Quantitative assessment of glomerular basement membrane collagen IV α chains in paraffin sections from patients with focal segmental glomerulosclerosis and Alport gene variants.

Focal segmental glomerulosclerosis (FSGS) lesions have been linked to variants in COL4A3/A4/A5 genes, which are also mutated in Alport syndrome. Although it could be useful for diagnosis, quantitative evaluation of glomerular basement membrane (GBM) type IV collagen (colIV) networks is not widely used to assess these patients. To do so, we developed immunofluorescence imaging for collagen α5(IV) and α1/2(IV) on kidney paraffin sections with Airyscan confocal microscopy that clearly distinguishes GBM collagen α3α4α5(IV) and α1α1α2(IV) as two distinct layers, allowing quantitative assessment of both colIV networks. The ratios of collagen α5(IV):α1/2(IV) mean fluorescence intensities (α5:α1/2 intensity ratios) and thicknesses (α5:α1/2 thickness ratios) were calculated to represent the levels of collagen α3α4α5(IV) relative to α1α1α2(IV). The α5:α1/2 intensity and thickness ratios were comparable across all 11 control samples, while both ratios were significantly and markedly decreased in all patients with pathogenic or likely pathogenic Alport COL4A variants, supporting validity of this approach. Thus, with further validation of this technique, quantitative measurement of GBM colIV subtype abundance by immunofluorescence, may potentially serve to identify the subgroup of patients with FSGS lesions likely to harbor pathogenic COL4A variants who could benefit from genetic testing.

Exploring hospital practice types and their impact on glomerular pathologic patterns: Insights from the largest kidney biopsy cohort in Thailand.

BACKGROUND: This study aims to investigate the influence of different kidney biopsy practices on the prevalence of glomerular pathologic patterns in the largest kidney biopsy registry in Thailand. METHODS: We conducted a retrospective review of kidney biopsy records from the period between 2000 and 2014. The records were obtained from 2 major institutions: King Chulalongkorn Memorial Hospital, a large university-based hospital, and the Kidney Center Bangkok Hospital, which provides pathology services to hospitals throughout Thailand. The study included native kidney biopsies from all provinces in Thailand, excluding paediatric patients, kidney transplant recipients, and cases of inadequate and repeated biopsies. Patient demographics, indications for biopsy, and final glomerular diagnoses were compared across different hospital practice settings: university (UVH), private (PVH) and public (PBH). RESULTS: A total of 5893 eligible native kidney biopsies were identified from a pool of 7005 biopsies conducted over a 15-year period in 25 provinces throughout Thailand. The 3 most common indications for biopsy were suspected kidney involvement in systemic lupus erythematosus (SLE) (29%), nephrotic syndrome (NS) (29%), and acute glomerulonephritis (AGN)/rapidly progressive glomerulonephritis (RPGN) (13%). The leading indication for biopsy differed across practice types, with suspected kidney involvement in SLE being the primary indication in UVH, while NS took precedence in both PBH and PVH practices. Notably, UVH performed fewer kidney biopsies for asymptomatic urinary abnormalities and diabetes-related indications compared with PVH and PBH. The leading glomerular diagnoses correlated with the biopsy indications, with lupus nephritis (LN) being the most common diagnosis in UVH and PBH practices, whiles immunoglobulin A nephropathy was the predominant diagnosis in PVH practice. CONCLUSION: Hospital practice types significantly impact the prevalence of glomerular pathologic diagnosis patterns in kidney biopsy data, highlighting the importance of considering this influence in epidemiological comparisons.

Pathogenic variant detection rate by whole exome sequencing in Thai patients with biopsy-proven focal segmental glomerulosclerosis.

The spectra of underlying genetic variants for various clinical entities including focal segmental glomerulosclerosis (FSGS) vary among different populations. Here we described the clinical and genetic characteristics of biopsy-proven FSGS patients in Thailand. Patients with FSGS pathology, without secondary causes, were included in our study. Clinical laboratory and pathological data were collected. Whole-exome sequencing (WES) was subsequently performed. 53 unrelated FSGS patients were recruited. 35 patients were adults (66.0%), and 51 patients were sporadic cases (96.2%). Clinical diagnosis before kidney biopsy was steroid-resistant nephrotic syndrome (SRNS) in 58.5%, and proteinuric chronic kidney disease in 32.1%. Using WES, disease-associated pathogenic/likely pathogenic (P/LP) variants could be identified in six patients including the two familial cases, making the P/LP detection rate of 11.3% (6/53). Of these six patients, two patients harbored novel variants with one in the COL4A4 gene and one in the MAFB gene. Four other patients carried previously reported variants in the CLCN5, LMX1B, and COL4A4 genes. Four of these patients (4/6) received immunosuppressive medications as a treatment for primary FSGS before genetic diagnosis. All four did not respond to the medications, emphasizing the importance of genetic testing to avoid unnecessary treatment. Notably, the mutation detection rates in adult and pediatric patients were almost identical, at 11.4% and 11.1%, respectively. In conclusion, the overall P/LP variant detection rate by WES in biopsy-proven FSGS patients was 11.3%. The most identified variants were in COL4A4. In addition, three novel variants associated with FSGS were detected.

Whole-Exome Sequencing Solved over 2-Decade Kidney Disease Enigma.

Chronic kidney disease of unknown etiology (CKDu) has been a problem in renal practice as indefinite diagnosis may lead to inappropriate management. Here, we report a 54-year-old father diagnosed with CKDu at 33 years old and his 8-year-old son with steroid-resistant nephrotic syndrome. Using whole-exome sequencing, both were found to be heterozygous for c.737G>A (p.Arg246Gln) in LMX1B. The diagnosis of LMX1B-associated nephropathy has led to changes in the treatment plan with appropriate genetic counseling. The previously reported cases with this particular mutation were also reviewed. Most children with LMX1B-associated nephropathy had nonnephrotic proteinuria with normal renal function. Interestingly, our pediatric case presented with steroid-resistant nephrotic syndrome at 8 years old and progressed to ESRD requiring peritoneal dialysis at the age of 15 years. Our report emphasized the need of genetic testing in CKDu for definite diagnosis leading to precise management.

Pleiotropic effects of antidiabetic agents on renal and cardiovascular outcomes: a meta-analysis of randomized controlled trials.

BACKGROUND: This meta-analysis was conducted to examine the pleiotropic effects of all available antidiabetic agents except insulin for type 2 diabetes on renal and cardiovascular outcomes. METHODS: A systematic literature search was performed in PubMed, EMBASE, and Cochrane database to identify randomized-controlled trials which compared the effectiveness between all antidiabetic agents apart from insulin regarding all aspects of renal and cardiovascular outcomes. Random effect model was utilized to compute for hazard ratio. RESULTS: Nineteen articles with 140,851 participants were included in this meta-analysis. When compared with placebo, SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors exhibited significantly lower hazard ratios of progression of albuminuria. SGLT-2 inhibitors and DPP-4 inhibitors showed a significantly higher hazard ratio of regression of albuminuria. Only SGLT-2 inhibitors illustrated significantly lower hazard ratios of doubling of serum creatinine and incidence of renal replacement therapy (RRT). A significantly lower hazard ratio of composite renal outcome was detected in both SGLT-2 inhibitors and GLP-1 agonists. A significantly lower hazard ratio of all-cause mortality was identified in SGLT-2 inhibitors and GLP-1 agonist. Furthermore, a significantly lower hazard ratio of cardiovascular mortality was found in both SGLT-2 inhibitors and GLP-1 agonists. CONCLUSION: Comparing across all antidiabetic agents apart from insulin, SGLT-2 inhibitors provided extensively renoprotective effects among diabetic patients as well as reduced hazard ratios of heart failure, cardiovascular mortality, and all-cause mortality. GLP-1 agonists yielded benefits regarding progression of albuminuria, composite renal outcome, and cardiovascular and all-cause mortalities. DPP-4 inhibitors offered only renal protection including progression and regression of albuminuria.

Dialysis Therapy and Conservative Management of Advanced Chronic Kidney Disease in the Elderly: A Systematic Review.

BACKGROUND: Dialysis in older adults with chronic kidney disease (CKD) and comorbidities may not be associated with improved life expectancy compared to conservative management. To inform clinical practice, we performed a systematic review of all available studies examining this hypothesis. METHODS: We performed a systematic review of retrospective and prospective cohort studies of older adults with stage-5 CKD who chose dialysis (hemodialysis or peritoneal dialysis) or opted for conservative management (including management of complications of CKD and palliative care). Outcomes of interest included hospitalizations and mortality. RESULTS: Twelve cohort studies (11,515 patients) were identified with most of them focusing on older adults. Patients choosing dialysis were younger compared to those opting for conservative management and were less functionally impaired. Patients opting for conservative management received care in a multidisciplinary setting focusing on palliative care and management of complications of CKD. Patients choosing dialysis and conservative management had a median survival time of 8-67 and 6-30 months, respectively. In a subset of studies of patients 65 years and older with an estimated glomerular filtration rate <15 mL/min/1.73 m2, and where the multivariable analyses included age and comorbidities, by meta-analysis, patients choosing dialysis had a pooled adjusted hazard ratio for mortality of 0.53 (95% CI 0.30-0.91, p = 0.02) relative to those opting for conservative management; however, significant heterogeneity precluded definitive conclusions. CONCLUSIONS: When caring for older adults with advanced CKD who are contemplating dialysis therapy vs. conservative management, efforts must focus on promoting patient values and preferences, shared decision-making, and symptom burden alleviation.