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Cell Metabolism Oct 2019Fibrosis is the final common pathway leading to end-stage renal failure. By analyzing the kidneys of patients and animal models with fibrosis, we observed a significant...
Fibrosis is the final common pathway leading to end-stage renal failure. By analyzing the kidneys of patients and animal models with fibrosis, we observed a significant mitochondrial defect, including the loss of the mitochondrial transcription factor A (TFAM) in kidney tubule cells. Here, we generated mice with tubule-specific deletion of TFAM (Ksp-Cre/Tfam). While these mice developed severe mitochondrial loss and energetic deficit by 6 weeks of age, kidney fibrosis, immune cell infiltration, and progressive azotemia causing death were only observed around 12 weeks of age. In renal cells of TFAM KO (knockout) mice, aberrant packaging of the mitochondrial DNA (mtDNA) resulted in its cytosolic translocation, activation of the cytosolic cGAS-stimulator of interferon genes (STING) DNA sensing pathway, and thus cytokine expression and immune cell recruitment. Ablation of STING ameliorated kidney fibrosis in mouse models of chronic kidney disease, demonstrating how TFAM sequesters mtDNA to limit the inflammation leading to fibrosis.
Topics: Animals; DNA, Mitochondrial; DNA-Binding Proteins; Epithelial Cells; Fibrosis; Humans; Inflammation; Kidney Tubules; Male; Membrane Proteins; Mice; Mitochondria; Mitochondrial Proteins; RAW 264.7 Cells; Renal Insufficiency, Chronic; Transcription Factors
PubMed: 31474566
DOI: 10.1016/j.cmet.2019.08.003 -
Romanian Journal of Internal Medicine =... Sep 2021Hepatorenal syndrome (HRS) is a functional renal failure that develops in patients with advanced hepatic cirrhosis with ascites and in those with fulminant hepatic... (Review)
Review
Hepatorenal syndrome (HRS) is a functional renal failure that develops in patients with advanced hepatic cirrhosis with ascites and in those with fulminant hepatic failure. The prevalence of HRS varies among studies but in general it is the third most common cause of acute kidney injury (AKI) in cirrhotic patients after pre-renal azotemia and acute tubular necrosis. HRS carries a grim prognosis with a mortality rate approaching 90% three months after disease diagnosis. Fortunately, different strategies have been proven to be successful in preventing HRS. Although treatment options are available, they are not universally effective in restoring renal function but they might prolong survival long enough for liver transplantation, which is the ultimate treatment. Much has been learned in the last two decades regarding the pathophysiology and management of this disease which lead to notable evolution in the HRS definition and better understanding on how best to manage HRS patients. In the current review, we will summarize the recent advancement in epidemiology, pathophysiology, and management of HRS.
Topics: Acute Kidney Injury; Ascites; Hepatorenal Syndrome; Humans; Liver Cirrhosis; Liver Failure, Acute; Liver Transplantation; Renal Replacement Therapy
PubMed: 33544554
DOI: 10.2478/rjim-2021-0006 -
Journal of Feline Medicine and Surgery Jul 2022Both hyperthyroidism and chronic kidney disease (CKD) are common long-term conditions in older cats, which might be diagnosed concurrently or develop at different times.... (Review)
Review
PRACTICAL RELEVANCE
Both hyperthyroidism and chronic kidney disease (CKD) are common long-term conditions in older cats, which might be diagnosed concurrently or develop at different times. Hyperthyroidism may mask the presence of CKD, and vice versa, by various mechanisms that are described in this review. Hyperthyroidism treatment options should be carefully considered when CKD has also been diagnosed.
CLINICAL CHALLENGES
Although it can be difficult to diagnose hyperthyroidism and CKD simultaneously, given that one condition may mask the other, it is important to consider the presence of both diseases when examining an older cat presenting with vomiting, weight loss, polyuria/ polydipsia, anorexia or sarcopenia. The concurrent presence of hyperthyroidism and CKD requires careful monitoring of glomerular filtration rate biomarkers, and adequate and prompt support of kidney function when normal thyroid function is re-established. Iatrogenic hypothyroidism is a recognised complication of all of the treatment options for hyperthyroidism, and increases the risk of azotaemia. Therapy with levothyroxine is recommended for cats that are hypothyroid and azotaemic.
EVIDENCE BASE
The information in this review draws on current literature and guidelines related to the pathophysiology, diagnosis and treatment recommendations for feline hyperthyroidism and CKD.
Topics: Animals; Cat Diseases; Cats; Glomerular Filtration Rate; Hyperthyroidism; Hypothyroidism; Renal Insufficiency, Chronic; Thyroxine
PubMed: 35481810
DOI: 10.1177/1098612X221090390 -
Australian Veterinary Journal Sep 2022Hyperthyroidism and chronic kidney disease (CKD) are common diseases of geriatric cats, and often occur concurrently. Thus, a thorough understanding of the influence of... (Review)
Review
Hyperthyroidism and chronic kidney disease (CKD) are common diseases of geriatric cats, and often occur concurrently. Thus, a thorough understanding of the influence of thyroid function on renal function is of significant value for all feline practitioners. Among other effects, hyperthyroidism causes protein catabolism and increases renal blood flow and glomerular filtration rate (GFR). These effects render traditional renal markers insensitive for the detection of CKD in cats with uncontrolled hyperthyroidism. Furthermore, the development of iatrogenic hypothyroidism with over treatment of hyperthyroidism can be detrimental to renal function and may negatively affect long-term survival. This review discusses important diagnostic considerations of feline hyperthyroidism, as well as key treatment modalities, with an emphasis on the use of radioiodine and the importance of post treatment monitoring of thyroid and renal parameters. In Australia, a common curative treatment for cats with benign hyperthyroidism (i.e. thyroid hyperplasia or adenoma) is a fixed dose of orally administered radioiodine, regardless of the serum total thyroxine concentration at the time of diagnosis. This review discusses the long term outcomes of this standard of care in comparison with current, relevant research literature from around the world. Finally, this review explores the use of symmetric dimethylarginine (SDMA) in assessing renal function before and after treatment in hyperthyroid cats. SDMA correlates well with GFR and creatinine in non-hyperthyroid cats, but our understanding of its performance in hyperthyroid cats remains in its infancy.
Topics: Animals; Cat Diseases; Cats; Glomerular Filtration Rate; Hyperthyroidism; Iodine Radioisotopes; Kidney; Renal Insufficiency, Chronic
PubMed: 35711100
DOI: 10.1111/avj.13179 -
The Journal of Clinical Investigation Oct 2021Coding variants in apolipoprotein L1 (APOL1), termed G1 and G2, can explain most excess kidney disease risk in African Americans; however, the molecular pathways of...
Coding variants in apolipoprotein L1 (APOL1), termed G1 and G2, can explain most excess kidney disease risk in African Americans; however, the molecular pathways of APOL1-induced kidney dysfunction remain poorly understood. Here, we report that expression of G2 APOL1 in the podocytes of Nphs1rtTA/TRE-G2APOL1 (G2APOL1) mice leads to early activation of the cytosolic nucleotide sensor, stimulator of interferon genes (STING), and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. STING and NLRP3 expression was increased in podocytes from patients with high-risk APOL1 genotypes, and expression of APOL1 correlated with caspase-1 and gasdermin D (GSDMD) levels. To demonstrate the role of NLRP3 and STING in APOL1-associated kidney disease, we generated transgenic mice with the G2 APOL1 risk variant and genetic deletion of Nlrp3 (G2APOL1/Nlrp3 KO), Gsdmd (G2APOL1/Gsdmd KO), and STING (G2APOL1/STING KO). Knockout mice displayed marked reduction in albuminuria, azotemia, and kidney fibrosis compared with G2APOL1 mice. To evaluate the therapeutic potential of targeting NLRP3, GSDMD, and STING, we treated mice with MCC950, disulfiram, and C176, potent and selective inhibitors of NLRP3, GSDMD, and STING, respectively. G2APOL1 mice treated with MCC950, disulfiram, and C176 showed lower albuminuria and improved kidney function even when inhibitor treatment was initiated after the development of albuminuria.
Topics: Animals; Apolipoprotein L1; Humans; Kidney Diseases; Membrane Proteins; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Podocytes
PubMed: 34651582
DOI: 10.1172/JCI136329 -
Clinical Journal of the American... Jul 2022AKI is a syndrome, not a disease. It results from many different primary and/or secondary etiologies and is often multifactorial, especially in the hospitalized patient.... (Review)
Review
AKI is a syndrome, not a disease. It results from many different primary and/or secondary etiologies and is often multifactorial, especially in the hospitalized patient. This review discusses the pathophysiology of three etiologies that cause AKI, those being kidney hypoperfusion, abdominal compartment syndrome, and urinary tract obstruction. The pathophysiology of these three causes of AKI differs but is overlapping. They all lead to a low urine flow rate and low urine sodium initially. In all three cases, with early recognition and correction of the underlying process, the resulting functional AKI can be rapidly reversed. However, with continued duration and/or increased severity, cell injury occurs within the kidney, resulting in structural AKI and a longer and more severe disease state with increased morbidity and mortality. This is why early recognition and reversal are critical.
Topics: Acute Kidney Injury; Azotemia; Biomarkers; Humans; Intra-Abdominal Hypertension; Kidney
PubMed: 35584927
DOI: 10.2215/CJN.15341121 -
Clinical Journal of the American... Nov 2022AKI is commonly encountered in patients with decompensated cirrhosis, and it is associated with unfavorable outcomes. Among factors specific to cirrhosis, hepatorenal...
AKI is commonly encountered in patients with decompensated cirrhosis, and it is associated with unfavorable outcomes. Among factors specific to cirrhosis, hepatorenal syndrome type 1, also referred to as hepatorenal syndrome-AKI, is the most salient and unique etiology. Patients with cirrhosis are vulnerable to traditional causes of AKI, such as prerenal azotemia, acute tubular injury, and acute interstitial nephritis. In addition, other less common etiologies of AKI specifically related to chronic liver disease should be considered, including abdominal compartment syndrome, cardiorenal processes linked to cirrhotic cardiomyopathy and portopulmonary hypertension, and cholemic nephropathy. Furthermore, certain types of GN can cause AKI in cirrhosis, such as IgA nephropathy or viral hepatitis related. Therefore, a comprehensive diagnostic approach is needed to evaluate patients with cirrhosis presenting with AKI. Management should be tailored to the specific underlying etiology. Albumin-based volume resuscitation is recommended in prerenal AKI. Acute tubular injury and acute interstitial nephritis are managed with supportive care, withdrawal of the offending agent, and, potentially, corticosteroids in acute interstitial nephritis. Short of liver transplantation, vasoconstrictor therapy is the primary treatment for hepatorenal syndrome type 1. Timing of initiation of vasoconstrictors, the rise in mean arterial pressure, and the degree of cholestasis are among the factors that determine vasoconstrictor responsiveness. Large-volume paracentesis and diuretics are indicated to relieve intra-abdominal hypertension and renal vein congestion. Direct-acting antivirals with or without immunosuppression are used to treat hepatitis B/C-associated GN. In summary, AKI in cirrhosis requires careful consideration of multiple potentially pathogenic factors and the implementation of targeted therapeutic interventions.
Topics: Humans; Hepatorenal Syndrome; Antiviral Agents; Biomarkers; Hepatitis C, Chronic; Acute Kidney Injury; Liver Cirrhosis; Vasoconstrictor Agents; Nephritis, Interstitial
PubMed: 35902128
DOI: 10.2215/CJN.03040322 -
Journal of Veterinary Internal Medicine Jul 2021Use of telmisartan for the treatment of proteinuria in dogs has not been thoroughly investigated.
BACKGROUND
Use of telmisartan for the treatment of proteinuria in dogs has not been thoroughly investigated.
HYPOTHESIS/OBJECTIVES
Telmisartan can be effective for the treatment of proteinuria in dogs.
ANIMALS
Forty-four client-owned dogs with proteinuria.
METHODS
Retrospective study. Dogs diagnosed with clinically relevant proteinuria (nonazotemic dogs with a urine protein-to-creatinine ratio [UPC] ≥2 and azotemic dogs with UPC ≥0.5) were separated into 3 groups: telmisartan alone, with benazepril, or with mycophenolate. The UPC was recorded before treatment and at subsequent follow-ups (1, 3, 6, and 12 months, as available). Response to treatment was categorized as complete (UPC ˂0.5), partial (UPC decreased by ≥50% but still ≥0.5), or no response (UPC decreased by <50%). Serum creatinine and potassium concentrations and arterial pressure also were recorded.
RESULTS
In the telmisartan group, treatment response (UPC ˂0.5 or decreased by ≥50%) was observed in 70%, 68%, 80%, and 60% of dogs at 1, 3, 6, and 12 months follow-up, respectively. No significant changes were noted in serum creatinine or potassium concentrations, or in arterial blood pressure at all follow-up times. Adverse effects consisted of mild self-limiting gastrointestinal signs in 5 dogs. Two dogs developed clinically relevant azotemia that required discontinuation of the treatment before the first follow-up.
CONCLUSIONS AND CLINICAL IMPORTANCE
Telmisartan can be considered for treatment of proteinuria in dogs, alone or in combination with other treatments for proteinuria.
Topics: Animals; Creatinine; Dog Diseases; Dogs; Proteinuria; Retrospective Studies; Telmisartan
PubMed: 33969924
DOI: 10.1111/jvim.16146