Why does diabetes cause polyuria

Eur J Endocrinol. Merck Manual Professional Version. National Kidney Foundation. Lithium and Chronic Kidney Disease. National Library of Medicine.

Urination - excessive amount. Lithium nephrotoxicity. Int J Bipolar Disord. Afra K, James MT. Hyponatremia and polyuria in an older woman. Lithium-induced nephrogenic diabetes insipidus: renal effects of amiloride. Clin J Am Soc Nephrol. Polyuria and cerebral vasospasm after aneurysmal subarachnoid hemorrhage. BMC Neurol. Published Oct Diabetes insipidus: The other diabetes. Indian J Endocrinol Metab. Your Privacy Rights. To change or withdraw your consent choices for VerywellHealth.

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What causes frequent urination with diabetes? Be the first to know about T1D news, local events and more. This field is for validation purposes and should be left unchanged. Most of these invoke high glucose levels and the increased proportion of glycation of structural and regulatory cell proteins and extracellular proteins such as glycated albumin and modified ultrafiltered proteins at the initiation of an injury cascade.

Chemokines attract and activate immigrating macrophages that, in turn, elaborate many bioactive molecules. Cytokines act by autocrine modes on tubular cells initiating a pro-fibrogenic gene expression programme but also in paracrine modes on residential fibroblasts and pericytes causing pro-fibrogenic transformation of these two latter cells Figure 1.

Most mechanistic hypotheses describing the development and progression of interstitial injury in diabetic nephropathy use all or some of these paradigms. Clinical observations showing that tight glycaemic control reduces the onset and progression of diabetic nephropathy are compatible with these theories but also support other mechanistic views.

Moreover, several observations do not appear to be well compatible with the notion that glycemia and glycated proteins induce interstitial fibrogenesis in diabetic nephropathy through mechanisms that are, in fact, identical to those thought to cause tubular atrophy and progressive interstitial fibrosis in virtually every other renal disease leading to complete renal failure.

In this narrative we attempt to develop another hypothesis of tubulo-interstitial injury in diabetic nephropathy that is based on polyuria that is associated with poor glycaemic control. Cartoon summarizing current theories of tubulo-interstitial injury through high glucose, glycated proteins and ultrafiltered albumin, modified albumins and bioactive growth factors as well as tubular fluid glucose.

FA-Alb, fatty acid—laden albumin; glyAlb, glycated albumin; glyProteins, glycated proteins. Even in advanced renal failure in diabetic nephropathy kidneys have normal or near-normal size and appearance on imaging studies. Simple renal utrasonography demonstrates that kidneys in patients with advanced renal failure from diabetic nephropathy are typically normal in length and parenchymal thickness. This is much in contrast to most other renal diseases where kidneys in advanced, chronic renal failure are more or less size-reduced with parenchymal atrophy Figure 2.

Renal ultrasonography allows also for the assessment of echogenicity. Sonographic hypoechogenicity is seen when tubules contain relatively large amounts of fluid [ 14 ]. Under this condition, even in the presence of advanced interstitial fibrosis, the renal echogenicity may be normal or only slightly increased. Whereas end-stage renal disease under most conditions presents sonographically with small and hyperechoic kidneys, this is different in advanced diabetic nephropathy: kidneys have usually normal size and normal or only modestly increased echogenicity Figure 2.

This unusual sonographic appearance is caused by an increased nephron fluid content in addition to nephron enlargement by cell hypertrophy and hyperplasia.

Comparison of renal ultrasound appearance of a right kidney from a normal subject A , the right kidney from a patient with diabetic nephropathy and end-stage renal disease about to begin chronic maintenance haemodialysis B and the right kidney of a patient with end-stage renal disease due to idiopathic FSGS C. The diabetic milieu, like hyperglycaemia and elevated interstitial fluid glucose levels per se , causes hypertrophy and perhaps moderate hyperplasia of the nephron [ 21,22 ]. Current models for glycemic cell hypertrophy are based on glucose-induced activation of the mammalian target of rapamycin complex-1 mTORC-1 that increases ribosomal translational activity and raises levels and activity of the cyclin inhibitors p21 Cip1 and p27 Kip1 also downstream of mTORC-1, both of which are inhibited by rapamycin therapy of the diabetic animals [ 23 ].

It is one of the pathophysiological enigmas that cell enlargement does not occur in other epithelial organs or tissues; perhaps, the difference is that tubular fluid glucose levels in poorly controlled diabetes are much higher compared to blood levels and it is these superglycaemic levels that are causative in tubular epithelial cell hypertrophy.

Nephron enlargement is an early event in diabetes but by all means does not account for the maintenance of a normal or supra-normal kidney size at later stages of progressive renal failure in diabetic nephropathy because nephron dropout and interstitial fibrosis prevail. In addition to tubular cell englargement, dilatation and increased fluid content of tubules, mainly collecting ducts, contribute substantially to the maintenance of kidney size in diabetic nephropathy with advanced chronic renal failure.

The earliest clinical renal symptom in untreated or poorly controlled diabetes in addition to glucosuria is, in fact, osmotic polyuria. The degree of polyuria, and hence, the accelerated tubular fluid flow rate, is defined by the glucose concentration—dependent osmotic forces, especially in the distal nephron. Polyuria due to osmotic forces changes the rheology of tubular flow and increases flow rate, especially in the distal nephron where flow rates and flow velocity are physiologically low.

Three decades ago Marsh and Martin examined the tubular pressure effects of acute osmotic polyuria by micropuncture in hamsters receiving an intravenous injection of mannitol [ 15 ]. Compared to baseline the osmotic challenge raises tubular fluid pressure in all tubular segments Figure 3.

However, the greatest pressure gain occurs in the distal nephron, especially in cortical-collecting ducts suggesting that this segment provides the greatest resistance to increased flow. These effects of osmotic diuresis are also well demonstrated with intra-vital microscopy Figure 4. Recent studies by Simeoni and co-workers are most illustrative in this context [ 24 ]. Figure 4 depicts a sequence of images before and at 5, 10 and 15 min after the administration of mannitol to a rat [ 24 ].

Shown is a proximal tubule segment in the left upper corner of each image and a distal tubule in the center Figure 4. During the min period of time after the osmotic challenge, the diameter of the proximal tubule changes little, if any Figure 4.

In contrast, the luminal opening of the distal tubule segment increases at least 3-fold Figure 4 [ 24 ]. This observation nicely illustrates the effect of osmotically increased fluid flow rates on the distal nephron. These findings are also illustrative of relatively good compliance of the distal tubule, at least acutely, and the relatively high resistance of the collecting ducts, and thus, confirm data from Marsh and Martin [ 15 ].

Comparison of tubular fluid pressures in hamsters before and after administration of mannitol to induce osmotic diuresis. Data are means of multiple measurements and are obtained from Marsh and Martin [ 15 ].

Intra-vital microscopic sequence of tubules before and at 5, 10 and 15 min after induction of forced diuresis as published by Simeoni et al. In each image a proximal tubule P is shown in the left upper corner, and a distal tubule segment D is depicted in the center.

Note the multiple-fold dilatation of the distal but not the proximal tubule. Reproduced with permission from Blackwell Publishing, Ltd. Distal nephron dilatations due to increased pressure are the hallmark of acute obstructive nephropathy as mimicked by ureteral ligation in the rat. In this renal disease model, distal nephron luminal pressure increases.

Studies using this model of renal injury have demonstrated the relative importance of this cytokine in renal fibrogenesis of obstructive nephropathy similar to diabetic nephropathy [ 10 , 16 ]. In fact, there are also several structural similarities between obstructive and early experimental diabetic nephropathy Figure 5. Comparison of the histological appearance of tubules in the obstructed kidney 7 days after unilateral ureteral ligation in a rat obstructive nephropathy A with the appearance of tubules in a diabetic rat at 30 weeks after induction of diabetes with streptozotocin B.

Note that collecting ducts are dilated to comparable degrees under both conditions. Hyperglycaemia-induced polyuria with increased tubular fluid pressure in the distal nephron, especially collecting ducts, is quite obviously the cause of tubular dilatations that are observed in rodent models of diabetes mellitus.

Given that osmotic diuresis induces increased tubular fluid pressure in collecting ducts, it is not surprising that in hyperglycaemic rats, collecting ducts are dilated Figure 6 B, C, D, F and G and the number of dilated tubules increases with time of hyperglycaemia Figure 6 D.

It is highly remarkable that cells in these dilated tubules and not in other non-dilated proximal tubules express those cytokines that have been shown to play important roles in renal interstitial fibrogenesis. These dilated collecting ducts are not atrophic; if any, there may be some degree of hyperplasia reminiscent of cystogenesis Figure 6 G.

These observations that molecules thought to be pathogenic in diabetic tubulo-interstitial nephropathy are expressed preferably or exclusively in dilated segments of the distal nephron have not only been made in this laboratory but are, in fact, shown in numerous publications for decades.