Stochastic Pharmacokinetic-Pharmacodynamic Modeling for Assessing the Systemic Health Risk of Perfluorooctanoate (PFOA)

A phase 1 dose-escalation trial assessed the chemotherapeutic potential of ammonium perfluorooctanoate (APFO). Forty-nine primarily solid-tumor cancer patients who failed standard therapy received weekly APFO doses (50mg-1200mg) for six-weeks. Clinical chemistries and plasma PFOA (anionic APFO) were measured pre-dose and weekly thereafter. Several clinical measures including total cholesterol, high-density lipoproteins (HDL), thyroid stimulating hormone (TSH), and free thyroxine (fT4), relative to PFOA concentrations, were examined by: standard statistical analyses using general estimating equations (GEE) and a probabilistic analysis using probability distribution functions (pdf) at various PFOA concentrations; and a two-compartment pharmacokinetic/pharmacodynamic (PK/PD) model to directly estimate mean changes. Based on the GEE, the average rates of change in total cholesterol and fT4 associated with increasing PFOA were approximately -1.2x10−3mmol/L/μM and 2.8x10−3pmol/L/μM, respectively. The PK/PD model predicted more closely the trends observed in the data as well as the pdfs of biomarkers. A decline in total cholesterol was observed, with a clear transition in shape and range of the pdfs, manifested by the maximum value of the Kullback-Leibler (KL) divergence, that occurred at plasma PFOA between 420 and 565 μM (175,000–230,000 ng/mL). HDL was unchanged. An increase in fT4 was observed at a higher PFOA transition point, albeit TSH was unchanged. Our findings are consistent with some animal models and may motivate re-examination of the epidemiological studies to PFOA at levels several orders of magnitude lower than this study. These observational studies have reported contrary associations, but currently understood biology does not support the existence of such conflicting effects

The importance of bone biopsy in chronic kidney disease–Mineral bone disorders

Renal osteodystrophy (ROD) is not a uniform bone disease; it is a heterogeneous group of metabolic bone diseases due to chronic kidney disease (CKD). The traditional term of ROD does not accurately include the wide spectrum of “CKD–mineral and bone disorder” (CKD–MBD) and has been restricted to define the several specific histologic disturbances of bone disease associated with CKD. Circulating parathyroid hormone (PTH) and total alkaline phosphatase levels do not always reflect bone turnover in CKD–MBD, whereas bone biopsy provides precise information regarding bone pathology. Given the lack of specificity of several biomarkers and noninvasive tools regarding ROD, bone biopsy is required for precise diagnosis and for the determination of therapeutic strategies. In clinical practice, bone biopsy is not performed due to lack of enthusiasm among nephrologists for several reasons including the invasiveness of the procedure, the potential pain, and lack of technical training. Since the application of bone biopsy in clinical practice is unrealistic, several biomarkers with specificity for bone disease should be studied

Obstructive nephropathy

Obstructive uropathy (OU) is a common condition in the elderly, particularly in men due to prostate disease. Besides the reversible effects of acute urinary tract obstruction on kidney function, with reduction of renal blood flow (RBF), glomerular filtration rate (GFR) and a tubular dysfunction, chronic obstruction can additionally cause permanent kidney injury. In this context, prolonged and untreated OU results in obstructive nephropathy (ON). ON is a nonspecific tubulointerstitial nephropathy, which can lead to chronic kidney disease (CKD) and to end-stage renal disease (ESRD). ON is one of the leading causes of ESRD in the elderly. Experimental ON models ureteral obstruction-mediated kidney injury and helps unravel key processes of the CKD pathogenesis. Apart from reversing obstruction, treatment strategies of ON consist of selective targeting on molecular mechanisms implicated in apoptosis, inflammation, and renal fibrosis. © 2019 Elsevier Inc. All rights reserved

Prevalence of anemia in patients with type II diabetes and mild to moderate chronic kidney disease and the impact of anti-RAS medications

Anemia is a common feature of diabetes and chronic kidney disease (CKD) mainly due to erythropoietin (EPO) deficiency and uremic toxicity. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been established as first-choice medications for the treatment of diabetic nephropathy. However, there are conflicting data regarding their impact on hemoglobin levels in patients with diabetic nephropathy. We evaluated the prevalence of anemia in 101 patients with diabetes mellitus type II and CKD at stage III-IV (group A) compared with 101 non-diabetic patients with similar renal function (group B). Moreover, we evaluated the impact of ACE inhibitors and ARBs on patients′ anemia. Anemia was observed in 60 patients in group A and in 47 patients in group B (P < 0.01). Thirty-one (31) patients in group A and 19 patients in group B were receiving exogenous EPO for correction of renal anemia (P <0.05). Mean values of hemoglobin did not show significant differences (12.5 ± 1.8 vs 12.6 ± 1.7 g/dL) between the two groups. Seventy-five patients in group A and 52 patients in group B were receiving ACE inhibitors and/or ARBs (P <0.01), but, after multivariate analysis, we could not detect any association between anemia and the prescription of these medications. Anemia is more common in diabetic patients with CKD stage III-IV than in non-diabetic patients with similar renal function. Our results indicate that ACE inhibitors and ARBs are not a significant cause of anemia for both populations

Bimodal Solutions or Twice-Daily Icodextrin to Enhance Ultrafiltration in Peritoneal Dialysis Patients

The efficacy and safety of icodextrin has been well established. In this paper, we will discuss the pharmacokinetics and biocompatibility of icodextrin and its clinical effect on fluid management in peritoneal dialysis patients. Novel strategies for its prescription for peritoneal dialysis patients with inadequate ultrafiltration are reviewed.Peer Reviewe

Pathogenesis and management of intradialytic hypertension

Hypertension is common in chronic kidney disease patients especially in those undergoing hemodialysis (HD). Usually, blood pressure falls after the HD session but in some patients a paradoxical increase has been observed during or immediately after HD. This phenomenon is referred as intradialytic hypertension. HD patients with intradialytic hypertension or increased blood pressure during HD present higher cardiovascular (CV) morbidity and mortality rates. The underlying mechanism of intradialytic hypertension is multifactorial. Activation both of renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, volume and sodium overload with concomitant increase in cardiac output, and endothelial dysfunction have been implicated in the pathogenesis of intradialytic hypertension. Given the lack of clinical trials regarding the pathophysiology and management of intradialytic hypertension, current treatment strategies are based mainly on experts’ opinion. The purpose of this review is to describe the pathophysiology of intradialytic hypertension and discuss current strategies in order to improve intradialytic blood pressure management and concomitant HD patients’ outcomes. © 2014 Bentham Science Publishers

Thirty years survivor on hemodialysis: A case report

Hemodialysis is a widely performed and safe procedure; therefore, the numbers of long-term survivors on hemodialysis therapy have been increasing. We present a woman who had been on uninterrupted hemodialysis for 30 years and did well for much of her time on hemodialysis, despite a long-standing uneven course. The literature of extremely long-lived patients on un-interrupted hemodialysis is reviewed and the clinical characteristics and complications encountered in these patients are discussed