ACE gene variant linked to early kidney damage in children with type 1 diabetes

A cross-sectional study of 48 children and adolescents with type 1 diabetes at a single Egyptian university hospital reports that a common variant in the angiotensin-converting enzyme (ACE) gene is significantly associated with early markers of diabetic kidney disease. The work, published in the Egyptian Pediatric Association Gazette, found that the deletion (D) allele of the ACE insertion/deletion polymorphism was significantly more common among children who already showed albumin in their urine, and that it was linked to a fivefold higher odds of having both albuminuria and reduced estimated glomerular filtration rate (eGFR). The researchers suggest that genotyping could help identify young patients at high risk before conventional clinical markers become abnormal.

Diabetic nephropathy is one of the most feared long-term complications of diabetes. It is a leading cause of chronic kidney disease worldwide, and a considerable proportion of patients with type 1 diabetes eventually develop renal involvement, with some progressing to end-stage renal disease. In children, the condition often develops silently: albuminuria and changes in kidney function may only become detectable after structural glomerular damage has already begun. The study’s authors argue that this silent window is precisely why earlier risk stratification matters, because interventions such as ACE inhibitors may be able to slow renal decline if started before clinical onset.

The research team, led by Mona Hamed Gehad and colleagues at Zagazig University, enrolled children aged 10 to 18 years who had lived with type 1 diabetes for at least five years and who attended the pediatric diabetes outpatient clinic over a twelve-month period from February 2025 to February 2026. The sample size was calculated in advance to detect the expected frequency of the DD genotype, with 80 percent statistical power and a 95 percent confidence level, yielding a target of 48 participants. Children with other endocrine disorders, type 2 diabetes, congenital diabetes, unrelated kidney or urological disease, heart disease, chronic systemic illness, or medications affecting renal function were excluded.

Participants were divided into three groups according to renal status. Group I comprised 28 patients (58.3 percent) without evidence of diabetic nephropathy. Group II included 13 patients (27.1 percent) with albuminuria but preserved eGFR, and Group III contained 7 patients (14.6 percent) with both albuminuria and reduced eGFR. Taken together, nearly 42 percent of the cohort already showed early or established renal involvement, a distribution the authors describe as clinically important for early screening strategies. Each child underwent clinical evaluation, including anthropometric measurements and blood pressure assessment, along with laboratory testing of HbA1c, serum creatinine, lipid profile, urinary albumin and creatinine, and calculated eGFR using the pediatric Schwartz formula. Microalbuminuria was defined as urinary albumin excretion of 30 to 300 mg/g creatinine.

Genotyping was performed on DNA extracted from peripheral blood. The ACE insertion/deletion polymorphism, located within intron 16 of the gene on chromosome 17q23, was analyzed by polymerase chain reaction using allele-specific primers, with the insertion allele appearing as a 490-base-pair band and the deletion allele as a 190-base-pair band on gel electrophoresis. This polymorphism produces three genotypes: II, ID, and DD. The presence of the D allele, and particularly the DD genotype, is strongly associated with elevated circulating and tissue ACE enzymatic activity, which in turn increases production of angiotensin II, raises intraglomerular pressure, and promotes inflammatory and fibrotic pathways in the kidney.

The results showed a clear gradient of disease severity across the groups. Age differed significantly (p = 0.001), with older children showing more advanced nephropathy, and body mass index was modestly higher in the most affected group (p = 0.028). Duration of diabetes increased across stages, from a median of 5.5 years in Group I to 8 years in Group II and 13 years in Group III (p = 0.001). Glycemic control was poorer in the affected groups, with significantly elevated HbA1c (p < 0.001), and markers of renal injury, including albumin-to-creatinine ratio, microalbuminuria, and serum creatinine, were markedly elevated while eGFR declined significantly (p < 0.001). Cholesterol and triglycerides were also higher in the most advanced group (p = 0.011 and p = 0.01, respectively).

The genetic findings were the study’s central result. ACE genotype distribution differed significantly across the three groups (p = 0.004), with the DD genotype more frequent among patients with diabetic nephropathy, particularly in Groups II and III, where it was linked with a higher likelihood of albuminuria, reported as 33-fold and 44-fold respectively in those groups. The D allele was significantly more prevalent in the affected groups (p < 0.001), associated with 2.88-fold higher odds of albuminuria and 5.28-fold higher odds of combined albuminuria with reduced eGFR. Within genotypes, children carrying the DD genotype had higher HbA1c than those with the DI genotype (p = 0.024), elevated albumin-to-creatinine ratio and microalbuminuria (p < 0.05), higher serum creatinine than DI carriers (p = 0.026), and significantly lower eGFR than II carriers (p = 0.003). No significant associations were found between the polymorphism and lipid levels or acute presentations such as diabetic ketoacidosis, hypoglycemia, or polyuria.

The authors interpret these associations through the known physiology of the renin-angiotensin system. Because the D allele drives higher ACE activity and consequently greater angiotensin II generation, carriers may experience amplified intraglomerular hypertension and accelerated microvascular damage when exposed to the metabolic stress of chronic hyperglycemia. The findings align with prior literature linking the D allele and DD genotype to diabetic kidney disease risk in adult and other pediatric populations, including studies in Egyptian, Asian Indian, and other ethnic groups, although the authors note that some studies, including work in Tunisian patients, found no such link. They attribute these discrepancies to ethnic variation in genotype distribution, sample size, and study design, and they suggest the D allele may contribute more to disease progression than to disease initiation.

Several important limitations temper the conclusions. The study was cross-sectional, single-center, and small, with only 48 participants, so it cannot track disease progression over time or establish that the gene variant causes kidney damage. The analysis was univariate only; multivariate analysis was not performed, which restricts the ability to identify independent predictors while controlling for confounders such as age, diabetes duration, and glycemic control, all of which differed across the groups. Serum ACE concentrations were not measured due to sample availability constraints. The detection of the D allele among children without nephropathy also indicates that genetic factors alone are not sufficient for disease development, and those cases may require longer follow-up to clarify their risk.

Despite these constraints, the authors argue that ACE genotyping could serve as a non-invasive predictive biomarker to identify high-risk pediatric patients for early nephroprotective interventions. They recommend large-scale, multicenter longitudinal cohort studies to follow pediatric patients over extended periods, exploration of multi-gene panels to capture polygenic risk, and pharmacogenetic investigations of whether DD genotype carriers show differential responses to ACE inhibitor therapy. For now, the study adds pediatric evidence from a region where such data remain limited, and it underscores that genetic susceptibility, glycemic control, and disease duration together shape the early trajectory of kidney disease in children living with type 1 diabetes.

Subject of Research: Association of ACE gene insertion/deletion polymorphism with early diabetic nephropathy in children with type 1 diabetes

Article Title: Angiotensin-converting enzyme gene polymorphism as an early predictor of diabetic nephropathy in pediatric type 1 diabetes

Article References: Gehad, M. H., Abdelrahman, H. M., Sameh, H., Abd Elkareem Ali, H. E., & El Sharkawy, M. M. (2026). Angiotensin-converting enzyme gene polymorphism as an early predictor of diabetic nephropathy in pediatric type 1 diabetes. Egyptian Pediatric Association Gazette, 74(1), Article 124. https://doi.org/10.1186/s43054-026-00621-5

Image Credits: AI Generated

DOI: 10.1186/s43054-026-00621-5

Keywords: ACE gene polymorphism, diabetic nephropathy, type 1 diabetes, pediatric nephrology, albuminuria, eGFR, genetic risk marker, DD genotype, cross-sectional study, kidney disease, renin-angiotensin system, HbA1c