Influence of sex on hyperfiltration in patients with uncomplicated type 1 diabetes

Abstract

The aim of this analysis was to examine sex-based differences in renal segmental resistances in healthy controls (HCs) and patients with type 1 diabetes (T1D). We hypothesized that hyperfiltration—an early hemodynamic abnormality associated with diabetic nephropathy—would disproportionately affect women with T1D, thereby attenuating protection against the development of renal complications. Glomerular hemodynamic parameters were evaluated in HC (n = 30) and in normotensive, normoalbuminuric patients with T1D and either baseline normofiltration [n = 36, T1D-N, glomerular filtration rate (GFR) 90–134 ml·min⁻¹·1.73 m²] or hyperfiltration (n = 32, T1D-H, GFR ≥ 135 ml·min⁻¹·1.73 m²) during euglycemic conditions (4–6 mmol/l). Gomez’s equations were used to derive efferent (R_E) and afferent (R_A) arteriolar resistances, glomerular hydrostatic pressure (P_GLO) from inulin (GFR) and paraaminohippurate [effective renal plasma flow (ERPF)] clearances, plasma protein and estimated ultrafiltration coefficients (K_FG). Female patients with T1D with hyperfiltration (T1D-H) had higher R_E (1,985 ± 487 vs. 1,381 ± 296 dyne·sec⁻¹·cm⁻⁵, P < 0.001) and filtration fraction (FF, 0.20 ± 0.047 vs. 0.16 ± 0.03 P < 0.05) and lower ERPF (876 ± 245 vs. 1,111 ± 298 134 ml·min⁻¹·1.73 m² P < 0.05) compared with male T1D-H patients. Overall, T1D-H patients had higher P_GLO and lower R_A vs. HC subjects, although there were no sex-based differences. In conclusion, female T1D-H patients had higher R_E and FF and lower ERPF than their male counterparts with no associated sex differences in R_A. Prospective intervention studies should consider sex as a modifier of renal hemodynamic responses to renal protective therapies.

diabetes mellitus (DM) is the most common cause of chronic kidney disease (CKD) in North America, leading to great morbidity, mortality, and societal cost (1, 58a). In patients with nondiabetic CKD, women have a lower risk of progression to end-stage renal disease (ESRD). Conversely, in patients with diabetes, the association between sex and CKD risk is less clear, and the protective effect of female sex in patients with diabetes is generally attenuated (3, 19, 27).

To investigate the role of hemodynamic factors that may contribute to sex-related differences in the risk for CKD progression, previous studies have examined the relationship between sex and renal hemodynamic function, since renal hyperperfusion and hyperfiltration are risk factors for the initiation and progression of diabetic nephropathy (DN) (33, 44). Studies in the 1940s and 1950s examined renal hemodynamic function in healthy nondiabetic humans and demonstrated that women exhibited lower renal blood flow (RBF) than men (52). Similar findings have been documented in healthy patients with type 1 diabetes (T1D) (14). Despite these interesting observations, the mechanisms responsible for these sex differences in renal hemodynamic function—and possible relationships with risk factors for the development of renal disease—have not been established.

To better characterize sex differences in renal function, previous animal and human physiology experiments have characterized important modulators of renal hemodynamic function, such as activation of the renin angiotensin aldosterone system (RAAS). In animals, nondiabetic female rats have higher afferent and efferent arteriolar resistances and lower RBF compared with male rats (38). Despite the inability to directly measure segmental resistances in human kidney function, glomerular hemodynamic parameters such as afferent (R_A) and efferent (R_E) arteriolar resistances and glomerular hydrostatic pressure (P_GLO) can be indirectly calculated by using equations that were derived by Gomez and colleagues in the 1950s (2, 22). Subsequently, these equations have been used in studies of nephrology, hypertension, and endocrinology (42, 50, 51, 57, 58). To our knowledge, these principles have not been applied to study sex differences in glomerular hemodynamic function in states of health or disease.

To better understand previously documented differences in renal hemodynamic function in men and women, our aim was to determine the sex differences in the glomerular hemodynamic profile estimated using Gomez’s equations (R_A, R_E, P_GLO) of healthy control (HC) subjects compared with patients with T1D with hyperfiltration (T1D-H) and normofiltration (T1D-N). Differences in renal segmental resistances may offer insight into sex differences in responses to current and future renal protective therapies—such as RAAS inhibitors—that act by modulating renal arteriolar resistances. In this exploratory post hoc analysis, we hypothesized that women with T1D-H would exhibit a renal hemodynamic profile that could predispose them to renal injury such as lower R_A and an increase in R_E compared with men with T1D-H.

METHODS

A total of 30 HC patients, 36 T1D patients with normofiltration [TID-N, glomerular filtration rate (GFR) 90–134 ml·min⁻¹·1.73 m²], and 32 T1D-H patients (GFR ≥ 135 ml·min⁻¹·1.73 m²) were included in this retrospective post hoc analysis from previously completed studies (12, 16, 17, 36). Some previous studies included in the current analyses related to sex, as well as physiological effects of pharmacological agents in renal hemodynamic function. With this convenience sample, our aim was to gain further insight into sex-related differences by calculating renal segmental resistances by using the Gomez equations (discussed below). In this analysis, we included data from subjects who participated in four previously published studies, who had plasma protein data available to estimate oncotic pressure, and who met the inclusion criteria: T1D duration > 1 yr (T1D cohort), age > 18 yr, blood pressure < 140/90 mmHg, and normoalbuminuria. Patients were not taking medications that alter blood pressure or cardiovascular parameters. The study was approved by the Research Ethics Board at the University Health Network. All subjects provided informed consent before start of the study procedures.

Subjects adhered to a sodium replete (>140 mmol/day) and moderate protein (<1.5 g·kg⁻¹·day⁻¹) diet during the 7 days preceding the experiment as previously described (15). All studies were performed in the Renal Physiology Laboratory at the Toronto General Hospital. A modified glucose clamp technique was used to maintain euglycemic (4–6 mmol/l) conditions. Constant inulin and paraaminohippurate (PAH) infusions were used to determine GFR and effective renal plasma flow (ERPF). After a 10-min equilibration period, blood samples were collected for inulin, PAH, and hematocrit (Hct), with additional blood work drawn 30 min later. Two independent clearance periods were used for calculations, and the results averaged. All hemodynamic measurements were adjusted for body surface area.

Equations established by Gomez were used to estimate renal segmental resistances in the study cohorts (22). Gomez’s equations necessitate the following postulates: 1) intrarenal vascular resistances are divided into afferent, postglomerular, and efferent; 2) hydrostatic pressures within the renal tubules, venules, Bowman’s space, and interstitium are in equilibrium and given a value of 10 mmHg; 3) filtration disequilibrium in the glomerulus is assumed; 4) the gross filtration coefficient K_FG is assumed to be 0.1733 ml/s per mmHg (25) in HC given a normal kidney physiology where GFR = 130 ml/min, P_GLO = 60 mmHg, given Winton’s estimates in dog that glomerular pressure is roughly two-thirds of MAP (60) and normal glomerular oncotic pressure (π_G) is 25 mmHg. Previous micropuncture studies in Munich-Wistar rats suggest different P_GLO values in diabetic and control conditions. To replicate potential differences in HC vs. T1D patients, Gomez’s equations were modified in the T1D to calculate intraglomerular hemodynamic parameters assuming P_GLO values of 56.4 mmHg (K_FG = 0.1012 ml/s per mmHg) for T1D participants (30). To evaluate potential differences between male and female sex characteristics, K_FG values were modified according to prior animal studies whereby male rats had measured K_FG values higher by a correction factor of 1.84 compared with female rats (38, 43). We multiplied our previously determined K_FG values by this correction factor to estimate male K_FG values: HC male K_FG = 0.318 ml/s per mmHg; HC female K_FG = 0.1733 ml/s per mmHg; T1D male K_FG = 0.186 ml/s per mmHg; T1D female K_FG = 0.1012 ml/s per mmHg.

Clinical parameters including MAP (mmHg), ERPF (ml/s), GFR (ml/s), Hct (%), and TP (g/dl) were used to calculate R_E (dyne·sec⁻¹·cm⁻⁵) and R_A (dyne·sec⁻¹·cm⁻⁵) renal arteriolar resistances, P_GLO (mmHg), and π_G (mmHg): FF = GFR/RPF RBF = RPF/(1 – Hct). The filtration pressure across glomerular capillaries (ΔP_F) is calculated by ΔP_F = GFR/K_FG. The π_G is calculated from the plasma protein mean concentration (C_M) within the capillaries: C_M = TP/FF × ln(1/1−FF) and π_G = 5 × (C_M – 2). By substituting ΔP_F, π_G, and given that hydrostatic pressure in Bowman’s space (P_Bow) is assumed to be 10 mmHg, P_GLO is calculated: P_GLO = ΔP_F + P_Bow + π_G and P_GLO = (GFR/K_FG) + 10 mmHg + [5 × (TP/FF × ln(1/1−FF)−2)]. To calculate R_A and R_E using principles of Ohm’s law, where 1,328 is the conversion factor to dyne·sec⁻¹·cm⁻⁵ (22): R_A = [(MAP-P_GLO)/RBF] × 1,328 and R_E = [GFR/(K_FG × (RBF−GFR)] × 1,328.

Statistical analysis.

Differences in continuous variables across the groups were examined by one-way ANOVA. Analyses with significant one-way ANOVA tests were examined for between-group differences using Tukey’s test. Differences were considered statistically significant at P < 0.05. Additional adjustments were not made for multiple comparisons as these data are considered hypothesis generating. Data are expressed as means ± SD. All statistical analyses were done with GraphPad Prism software (Version 5.0).

RESULTS

Baseline characteristics.

Clinical and demographic characteristics were similar among HC, T1D-N, and T1D-H patients (Table 1). In terms of sex, baseline characteristics were similar aside from the expected higher hematocrit and height values of female HC and T1D subjects in comparison to men. Within T1D-H subjects, women had lower systolic blood pressure (111 ± 8 vs. 121 ± 10 mmHg, P < 0.05), ERPF (876 ± 245 vs. 1,111 ± 298 ml·min⁻¹·1.73 m², P < 0.05), and RBF (1,326 ± 352 vs. 1,831 ± 465 ml·min⁻¹·1.73m², P < 0.001), with corresponding higher FF (0.20 ± 0.05 vs. 0.16 ± 0.03, P < 0.05) compared with men with T1D-H.

Table 1.

Clinical baseline characteristics of male and female normal healthy control subjects and patients with type 1 diabetes and either renal normofiltration or hyperfiltration

	HC Male	HC Female	T1D-N Male	T1D-N Female	T1D-H Male	T1D-H Female
N	12	18	23	13	16	16
Age, yr	27.0 ± 5.1	27.6 ± 7.8	24.8 ± 6.2	23.0 ± 2.7	23.0 ± 4.3	23.7 ± 4.0
Diabetes duration, yr	—	—	18.9 ± 6.2	18.8 ± 3.6	16.5 ± 6.7	14.9 ± 7.5
Weight, kg	75.6 ± 12	66.8 ± 9.2	75.0 ± 10.4	71.0 ± 16	73.0 ± 9.3	70.0 ± 11.5
Height, m	1.79 ± 0.06	1.69 ± 0.08*	1.78 ± 0.06	1.65 ± 0.08*	1.75 ± 0.06	1.66 ± 0.06*
Body mass index, kg/m2	23.5 ± 3.3	23.2 ± 2.7	23.4 ± 2.4	25.8 ± 4.5	23.4 ± 2.4	25.3 ± 3.0
HbA1C - %, mmol/mol	—	—	8.2 ± 1.6	8.5 ± 1.5	8.5 ± 1.3	7.8 ± 0.9
24 h urine sodium, mmol	174 ± 65	177 ± 58	182 ± 108	162 ± 97	168 ± 84	166 ± 78
24 h urine urea, mmol	349 ± 109	284 ± 84	366 ± 100	245 ± 66*	369 ± 140	291 ± 113
Hematocrit	0.41 ± 0.03	0.37 ± 0.03*	0.39 ± 0.02	0.35 ± 0.01*	0.39 ± 0.03	0.34 ± 0.03§
Systemic hemodynamic function
HR	58 ± 9	59 ± 9	64 ± 11	75 ± 10	73 ± 13†	77 ± 12
SBP	112 ± 8	109 ± 10	116 ± 8	107 ± 6	121 ± 10	111 ± 8*
DBP	65 ± 6	66 ± 8	66 ± 7	64 ± 7	67 ± 7	65 ± 6
MAP	81 ± 6	81 ± 8	82 ± 6	78 ± 6	85 ± 6	80 ± 6
Renal Hemodynamic function
ERPF	645 ± 100	673 ± 205	652 ± 85	620 ± 103	1,111 ± 298†‡	87*6 ± 245*†‡
GFR	114 ± 11	119 ± 11	115 ± 11	116 ± 9	167 ± 25†‡	165 ± 22†‡
FF	0.18 ± 0.03	0.19 ± 0.05	0.18 ± 0.02	0.19 ± 0.03	0.16 ± 0.03	0.20 ± 0.05*
RBF	1,086 ± 164	1,077 ± 349	1,066 ± 151	958 ± 159	1,831 ± 465†‡	1,326 ± 352§‡
RVR	76 ± 12	80 ± 23	79 ± 13	83 ± 14	49 ± 13†‡	65 ± 16†‡

Values are means ± SD. HC, healthy control; H, hyperfiltration; N, normofiltration; T1D, type 1 diabetes; HR, heart rate (beats per minute); SBP, systolic blood pressure (mmHg); DBP, diastolic blood pressure (mmHg); MAP, mean arterial pressure (mmHg); ERPF, effective renal plasma flow (ml·min⁻¹·1.73m²); GFR, glomerular filtration rate (ml·min⁻¹·1.73m²); FF, filtration fraction; RBF, renal blood flow (ml·min⁻¹·1.73m²); RVR, renal vascular resistance (mmHg·l⁻¹·min⁻¹); P_GLO, glomerular hydrostatic pressure (mmHg); π_G, oncotic pressure (mmHg); R_A, afferent arteriolar resistance (dyne·sec⁻¹·cm⁻⁵); R_E, efferent arteriolar resistance (dyne·sec⁻¹·cm⁻⁵).

^*P < 0.05 vs. opposite sex within group.

^§P < 0.001 vs. opposite sex within group.

^†P < 0.05 vs. same sex healthy control group.

^‡P < 0.05 vs. same sex type 1 diabetes and normofiltration group.

Glomerular hemodynamic parameters.

When using differential K_FG values for normal and T1D subjects, but without making additional changes in K_FG based on sex, female T1D-H subjects had significantly higher R_E than men (1,985 ± 487 vs. 1,381 ± 296 dyne·sec⁻¹·cm⁻⁵, P < 0.001, Fig. 1, Table 2), while no sex differences were observed for R_A or P_GLO. Similar to our previous studies, T1D-H subjects had significantly lower R_A and higher P_GLO compared with T1D-N and HC (Fig. 1).

Fig. 1.

Glomerular hemodynamics estimated by Gomez’s equations in normal healthy controls (HC), and patients with type 1 diabetes (T1D), renal normofiltration (T1D-N), and hyperfiltration (T1D-H) according to sex. P_GLO, glomerular hydrostatic pressure; R_A, afferent arteriolar resistance; R_E, efferent arteriolar resistance. §P < 0.001 vs. opposite sex within group, †P < 0.05 vs. same sex healthy control group, ‡P < 0.05 vs. same sex Type 1 diabetes and normofiltration group using post hoc Tukey’s test after ANOVA analysis.

Table 2.

Glomerular hemodynamics calculated using differential K_FG values for normal and T1D subjects

	HC Male	HC Female	T1D-N Male	T1D-N Female	T1D-H Male	T1D-H Female
Glomerular hemodynamic parameters
N	12	18	23	13	16	16
PGLO	48.8 ± 1.9	47.2 ± 2.6	51.3 ± 3.1	51.7 ± 3.5†	60.8 ± 6.2†‡	61.4 ± 4.2†‡
πG	27.7 ± 2.4	25.7 ± 2.4	22.3 ± 2.3†	22.6 ± 2.9†	23.3 ± 3.0†	24.1 ± 2.4
RA	2,359 ± 549	2,665 ± 1,019	2,383 ± 581	2,266 ± 599	1,144 ± 565†‡	1,206 ± 508†‡
RE	922 ± 153	1,049 ± 317	1,613 ± 256†	1,867 ± 354†	1,381 ± 296†	1,985 ± 487§†

Values are means ± SD. P_GLO, glomerular hydrostatic pressure (mmHg); π_G, oncotic pressure (mmHg); R_A, afferent arteriolar resistance (dyne·sec⁻¹·cm⁻⁵); R_E, efferent arteriolar resistance (dyne·sec⁻¹·cm⁻⁵).

^§P < 0.001 vs. opposite sex within group.

^†P < 0.05 vs. same sex healthy control group.

^‡P < 0.05 vs. same sex Type 1 diabetes and normofiltration group.

When using estimated K_FG values that differed based on sex and T1D status, we saw similar changes in R_E: female T1D-H subjects had significantly higher R_E than men (1,985 ± 487 vs. 751 ± 161 dyne·sec⁻¹·cm⁻⁵, P < 0.001, Table 3). Under these assumptions, female T1D-N subjects had significantly higher R_E than T1D-N males (1,867 ± 354 vs. 878 ± 139 dyne·sec⁻¹·cm⁻⁵, P < 0.001, Table 3), and female HC subjects also had significantly higher R_E than HC males (1,046 ± 317 vs. 501 ± 83 dyne·sec⁻¹·cm⁻⁵, P < 0.001, Table 3). Sex differences in P_GLO were seen where T1D-H females had significantly higher P_GLO than T1D-H males (61.4 ± 4.2 vs. 48.3 ± 4.6 mmHg, P < 0.001, Table 3), and T1D-N females had significantly higher P_GLO than T1D-N males (51.7 ± 3.5 vs. 42.7 ± 2.7 mmHg, P < 0.001, Table 3).

Table 3.

Glomerular hemodynamics using differential K_FG values for sex within normal and T1D subjects

	HC Male	HC Female	T1D-N Male	T1D-N Female	T1D-H Male	T1D-H Female
Glomerular hemodynamic parameters
N	12	18	23	13	16	16
PGLO	43.8 ± 2.1	47.2 ± 2.7	42.7 ± 2.7	51.7 ± 3.5§†	48.3 ± 4.6†‡	61.4 ± 4.2§†‡
πG	27.7 ± 2.4	25.7 ± 2.4	22.3 ± 2.3†	22.6 ± 2.9†	23.3 ± 3.0†	24.1 ± 2.4
RA	2,734 ± 588	2,665 ± 1,019	3,036 ± 623	2,266 ± 599*	1,711 ± 633†‡	1,206 ± 508†‡
RE	501 ± 83	1,049 ± 317§	878 ± 139	1,867 ± 354§†	751 ± 161†	1,985 ± 487§†

Values are means ± SD. P_GLO, glomerular hydrostatic pressure (mmHg); π_G, oncotic pressure (mmHg); R_A, afferent arteriolar resistance (dyne·sec⁻¹·cm⁻⁵); R_E, efferent arteriolar resistance (dyne·sec⁻¹·cm⁻⁵).

^*P < 0.05 vs. opposite sex within group.

^§P < 0.001 vs. opposite sex within group.

^†P < 0.05 vs. same sex healthy control group.

^‡P < 0.05 vs. same sex Type 1 diabetes and normofiltration group.

DISCUSSION

Measurements of afferent and efferent arteriolar resistances within the human glomerulus are not feasible. As a result, it is not clear how sex impacts renal segmental resistance and glomerular physiology in the presence or absence of diabetes. Previous studies have characterized human renal physiological responses to RAAS inhibition on the basis of sex (36), and shown that nondiabetic men may require higher doses of angiotensin receptor blockade therapy than nondiabetic women. To further clarify the preglomerular vs. postglomerular factors that are responsible for mediating sex-based pathophysiological differences in renal function early in the natural history of diabetes, we applied the equations derived by Gomez et al. (22) to calculate glomerular hemodynamic parameters in both male and female HC and T1D patients. It was important to separate T1D patients based on hyperfiltration status since patients with T1D-N vs. T1D-H respond differently to a variety of stimuli, including cyclooxygenase 2 inhibition, nitric oxide inhibition, angiotensin I-converting enzyme (ACE) inhibition, and sodium glucose cotransport-2 inhibition (7, 9–11, 53).

Long-term studies have shown that nondiabetic CKD progresses to ESRD more slowly in women than in men (23, 28, 40), especially before menopause (18, 49). Mass screening programs have similarly shown that ESRD incidence starts to rise 10 yr later in women compared with male age-matched controls (26). In addition to later onset of CKD, women with nondiabetic renal disease may also maintain better preservation of renal function over time compared with men (40). To further understand the influence of sex hormones on renal disease progression, in vitro studies have examined sex hormone effects on physiological factors that increase the risk of renal disease and have shown attenuated activation of profibrotic pathways under the influence of estrogen (29, 48). In the in vivo spontaneous hypertensive rat model, urine albumin excretion is greater in males than females—an effect that is attenuated by castration (55) or oophorectomy (24). In contrast with observations in nondiabetic CKD, the role of sex on renal outcomes in the context of diabetes is less clear.

As suggested from prior studies (14), T1D-H female subjects had lower RBF than their male counterparts. In the current analysis, we calculated that the lower RBF phenomenon may be due to a higher R_E in T1D-H females. When reanalysis was done using altered K_FG values for sex, T1D-N females also had higher R_E, but there were no observed changes in RBF in this cohort. In contrast, in previous analyses, none of these hemodynamic parameters differed significantly in the HC or T1D-N groups based on sex (14). In terms of implications for the treatment of CKD, the higher baseline R_E in T1D-H women is interesting because nondiabetic healthy women exhibit enhanced responsiveness to aldosterone receptor blockade therapy and greater responsiveness to ACE inhibition in the context of T1D (36). If R_E was in fact elevated in women with T1D on the basis of RAAS activation in our previous work, then the greater responsiveness to RAAS inhibition may be on the basis of augmented blockade of the intrarenal RAAS leading to efferent arteriolar vasodilatation.

Although the mechanisms responsible for the increased R_E and lower RBF in T1D-H women compared with their males with T1D-H are not known, intrarenal RAAS activation is a possible candidate mediator. Previous studies in rodents have demonstrated that males exhibit higher levels of angiotensinogen mRNA in kidney tissue compared with females, and that estrogen attenuates the renal hemodynamic responses to angiotensin II, as well as histological and molecular markers of renal injury—overall effects consistent with RAAS suppression (4, 6, 21, 34). Similarly, in humans, women exhibit lower systemic blood pressures compared with men—a pattern that is consistent with overall blood pressure levels seen in the current analysis, which have in the past been attributed to suppression of the RAAS (20, 47, 59). Similarly, estrogen decreases ACE activity (5), angiotensin I receptor density (41), and aldosterone (35), but activates angiotensin II receptor density (31) and natriuretic peptides (32)—a profile that would generally be consistent with vasodilatation and blood pressure lowering. Nevertheless, given the lack of direct measures of intrarenal RAAS activation in the current analysis, the role of the RAAS remains speculative.

With the overall suppression of the RAAS system in women presumably due to estrogen, renal efferent arteriolar vasodilatation (lower R_E) would be expected. Instead, we observed an opposite interaction, with higher R_E in women with T1D-H. While the factors responsible for increased R_E levels in women with T1D-H are not yet known, several possible explanations exist. First, observations in women without diabetes demonstrating blunted ERPF and FF responses to an infusion of exogenous angiotensin II compared with men, suggesting maximal baseline upregulation of the RAAS resulting in attenuated angiotensin II responsiveness (35). Therefore, lower levels of RAAS mediators in the systemic circulating in animals and humans with diabetes may not accurately reflect functional intrarenal RAAS activation in women leading to increased R_E, as suggested by others (37). Alternatively, other non-RAAS mediators may have important roles in altering renal hemodynamic based on sex. For example, endothelin infusion is associated with a primary efferent arteriolar vasoconstrictive effect, which is likely mediated by the endothelin-1 type A receptor (45, 54). At the afferent arteriole, nitric oxide and vasodilatory prostanoids have been implicated in the pathogenesis of hyperfiltration (8, 17), and may also mediate sex-based renal function differences in humans (13). Whether there are major functional contributions from other neurohormonal mediators such as endothelin, nitric oxide, or prostanoids to differences in R_E based on sex requires further study.

The difference in the renal hemodynamic profile observed in women vs. men was characterized by an increased FF and lower RBF in the context of similar GFR levels, which merits additional comment. These differences may have been on the basis of several mechanisms, including an increase in R_E, or an increase in K_FG with concomitant increases in R_A and R_E. If on the basis of efferent arteriolar vasoconstriction as estimated by the Gomez equations, it must be assumed that tubular hydraulic pressure and K_FG remained constant in the presence of filtration disequilibrium (Fig. 2), which may not be the case in the setting of hyperfiltration (39, 46). For example, Scholey et al. (46) demonstrated that independent of insulin administration or ambient hyperglycemia, proximal tubular hydraulic pressure was ~3 mmHg lower in hyperfiltering animals with diabetes compared with nondiabetic control animals. In addition, in this model, the authors reported continued hyperfiltration despite a normalization of the glomerular transcapillary hydrostatic pressure difference in insulin-treated animals, which was due to an increase in calculated K_FG. It is therefore important to recognize that in addition to the effect of sex on K_FG, both tubular hydraulic pressure and K_FG may change under dynamic physiological conditions. Therefore, when we repeated our glomerular hemodynamic calculations with alternate estimated K_FG values for sex differences noted in animals, we observed consistent increased values for R_E in both T1D-H and T1D-N females as well as HC subjects, highlighting that our main observation is maintained in the context of changing K_FG values. Under this assumption, P_GLO was also increased in both T1D-H and T1D-N females compared with men in the same groups(Table 3), although this was not seen in our primary analysis with constant K_FG values (Table 2). Our main observation of higher R_E in T1D-H females compared with men is consistent across analyses of constant and differential K_FG values, highlighting the importance of understanding assumptions of filtration disequilibrium and the relevant physiological assumptions when doing calculations using Gomez formulae.

Fig. 2.

Intrarenal determinants of GFR. GFR, glomerular filtration rate; P_GLO, glomerular hydrostatic pressure; RBF, renal blood flow; R_A, afferent arteriolar resistance; R_E, efferent arteriolar resistance; P_TUB, tubular pressure.

The present study has limitations that are worth mentioning. First, the sample size in this analysis was small and may have limited our ability to detect between-group differences in HC and TID-N subjects. However, to minimize the effect of the sample size, we used careful physiological measurements, including RBF and GFR assessments by paraaminohippurate and inulin clearance, accepted as the gold standard methods. We also normalized glucose with a modified glucose clamp technique and standardized diet to eliminate the confounding impacts of acute glycemia and macronutrient content on renal measures. Another limitation is that the Gomez equations used in these calculations to determine glomerular hemodynamics only allow for indirect calculations of segmental resistance. The calculations of these parameters inferred ultrafiltration coefficients of normal and diabetic glomeruli determined from rat studies as described. With regard to mechanistic insights into the observed sex-based differences in renal hemodynamic function, mechanistic studies are now required to support our hypotheses. Finally, the observations described in this analysis are retrospective and cross-sectional and should therefore be considered to be exploratory and hypothesis generating. All experiments from the studies were performed in the one laboratory by the same clinical nurse and clinical supervisor with equivalent protocols to decrease potential confounders.

In conclusion, we have shown the first evidence in humans that women with T1D-H have higher R_E compared with men. Our findings may help to explain some of the observed clinical and experimental differences in sex-based responses to RAAS blockade.

GRANTS

The studies that provided data for this pooled analysis were funded by CIHR, Heart and Stroke Foundation of Canada and Boehringer Ingelheim & Eli Lilly, and Company Diabetes Alliance. D. Cherney was also supported by a Kidney Foundation of Canada Scholarship and a Canadian Diabetes Association-KRESCENT Program Joint New Investigator Award.

DISCLOSURES

D. Z. I. Cherney has received speaker/consultant honoraria from Boehringer-Ingelheim, Eli Lilly, AstraZeneca, Sanofi, Merck, Mitsubishi-Tanabe and Janssen and has received operational funding for clinical trials from Boehringer-Ingelheim, Merck, Janssen and AstraZeneca.

AUTHOR CONTRIBUTIONS

D.Z.I.C., Y.L., and M.Š. performed analyses, interpreted data, and drafted the manuscript. P.B. contributed to data analysis, drafting the manuscript, and reviewed and edited the manuscript. H.N.R., J.W.S., P.Y., E.B.S., and B.P. contributed to the interpretation of data and reviewed and edited the manuscript. All authors approved the final version.