Diabetes Q&A

What Do You Need to Know About Type 2 Diabetes and Kidney Disease?

Volume 59 - Issue 11 - November 2019

Authors:
Kelley Williams, MD, and Kim A. Carmichael, MD—Series Editor

Citation:
Williams K, Carmichael KA. What do you need to know about type 2 diabetes and kidney disease? Consultant. 2019;59(11):337-338.

Q. How prevalent is chronic kidney disease (CKD) in diabetes?

A. In the United States, more than 58,000 persons have end-stage kidney disease (ESKD) attributed to diabetes.1 CKD is present in 25% to 40% of people with diabetes, which is the leading cause of ESKD and accounts for approximately 50% of all people on dialysis.2

 

Q. How does diabetes affect kidney function?

A. Hyperglycemia produces reactive oxygen species that are proinflammatory and profibrotic, causing cellular injury. Hyperinsulinemia and insulin resistance also incite some of these mechanisms (contributing to histological differences between type 1 and type 2 diabetes). Hyperglycemia activates the renin-angiotensin-aldosterone system (RAAS), which triggers kidney hypertrophy and causes an increased glomerular filtration rate (GFR).3 The increased filtration mostly results from greater reduction of afferent vs efferent arteriolar resistance.4 It is this imbalance that increases intraglomerular pressure, causing sclerosis.5

Q. What is the new terminology for diagnosing kidney disease?

A. Microalbuminuria was the previous term to signify urine albumin excretion between 30 and 300 mg/day. This is now termed moderately increased albuminuria, whereas albuminuria greater than 300 mg/day is termed severely increased albuminuria. These terms better reflect the severity of albuminuria, since severely increased albuminuria has a worse prognosis, including an increased risk of ESKD and cardiovascular events.

Q. How should a provider screen for kidney disease in patients with type 2 diabetes?

A. The most common laboratory abnormality of diabetic kidney disease is persistently elevated albuminuria and/or a persistently decreased estimated GFR (eGFR).

The American Diabetes Association (ADA) recommends annual testing of creatinine levels, eGFR, and urine albumin levels. Abnormal results should prompt repeated testing in 3 to 6 months to confirm whether the initial screening results were actually abnormal.6 

Patients with type 2 diabetes should be tested at the time of diagnosis and then annually thereafter. Of note, in patients with type 2 diabetes, the results of these screening tests are not as predictive of the progression of kidney damage as in patients with type 1 diabetes.

Q. What are the diagnostic criteria for diabetic kidney disease?

A. The persistence of urine albumin excretion greater than 30 mg/day and/or an eGFR less than 60 mL/min for at least 3 months are used for diagnosis. It is important to note that newer studies show that albuminuria can regress, even from a severely increased range. Estimated GFR can also markedly decrease before any albuminuria is present. Therefore, the presence of albuminuria is not necessarily required for diagnosis.

Q. What about kidney disease progression?

A. The progression of diabetic kidney disease is quite variable. Without intervention, a patient with severely increased albuminuria will, on average, progress to ESKD within 6 to 7 years.7 Faster decline is seen with higher levels of albuminuria, glycated hemoglobin (HbA1c) concentration, and systolic blood pressure.7

Q. What is the role of strict glycemic control in treatment of diabetic kidney disease?

A. The benefit of strict glycemic control should not be underestimated. Intensive insulin therapy to near-normal glycemia slows the onset or progression of diabetic kidney disease.8 Studies have shown that lower HbA1c levels are associated with reversal of hyperfiltration,9,10 rapid eGFR decline,11,12 and the development of stage 3 (moderate) CKD.13

Q. Is dietary protein restriction helpful?

A. There are no firm data to show that dietary protein restriction slows the progression of kidney disease in patients with diabetes.

Q. How do angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) work?

A. The general goal with RAAS inhibition in patients with diabetic nephropathy is to reduce blood pressure. ACEIs and ARBs also decrease resistance in the renal efferent arteriole, which decreases glomerular pressure, thus reducing sclerosis and leading to a decrease in protein excretion.14 

A strong association has been found between decreased proteinuria, the slowed progression of kidney disease, and the risk of eventual ESKD.15,16

Q. How do ACEIs and ARBs affect outcomes?

A. The results of a systematic review evaluating the impact of ACE inhibitors and ARBs on renal and mortality outcomes in people with type 2 diabetes suggested that these medications may reduce the risk of ESKD by 21% and decrease proteinuria progression by 51%; the regression of proteinuria was increased by 55% vs control groups.17 However, these medications have not been associated with all-cause mortality or cardiovascular risk.

Q. What are the adverse effects of RAAS inhibition?

A. Reduction in eGFR and an increase in the serum creatinine level are two adverse effects of ACEIs and ARBs. This results from the initial reduction in glomerular capillary pressure. An elevated serum creatinine level up to 35% above baseline that stabilizes is considered acceptable for continued therapy. It is important to note that an increase in serum creatinine does not always mean that function is declining.17

Q. What is the ADA guideline regarding RAAS inhibition?

A. Guidelines recommend ACEIs or ARBs at the maximum tolerated dose for blood pressure management as first-line agents in people with diabetes who have proteinuria.17 ACEIs and ARBs are generally thought to be equal in efficacy.

Q. What about sodium-glucose cotransporter-2 (SGLT2) inhibitors and kidney disease?

A. The recent CREDENCE trial showed that canagliflozin reduces the risk of ESKD, doubling of serum creatinine from baseline, and death from renal or cardiovascular disease compared with placebo.8 SGLT2 inhibitors may be recommended in patients with type 2 diabetes with nephropathy and with an eGFR greater than 30 mL/min,8 although Food and Drug Administration (FDA) approval for the use of this medication class is limited to patients with an eGFR greater than 45 mL/min. 

Estimated GFR recommendations differ among the different SGLT2 inhibitors. The FDA recently approved canagliflozin to reduce the risk of ESKD, worsening kidney function, and cardiovascular death in patients with type 2 diabetes and diabetic kidney disease.

Q. Are glucagon-like peptide-1 (GLP-1) receptor agonists good for renal disease in diabetes?

A. In a recent clinical trial,18 liraglutide reduced the incidence of new onset albuminuria greater than 300 mg/day, doubling of serum creatinine, end-stage renal disease or renal death. However, there is no FDA-approved indication for the use of GLP-1 agonists to prevent or treat renal disease.

 

Kelley Williams, MD, is a clinical fellow in the John T. Milliken Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, at the Washington University School of Medicine in St Louis, Missouri.

Kim A. Carmichael, MD, is a professor of medicine in the John T. Milliken Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, at the Washington University School of Medicine in St Louis, Missouri. 

 

REFERENCES:

  1. Incidence, prevalence, patient characteristics, and treatment modalities. In: United States Renal Data System. Annual Data Report 2018: Epidemiology of Kidney Disease in the United States. Vol 2. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2018:291-332. https://www.usrds.org/2018/download/v2_c01_IncPrev_18_usrds.pdf. Accessed October 30, 2019.
  2. Cho NH, Shaw JE, Karuranga S, et al. IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018;138:271-281.
  3. Pichler R, Afkarian M, Dieter BP, Tuttle KR. Immunity and inflammation in diabetic kidney disease: translating mechanisms to biomarkers and treatment targets. Am J Physiol Renal Physiol. 2017;312(4):F716-F731.
  4. Brenner BM, Lawler EV, Mackenzie HS. The hyperfiltration theory: a paradigm shift in nephrology. Kidney Int. 1996;49(6):1774-1777.
  5. Hostetter TH. Hyperfiltration and glomerulosclerosis. Semin Nephrol. 2003;23(2):194-199.
  6. American Diabetes Association. 11. Microvascular complications and foot care: Standards of Medical Care in Diabetes—2019. Diabetes Care. 2019;42(suppl 1):S124-S138.
  7. Biesenbach G, Janko O, Zazgornik J. Similar rate of progression in the predialysis phase in type I and type II diabetes mellitus. Nephrol Dial Transplant. 1994;9(8):1097-1102.
  8. Perkovic V, Jardine MJ, Neal B, et al; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295-2306.
  9. Tuttle KR, Bruton JL, Perusek MC, Lancaster JL, Kopp DT, DeFronzo RA. Effect of strict glycemic control on renal hemodynamic response to amino acids and renal enlargement in insulin-dependent diabetes mellitus. N Engl J Med. 1991;324(23):1626-1632.
  10. Tuttle KR, Bruton JL. Effect of insulin therapy on renal hemodynamic response to amino acids and renal hypertrophy in non-insulin-dependent diabetes. Kidney Int. 1992;42(1):167-173.
  11. Skupien J, Warram JH, Smiles AM, et al. The early decline in renal function in patients with type 1 diabetes and proteinuria predicts the risk of end-stage renal disease. Kidney Int. 2012;​82(5):589-597.
  12. Zoppini G, Targher G, Chonchol M, et al. Predictors of estimated GFR decline in patients with type 2 diabetes and preserved kidney function. Clin J Am Soc Nephrol. 2012;7(3):​401-408.
  13. de Boer IH, Afkarian M, Rue TC, et al; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group. Renal outcomes in patients with type 1 diabetes and macroalbuminuria. J Am Soc Nephrol. 2014;25(10):2342-2350.
  14. Ibrahim HN, Rosenberg ME, Hostetter TH. Role of the renin-angiotensin-aldosterone system in the progression of renal disease: a critical review. Semin Nephrol. 1997;17(5):431-440.
  15. de Zeeuw D, Remuzzi G, Parving H-H, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int. 2004;65(6):2309-2320.
  16. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD; Collaborative Study Group. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993;329(20):​1456-1462.
  17. Coleman CI, Weeda ER, Kharat A, Bookhart B, Baker WL. Impact of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers on renal and mortality outcomes in people with type 2 diabetes and proteinuria [published online August 12, 2019]. Diabet Med. doi:10.1111/dme.14107.
  18. Mann JFE, Ørsted DD, Brown-Frandsen K, et al; LEADER Steering Committee and Investigators. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med. 2017;377(9):839-848.