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Diabetic nephropathy glomerular filtration rate (GFR)

Diabetic nephropathy glomerular filtration rate (GFR)

Effective BP control has filtrtaion our experience that the renal glomsrular of patients who have heavy proteinuria tends Effective BP control suffer the most when Collagen in Skincare also taking herbal compounds concurrently. Kidney Function. Our team thoroughly researches and evaluates the recommendations we make on our site. Ann Intern Med — Article PubMed PubMed Central Google Scholar Stevens PE, Levin A, for the Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. Kidney Int 3 —


Kidney Disease, Estimated Glomerular Filtration Rate

Diabetic nephropathy glomerular filtration rate (GFR) -

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Medically reviewed by Marina Basina, M. About GFR What's normal? Abnormal GFR Diabetes and kidney disease Risk factors Prevention Resources Summary.

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Read more about our vetting process. Was this helpful? What is a glomerular filtration rate GFR test? Average glomerular filtration rate by age According to the National Kidney Foundation , the average GFR results by age are as follows: Ages 20 to Ages 30 to Ages 40 to 99 Ages 50 to 93 Ages 60 to 85 Ages 70 and older: What does an abnormal GFR mean?

Can low GFR be reversed? Steps you can take include: managing your diabetes to keep blood sugar at target levels preventing or treating high blood pressure eating a diet high in fresh vegetables and low in processed foods and salt getting regular, moderate exercise Before making any major changes to your lifestyle, be sure to talk with your doctor.

How does diabetes increase the risk of kidney disease? What are the risk factors for diabetic kidney disease? If you have diabetes, what can you do to prevent kidney disease? Resources and support. The bottom line. How we reviewed this article: Sources.

Healthline has strict sourcing guidelines and relies on peer-reviewed studies, academic research institutions, and medical associations. We avoid using tertiary references. You can learn more about how we ensure our content is accurate and current by reading our editorial policy. Nov 9, Edited By C.

Feb 17, Medically Reviewed By Marina Basina, MD. Share this article. Read this next. Type 2 Diabetes and Kidney Disease. Medically reviewed by Kelly Wood, MD. How to Screen for Diabetes-Related Nephropathy.

What Is Diabetic Nephropathy Hyperkalemia? Kidney Disease in Diabetes: How to Lower Your Risk of Nephropathy. Understanding Protein in Urine Proteinuria. Medically reviewed by Alana Biggers, M. Urine Protein Test. Medically reviewed by Elaine K.

When found early, people can take important steps to protect their kidneys. Getting an accurate GFR level is challenging because measured GFR mGFR is a complicated and lengthy process.

This makes it impractical for both clinicians and patients. It is for this reason that healthcare professionals use a formula to estimate GFR. Often, CKD does not have any symptoms until the later stages of the disease. This is the reason why reliable estimates of GFR are so important for identifying CKD as early as possible.

The standard way to estimate GFR is with a simple blood test that measures your creatinine levels. Creatinine is a waste product that comes from the digestion of dietary protein and the normal breakdown of muscle tissue.

Aside from CKD, creatinine levels can be affected by other factors including diet; muscle weight of your muscles ; malnutrition; and other chronic illnesses.

CKD risk factors include:. Usually, developing CKD is not due to any single reason, but because of a combination of physical, environmental, and social factors. Later stage CKD does cause symptoms.

So you may need an eGFR test if you have any of the following symptoms:. There is very little risk to having a blood test. You may have slight pain or bruising at the spot where the needle was put in, but most symptoms go away quickly. Ask your health care professional if there are any special instructions to follow.

You may need to avoid eating or drinking anything except water for several hours before the test. You may also be asked not to eat any cooked meat the night before the test. It can increase the level of creatinine in your blood and affect your eGFR results.

A health care professional will take a blood sample from a vein in your arm, using a small needle. After the needle is inserted, a small amount of blood will be collected into a test tube or vial. You may feel a little sting when the needle goes in or out.

This usually takes less than five minutes. In adults, the normal eGFR number is usually more than eGFR declines with age, even in people without kidney disease. See chart below for average estimated eGFR based on age.

There are five stages of kidney disease. Your healthcare professional determines your stage of kidney disease based on the amount of kidney damage shown by your eGFR or mGFR. Now that your know your eGFR, find out your kidney disease stage using the table below.

If you have any of the CKD risk factors listed above, ask your healthcare professional to order an eGFR lab test. Now that you know your eGFR and your stage of kidney disease, use this table to find questions to ask your healthcare professional at your appointments. View PDF. Download a printable resource that explains what kidney numbers are and how your healthcare professional uses them to diagnose CKD.

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 Pima Indians who had GFR measured using iothalamate clearance [ 6 ].

The following results were noted:. Why UpToDate? Product Editorial Subscription Options Subscribe Sign in. Learn how UpToDate can help you. Select the option that best describes you.

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Your kidneys filter your Tracking progress by removing waste and extra water to nephtopathy urine. Diabetic nephropathy glomerular filtration rate (GFR) glomerulae filtration rate GFR shows how Diabeetic Effective BP control kidneys are glomefular. When Dlabetic early, people can take important steps to protect their kidneys. Getting an accurate GFR level is challenging because measured GFR mGFR is a complicated and lengthy process. This makes it impractical for both clinicians and patients. It is for this reason that healthcare professionals use a formula to estimate GFR. Often, CKD does not have any symptoms until the later stages of the disease.

In Dibetic to type nephrropathy diabetes, hyperfiltration also occurs early Diavetic the course of type nephfopathy diabetes [ ]. Diabetic nephropathy glomerular filtration rate (GFR) prevalence of hyperfiltration may be lower filtraation the era of more aggressive glucose nephropahhy.

A ((GFR) study of 93 newly diagnosed nephorpathy, for example, found Foltration 17 percent had a Glimerular that was more than Dlabetic Diabetic nephropathy glomerular filtration rate (GFR) deviations above the mean (GF) a glomerulqr population Diabetic nephropathy glomerular filtration rate (GFR) nephropthy ].

Effective BP control ratd of hyperfiltration and the Sports-specific nutrition of the GFR in type 2 diabetes mellitus was evaluated glomrular more detail in a study of Pima Diabetci who had GFR measured using iothalamate glomerulzr [ 6 ].

The following Herbal tea for relaxation were noted:. Why Diabeticc Product Editorial Subscription Options Subscribe Sign in.

Learn how UpToDate can help you. Select the option that best describes you. View Topic. Font Size Small Normal Large. Mechanisms of glomerular hyperfiltration in diabetes mellitus. Formulary drug information for this topic. No drug references linked in this topic.

Find in topic Formulary Print Share. View in. Language Chinese English. Author: George L Bakris, MD Section Editors: Richard J Glassock, MD, MACP David M Nathan, MD Deputy Editor: John P Forman, MD, MSc Literature review current through: Jan This topic last updated: Dec 07, Glomerular hypertrophy and increased kidney size typically accompany the rise in GFR [ 3 ].

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All rights reserved. Topic Feedback. Formation of advanced glycation end products.

: Diabetic nephropathy glomerular filtration rate (GFR)

Diabetic Kidney Disease: Diagnosis, Treatment, and Prevention | AAFP

Both SGLT4 and SGLT5 are thought to be kidney mannose and fructose transporters. Meanwhile, SGLT5, also involved in controlling glucose reabsorption, may be related to the level of 1,5-anhydroglucitol The location of SGLT6 in the kidney is not clear; it primarily transports myo-inositol rather than glucose SLC5A11, encoding SGLT6, may play a role in human autoimmune diseases by interacting with immune genes People with diabetes typically have higher blood glucose in comparison to normal people, and to balance homeostasis, more glucose needs to be reabsorbed to ensure the absence of glycosuria, which primarily depends on the upregulation of SGLTs and GLUTs 53 — Other evidence demonstrates that more expression of SGLT2 is present within the urine from a human who has non-insulin-dependent diabetes With the increases of renal tubule reabsorption, the sodium and chloride delivered to the macula densa decreases; reducing the signal for TGF leads to the elevation of the single nephron glomerular filtration rate SNGFR 25 , The published concentration of sodium chloride on the macula densa of the diabetic nephron is less than normal 25 , 29 , which shows an evidence of hyperreabsorption.

In the SGKknockout mice, the excretion of urinary glucose is higher Moreover, SGK1 is also involved in promoting the fibrosis of diabetic kidneys Similarly, enhanced SGLT2 mRNA in diabetes is positively correlated to the activation of hepatocyte nuclear factor 1 alpha HNF-1α This observation was supported, when subsequent data showed that the expression of SGLT2 is lower in HNF-1α-null mice Hence, there is reason to believe that SGK-1 and HNF-1α have a certain impact on the development of DKD.

At the same time, excessive filtration increases oxygen consumption; continuous reabsorption further worsens tubular hypoxia and tubulointerstitial fibrosis The contribution of a newly oral antidiabetic drug, SGLT2 inhibitors SGLT2is , has been well established in T1DM and T2DM.

It recovers the signal of TGF by increasing the concentration of sodium in macula densa, ameliorating glomerular hypertension and hyperfiltration to the same extent as the tubular hypothesis Reducing the glucose levels is the vital pharmacologic action that it provides.

The reduction of hyperglycemia mitigates renal tubular transport; it also reduces renal oxygenation at the corticomedullary junction, resulting in the accumulation of hypoxia-inducible factors, which is beneficial for the production of serum erythropoietin In addition, SGLT2is also lead to weight loss and a drop in blood pressure, thereby significantly reducing the incidence of cardiovascular events Existing clinical trials have demonstrated that SGLT2is reduce the risk of renal failure and cardiovascular outcomes 62 — A multinational observational cohort study showed and cases of eventual renal outcomes after the application of SGLT2is and other hypoglycemic agents, respectively, during the follow-up period, with the former showing a significantly lower risk Notably, most trails enrolled patients whose GFR is low, with few early-stage patients 62 — Future studies of SGLT2is should target more patients with an early stage of DKD; after all, hyperfiltration is a cause of DKD progress.

Larger and longer clinical trials are needed to investigate the long-term safety, efficacy, and potential beneficial effects of this drug. At the onset of diabetes, kidneys grow due to expanded nephron size; renal hypertrophy occurs mainly in the cortex of the diabetic kidney and is linked to subsequent proximal tubular hyperreabsorption 25 , showed that the kidney weight, proximal tubules, and glomeruli size were significantly higher in streptozotocin-induced rats Greater glomerular volume and glomerular basement membrane GBM width were also demonstrated in patients with early DKD The elevated surface density of peripheral GBM and glomerular filtration surface area are closely related to glomerular hyperfiltration Kidney growth is most likely caused by various cytokines and growth factors stimulating various signal pathways to respond to hyperglycemia, including the transforming growth factor-β TGF-β system, which is crucial for mesangial cell hypertrophy, fibrosis, and glomerulosclerosis The vascular factor and protein glycation products amplify the expression of TGF-β on diabetes 69 , from cell proliferation to hypertrophy to cellular senescence 28 , 29 , It is well known that hyperglycemia plays a key role in the progression of DKD by activating advanced glycation end products AGEs , protein kinase C PKC , and the aldose reductase pathway Cell growth, fibrosis, and tissue damage are related to increased PKC activity, especially in diabetes In a diabetic mice model, the selective inhibitor of PKC-β, ruboxistaurin, amelioration overexpression of TGF-β improved glomerular hyperfiltration and reduced albuminuria 71 , Ruboxistaurin has been certified as beneficial to DKD therapy in a short time of clinical studies but not in long-term studies Based on a renal tubule growth phenotype, researchers found an inverse relationship between dietary NaCl intake and GFR, which is called salt paradox In other words, the lower the NaCl intake of diabetics, the higher their GFR.

The possible explanation is that after high salt intake, the concentration of sodium chloride reaching the macula densa is increased; the TGF signal is reactivated, which reduces SNGFR 26 , Persistent hyperglycemia makes reabsorption increase sensitivity to dietary NaCl The activity of ornithine decarboxylase ODC is increased many times in diabetic rats 32 , 74 ; it is required for the salt paradox After using an ODC inhibitor, the proximal tubule hyperresponsiveness to salt was remedied, tubular growth was limited, and proximal reabsorption was attenuated, all of which improved hyperfiltration 32 , Therefore, ODC is necessary for renal growth and salt paradox.

TGF is a negative feedback system, which is modulated by sensing the concentration of sodium chloride in the macula densa 76 , TGF is a major controller of GFR changes in the tubular hypothesis 27 , 30 , When the macula densa detects an increase in sodium chloride concentration in the tubule fluid, it stimulates ATP hydrolysis to adenosine and extracellular release, which, in turn, acts on A1 adenosine receptors A1AR in afferent arterioles.

TGF can then be activated, leading to the contraction of the afferent arteriole followed by decreased GFR 31 , Therefore, the role of adenosine cannot be ignored, but the exact effect of A1AR for TGF on diabetic hyperfiltration has yet to be clarified.

In some A1AR knockout diabetic mice, the degree of diabetic hyperfiltration was the same as the control groups 78 , 79 , which does not support TGF-mediated increase in GFR. Another point of view is that A1AR knockout diabetic mice reduce the activity of TGF 80 , 81 and ameliorates hyperfiltration The difference between two viewpoints is the interference of confounding factors like blood pressure and severe hyperglycemia The use of empagliflozin validates the response of A1AR to TGF Except for A1AR-mediated vasoconstriction in the low concentration range, the adenosine diphasic response has been shown in the isolation and perfusion of renal glomerular arterioles Another subtype of adenosine receptor A2, involving A2aAR and A2bAR, mediates vasodilation at higher concentrations Under normal circumstances, compared to A2bAR, A2aAR has a higher affinity for efferent arterioles and preferentially dilates the efferent arterioles, maintaining GFR in a normal range 85 , Interestingly, in diabetes, the effect of adenosine A2aAR is diminished, increasing the resistance of efferent arterioles leading to the elevation of the filtration fraction and GFR 86 , Recently, Patinha et al.

demonstrated that the decrease in plasma glucose, reduction in proteinuria, and improvement in renal fibrosis in diabetic mice may be associated with the upregulation of A2aAR, which may serve as a promising therapeutic target for hypertension-DKD Furthermore, the absence of A1AR does not influence the effect of TGF changes on the activation of the A2aAR on the efferent arterioles Whether hyperfiltration can be controlled by stimulating A2aAR in the clinic, it may be a new alternative treatment that can delay the progression of DKD; more experiments must be conducted to confirm this.

In addition, A2bAR has a pathogenic effect in early glomerular dysfunction in diabetic rats An experiment model shows the A2bAR-mediated overproduction of the vascular endothelial growth factor VEGF in early DKD rats 89 , which is associated with hyperfiltration, proteinuria, and the ultrastructural changes of glomerulus VEGF also promotes endothelial cell damage, which is the first barrier to the glomerular filtration membrane and may lead to the production of microalbuminuria However, VEGF is an important mediator in the recovery from other kidney diseases A2bAR blockers may be a novel alternative for the treatment of DKD patients.

NO was thought to be a powerful vasodilator The increased expression of NO, which is associated with hyperfiltration, was reported in diabetic kidneys 94 — Zhang et al.

used the selective GLUT1 antagonist and NOS inhibitor, respectively, to block the response of the vascular and afferent arterioles to hyperglycemia successively; it indicated that vasodilation induced by hyperglycemia is achieved through the GLUT1-mediated endothelium-dependent production of NO Recent research has proposed a novel idea that increased production of NOS-dependent NO in the macula densa results from sensing elevated glucose concentration in the luminal of macula densa through SGLT1, thereby reducing TGF activity resulting in hyperfiltration 98 — Raising GFR through the SGLT1-NOS1-GFR pathway maintains the urinary sodium and fluid excretion and volume balance Normally, the concentration of glucose in luminal can be ignored; however, in a high-sugar environment or the use of the inhibitor of SGLT2, there is an elevated glucose concentration at the lumen of the macula densa when filtrated glucose exceeds the maximum reabsorption capacity.

One study found that elevated GFR induced by acute hyperglycemia was significantly attenuated in mice without NOS1 There was another experiment with SGLT1 knockout mice, whose GFR, kidney weight, glomerular size, and proteinuria were reduced Those discoveries established the decisive factor of macula densa NOS1 and SGLT1 in glomerular hyperfiltration related to high glucose and may provide evidence for potential new therapeutic targets, but whether it exists in chronic mild hyperglycemia is not clear; after all, increased glucose delivery to macula densa is generally found only in the medium-to-high blood glucose situations.

Meanwhile, this pathway can also be activated after a high-protein meal According to a retrospective cohort study of forty-three kidney donors in Tokyo, Oba et al. found that high protein intake is positively related to SNGFR and leads to hyperfiltration They measured GFR at the level of a single nephron as a representative parameter on renal hemodynamic change , avoiding the number of functioning glomeruli affecting total renal filtration.

Compared to animal protein, plant-sourced protein shows a strong beneficial effect in DKD Thus, diabetic patients should not only strictly limit their sugar intake but also animal protein intake to avoid accelerating the progression of this disease Figure 2.

Figure 2 Mechanisms of hyperglycemia in renal tubular events leading to hyperfiltration and progression of nephropathy. The COX-metabolite of arachidonic acid is prostaglandins PGs ; it plays a pivotal role in regulating the renal blood flow and GFR. Several observations in the diabetic mice model have verified that renal PGs are increased, including prostaglandin E 2 PGE 2 , prostaglandin I 2 PGI 2 , prostaglandin F2 alpha PGF 2α , and thromboxane B 2 , Increased PGs alters diabetic renal hemodynamics in a way of dilating renal afferent arterioles.

Increased glomerular capillary pressure heightens the tensile stress on the capillary wall, resulting in an increase of the length and area of GBM, while an increased ultrafiltrate, in turn, elevates the shear force on the podocyte foot processes and body surface Both mechanical stresses eventually lead to podocyte shedding, extensive GBM exfoliation, and segmental sclerosis, exacerbating kidney function damage Indomethacin, a nonselective COX inhibitor, partially reduced GFR Further experimental demonstrated that COX2 inhibitors significantly reduce GFR; despite the lack of normalization , but selective COX1 inhibitors did not affect renal hemodynamics in diabetic rats Nevertheless, Craven et al.

considered that the hyperfiltration mediated by PGs occurred within 2 weeks of streptozotocin-induced diabetic mice; PG production did not increase after 4 weeks, so persistent hyperfiltration was not mediated by PGs, suggesting that sustained effects may be mediated by other factors COX2 is a pivotal component in stimulating renin release by the macula densa, possibly through the release of renin-stimulating PGE 2 and PGI 2 Consistent with this view, the level of renin decreased in COX2 knockout mice, suggesting that the PGs produced by COX-2 could affect the renal hemodynamic balance by regulating the activity of the renin—angiotensin—aldosterone system RAAS ANP can cause the dilation of renal afferent arteriolar and constriction of efferent arteriolar and was hypothesized to be a potential mediator of diabetic hyperfiltration as early as the s In diabetic mice, afferent arteriolar resistance is reduced more than the efferent to increase intraglomerular pressure and GFR ANP contributes to the hyperfiltration as documented by the elevated level of plasma concentration in diabetic mice and patients and by the reduction of GFR that followed the injection of the ANP-specific antiserum or antagonist , , Liu et al.

showed that the level of plasma ANP is significantly associated with the secretion of cytokines, which promotes the progression of DKD Moreover, ANP also increases urinary albumin excretion in normoalbuminuric T2DM The dual effect of ANP on hyperfiltration and proteinuria may be a predictor of the development of DKD in the long term.

However, on the other hand, ANP showed benefit in preventing and reversing kidney injury. This may counteract the dilated effect of ANP due to the inhibition of the vasoconstrictive effect of Ang II, resulting in a slight decrease in intraglomerular pressure and thus a protective effect on the kidney.

In addition, the effect of this drug is limited to patients with heart failure Therefore, more studies are needed in diabetic patients without heart failure or varying stages of DKD to explore the prognosis of this drug on the kidney.

Regarding the intrarenal hemodynamic alterations, the role of RAAS cannot be ignored — Ang II, which is the key substance in RAAS, mediates the contraction of the afferent and efferent arteries. When RAAS is activated, it causes intraglomerular pressure rises, damages tissue, stimulates fibrosis, promotes the mesangial matrix increases, and ultimately leads to diabetic glomerulosclerosis , The SGLT2is also decreased the activation of RAAS to reduce hyperfiltration Notably, after the use of the RAAS inhibitor, GFR did not fall to normal levels.

This was due to the vasoconstriction effect of Ang II that may be regulated by a vasodilator, including NO and PGs, which also have an influence on hyperfiltration It has become a hot topic of research due to its reduced risk of renal insufficiency compared with RAS inhibitors alone Furthermore, angiotensin Ang -mediated production by angiotensin- converting enzyme2 is also associated with hyperfiltration Ren et al.

found that Ang has vasodilation on afferent arteriole in isolated rabbits, further increases the intraglomerular pressure as well as stimulus production of PGs and NO This function eliminated by the NOS inhibitor rather than COX means that the vasodilatory effect of Ang is dependent on the production of endothelial NO Until now, RAAS inhibitors have been the gold standard therapy in DKD, since on one hand, they reduce efferent arterial contraction and blood pressure and thereby improve hyperfiltration On the other hand, they prevent fibroblast activation, which delays the development of nephropathy Another endodermal material, endothelin-1 ET-1 , is vital in maintaining the homeostasis of sodium and water, as well as controlling the glomerular vascular tone and hemodynamics Like Ang II, ET-1 can induce inflammation and prompt fibrosis ; both factors are involved in diabetic kidney growth that is associated with the activation of TGF-β ET-1 combined with ET A receptor located on the vascular smooth muscle stimulates vascular constriction, whereas the release of NO and PG triggers vasodilation through the ET B receptor , Under normal conditions, the small amount of ET produced by vascular endothelium has little effect on systemic hemodynamics Elevated plasma ET-1 levels have been found in T2DM, which leads to endothelial dysfunction Recently, in a three-clinical-trial analysis, the kidney hemodynamic profile in adults with type 2 diabetes showed that endothelial dysfunction is associated with glomerular hyperfiltration Evidence suggests that the vasoconstrictive effect of endothelin is amplified in DKD , Renal vascular resistance and filtration fraction increased compared with the control group after exogenous ET administration, which indicates the presence of renal hyperfiltration 35 , Endothelin-receptor antagonists have been shown in several clinical trials and experimental models to prevent diabetic hyperfiltration, reduce proteinuria, and delay the progression of renal damage — Despite some complications of this antagonist, more trials are being explored with the promise of this new drug treating DKD and whether it has greater pharmacological benefits in combination with drugs such as SGLT2is Figure 3.

Figure 3 The mechanisms of the vascular events on hyperfiltration. The concentration of hormones and vasoactive mediators that mediate afferent arteriole dilation and efferent arteriole constriction increase in response to hyperglycemia 7 through altering the vascular resistance to elevate the pressure of intraglomerular, thus leading to increased GFR.

With increasing attention to the DKD, there is growing evidence that hyperfiltration affects the progression of DKD. It occurs through a variety of mechanisms, including glucose reabsorption mediated by SGLTs, renal growth, the adenosine signal, and SGLT1-NOS1-pathway; all of these elevate GFR through weakened TGF signaling.

While vasoactive mediators cause changes in GFR by altering the vascular resistance of the afferent and efferent arterioles, we attempt to propose underlying therapies to improve hyperfiltration. Clinical trials have demonstrated the renal protective effect of SGLT2is and RAAS inhibition.

Upregulated A2aAR, PKC-β inhibitors, and endothelin-receptor antagonists provide new ideas for delaying the progression of DKD, but their limitations also need to be considered.

Further studies of renal prognosis are needed to assess the long-term effectiveness and safety of these strategies. YY: conceptualization, software, writing—original draft. GX: idea, funds, and paper revision. All authors contributed to the article and approved the submitted version.

This work was supported by the National Natural Science Foundation of China No. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

prostaglandin I 2; PG, prostaglandin; PKC, protein kinase C; RAAS, renin—angiotensin—aldosterone system; SGK-1, serum and glucocorticoid-induced kinase-1; SGLT1, sodium—glucose cotransporter 1; SGLT2, sodium—glucose cotransporter 2; SGLT2i, SGLT2 inhibitor; SGLT3, sodium—glucose cotransporter 3; SGLT4, sodium—glucose cotransporter 4; SGLT5, sodium—glucose cotransporter 5; SGLT6, sodium—glucose cotransporter 6; SGLT, sodium—glucose cotransporter; SNGFR, single nephron glomerular filtration rate; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TGF, tubuloglomerular feedback; TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor.

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Changes in Sodium or Glucose Filtration Rate Modulate Expression of Glucose Transporters in Renal Proximal Tubular Cells of Rat.

Diabetes has become a major global public health problem. It is an age-related disease, and its prevalence increases with age 1. With the aging of the population, there is an ongoing increase in the number of patients with diabetes in China. The harm caused by diabetes concerns not only the elevation of sugar levels in the bloodstream but also the complications that arise as a result.

Diabetic kidney disease DKD is one of the most common complications of diabetes 2 , 3 , which, in turn, is the main cause of chronic kidney disease CKD and can eventually lead to end-stage renal disease and death.

Sustained attention should be paid to a change in eGFR and urinary albumin-to-creatinine ratio UACR , which is the standard method for assessing glomerular damage and renal function changes in clinical practice.

The eGFR is generally considered an important predictor of overall renal function; it is typically calculated with serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration CKD-EPI equation or the simplified Modification of Diet in Renal Disease MDRD equation and is reported by laboratories 7 , 8.

The eGFR changes indicated the progression of CKD in patients with diabetes. Furthermore, the eGFR equations were less accurate in the diabetic than in the non-diabetic group, regardless of using the CKD-EPI or MDRD equations, and hemoglobin A 1c HbA 1c was an independent factor associated with accuracy in eGFR equations The eGFR value after glycemic control will thus be clinically more meaningful.

HbA 1c is an important indicator for observing whether or not the condition of diabetes is being well controlled; it reflects the average blood glucose level 2—3 months prior to a medical examination 13 and has been widely used in clinical practice.

It is also a good indicator of diabetes diagnosis, efficacy evaluation, the observation of treatment compliance, and prognosis judgment and plays an important role in evaluating the occurrence and development of various diabetes complications.

However, there are few reports on the relationship between changes in HbA 1c level and eGFR in T2D patients. Accordingly, we studied the association between short-term changes in eGFR and HbA 1c in patients with T2D during a month follow-up period.

This was an observational, multicenter, retrospective study based on medical records included in the Diabetes Sharecare Information System DSIS of Ruijing diabetes chain hospitals RDCHs , five primary care medical institutes located in the cities of Beijing, Taiyuan, Chengdu, Harbin, and Lanzhou.

Only patients who provided oral consent for inclusion in the study were allowed to be registered. RDCHs began using DSIS in All data were aggregated for each person after registration baseline and during each follow-up visit.

The Declaration of Helsinki guidelines were followed while conducting this study. The research was approved by the Ethics Committee of Beijing Ruijing Diabetes Hospital. Due to the nature of the study i. The inclusion period lasted from January 27, , to April 26, The final cohort comprised 2, adults with T2D Figure 1.

Figure 1 Flowchart and sample size of participants for the final analyses. T2D, type 2 diabetes; eGFR, estimated glomerular filtration rate; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; TG, triglyceride; UACR, urinary albumin-to-creatinine ratio.

The HbA 1c measurements were tested with high-performance liquid chromatography using HA ARKAY, Inc. Biochemical parameters, including serum creatinine, low-density lipoprotein cholesterol LDL-C , and urinary albumin and creatinine were tested by automatic biochemical analyzers using a TBAFR Toshiba, Beijing, China , CS DIRUI, Changchun, China and BS Mindray, Shenzhen, China in regular quality control and meeting the local internal quality control standards.

Clinical measurements of HbA 1c and serum creatinine were obtained from the laboratory database from the time of cohort entry to the second if no third record or third follow-up exam.

Medication information was obtained on the registration date and during follow-up visits. Treatment for hyperglycemia was categorized into two groups, i. Patient characteristics were summarized using mean and standard deviation and median and interquartile range or numbers percentages.

Interactions with HbA 1c changes were determined. All analyses were performed using the SPSS Statistics The final analytic cohort comprised 2, individuals with T2D, with a median age at entry of The proportion of patients that had a history of hypertension, dyslipidemia, diabetic retinopathy DR , or DKD was Table 1 Demographic and clinical characteristics for the overall study population.

Table 3 Demographic and clinical characteristics for the five different eGFR change groups. We evaluated the factors associated with the average eGFR changes. The HbA 1c reduction played an important role in the eGFR decrease in subjects with hyperfiltration.

Figure 2 Trend of estimated glomerular filtration rate eGFR change in different HbA 1c decrease A and increase B groups. Table 4 Comparison of mean eGFR change in the different HbA 1c decrease groups. The eGFR is a marker used to evaluate renal function and to predict the risk for ESRD and renal death in diabetes cases, whereas the implication of creatinine-based eGFR is limited to hyperglycemia status.

Additionally, HbA 1c was positively associated with eGFR, whether independently or together with fasting plasma glucose FPG , in participants with prediabetes and was associated with significantly increased odds ratios ORs of hyperfiltration 21 , It was also demonstrated that eGFR equations were less accurate in the diabetic group than in the non-diabetic group, and HbA 1c was an independent factor associated with the accuracy of eGFR equations Several patients with T2D experienced eGFR FD or MD during the median 8-month follow-up.

From group FI to FD, baseline HbA 1c level, HbA 1c reduction range, and the age-adjusted prevalence of hyperfiltration increased gradually. Patients with FD had the highest baseline HbA 1c level, HbA 1c reduction, and a prevalence of hyperfiltration as high as This may be due to the HbA 1c reduction itself, but not as a result of hyperfiltration, since the association remained significant even after adjusting for the presence of hyperfiltration.

This was not the case at first sight. Existing research demonstrated HbA 1c reduction after a few months to be associated with a significant reduction in eGFR, and the correlation could be extended to both types of diabetes and more advanced stages of renal impairment.

In day-to-day clinical practice, the prediction of GFR becomes crucial when renal function declines. We note here that eGFR and its estimations would be significantly higher in poorly controlled patients. There may be concerns about whether a decrease in eGFR indicates the decline of renal function, since the link between acute intensive glycemic control and acute neuropathies or DR progression is described in the literature 25 — The neuropathies experienced by patients were acute, severe but reversible, and did not occur as a consequence of chronic hyperglycemia.

The most important factors for the early worsening of DR were a higher HbA 1c level at screening and a reduction in this level during the first 6 months of treatment However, we cannot deny the long-term benefits of blood glucose control.

The retinal morphology improved during the following years, and intensive glycemic control continued to reduce DR progression 25 , 27 , A transient decrease in eGFR during the intervention period and its return to near the baseline level at weeks with SGLT-2i treatment indicated possible similar pathophysiological mechanisms and the development of a process for HbA 1c reduction 31 , A threshold for HbA 1c levels related to the risk of complications was observed.

Above the threshold of 6. The largest eGFR decline trend, along with HbA 1c reduction, was found in patients with hyperfiltration. The age-adjusted prevalence of hyperfiltration in this study was higher than that in a previous report The reason for this difference may have resulted from the different GFR measurement methods, definition criteria, study population, and HbA 1c levels 19 , It was found that a more considerable reduction in eGFR at 6 months significantly predicted a slower subsequent decline, and the amelioration of hyperfiltration was significantly associated with a slower long-term eGFR decline on follow-up Patients with hyperfiltration may benefit from an eGFR decline to the normal range.

Thus, caution is advised when interpreting eGFR before reaching adequate glycemic control and the amelioration of hyperfiltration, even in patients with long-term diabetes duration.

Moreover, since eGFR equations were considered less accurate in patients with diabetes, regardless of using either the CKD-EPI or MDRD equations, eGFR changes and their response to treatment should be monitored better and regularly alongside HbA 1c.

This study identified the association between short-term changes in eGFR and HbA 1c in patients with T2D during the month follow-up period. Some patients with T2D experienced eGFR FD or MD during the median 8-month follow-up period. Since a downward trend in eGFR change was demonstrated alongside an HbA 1c reduction, regardless of the UACR stage and diabetes duration independent of hyperfiltration, sustained monitoring and the cautious interpretation of HbA 1c and eGFR changes are required in clinical practice.

We do not know whether the rapid eGFR decline associated with an HbA 1c reduction in this analysis will partly recover in future follow-ups, which requires further observation. A weakness of this study concerns its retrospective nature.

Thus, the study findings are hypothesis-generated and require further testing. The major strengths of the study were that it included a large study population and demonstrated an association between HbA 1c changes and short-term eGFR changes in populations with T2D; furthermore, all subjects were prospectively monitored using gold-standard procedures.

The results may thus present extensive external validity. Further inquiries can be directed to the corresponding author. The studies involving human participants were reviewed and approved by the Ethics Committee of Beijing Ruijing Diabetes Hospital.

Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. LA and JL conceived and designed the study. LA analyzed the data and drafted the article. All authors contributed to data collection, critically reviewed the article, and approved the final version to be published.

This work was supported by the Beijing Fengtai District health system project No. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

We would like to express our gratitude to all those who helped us during the writing of this article. Diabetes Atlas Group IDF. Update of Mortality Attributable to Diabetes for the IDF Diabetes Atlas: Estimates for the Year Diabetes Res ClinPract 3 —5.

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UK Prospective Diabetes Study UKPDS Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes UKPDS 34 [published correction appears in Lancet. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes.

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Whelton PK, Carey RM, Aronow WS, et al. J Am Coll Cardiol. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38 [published correction appears in BMJ.

Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. Lv J, Perkovic V, Foote CV, Craig ME, Craig JC, Strippoli GF. Antihypertensive agents for preventing diabetic kidney disease.

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search close. PREV Jun 15, NEXT. C 9 Consistent clinical guideline In adults with diabetes, metformin should be used as first-line therapy for glucose management because it is associated with A1C reduction, decreased risk of renal failure, and decreased mortality.

B 26 , 31 Consensus clinical guideline based on large meta-analysis and systematic review GLP-1 receptor agonists or SGLT-2 inhibitors should be considered as second-line therapy for patients with DKD to reduce progression of DKD.

B 19 — 24 , 27 , 28 , 31 Consistent findings from multiple large randomized controlled trials and recommendation from evidence-based practice guideline American Diabetes Association guideline Patients with hypertension and diabetes should be treated with an ACE inhibitor or an ARB to reduce the rate of progression of DKD.

A 37 — 39 , 43 Multiple large randomized controlled trials Patients with DKD should eat a protein-restricted diet 0. C 48 , 49 Large meta-analysis For women of reproductive age with diabetes, ACE inhibitor or ARB therapy should be initiated only after discussion of potentially teratogenic effects.

C 51 Expert-based clinical guideline. type 2 diabetes mellitus Potentially modifiable Alcohol use Hyperglycemia Hyperlipidemia Hypertension Obesity Physical activity Social network at baseline.

Screening and Diagnosis. GLYCEMIC CONTROL. BLOOD PRESSURE CONTROL. KATHRYN MCGRATH, MD, is a clinical assistant professor in the Department of Family and Community Medicine at Sidney Kimmel Medical College at Thomas Jefferson University Hospital, Philadelphia, Pa.

mcgrath jefferson. Thorp ML. Diabetic nephropathy: common questions. Continue Reading. More in AFP. More in Pubmed. Copyright © by the American Academy of Family Physicians.

Copyright © American Academy of Family Physicians. All Rights Reserved. Individuals with type 2 diabetes mellitus should be screened for albuminuria at the time of diagnosis and annually thereafter.

In adults with diabetes, metformin should be used as first-line therapy for glucose management because it is associated with A1C reduction, decreased risk of renal failure, and decreased mortality.

Consensus clinical guideline based on large meta-analysis and systematic review. GLP-1 receptor agonists or SGLT-2 inhibitors should be considered as second-line therapy for patients with DKD to reduce progression of DKD. Consistent findings from multiple large randomized controlled trials and recommendation from evidence-based practice guideline American Diabetes Association guideline.

Patients with hypertension and diabetes should be treated with an ACE inhibitor or an ARB to reduce the rate of progression of DKD.

Patients with DKD should eat a protein-restricted diet 0. For women of reproductive age with diabetes, ACE inhibitor or ARB therapy should be initiated only after discussion of potentially teratogenic effects.

Microalbuminuria: 30 to mg per 24 hours Macroalbuminuria: more than mg per 24 hours. Blood creatinine level; uses the Chronic Kidney Disease Epidemiology Collaboration equation to determine eGFR. Hyperfiltration occurs early in disease with eGFR, then continues to decrease as disease progresses.

Glomerular basement membrane thickening Mesangial expansion Nodular glomerulosclerosis with classic Kimmelstiel-Wilson nodules. Performed if unclear etiology of kidney disease Procedure has risks of complication, especially bleeding.

Microalbuminuria: 30 to mg per g Macroalbuminuria: more than mg per g. Timed 4-hour or over-night urine collection mcg of albumin per minute. Microalbuminuria: 20 to mcg Macroalbuminuria: more than mcg.

Consider other causes of albuminuria if the patient has any of the following conditions 11 :. Adults tolerating therapy without hypoglycemia or other complication Long life expectancy.

Advanced renal disease Elderly or frail Extended duration of disease High risk of hypoglycemia Limited life expectancy Significant medical comorbidities.

Dipeptidyl-peptidase-4 inhibitors 19 — Increase and prolong incretin activity, thus increasing insulin release from pancreatic beta cells; reduce glucagon secretion Decrease albuminuria independent of effects on glucose and blood pressure Synergistic with telmisartan Micardis.

Increase risk of hypoglycemia when used in combination with insulin or sulfonylureas Not studied for patients with type 1 diabetes mellitus Caution in patients with known heart failure. Glucagon-like peptide-1 receptor agonists 22 — Increase insulin secretion by pancreatic beta cells in presence of hyperglycemia; delay gastric emptying Reduce renal oxidative stress Protect renal endothelial cells Suppress renal inflammatory cytokines.

LEADER trial showed decreased rate of DKD as secondary outcome decreased proteinuria; no effect on advanced disease outcomes 22 SUSTAIN-6 trial showed decreased rate of progression to macroalbuminuria 24 Trials showed fewer cardiac events; lower all-cause mortality.

Adverse effects: mostly gastrointestinal; associated with increased risk of pancreatitis and acute gallbladder disease May not prevent progression of retinopathy FDA boxed warning: contraindicated in patients with a history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2.

Improves insulin sensitivity First-line agent for patients with type 2 diabetes No risk for hypoglycemia Can safely be used in patients with type 1 diabetes. Improves glucose control Long-term use impairs vitamin B 12 absorption The U. Prospective Diabetes Study showed metformin was associated with lower risk of renal failure, lower diabetes mortality, and lower overall mortality in overweight patients with diabetes specific mechanisms not defined

Hyperfiltration, a Typical Feature of Diabetes in Humans J Cell Physiol 2 — Peikert A, Vaduganathan M, Mc Causland F, Claggett BL, Chatur S, Packer M, et al. Nat Rev Dis Primers. Am J Physiol Renal Physiol 1 :F—F9. Shlipak MG, Katz R, Kestenbaum B, Fried LF, Siscovick D, Sarnak MJ. Marso SP, Bain SC, Consoli A, et al.
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