryonic development, which may be related to alterations in the mechanism that ...directs the proper segregation of chromosomes. Because we demonstrated that progesterone receptor membrane component 1 (PGRMC1) is involved in chromosome congression and metaphase II (MII) plate formation, the present study was designed to determine 1) if the decrease in oocyte developmental competence observed in dairy cows with a reduced AFC is due to a higher incidence of aneuploidy and 2) whether alterations in PGRMC1 contributes to the incidence of aneuploidy. Oocytes from ovaries with reduced AFC and age-matched controls were matured in vitro and the occurrence of aneuploidy determined as well as the mRNA level and localization of PGRMC1. Although oocytes from ovaries with reduced AFC were capable of undergoing meiosis in vitro, these oocytes showed a 3-fold increase in aneuploidy compared to oocytes isolated from control ovaries (P < 0.05). Although Pgrmc1 mRNA levels were not altered, PGRMC1 and aurora kinase B (AURKB) failed to localize to precise focal points on MII chromosomes of oocytes from ovaries with reduced AFC. Furthermore, when oocytes of control ovaries were cultured with an inhibitor of AURKB activity, their MII plate was disrupted and PGRMC1 was not properly localized to the chromosomes. These results suggest that alterations in PGRMC1 and/or AURKB localization account in part for the increased aneuploidy and low development competence of oocytes from ovaries with reduced AFC.
Evidence-based preventive interventions for adolescent substance use, violence, and mental health issues are increasingly being adapted and disseminated internationally. In the present paper, we ...report the results of an effectiveness study that was part of a comprehensive initiative by a coalition of health promotion organizations in the Lombardy region of Italy to select, culturally adapt, implement, evaluate, and sustain an evidence-based drug abuse prevention program developed in the USA. Findings are presented from a large-scale effectiveness study of the Life Skills Training prevention program among over 3000 students attending 55 middle schools in Italy. The prevention program taught drug refusal skills, antidrug norms, personal self-management skills, and general social skills. Relative to comparison group students, students who received the prevention program were less likely to initiate smoking at the post-test and 2-year follow-up, and less likely to initiate weekly drunkenness at the 1-year follow-up. The program had direct positive effects on several cognitive, attitudinal, and skill variables believed to play a protective role in adolescent substance use. The findings from this study show that a drug abuse prevention program originally designed for adolescents in the USA is effective in a sample of Italian youth when a rigorous and systematic approach to cultural adaptation is followed that incorporates the input of multiple stakeholders.
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