Fetal Exposure to Maternal Type 1 Diabetes Is Associated With Renal Dysfunction at Adult Age

OBJECTIVE

In animal studies, hyperglycemia during fetal development reduces nephron numbers. We tested whether this observation translates into renal dysfunction in humans by studying renal functional reserve in adult offspring exposed in utero to maternal type 1 diabetes.

RESEARCH DESIGN AND METHODS

We compared 19 nondiabetic offspring of type 1 diabetic mothers with 18 offspring of type 1 diabetic fathers (control subjects). Glomerular filtration rate (⁵¹Cr-EDTA clearance), effective renal plasma flow (¹²³I-hippurate clearance), mean arterial pressure, and renal vascular resistances were measured at baseline and during amino acid infusion, which mobilizes renal functional reserve.

RESULTS

Offspring of type 1 diabetic mothers were similar to control subjects for age (median 27, range 18–41, years), sex, BMI (23.1 ± 3.7 kg/m²), and birth weight (3,288 ± 550 vs. 3,440 ± 489 g). During amino acid infusion, glomerular filtration rate and effective renal plasma flow increased less in offspring of type 1 diabetic mothers than in control subjects: from 103 ± 14 to 111 ± 17 ml/min (8 ± 13%) vs. from 108 ± 17 to 128 ± 23 ml/min (19 ± 7%, P = 0.009) and from 509 ± 58 to 536 ± 80 ml/min (5 ± 9%) vs. from 536 ± 114 to 620 ± 140 ml/min (16 ± 11%, P = 0.0035). Mean arterial pressure and renal vascular resistances declined less than in control subjects: 2 ± 5 vs. −2 ± 3% (P = 0.019) and 3 ± 9 vs. −14 ± 8% (P = 0.001).

CONCLUSIONS

Reduced functional reserve may reflect a reduced number of nephrons undergoing individual hyperfiltration. If so, offspring of type 1 diabetic mothers may be predisposed to glomerular and vascular diseases.A reduced number of nephrons may cause hypertension and favor renal and cardiovascular risks in humans (1). Autopsy findings support this assumption (2). In addition, birth weight is a determinant of nephron numbers in humans (3). In animal models, moderate hyperglycemia during pregnancy affects birth weight and nephron numbers in offspring (4), and favors the development of hypertension in adulthood (5). In addition, angiogenesis affects kidney development (6,7). In this respect, moderate hyperglycemia induces a defect in angiogenesis as reported in experimental conditions (8).We hypothesized that the effects of moderate hyperglycemia on kidney development reported in animal studies might have clinical relevance in humans. Thus, we studied kidney function in subjects who had been exposed to hyperglycemia during their fetal development. For this purpose, we investigated, as previously (9), adults whose mothers had type 1 diabetes at the time of their conception and used the offspring of type 1 diabetic fathers as control subjects to minimize potential genetic heterogenicity between groups. Type 1 diabetes as a source of hyperglycemia during fetal development also minimizes confounding factors associated with type 2 diabetes such as hypertension. Counting nephron numbers and/or visualizing glomerular size by noninvasive methods is not currently feasible in humans. Thus, we measured global kidney function at baseline and during vasodilatation produced by amino acid infusion, i.e., renal functional reserve. Reduction in renal functional reserve can be interpreted as reflecting a reduced surface available for filtration, suggesting that the number of functional nephrons is reduced. As a result, the global hemodynamic load provokes hyperfiltration at the single nephron level (1). This disturbance in renal hemodynamics was associated with renal and vascular diseases, both in experimental models (1,4,5) and clinical settings (10–13). We report here that renal functional reserve is reduced in offspring of type 1 diabetic mothers.