Mechanisms of glomerular hyperfiltration in diabetes mellitus

INTRODUCTION — A 25 to 50 percent elevation in the glomerular filtration rate (GFR) is seen early in the course in up to one-half of patients with type 1 diabetes mellitus [1,2], an abnormality that is exaggerated after ingestion of a protein load [3]. Glomerular hypertrophy and increased kidney size typically accompany the rise in GFR [3].

In addition to type 1 diabetes, hyperfiltration also occurs early in the course of type 2 diabetes [4-6]. In an original report of 110 newly diagnosed patients with type 2 diabetes mellitus, for example, the GFR was above 140 mL/min in 16 percent and more than two standard deviations above the mean of a control population in 45 percent [5]. The prevalence of hyperfiltration may be lower in the era of more aggressive glucose control. A later study of 93 newly diagnosed patients, for example, found that 17 percent had a GFR that was more than two standard deviations above the mean of a control population [7].

The degree of hyperfiltration and the course of the GFR in type 2 diabetes mellitus was evaluated in more detail in a study of 194 Pima Indians who had GFR measured using iothalamate clearance [6]. The following results were noted:

●In 31 patients with a normal glucose tolerance test, the mean GFR was 123 mL/min.

●In 29 patients with impaired glucose tolerance, the mean GFR was 135 mL/min.

●In 30 patients with newly diagnosed type 2 disease, the mean GFR was 143 mL/min.

●In 70 patients with overt diabetes for more than five years and either normal albumin excretion or moderately increased albuminuria (formerly called "microalbuminuria"), the mean GFR was 153 mL/min; in 34 similar patients with overt proteinuria, the mean GFR was 124 mL/min.

After four years of follow-up, the GFR rose 14 percent in patients with impaired glucose tolerance, 18 percent in newly diagnosed patients, was stable in those with moderately increased albuminuria, and fell 35 percent in those with overt proteinuria. The rate of fall in GFR in the last group was 0.93 mL/min per month, a rate similar to that seen in type 2 diabetes with overt proteinuria.

These hemodynamic and structural changes may be important clinically because intraglomerular hypertension (which is responsible for part of the rise in GFR) and glomerular hypertrophy (which increases shear stress on the glomerular capillary wall) may play an important role in the development and progression of diabetic nephropathy [8].

Although hyperfiltration is exacerbated by a dietary protein load [3], long-term trials in patients with obesity who had type 2 diabetes mellitus found that high-protein diets had little to no effect on kidney function [1,9]. (See "Diabetic kidney disease: Pathogenesis and epidemiology".)

Measurement of GFR is usually required to detect hyperfiltration because estimation equations, such as the Modification of Diet in Renal Disease (MDRD) study equation, usually underestimate the true GFR when it is normal or above normal. (See "Assessment of kidney function" and "Assessment of kidney function", section on 'Measurement of GFR with plasma clearance'.)

MECHANISM — Studies in experimental animals indicate that dilatation of the afferent (precapillary) glomerular arteriole plays an important role in the hyperfiltration response, by raising both the intraglomerular pressure and renal blood flow [2]. Why these hemodynamic changes occur is not well understood, but the following factors appear to contribute.

Hormones — A role for hormones is suggested by the ability of a chronic infusion of a somatostatin analogue (octreotide) to partially reverse both the early hyperfiltration and the increase in kidney size in type 1 diabetic patients [10]. In this study, glucose control and plasma glucagon and growth hormone levels were unchanged. There was, however, a fall in the plasma concentration of insulin-like growth factor 1 (IGF1), which is produced, in part, within the kidney.

Although the pathogenetic role of IGF1 is unproven, it is of interest that infusion of this hormone in normal subjects can replicate the findings seen in diabetics: renal vasodilatation and an elevation in glomerular filtration rate (GFR) [11]. Similar hemodynamic changes plus kidney hypertrophy can be induced by IGF1 in experimental animals [12].

In addition to IGF1 and other hormones, atrial natriuretic peptide had been postulated to contribute to hyperfiltration, but this is unproven [13,14]. Volume expansion due to increased sodium reabsorption may trigger its secretion, which can result in dilation of the afferent arteriole. (See 'Increased sodium reabsorption and tubuloglomerular feedback' below.)

Increased nitric oxide and cyclooxygenase 2 (COX-2)-derived prostanoids have also been implicated in vasodilatation of the afferent arteriole [15,16]. Theoretically, glomerular hyperfiltration in the early stages of diabetes occurs mainly in response to signals passed from the tubule to the glomerulus. Taken together, these studies suggest that the renin-angiotensin-aldosterone axis, COX-2, and nitric oxide systems are involved in the regulation of glomerular arteriolar tone in diabetes [17].

Sex hormones may affect the degree of glomerular hyperfiltration. In one study, females had a reduction in renal plasma flow and renal blood flow and decreased renal vascular resistance in response to hyperglycemia, but no change was detected in males [18]. With angiotensin-converting enzyme (ACE) inhibition, both sexes had a reduction in arterial pressure, but only females exhibited reduction in GFR.

Sorbitol — Several other factors directly related to hyperglycemia also may be important, including the intracellular accumulation of sorbitol and the formation of glycosylated proteins. The enzyme aldose reductase converts intracellular glucose to sorbitol, which then accumulates within the cells. Studies in hyperfiltering humans with type 1 diabetes have shown that the chronic administration of an aldose reductase inhibitor (tolrestat) lowers the GFR toward normal. In one study of patients who also had moderately increased albuminuria (formerly called "microalbuminuria"), for example, the GFR fell from 156 to 124 mL/min and albumin excretion fell from 197 to 158 mg/day after six months of tolrestat [19]. The possible efficacy of this regimen to prevent diabetic nephropathy remains to be determined.

Glycation products — In chronic hyperglycemia, some of the excess circulating glucose combines with free amino acids on circulating or tissue proteins. This nonenzymatic process initially forms reversible early glycation products and later irreversible advanced glycation end products, which may accumulate in tissues and contribute to the kidney and microvascular complications of diabetes (figure 1) [20]. (See "Diabetic kidney disease: Pathogenesis and epidemiology".)

In normal rats, the infusion of early glycation products to achieve plasma concentrations similar to that seen in diabetic rats can induce the increases in renal plasma flow, GFR, and intraglomerular pressure typical of untreated diabetes [21]. The applicability of this observation to humans is at present unproven.

Increased sodium reabsorption and tubuloglomerular feedback — Enhanced tubular sodium reabsorption, due to augmented sodium-glucose cotransport, leading to extracellular fluid volume expansion may be an additional factor contributing to the rise in GFR [2,22]. Hyperinsulinemia (due to subcutaneous administration) and mild hyperglycemia can also stimulate sodium reabsorption, the latter via increased sodium-glucose cotransport in the proximal tubule [23,24]. The rise in proximal reabsorption initially decreases distal fluid delivery that, by activating the tubuloglomerular feedback mechanism in the macula densa, can then raise the GFR via dilatation of the afferent arteriole [23]. Additional evidence to support this concept comes from studies using blockers of the sodium-glucose transporters in both patients with type 1 and type 2 diabetes [25-27].

High concentrations of glucose in the glomerular filtrate drive greater sodium-coupled glucose reabsorption through sodium-glucose cotransporter 2 (SGLT2) in the proximal tubule. Reduced sodium chloride delivery to the macula densa inhibits adenosine triphosphate conversion into adenosine, leading to lower levels of this vasoconstrictor and a reduction in afferent arteriolar tone. This results in increased blood flow and raises intraglomerular pressure [28].

SGLT1 transporters may also play a role in hyperfiltration [29]. Increased luminal glucose at the macula densa is sensed by SGLT1, consequently upregulating nitric oxide synthase 1 expression and activity and thereby reducing vasoconstrictor tone.

Thus, both SGLT2 and SGLT1 pathways may additively promote glomerular hyperfiltration in diabetes.

The hyperfiltration in this setting is appropriate from a kidney viewpoint since it counteracts the effect of enhanced proximal reabsorption, thereby returning distal sodium and water delivery toward normal and preventing excess fluid retention.

SUMMARY

●Elevations in the glomerular filtration rate (GFR) are seen early in the course in many patients with diabetes mellitus. Glomerular hypertrophy and increased kidney size typically accompany the rise in GFR. Intraglomerular hypertension and glomerular hypertrophy may play an important role in the development and progression of diabetic nephropathy. (See 'Introduction' above and "Diabetic kidney disease: Pathogenesis and epidemiology".)

●Dilatation of the afferent (precapillary) glomerular arteriole plays an important role in hyperfiltration. Factors that may contribute to afferent arteriole dilatation include insulin-like growth factor 1 (IGF1), atrial natriuretic peptide, sex hormones, intracellular sorbitol, early glycation products, and enhanced tubular sodium reabsorption in the proximal tubule. (See 'Mechanism' above.)