Col4a3^−/− Alport mice serve as an animal model for renal fibrosis. MicroRNA-21 (miR-21) expression has been shown to be increased in the kidneys of Alport syndrome patients. Here, we investigated the nephroprotective effects of Lademirsen anti-miR-21 therapy. We used a fast-progressing Col4a3^−/− mouse model with a 129/SvJ background and an intermediate-progressing F1 hybrid mouse model with a mixed genetic background, with angiotensin-converting enzyme inhibitor (ACEi) monotherapy in combination with anti-miR-21 therapy. In the fast-progressing model, the anti miR-21 and ACEi therapies showed an additive effect in the reduction in fibrosis, the decline of proteinuria, the preservation of kidney function and increased survival. In the intermediate-progressing F1 model, the anti-miR-21 and ACEi therapies individually improved kidney pathology. Both also improved kidney function and survival; however, the combination showed a significant additive effect, particularly for survival. RNA sequencing (RNA-seq) gene expression profiling revealed that the anti-miR-21 and ACEi therapies modulate several common pathways. However, anti-miR-21 was particularly effective at normalizing the expression profiles of the genes involved in renal tubulointerstitial injury pathways. In conclusion, significant additive effects were detected for the combination of anti-miR-21 and ACEi therapies on kidney function, pathology and survival in Alport mouse models, as well as a strong differential effect of anti-miR-21 on the renal expression of fibrotic factors. These results support the addition of anti-miR-21 to the current standard of care (ACEi) in ongoing clinical trials in patients with Alport syndrome.

To analyze the clinical audiological characteristics of X-Linked Alport syndrome (XLAS) in males and their relationships with genotypes. The clinical data of 87 male patients with AS were reviewed. Hearing levels were evaluated using pure tone audiometry (PTA) testing, acoustic immittance, and otoacoustic emissions (OAE) testing. The genotypes of COL4A5 and the pathogenic variants were analyzed. The relationships between auditory phenotypes and genotypes were analyzed. Among the 87 patients, the number of patients with normal hearing and hearing loss were 32 and 55, respectively. In all cases, the hearing loss was characterized as bilateral symmetrical sensorineural deafness. Majority of the patients had mild-to-moderate hearing loss. Hearing loss usually started in the middle frequency range and gradually affected high frequencies, at school age and gradually increased with increasing age. However, it maintained a relatively steady level of 50–60 dB HL during the teenage years. The audiometric curves included groove-type in 51 cases (92.73%). Patients were identified to have 60 different COL4A5 pathogenic variants. Of the 49 patients who were followed-up for more than 2 years, 28 cases presented a decreasing trend in the hearing level of about 5 dB per year. The degree of hearing loss was positively correlated with gene mutation type and renal function. Hearing loss in males with XLAS is symmetrical sensorineural, and progressive with increasing age. There is a significant correlation between the degree of hearing loss and genotype, renal function, and age.

Angiotensin-converting enzyme inhibitors (ACEi) delay progression of the inherited renal disease Alport syndrome. However, the effect of ACEis weakens gradually due to an “aldosterone escape”. Here, we investigate if an aldosterone antagonist can counteract loss of ACEi-efficacy. COL4A3-/- mice were treated with ramipril (ACEi), starting at 4.5 weeks of age, and spironolactone was added at 7 weeks of age. Lifespan until renal failure, as well as kidney function parameters, were investigated. Dual therapy decreased proteinuria levels compared to ACEi monotherapy. Matrix accumulation, as well as tubulointerstitial and glomerular scar-tissue formation, were significantly reduced compared to untreated mice and ACEi-monotherapy at 75 and 100 days. Lifespan in dual treated mice was extended compared to untreated mice. However, lifespan was not superior to ACEi monotherapy–despite improved urea-nitrogen levels in the dual therapy group. In conclusion, adding the aldosterone-antagonist spironolactone to ACEi therapy further improved kidney function and reduced proteinuria and fibrosis. However, survival was not improved further, possibly due to premature death from side effects of dual therapy such as hyperkalemia. Thus, dual therapy could offer an effective therapy option for Alport syndrome patients with progressive proteinuria. However, the risks of adverse events require close monitoring.

Background: During pregnancy, hyperfiltration and other factors are hypothesized to contribute to the progression of kidney disease in women with Alport syndrome. To evaluate the status of kidney disease, clinical data from mothers with Alport syndrome in China and Europe over the pregnancy were analyzed. Methods: This retrospective observational study collected data to evaluate proteinuria, kidney function and Alport stage prior to, during, and after pregnancy, respectively. Results: A total of 74 women were enrolled, 82% of them with X-linked Alport syndrome and 11% with autosomal Alport syndrome (unknown in 5 patients). Detailed information on the course of pregnancy was available for 62 pregnancies from 52 different women. No fetal malformations were observed. Mean gestational age was 37.9 ± 2.7 weeks ( n = 55). Complications included high blood pressure ( n = 8), abortion ( n = 5), preeclampsia ( n = 5), gestational diabetes ( n = 3), nephrotic syndrome ( n = 2), cervical insufficiency with fetal growth delay ( n = 2), premature rupture of membranes ( n = 1) and acute intrauterine fetal distress ( n = 1). Median proteinuria was 350 (30–2465) mg/day prior to pregnancy, 2390 (450–11,450) mg/day during pregnancy, and 590 (40–2650) mg/day at a mean postpartum follow-up time of 4.5 ± 2.1 years. Mean estimated glomerular filtration rate (eGFR) decreased by 17.2 ± 16.7 ml/min/1.73 m ² , from 96.1 ± 32.9 to 78.9 ± 37 ml/min/1.73 m ² after pregnancy ( n = 15; p = 0.003). The eGFR loss was higher in women with eGFR < 90 ml/min/1.73 m ² prior to pregnancy compared to women with normal renal function (– 21.5 ± 9.8 vs. – 14 ± 20 ml/min/1.73 m ² ), and in women with severe variants compared to women with less severe variants (– 21.5 ± 20.2 vs. – 11.3 ± 19.0 ml/min/1.73 m ² ). Progression of Alport stage after pregnancy was observed in 42% of the women, 31% remained in stage 0-1, and 23% remained in stage 2. Conclusions: This study provides important data on the natural history of Alport syndrome in women who have undergone a pregnancy. Women with severe variants of Alport syndrome, and women with eGFR below 90 ml/min/1.73 m ² face greater risks of kidney disease progression after pregnancy. Further prospective studies are required to confirm these findings. Graphical

Alport syndrome (AS) is an inherited kidney disease. The effect of pregnancy on the kidney disease progression in AS females remains controversial. Col4a3-