Diabetes and Diabetic Nephropathy
Etiology and Classification
Diabetes mellitus (DM), often referred to as diabetes, is a group of metabolic diseases characterized by high glucose levels that result from defects in insulin secretion, action, or both1-3. DM is the most common disorder of the endocrine system and has been classified into Type 1, Type 2 and gestational diabetes. Type I DM, previously known as juvenile or insulin dependent diabetes, accounts for 5%-10% of the total diabetic population1-3. In Type I DM, an autoimmune reaction destroys pancreatic beta cells which results in severe insulin deficiency or complete non-production of insulin1-3. Individuals with Type I DM typically require exogenous insulin replacement therapy and/or transplantation of pancreas or pancreatic islet cells in order to survive. Type I DM occurs most commonly in children and young adults, although disease onset can occur at any age. Type II DM, previously known as adult-onset or non-insulin dependent diabetes, accounts for 90%-95% of the diabetic population1-3. Type II DM is associated with insulin resistance and increased insulin levels. Over time a gradual reduction in insulin secretion by the pancreas is often seen, leading to decreasing hyperinsulinemia in later stages1-3. Management of Type II DM focuses on life style changes in combination with pharmacologic interventions. Increased risk for Type II DM is associated with older age, obesity, family history, physical inactivity, ethnicity, and a host of other factors1-3. Gestational diabetes is thought to be caused by insulin-interfering hormones produced during pregnancy. Although gestational diabetes usually disappears after the birth of the baby, women who have had gestational diabetes have a 40 to 60 percent chance of developing Type II DM within 5 to 10 years1-3.
The prevalence of diabetes in the United States has tripled since 1980, and is expected to continue to increase in the coming decades4, 5(see Figure 1). This growing prevalence of diabetes can be attributed to the longer life expectancy of the general population, improved detection techniques and diagnostic criteria, as well as a rise in both obesity and metabolic syndrome6, 7. Current statistics from the 2007 Centers for Disease Control and Prevention (CDC) National Diabetes Facts Sheet estimate that 23.6 million Americans (or 7.8% of the population) have diabetes, with nearly 6 million of those cases being undiagnosed. In addition, 57 million US adults age 20 years or older have impaired fasting glucose1 indicating that one quarter of the US adult population is at high risk of developing Type II DM.
Prevalence of diabetes
Figure 1: Number (in millions) of civilian/noninstitutionalized persons with diagnosed diabetes, United States, 1980–2007. Diabetes is becoming more common in the United States. From 1980 through 2007, the number of Americans with diabetes tripled (from 5.6 million to 17.4 million)4.
Childhood Type II DM has also increased over the past three decades, and seems to parallel the rising rates of childhood obesity8-11. Data from the 1976 to 2006 National Health and Nutrition Examination Surveys (NHANES) indicate that among children aged 2–5 years the prevalence of obesity increased from 5.0% to 12.4%; for those aged 6–11 years, prevalence increased from 6.5% to 17.0%; and for those aged 12–19 years, prevalence increased from 5.0% to 17.6%12. Studies have shown a strong correlation between obesity and diabetes; specifically, 25% of obese children have an impaired glucose tolerance and 1% to 2% of obese children develop Type II DM10. Thus, it’s not surprising that Type II DM accounts for nearly 45% of new cases of diabetes in the pediatric population, and that 2 million US adolescents under the age of 20 currently have impaired glucose tolerance1, 13.
The overall risk of death among diabetics is nearly twice that of people without diabetes1. Diabetic complications affect both the macrovasculature (such as coronary artery disease and peripheral vascular disease) and microvasculature (such as retinopathy, nephropathy, and neuropathy)3 and significantly impact mortality rates. In addition, diabetes is responsible for 71,000 amputations, 12,000 to 24,000 new cases of blindness1, and over 500,000 hospitalizations each year14.
These complications make diabetes an expensive disease, with an estimated annual cost of 174 billion dollars in 2007 (including both direct and indirect medical costs)1. It is further estimated that 1 out of every 10 health care dollars is spent due to diabetes or its complications15.
Screening and Diagnosis:
The American Diabetes Association (ADA) recommends testing for diabetes in all adults who are overweight or obese (BMI ≥ 25 kg/m2) and have one or more additional risk factors such as9:
- Physical inactivity
- Family history of diabetes
- Member of a high risk ethnic population (i.e., African American, Latino, Native American, Asian, or Pacific Islander)
- Hypertension ( ≥ 140/90 mmHg)
- HDL < 35 mg/dl or triglycerides > 250 mg/dl
- History of cardiovascular disease
If the requirements for testing are met, a diagnosis of diabetes can be made in individuals who exhibit one of the following9:
- Hemoglobin A1c ≥ 6.5%,
- Fasting plasma glucose ≥ 126 mg/dl
- 2-hour plasma glucose ≥ 200 mg/dl during an oral glucose tolerance test (OGTT)
- Classic symptoms of hyperglycemia plus a random plasma glucose ≥ 200 mg/dl.
In most instances, the diagnosis should be confirmed by repeat testing to rule out potential laboratory error, unless the diagnosis is clear on clinical grounds9. More information regarding the diagnosis and treatment of diabetes can be found on the American Diabetes Association website (professional.diabetes.org).
Diabetic Kidney Disease (Diabetic Nephropathy)
Prevalence and Screening:
Diabetic nephropathy (DN) refers to the presence of elevated urinary protein excretion in a person with diabetes in the absence of other renal disease16. Twenty to forty percent of individuals with diabetes will be diagnosed with DN and it is the single leading cause of end-stage renal disease (see Figure 2)9, 17. In addition, epidemic increases in obesity, metabolic syndrome, and Type II DM in the United States reflect the growing prevalence rates of DN16. The American Diabetes Association (ADA) and National Kidney Foundation (NKF) guidelines recommend annual screening for kidney damage starting at the diagnosis of Type II DM and 5 years after the diagnosis of Type I DM9,18. Free screenings for high risk individuals can be obtained through the NKF’s Kidney Early Evaluation Program (KEEP). For more information on KEEP, please visit www.kidney.org.
Development of diabetic nephropathy and other etiologies of ESRD
Figure 2: Incident counts & adjusted rates of primary kidney diseases that lead to end stage renal failure17.
Screening for DN is done through measurement of urinary albumin, as studies have shown proteinuria to be a strong predictor of renal injury and patient survival19-21.
The three most common methods for assessing urinary albumin are: (1) a 24-hour urine collection; (2) a timed urine collection (e.g., 4-hour or 10-hour overnight); or (3) measurement of the urine albumin-to-creatinine ratio in a random spot collection. The latter method is preferred because it is the most convenient and cost-effective2. After the urine specimen is collected and evaluated, results may be classified as microalbuminuria (an albumin-to-creatinine ratio between 30 and 299 ug/mg) or macroalbuminuria (an albumin-to-creatinine ratio ≥ 300 ug/mg). Classification should be confirmed with two additional samples collected during the next 3 to 6 month period9,18 to rule out transient albuminuria22. Although macroalbuminuria is more closely associated with frank nephropathy, microalbuminuria is also an important marker of kidney damage and a predictor of cardiovascular events18. Many individuals with Type II DM and microalbuminuria succumb to cardiovascular events before they progress to macroalbuminuria or renal failure16. An association between microalbuminuria and cardiovascular risks such as lipid abnormalities, impaired endothelial function, peripheral vascular disease, and a pro-thrombotic state has been noted23. Thus, in addition to renal dysfunction, microalbuminuria is a marker of generalized vascular dysfunction and endothelial injury23.
Pathophysiology and Classification:
The pathophysiology of diabetic nephropathy is complex and multifactorial. Two mechanisms have been proposed, both of which are initiated by hyperglycemia (see figure 3). The first mechanism is based on hyperglycemia leading to protein glycosylation that in turn causes glomerular hypertrophy and eventually leads to sclerosis. The second proposes hyperglycemia leading to vasodilatation followed by hyperfiltration, abnormal angiotensin II response, abnormal endothelin/nitrous oxide (NO) response, increased growth hormone secretion, hyperinsulinemia and sclerosis24-26.
Pathophysiology of diabetic nephropathy
Figure 3: Pathophysiology of diabetic nephropathy24,25,26. ESRD = End Stage Renal Disease. AGE = Advanced Glycosylation Endproduct(s)
Recently, Tervaert et al., commissioned by the Research Committee of the Renal Pathology Society, proposed a pathologic classification system for DN based on the severity of glomerular lesions27. Under this classification system, glomerular biopsies are divided into one of four classifications, with Class I being mild nephropathy and Class IV being severe.
- Class I: Glomerular basement membrane thickening: Isolated glomerular basement membrane thickening and only mild, nonspecific changes by light microscopy that do not meet the criteria of classes II through IV.
- Class II: Mesangial expansion, mild (IIa) or severe (IIb): Glomeruli classified as mild or severe mesangial expansion but without nodular sclerosis (Kimmelstiel–Wilson lesions) or global glomerulosclerosis in more than 50% of glomeruli.
- Class III: Nodular sclerosis (Kimmelstiel–Wilson lesions): At least one glomerulus with nodular increase in mesangial matrix (Kimmelstiel–Wilson) without changes described in class IV.
- Class IV: Advanced diabetic glomerulosclerosis: More than 50% global glomerulosclerosis with other clinical or pathologic evidence that sclerosis is attributable to diabetic nephropathy.
The proposed classification system may provide new insight in the complex pathways of DN. However, it should be noted that the study did not assess clinical outcomes because the researchers felt validation should be done in separate prospective studies with clearly defined clinical end points27.
Optimal therapy of DN continues to evolve. Guidelines from the ADA and NKF-KDOQI highlight the benefits of tight glycemic and blood pressure control as well as inhibition of the renin-angiotensin system in retarding the progression of diabetic nephropathy. Managing other risk factors for cardiovascular disease, such as dyslipidemia, is also critical due to the high rate of cardiovascular death in this population9,18. More information regarding the diagnosis and treatment of diabetic nephropathy can be found on the American Diabetes Association website (professional.diabetes.org) or the National Kidney Foundation (www.kidney.org).
- Department of Health and Human Services (DHHS) and Centers for Disease Control and Prevention (CDC). National Diabetes Fact Sheet 2007: General Information. Retrieved 10/07/2020 from https://www.cdc.gov/diabetes/basics/quick-facts.html
- Triplitt CL, Reasner CA, Isley WL, “Chapter 77. Diabetes Mellitus.” In: Joseph T. DiPiro, Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael Posey, eds. Pharmacotherapy: A Pathophysiologic Approach, 7e. The McGraw-Hill Companies, Inc, 2008. Retrieved 10/07/2020 from https://accesspharmacy.mhmedical.com/content.aspx?bookid=2577§ionid=228901946
- Funk Jant L, “Chapter 18 Disorders of the Endocrine Pancreas.” In: McPhee SJ, Hammer, GD, eds. Pathophysiology of Disease: An Introduction to Clinical Medicine, 6e. The McGraw-Hill Companies, Inc, 2010. Retrieved 10/07/2020 from https://accessmedicine.mhmedical.com/content.aspx?bookid=2468§ionid=198223689
- Centers for Disease Control and Prevention. Diabetes Data and Trends: Number (in Millions) of Civilian/Noninstitutionalized Persons with Diagnosed Diabetes, United States, 1980–2007. Retrieved 7/22/2010 from https://www.cdc.gov/diabetes/statistics/prev/national/figpersons.htm
- Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care 27:1047-53, 2004
- Geiss, Linda S. Changes in incidence of diabetes in U.S. adults, 1997-2003. Am J Prev Med 30:371-7, 2006
- Moore PA, Zgibor JC, Dasanayake AP. Diabetes: A growing epidemic of all ages. J Am Dent Assoc. 134: 11S-15S, 2003
- Amed S, Daneman D, Mahmud FH, Hamilton J. Type 2 diabetes in children and adolescents. Expert Rev Cardiovasc Ther 8:393-406, 2010
- American Diabetes Association. Standards of Medical Care in Diabetes—2010. Diabetes Care 33:S11-S61, 2010
- Soltesz, G. Diabetes in Children: Changes trends in an emerging epidemic. DiabetesVoice 52:special issue, 2007
- Copeland KC, Chalmers LJ, Brown RD. Type 2 diabetes in children: oxymoron or medical metamorphosis? Pediatr Ann 34:686-97, 2005
- Centers for Disease Control and Prevention. Overweight and Obesity: Childhood Overweight and Obesity Facts Page. Retrieved 10/07/2020 from https://www.cdc.gov/obesity/data/childhood.html
- Mohamadi A, Cooke DW. Type 2 diabetes mellitus in children and adolescents. Adolesc Med State 21:103-19, 2010
- Centers for Disease Control and Prevention. Diabetes Data and Trends: Distribution of First-Listed Diagnoses Among Hospital Discharges Adults Age 18 Years or Older. Retrieved 10/07/2020 from https://www.cdc.gov/diabetes/data/statistics-report/newly-diagnosed-diabetes.html
- American Diabetes Association. Economic Costs of Diabetes in the U.S. in 2007. Diabetes Care 31:596-615, 2008
- Lewis JB, Neilson, EG, “Chapter 277. Glomerular Diseases.” In: Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, et al: Harrison’s Principles of Internal Medicine, 17e. The McGraw-Hill Companies, Inc, 2008. Retrieved 10/07/2020 from https://accessmedicine.mhmedical.com/content.aspx?bookid=2129§ionid=192281295
- U S Renal Data System, USRDS 2009. Chapter 2: Incidence & Prevalence. Retrieved 10/07/2020 from https://www.usrds.org/annual-data-report/current-adr/
- National Kidney Foundation: Kidney Disease Outcome Quality Initiative. Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis 49:suppl 2, 2007.
- Borch-Johnsen K, Andersen PK, Deckert T. The effect of proteinuria on relative mortality in Type I (insulin-dependent) diabetes mellitus. Diabetologia 28:590-596, 1985
- Andersen AR, Sandahl Christiansen J, Andersen JK, Kreiner S, Deckert T. Diabetic neuropathy in Type I (insulin-dependent) diabetes: An epidemiologic study. Diabetologia 25:496-501, 1983
- Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, Shahinfar S, Snapinn S, Cooper ME, Mitch WE, Brenner BM. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 65:2309-20, 2004
- Mogensen, CE, Vestbo, E, Poulsen, PL, Christiansen C, Damsgaard EM, Eiskjaer H, Froland A, Hansen KW, Nielsen S, Pedersen MM. Microalbuminuria and potential confounders. A review and some observations on variability of urinary albumin excretion. Diabetes Care 18:572, 1995
- Karalliedde J and Viberti G. Microalbuminuria and Cardiovascular Risk. AJH 17:986–993, 2004
- Nathan DM. Long-term complications of diabetes mellitus. N Engl J Med 328:1676-1685, 1993
- Epstein M, Sowers JR. Diabetes mellitus and hypertension. Hypertension 19:403-418, 1992
- Sowers J, Epstein M. Diabetes mellitus and associated hypertension, vascular disease, and nephropathy: An update. Hypertension 26:869-879, 1995
- Tervaert TW, Mooyaart AL, Amann K, Cohen AH, Cook HT, Drachenberg CB, Ferrario F, Fogo AB, Haas M, De Heer E, Jon K, Noel LN, Radhakrishnan J, Seshan SV, Bajema IM, Bruijin JA. Pathologic classification of diabetic nephropathy. J Am Soc Nephrol 21:556-63, 2010
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