Genetic Causes of Nephrotic Syndrome and Focal and Segmental Glomerulosclerosis.

The field of nephrology has a long-standing interest in deciphering the genetic basis of nephrotic syndrome (NS), motivated by the mechanistic insights it provides in chronic kidney disease. The initial era of genetic studies solidified NS and the focal segmental glomerulosclerosis lesion as podocyte disorders. The likelihood of identifying a single gene (called monogenic) cause is higher if certain factors are present such as positive family history. Obtaining a monogenic diagnosis enables reproductive counseling and screening of family members. Now, with a new era of genomic studies facilitated by technological advances and the emergence of large genetically characterized cohorts, more insights are apparent. This includes the phenotypic breadth associated with disease genes, as evidenced in Alport syndrome and congenital NS of the Finnish type. Moreover, the underlying genetic architecture is more complex than previously appreciated, as shown by genome-wide association studies, suggesting that variants in multiple genes collectively influence risk. Achieving molecularly informed diagnoses also holds substantial potential for personalizing medicine, including the development of targeted therapeutics. Illustrative examples include coenzyme Q10 for ADCK4-associated NS and inaxaplin, a small molecule that inhibits apolipoprotein L1 channel activity, though larger studies are required to confirm benefit.

Alport Syndrome: Clinical Spectrum and Therapeutic Advances.

Alport syndrome is a hereditary disorder characterized by kidney disease, ocular abnormalities, and sensorineural hearing loss. Work in understanding the cause of Alport syndrome and the molecular composition of the glomerular basement membrane ultimately led to the identification of COL4A3, COL4A4 (both on chromosome 2q36), and COL4A5 (chromosome Xq22), encoding the α3, α4, and α5 chains of type IV collagen, as the responsible genes. Subsequent studies suggested that autosomal recessive Alport syndrome and males with X-linked Alport syndrome have more severe disease, whereas autosomal dominant Alport syndrome and females with X-linked Alport syndrome have more variability. Variant type is also influential-protein-truncating variants in autosomal recessive Alport syndrome or males with X-linked Alport syndrome often present with severe symptoms, characterized by kidney failure, extrarenal manifestations, and lack of the α3-α4-α5(IV) network. By contrast, mild-moderate forms from missense variants display α3-α4-α5(IV) in the glomerular basement membrane and are associated with protracted kidney involvement without extrarenal manifestations. Regardless of type, therapeutic intervention for kidney involvement is focused on early initiation of angiotensin-converting enzyme inhibitors. There are several therapies under investigation including sodium/glucose cotransporter 2 inhibitors, aminoglycoside analogs, endothelin type A antagonists, lipid-modifying drugs, and hydroxychloroquine, although targeting the underlying defect through gene therapy remains in preclinical stages.

Comparison of clinical characteristics and outcome measures of PCR-positive and PCR-negative patients diagnosed as COVID-19: Analyses focusing on the older adults.

PURPOSE: While the definitive diagnosis of COVID-19 relies on PCR confirmation of the virus, the sensitivity of this technique is limited. The clinicians had to go on with the clinical diagnosis of COVID-19 in selected cases. We aimed to compare PCR-positive and PCR-negative patients diagnosed as COVID-19 with a specific focus on older adults. METHODS: We studied 601 hospitalized adults. The demographics, co-morbidities, triage clinical, laboratory characteristics, and outcomes were noted. Differences between the PCR (+) and (-) cases were analyzed. An additional specific analysis focusing on older adults (≥65 years) (n = 184) was performed. RESULTS: The PCR confirmation was present in 359 (59.7 %). There was not any difference in terms of age, sex, travel/contact history, hospitalization duration, ICU need, the time between first symptom/hospitalization to ICU need, ICU days, or survival between PCR-positive and negative cases in the total study group and older adults subgroup. The only symptoms that were different in prevalence between PCR-confirmed and unconfirmed cases were fever (73.3 % vs. 64 %, p = 0.02) and fatigue/myalgia (91.1 % vs. 79.3 %, p = 0.001). Bilateral diffuse pneumonia was also more prevalent in PCR-confirmed cases (20 % vs. 13.3 %, p = 0.03). In older adults, the PCR (-) cases had more prevalent dyspnea (72.2 % vs. 51.4 %, p = 0.004), less prevalent fatigue/myalgia (70.9 % vs. 88.6 %, p = 0.002). CONCLUSION: The PCR (+) and (-) cases displayed very similar disease phenotypes, courses, and outcomes with few differences between each other. The presence of some worse laboratory findings may indicate a worse immune protective response in PCR (-) cases.

Effect of Lipid Emulsion on the Improvement of Renal Damage in Colistin- Induced Nephrotoxicity.

BACKGROUND: Colistin utilization has gradually increased worldwide with the rising of multidrug-resistant (MDR) gram-negative bacilli despite its nephrotoxicity. Lipid emulsion (LE) is widely used for the toxic overdose treatment of various drugs. OBJECTIVE: The aim of the present study is to evaluate the effect of lipid emulsion on the improvement of renal damage in colistin-induced nephrotoxicity with an experimental Sprague Dawley rat model. METHODS: Twenty-four male Sprague Dawley rats were initially assigned to 2 random groups. Sixteen rats were given a single dose of 20 mg/kg colistin, and eight rats received no medication (control group). Sixteen rats that were administered colistin were sub-divided into 2 groups. Group 1/LE rats (n = 8) were given 20 ml/kg solution of lipid emulsion, and group 2/S rats (n = 8) were given 20 ml/kg/day (i.p.) of 0.9% NaCl saline; both were administered for 10 days. Then tubular injury was evaluated histopathologically. Serum levels of blood urea nitrogen (BUN), Kidney Injury Molecule-1 (KIM-1), and creatinine were measured. Besides, malondialdehyde (MDA) levels were determined in tissue samples for the assessment of lipid peroxidation. RESULTS: The mean percent of tubular epithelial cell injury and tubular dilatation was found significantly higher in group 2/S than in control and group 1/LE (p < 0.0001 and < 0.001; respectively). KIM-1 and MDA levels were also statistically higher in group 2/S than in control and group 1/LE. (p < 0.0001 and < 0.0001; respectively). Additionally, serum BUN and creatinine levels of group 2/S were significantly greater than control and group 1/LE (p < 0.0001 and < 0.0001; respectively). CONCLUSION: In this present study, we determined that colistin-induced proximal tubular damage was decreased histopathologically and serologically by the effect of lipid emulsion. Thus, our findings may guide future studies on the clinical use of colistin, particularly in MDR positive intensive care infections.