Early treatment with 2-deoxy-d-glucose reduces proliferative proteins in the kidney and slows cyst growth in a hypomorphic Pkd1 mouse model of autosomal dominant polycystic kidney disease (PKD).

In autosomal dominant polycystic kidney disease (ADPKD) there is cyst growth in the kidneys that leads to chronic kidney disease often requiring dialysis or kidney transplantation. There is enhanced aerobic glycolysis (Warburg effect) in the cyst lining epithelial cells that contributes to cyst growth. The glucose mimetic, 2-Deoxy-d-glucose (2-DG) inhibits glycolysis.

Raising serum uric acid with a uricase inhibitor worsens PKD in rat and mouse models.

Humans are predisposed to gout because they lack uricase that converts uric acid to allantoin. Rodents have uricase, resulting in low basal serum uric acid. A uricase inhibitor raises serum uric acid in rodents.

Overview of Antibiotic-Induced Nephrotoxicity.

Drug-induced nephrotoxicity accounts for up to 60% of cases of acute kidney injury (AKI) in hospitalized patients and is associated with increased morbidity and mortality in both adults and children. Antibiotics are one of the most common causes of drug-induced nephrotoxicity. Mechanisms of antibiotic-induced nephrotoxicity include glomerular injury, tubular injury or dysfunction, distal tubular obstruction from casts, and acute interstitial nephritis (AIN) mediated by a type IV (delayed-type) hypersensitivity response.

Metformin does not slow cyst growth in the PCK rat model of polycystic kidney disease.

Metformin (MET) has the potential to activate p-AMPK and block mTORC1-induced proliferation of tubular cells in PKD kidneys. The aim of this study was to determine the effects of MET on cyst growth, kidney function, AMPK and mTOR signaling, and lactate levels in male PCK rats, a Pkhd1 gene mutation model of human autosomal recessive polycystic kidney disease (ARPKD). MET 300 mg/kg/day IP from days 28 to 84 of age resulted in a mean serum metformin level that was 10 times the upper limit of therapeutic, no effect on cyst indices, nephrotoxicity, and increased serum lactate.

Urine Complement Factor Ba Is Associated with AKI in Critically Ill Children.

Key Points: Complement activation, specifically factor B, is implicated in AKI pathogenesis in animal models. Urine Ba (an activation fragment of factor B) was significantly higher in critically ill children with stage 3 AKI and sepsis-AKI. If larger studies show similar association between urine Ba and AKI severity, clinical trials of factor B inhibition are warranted.

The Pathophysiology of Left Ventricular Hypertrophy, beyond Hypertension, in Autosomal Dominant Polycystic Kidney Disease.

Heart disease is one of the leading causes of death in autosomal dominant polycystic kidney disease (ADPKD) patients. Left ventricular hypertrophy (LVH) is an early and severe complication in ADPKD patients. Two decades ago, the prevalence of LVH on echocardiography in hypertensive ADPKD patients was shown to be as high as 46%.

A case report of pre-eclampsia-like endothelial injury in the kidney of an 85-year-old man treated with ibrutinib.

Background: Glomerular endotheliosis is the pathognomonic glomerular lesion in pre-eclampsia that has also been described in those taking tyrosine kinase inhibitors for cancer treatment. Ibrutinib is a Bruton's tyrosine kinase inhibitor used to treat chronic lymphocytic leukemia (CLL). We report the first known case of glomerular endotheliosis on kidney biopsy in a patient on ibrutinib monotherapy.

Surgical procedures suppress autophagic flux in the kidney.

Many surgical models are used to study kidney and other diseases in mice, yet the effects of the surgical procedure itself on the kidney and other tissues have not been elucidated. In the present study, we found that both sham surgery and unilateral nephrectomy (UNX), which is used as a model of renal compensatory hypertrophy, in mice resulted in increased mammalian target of rapamycin complex 1/2 (mTORC1/2) in the remaining kidney. mTORC1 is known to regulate lysosomal biogenesis and autophagy.

The effect of trehalose on autophagy-related proteins and cyst growth in a hypomorphic Pkd1 mouse model of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder characterized by kidney cyst growth often resulting in end-stage renal disease. There is growing attention on understanding the role of impaired autophagy in ADPKD. Trehalose (TRE) has been shown to increase both protein stability and aggregate clearance and induce autophagy in neurodegenerative diseases.

Increased mTOR and suppressed autophagic flux in the heart of a hypomorphic Pkd1 mouse model of autosomal dominant polycystic kidney disease.

Cardiac hypertrophy is common in autosomal dominant polycystic kidney disease (ADPKD) patients. We found increased heart weight in Pkd1 and Pkd2 mouse models of ADPKD. As there is a link between increased heart weight and mammalian target of rapamycin (mTOR), the aim of the study was to determine mTOR complex 1 and 2 signaling proteins in the heart in the Pkd1 mouse model of PKD.

The effect of MEK1/2 inhibitors on cisplatin-induced acute kidney injury (AKI) and cancer growth in mice.

In a clinically-relevant model of 4 week, low-dose cisplatin-induced AKI, mice were injected subcutaneously with non small cell lung cancer (NSCLC) cells that harbor an activating Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation. Phospho extracellular signal-regulated kinase1/2 (pERK1/2) expression in kidney and tumors was decreased by the MEK1/2 inhibitors, U0126 and trametinib, that potently inhibit pERK1/2. U0126 resulted in a significant improvement in kidney function, acute tubular necrosis (ATN) and tubular cell apoptosis in mice with AKI.

IL-6-mediated hepatocyte production is the primary source of plasma and urine neutrophil gelatinase-associated lipocalin during acute kidney injury.

Neutrophil gelatinase associated lipocalin (NGAL, Lcn2) is the most widely studied biomarker of acute kidney injury (AKI). Previous studies have demonstrated that NGAL is produced by the kidney and released into the urine and plasma. Consequently, NGAL is currently considered a tubule specific injury marker of AKI.

Apoptosis and autophagy in polycystic kidney disease (PKD).

Apoptosis in the cystic epithelium is observed in most rodent models of polycystic kidney disease (PKD) and in human autosomal dominant PKD (ADPKD). Apoptosis inhibition decreases cyst growth, whereas induction of apoptosis in the kidney of Bcl-2 deficient mice increases proliferation of the tubular epithelium and subsequent cyst formation. However, alternative evidence indicates that both induction of apoptosis as well as increased overall rates of apoptosis are associated with decreased cyst growth.

The consequences of increased 4E-BP1 in polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, characterized by cyst formation and growth. Hyperproliferation is a major contributor to cyst growth. At the nexus of regulating proliferation, is 4E-BP1.

Recent Advances in Models, Mechanisms, Biomarkers, and Interventions in Cisplatin-Induced Acute Kidney Injury.

Cisplatin is a widely used chemotherapeutic agent used to treat solid tumours, such as ovarian, head and neck, and testicular germ cell. A known complication of cisplatin administration is acute kidney injury (AKI). The development of effective tumour interventions with reduced nephrotoxicity relies heavily on understanding the molecular pathophysiology of cisplatin-induced AKI.

A study of sirolimus and mTOR kinase inhibitor in a hypomorphic mouse model of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (PKD) is characterized by cyst formation and growth, which are partially driven by abnormal proliferation of tubular cells. Proproliferative mechanistic target of rapamycin (mTOR) complexes 1 and 2 (mTORC1 and mTORC2) are activated in the kidneys of mice with PKD. Sirolimus indirectly inhibits mTORC1.

Biomarkers of Drug-Induced Kidney Toxicity.

Blood urea nitrogen and serum creatinine are imperfect markers of kidney function because they are influenced by many renal and nonrenal factors independent of kidney function. A biomarker that is released directly into the blood or urine by the kidney in response to injury may be a better early marker of drug-induced kidney toxicity than blood urea nitrogen and serum creatinine. Urine albumin and urine protein, as well as urinary markers kidney injury molecule-1 (KIM-1), β2-microglobulin (B2M), cystatin C, clusterin, and trefoil factor-3 (TFF-3) have been accepted by the Food and Drug Administration and European Medicines Agency as highly sensitive and specific urinary biomarkers to monitor drug-induced kidney injury in preclinical studies and on a case-by-case basis in clinical trials.

Catheter-based renal sympathetic denervation induces acute renal inflammation through activation of caspase-1 and NLRP3 inflammasome.

Objective: Catheter-based renal sympathetic denervation (RDN) is implemented as a strategy to treat resistant hypertension. Serum creatinine and estimated glomerular filtration rate have some limitations to predict the early stage of acute kidney injury (AKI). We investigated the changes of early inflammatory biomarkers in AKI following the RDN procedure.

IL-33 deficiency slows cancer growth but does not protect against cisplatin-induced AKI in mice with cancer.

The effect of IL-33 deficiency on acute kidney injury (AKI) and cancer growth in a 4-wk model of cisplatin-induced AKI in mice with cancer was determined. Mice were injected subcutaneously with murine lung cancer cells. Ten days later, cisplatin (10 mg·kg-¹·wk-¹) was administered weekly for 4 wk.

Urinalysis findings and urinary kidney injury biomarker concentrations.

Introduction: Urinary biomarkers of kidney injury are presumed to reflect renal tubular damage. However, their concentrations may be influenced by other factors, such as hematuria or pyuria. We sought to examine what non-injury related urinalysis factors are associated with urinary biomarker levels.

A Genome-Wide Association Study to Identify Single-Nucleotide Polymorphisms for Acute Kidney Injury.

Rationale: Acute kidney injury is a common and severe complication of critical illness and cardiac surgery. Despite significant attempts at developing treatments, therapeutic advances to attenuate acute kidney injury and expedite recovery have largely failed.

Objectives: Identifying genetic loci associated with increased risk of acute kidney injury may reveal novel pathways for therapeutic development.

Urinary Glycosaminoglycans Predict Outcomes in Septic Shock and Acute Respiratory Distress Syndrome.

Rationale: Degradation of the endothelial glycocalyx, a glycosaminoglycan (GAG)-rich layer lining the vascular lumen, is associated with the onset of kidney injury in animal models of critical illness. It is unclear if similar pathogenic degradation occurs in critically ill patients.

Objectives: To determine if urinary indices of GAG fragmentation are associated with outcomes in patients with critical illnesses such as septic shock or acute respiratory distress syndrome (ARDS).