Hereditary diseases of the glomerular filtration barrier are characterized by a more vulnerable glomerular basement membrane and dysfunctional podocytes. Recent clinical trials have demonstrated the ...nephroprotective effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in chronic kidney disease (CKD). SGLT2-mediated afferent arteriole vasoconstriction is hypothesized to correct the hemodynamic overload of the glomerular filtration barrier in hereditary podocytopathies. To test this hypothesis, we report data in a case series of patients with Alport syndrome and focal segmental glomerulosclerosis (FSGS) with respect of the early effect of SGLT2i on the kidney function. Mean duration of treatment was 4.5 (±2.9) months. Mean serum creatinine before and after SGLT-2i initiation was 1.46 (±0.42) and 1.58 (±0.55) mg/dL, respectively, with a median estimated glomerular filtration rate of 64 (±27) before and 64 (±32) mL/min/1.73 m2 after initiation of SGLT2i. Mean urinary albumin-creatinine ratio in mg/g creatinine before SGLT-2i initiation was 1827 (±1560) and decreased by almost 40% to 1127 (±854) after SGLT2i initiation. To our knowledge, this is the first case series on the effect and safety of SGLT2i in patients with hereditary podocytopathies. Specific large-scale trials in podocytopathies are needed to confirm our findings in this population with a tremendous unmet medical need for more effective, early on, and safe nephroprotective therapies.
Abstract Background and Aims Large-scale trials showed positive outcomes of SGLT2-inhibitors (SGLT2i) in elderly patients with CKD. Patients with Alport syndrome, a type IV collagen disease, develop ...CKD early in life. Whether the use of SGLT2i is safe and effective in patients with the type IV collagen disease Alport syndrome (and thus a different pathogenesis) has not yet been investigated specifically besides case reports. Method For the first time, this observational, multicenter, international study (NCT02378805) assessed 112 patients with AS from nine countries and 21 trial sites after start of SGLT2i at early stages of their chronic kidney disease (CKD). The study's primary endpoint was change of albuminuria in albumin/g creatinine after start of therapy with SGLT2i. Results Compared to the large randomized trials investigating the effect of SGLT2i in CKD, the adult patients in this trial were much younger (38 ± 14 years; n = 101), had a better eGFR (63 ± 35 ml/min/1.73m2; n = 98) and had a higher albuminuria (1699 ± 1472 mg/g creatinine; n = 51). At a mean time on SGLT2i-therapy of 6 ± 1 months, albuminuria decreased significantly (1727 ± 1564 vs. 1203 ± 1165 mg/g creatinine; n = 33; p = 0.01). Compared to baseline, at the first three follow-up visits after initiation of SGLT2i-therapy, a significant reduction of albuminuria >30% was observed. Mean loss of eGFR was 9 ± 12 ml/min/1.73 m² almost one year after initiation of SGLT2i-therapy (n = 35). At a mean follow up of 12 ± 2 month after initiation of SGLT2i-therapy, serum-albumin increased significantly from 3.7 ± 0.7 to 4.0 ± 0.4 g/dL (n = 18; p = 0.019). At a total of 68 patient-years at risk, adverse events occurred in 11/85 patients (13%). Two very serious adverse events (acute necrotizing pancreatitis and Fournier's gangrene) occurred. Conclusion This study demonstrated that SGLT2i, when added to RASi, have the potential to reduce the rate of albuminuria in adult patients with Alport Syndrome. The study will be continued to provide valuable data on the long-term course of CKD under SGLT2i-therapy in AS to investigate if the promising reduction of albuminuria results in a clinical relevant delay in renal failure. This observational study successfully formed the scientific basis for the current randomized controlled trial with SGLT2i in children and young adults with AS Double Protect Alport.
Abstract
BACKGROUND AND AIMS
Most hereditary diseases of the glomerular filtration barrier still progress to end-stage renal failure (ESRF)—raising the urgent need for add-on therapies. Recent ...randomized clinical trials (RCTs) demonstrated the nephroprotective effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in chronic kidney diseases (CKD). SGLT2-mediated afferent arteriole vasoconstriction, additive to efferent arteriole vasodilatation by angiotensin-converting enzyme inhibitors (ACEis), is postulated to correct the haemodynamic overload of the glomerular filtration barrier. For that reason, we investigated the nephroprotective effect of SGLT2i in hereditary glomerular diseases.
METHOD
In 2020, this monocentric prospective case series was started in six patients with Alport syndrome or FSGS, who consented to off-label therapy with empagliflozin or dapagliflozin. To our knowledge, this is the first case series on the effect of SGLT2i in patients with hereditary causes of CKD.
RESULTS
We report data on the use of SGLT2i in a case series of patients with Alport syndrome and FSGS in respect of the early effect on the kidney function and safety of initiation of therapy. The follow-up was 3–11 months. The mean age was 40 years (standard deviation, SD ± 17), the mean duration of treatment was 4.5 months (SD ± 2.9). The mean serum creatinine before and after SGLT2i initiation was 1.46 (SD ± 0.42) and 1.58 (SD ± 0.55). The mean urinary albumin-creatinine ratio in mg/g creatinine before SGLT2i was 1827 (SD ± 1560) and decreased to 1127 (SD ± 854) after SGLT2i initiation. The estimated glomerular filtration rate (eGFR) ‘dipped’ after initiation of SGLT2i in most patients. Overall, treatment was well tolerated, however, eGFR initially decreased by more than 30% in one patient with FSGS. The initial eGFR drop raises some safety concerns, which underlines the need to collect and evaluate the course of every patient with AS in which therapy with SGLT2i is started.
CONCLUSION
In conclusion, therapy with SGLT2i on top of ACEi was well tolerated and effective in terms of lowering albuminuria. As a proof of concept, SGLT2-mediated correction of the haemodynamic overload of the glomerular filtration barrier looks like a very promising therapeutic approach in hereditary diseases such as AS and FSGS. Specific RCTs are needed to confirm our findings in this genetically well-defined population with a tremendous unmet medical need for more effective, early on and safe nephroprotective therapies. Proteinuria is reported as a urinary albumin-creatinine ratio in mg/g creatinine. All male patients received SGLT2i additive to renin-angiotensin-aldosterone system (RAAS)-blockade. In the female patient, ACEi was stopped prior to the start of SGLT2i because of angioedema. In addition to ACEi and SGLT2i, one patient also received tacrolimus because of irritable bowel disease.
(A) eGFR (CKD-EPI formula) at baseline and at follow-up.
(B) UACr at baseline and at follow up.
m, male; f, female; FSGS, focal segmental glomerulosclerosis; XLAS, X-linked Alport syndrome; IBD, irritable bowel disease; aHT, arterial hypertension; sHP, secondary hyperparathyroidism; eGFR, estimated glomerular filtration rate; UACr, urine-albumin-creatinine ratio; Crea, serum-creatinine
Most adults with Alport syndrome (AS) suffer from progressive sensorineural hearing loss. However, little is known about the early characteristics of hearing loss in children with AS. As a part of ...the EARLY PRO-TECT Alport trial, this study was the first clinical trial ever to investigate hearing loss in children with AS over a timespan of up to six years Nine of 51 children (18%) had hearing impairment. Audiograms were divided into three age groups: in the 5-9-year-olds, the 4-pure tone average (4PTA) was 8.9 decibel (dB) (
15) in those with normal hearing and 43.8 dB (
2, 12%) in those with hearing impairment. Among the 10-13-year-olds, 4PTA was 4.8 dB (healthy,
12) and 41.4 dB (hearing impaired,
6.33%). For the 14-20-year-olds, the 4PTA was 7.0 dB (healthy;
9) and 48.2 dB (hearing impaired,
3.25%). On average, hearing thresholds of the hearing impaired group increased, especially at frequencies between 1-3 kHz. In conclusion, 18% of children developed hearing loss, with a maximum hearing loss in the audiograms at 1-3 kHz. The percentage of children with hearing impairment increased from 10% at baseline to 18% at end of trial as did the severity of hearing loss.
Early initiation of therapy in patients with Alport syndrome (AS) slows down renal failure by many years. Genotype–phenotype correlations propose that the location and character of the individual's ...variant correlate with the renal outcome and any extra renal manifestations. In‐depth clinical and genetic data of 60/62 children who participated in the EARLY PRO‐TECT Alport trial were analyzed. Genetic variants were interpreted according to current guidelines and criteria. Genetically solved patients with X‐linked inheritance were then classified according to the severity of their COL4A5 variant into less‐severe, intermediate, and severe groups and disease progress was compared. Almost 90% of patients were found to carry (likely) pathogenic variants and classified as genetically solved cases. Patients in the less‐severe group demonstrated a borderline significant difference in disease progress compared to those in the severe group (p = 0.05). While having only limited power according to its sample size, an obvious strength is the precise clinical and genetic data of this well ascertained cohort. As in published data differences in clinical progress were shown between patients with COL4A5 less‐severe and severe variants. Therefore, clinical and segregational data are important for variant (re)classification. Genetic testing should be mandatory allowing early diagnosis and therapy of AS.
The urinary albumin- and protein-to-creatinine ratios (UACR and UPCR, respectively) are key endpoints in most clinical trials assessing risk of progression of chronic kidney disease (CKD). For the ...first time, the current study compares the UACR versus the UPCR head-to-head at early stages of CKD, taking use of the hereditary podocytopathy Alport syndrome (AS) as a model disease for any CKD. Urine samples originated from the prospective randomized, controlled EARLY PRO-TECT Alport trial (NCT01485978). Urine samples from 47 children with confirmed diagnoses of AS at very early stages of CKD were divided according to the current stage of AS: stage 0 (UACR < 30 mg/g), stage 1 (30-300 mg/g) or stage 2 (>300 mg/g). The range of estimated glomerular filtration rate was 75-187.6 mL/min. The mean age was 10.4 ± 4.5 years. In children at stage 0, proteinuria in spot urine, confirmed in 24 h urine, was almost ten times higher than albuminuria (106.4 ± 42.2 vs. 12.5 ± 9.7;
< 0.05); it was "only" about three times higher in stage 1 (328.5 ± 210.1 vs. 132.3 ± 80.5;
< 0.05) and almost equal in stage 2 (1481.9 ± 983.4 vs. 1109.7 ± 873.6;
= 0.36). In 17 children, UACRs and UPCRs were measured simultaneously in 24 h urine and spot urine in the same study visit. Interestingly, the UACR (and UPCR) in 24 h urine vs. in spot urine varied by less than 10% (266.8 ± 426.4 vs. 291.2 ± 530.2). In conclusion, our study provides the first evidence that in patients with normal glomerular filtration rate (GFR) and low amounts of albuminuria, especially in children with podocytopathies such as AS, measuring the UACR and UPCR in spot urine is a reliable and convenient alternative to 24 h urine collection. Our study advocates both the UACR and the UPCR as relevant diagnostic biomarkers in future clinical trials in children with glomerular diseases because the UPCR seems to be a very significant parameter at very early stages of podocytopathies. The German Federal Ministry of Education and Research funded this trial (01KG1104).
Background
Autosomal recessive Alport syndrome (ARAS) is caused by pathogenic variants in both alleles of either
COL4A3
or
COL4A4
genes. Reports on ARAS are rare due to small patient numbers and ...there are no reports on renin-angiotensin-aldosterone system (RAAS) inhibition therapy in ARAS.
Methods
Retrospective study in 101 patients with ARAS from Chinese Registry Database of Hereditary Kidney Diseases and European Alport Registry. Genotype–phenotype correlations and nephroprotective effects of RAAS inhibition in ARAS were evaluated.
Results
Median age was 15 years (range 1.5–46 years). Twelve patients progressed to stage 5 chronic kidney disease (CKD5) at median age 20.5 years. Patients without missense variants had both higher prevalence and earlier onset age of hearing loss, nephrotic-range proteinuria, more rapid decline of eGFR, and earlier onset age of CKD5 compared to patients with 1 or 2 missense variants. Most patients (79/101, 78%) currently are treated with RAAS inhibitors; median age at therapy initiation was 10 years and mean duration 6.5 ± 6.0 years. Median age at CKD5 for untreated patients was 24 years. RAAS inhibition therapy delayed CKD5 onset in those with impaired kidney function (T-III) to median age 35 years, but is undefined in treated patients with proteinuria (T-II) due to low number of events. No treated patients with microalbuminuria (T-I) progressed to CKD5. ARAS patients with 1 or 2 missense variants showed better response to treatment than patients with non-missense-variants.
Conclusions
Our study provides the first evidence for early use of RAAS inhibition therapy in patients with ARAS. Furthermore, genotype in ARAS correlates with response to therapy in favor of missense variants.
Angiotensin-converting enzyme inhibitors (ACEis) have evolved as a first-line therapy for delaying end-stage renal failure (ESRF) in Alport syndrome (AS). The present study tested the hypothesis of a ...superior nephroprotective potential of an early ACEi intervention, examining a cohort with the COL4A5 missense variant p.(Gly624Asp).
In this observational cohort study (NCT02378805), 114 individuals with the identical gene variant were explored for age at ESRF and life expectancy in correlation with treatment as endpoints.
All 13 untreated hemizygous patients developed ESRF (mean age 48.9 ± 13.7 years), as did 3 very late treated hemizygotes (51.7 ± 4.2 years), with a mean life expectancy of 59.2 ± 9.6 years. All 28 earlier-treated estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 hemizygous patients were still alive and still had not reached ESRF. Therapy minimized the annual loss of their GFR, similar to the annual loss in healthy individuals. Of 65 heterozygotes, 4 untreated individuals developed ESRF at an age of 53.3 ± 20.7 years. None of the treated heterozygous females developed ESRF.
For the first time, this study shows that in AS, early therapy in individuals with missense variants might have the potential to delay renal failure for their lifetime and thus to improve life expectancy and quality of life without the need for renal replacement therapy. Some treated patients have reached their retirement age with still-functioning kidneys, whereas their untreated relatives have reached ESRF at the same or a younger age. Thus, in children with glomerular haematuria, early testing for Alport-related gene variants could lead to timely nephroprotective intervention.
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