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Gene & Protein in Disease Alport syndrome: Genetics, variability, and management

is mandatory to exclude other etiologies. The integration of experiencing better outcomes. 21,37 Nevertheless, regardless
genetic testing, including next-generation sequencing, has of the mutation severity, the early initiation of RAAS
enhanced diagnostic accuracy for familial hematuria and blockade has been linked to delayed progression to kidney
proteinuria, reducing reliance on invasive procedures such failure and improved renal outcomes, emphasizing its
as kidney biopsy. Furthermore, the reclassification of TBMN value as a cornerstone of therapy in AS management.
as part of the AS reinforces the risk of progression even in
patients previously thought to have benign disease. Early 6.2. Sodium-glucose cotransporter-2 inhibitors
6,14
diagnosis and timely intervention, particularly with renin- (SGLT2i)
angiotensin-aldosterone system (RAAS) blockade, have In recent years, SGLT2i has emerged as a promising
been shown to delay progression to ESKD, emphasizing therapeutic strategy in CKD, based on their well-
the importance of accurate differentiation and proactive documented efficacy in improving cardiovascular and
management in these patients. 6 renal outcomes, particularly in diabetic populations. 19,38

6. Therapeutic strategies However, the use of SGLT2i in AS remains in its
exploratory phase. Initial evidence is primarily derived
In recent years, the therapeutic options for AS have from small observational studies that suggest a significant
evolved with increasing focus on treatments that target reduction in proteinuria following SGLT2i initiation. These
the underlying mechanisms of the disease. At present, no preliminary findings indicate the potential for SGLT2i
specific therapy is approved for AS, but various options to slow renal disease progression in AS. A multicenter
are used to delay disease progression and improve life retrospective study involving 112 AS patients demonstrated
expectancy. a >30% decrease in the albumin-to-creatinine ratio (ACR)
after 3 months of therapy. In addition, a modest decline
6.1. Renin-angiotensin-aldosterone blockers
in the estimated glomerular filtration rate (eGFR) of
Although not specific for AS, RAAS blockers, including 9±12 mL/min/1.73 m over approximately 1 year was
2
angiotensin-converting enzyme inhibitors (ACEi) and observed, revealing a possible nephroprotective effect. 39
angiotensin II receptor blockers (ARB), have demonstrated Further evidence arises from a smaller cohort of patients
nephroprotective properties, including antifibrotic and with AS and FSGS, where a ~40% reduction in ACR was
anti-inflammatory effects, independent of their ability to reported within 3 – 11 months of SGLT2i use despite the
lower blood pressure, placing this class as the cornerstone limited sample size (n = 6) and short follow-up duration.
39
of AS treatment. 21,32 Clinical practice recommendations While these observational studies highlight the potential
emphasize the early initiation of RAAS blockade in males role of SGLT2i in reducing proteinuria and slowing CKD
with XLAS and both sexes with ARAS after 2 years of progression, randomized controlled trials are urgently
age. In contrast, females with XLAS and individuals with needed to establish their efficacy and safety conclusively.
ADAS only if persistent microalbuminuria is detected. At present, an ongoing randomized controlled trial aims
6,33
Among the RAAS blockers, ramipril, an ACE inhibitor, is to evaluate the impact of SGLT2i on renal function in AS
one of the most studied drugs. Studies in animal models patients and potentially clarify their role in this context. 40
and clinical trials, including those involving children as
young as 2 years old, demonstrate its safety and efficacy. The 2024 guidelines from the European Reference
It has shown a favorable safety profile in long-term trials, Network for Rare Kidney Diseases, European Renal
such as the EARLY PRO-TECT trial. 6,34 Association, and European Society of Paediatric
Nephrology recommend the addition of SGLT2i to
Due to mechanisms such as aldosterone escape, it adult patients with AS and CKD stage G2A3 or higher
is known that the effect of RAAS blockade diminishes who continue to exhibit albuminuria despite optimized
throughout time. This has prompted interest in combining treatment with RAAS blockers. However, the guidelines
RAAS blockade treatment with mineralocorticoid receptor do not support SGLT2i use in pediatric AS patients, nor
antagonists (MRA). There is currently an ongoing trial – as monotherapy in the absence of RAAS blockade, because
35
FIONA trial (NCT05196035) – recruiting pediatric patients their efficacy is maximized in combination therapy. 6
with glomerular diseases and proteinuria, including those
with AS. The aim of this trial is to assess the efficacy and 6.3. Endothelin type A receptor (ETAR) and
the safety of finerenone, an MRA, as an adjunct therapy to angiotensin II type 1 receptor inhibitors
RAAS blockade. 35
Endothelin-1 has gained attention as a research focus due
Genetic factors also influence the response to therapy, to its upregulation in AS glomeruli. In AS mouse models,
with patients having milder genetic variants often sparsentan, a dual ETAR/ARB inhibitor, demonstrated

Volume 4 Issue 2 (2025) 7 doi: 10.36922/gpd.7656