Pathophysiology of diabetic nephropathy

Pathophysiology of diabetic nephropathy

Sherril Sego

In the developed and industrialized world, diabetes is the leading cause of chronic kidney disease and kidney failure and the numbers of cases are increasing rapidly (Centers for Disease Control [CDC], 2005). Of the new end stage renal disease (ESRD) cases annually in the United States, about 44% are due to diabetes (United States Renal Data System [USRDS], 2007). With type 2 diabetes mellitus prevalence skyrocketing to over 21 million cases in the United States alone (CDC, 2005), catastrophic end organ diseases such as kidney failure will follow.

Diabetic nephropathy, or kidney damage due to diabetes, results from changes in blood flow in the small vessels of the glomerular capsule, the functional unit of the kidney (Eknoyan et al., 2003). Each of the approximately 2 million glomerular capsules is composed of thin-walled capillaries that facilitate hydrostatic filtration of toxins and fluid and maintain a delicate balance of vasoconstriction and dilation (Hall, 2006). The pathogenic changes of diabetic nephropathy involve several different complex chains of reactions that culminate in damaging, oxidative remodeling of the vessel walls of the glomerular capsule. The subsequent decreased flow of oxygenated blood, loss of vasodilatory tone, and impairment of vascular wall integrity lead to irreversible damage to glomerular capillaries and, ultimately, to loss of kidney function (see Table 1).

Pathaphysiology of Diabetic Nephropathy

Diabetic nephropathy is characterized by the abnormal deposition of matrix material in the glomerular mesangium, leading to a thickened, sclerotic glomerular lining (Hall, 2006). Studies have shown that glucose reacts with proteins in the blood, chemically forming permanent cross-linked protein complexes (Makita et al., 1991). The excessive accumulation of these complexes, or advanced glycosylated end products (AGEs) is believed to directly accelerate the vascular complications of diabetes (Makita et al., 1991). Years of continued hyperglycemia and dyslipidemia, often in the presence of hypertension, promote the deposition of an accumulating layer of AGEs (Makita et al., 1991).

The arterial microvascular structure consists of a five-layer vessel wall (Stare et al., 2006). These layers, much like an automobile tire, are wrapped and bonded to form an intricate system of support and function. The intima, or innermost wrapping, consists of a layer of endothelial cells, or endothelium. The endothelium is responsible for vascular tone, regulation of leukocyte and platelet adhesion, and controlling permeability to proteins and nitric oxide (Stam et al., 2006).

Especially important to note is the function of nitric oxide in the microvasculature. It is a potent endothelial-derived vasodilator that participates in maintaining the normal endovascular pressure. Also known as ‘endothelium-derived relaxing factor,’ nitric oxide functions as a signaling molecule in a complex chain of events. Manufactured in the endothelium from arginine and oxygen via an enzyme system, nitric oxide is an unstable free radical that “signals” the smooth muscle band of the vessel wall to relax, thus producing vasodilatation and increased blood flow (Tuteja, Chandra, Tuteja, & Misra, 2004). The endothelium is the layer that becomes most damaged by the long-term effects of hyperglycemia (Stam et al., 2006). As elevated glucose levels persist with subsequent formations of AGEs, the endothelium gradually thickens, loses its permeability to nitric oxide and becomes subject to increased platelet and leukocyte adhesion. As this adhesive layer thickens, once tightly controlled transport pores become stiff and open, leading to leakage of serum proteins from the vasculature (Stam et al., 2006).

First described by Brownlee, Vlassara and Cerami (1984), this process of AGE formation is defined as the covalent bonding, or, glycosylation, of glucose to red blood cells. In the formation of AGEs, excess serum glucose combines with serum or tissue proteins, eventually forming an irreversible collagen-like complex. As these protein-collagen complexes deposit on the ever-thickening vascular wall, they accelerate endothelial dysfunction (Brownlee et al., 1984). It has been suggested that the thickening accumulation of these circulating end products within the vascular wall might serve as a trap for even more undesirable circulating molecules such as immunoglobulins and lipoproteins (Brownlee et al., 1984).

Kidney function depends on the intact function of the intricate glomerular micro-vasculature (Brownlee et al., 1984). As endothelial damage progresses the intimal integrity is impaired, albuminuria, or protein loss, begins (Brownlee et al., 1984). The typical diabetic co-morbidities of hypertension and hyperlipidemia accelerate the destruction of the vascular wall integrity.

Uremia in diabetic nephropathy is associated with both an increased serum level of AGEs and accelerated micro and macrovascular angiopathy (Friedman, 1999). Though the normal system constantly produces AGEs, this continuous process is magnified by high ambient glucose concentrations. The link between uncontrolled hyperglycemia and the development of vascular complications has been well established (Odetti et al., 1998).

Normally excreted by the kidney, the concentration of advanced glycosylated end products is inversely proportionate to the glomerular filtration rate (Odetti et al., 1998). The extent of this protein/collagen cross linking is directly related to the degree and duration of hyperglycemia (Odetti et al., 1998). It is easy to see that this becomes a vicious cycle of AGE production and deposition, vascular injury and dysfunction, decreased kidney excretion, and further accumulation of toxic products.

Cost-effective ways of measuring serum concentrations of AGEs in the clinical setting are being sought so that by monitoring AGE amounts, early signs of nephropathy might be predicted sooner than with current methods (Kanauchi, Tsujimoto, & Hashimoto, 2001). Kanauchi and colleagues devised a laboratory assay that validates the proportionate decrease in glomerular filtration rate with the increase in free-circulating AGEs. This testing process involves a flow injection assay (FLA) to produce a high performance liquid chromatography (HPLC) that detects the relatively low molecular mass of AGEs (Zilin, Naifeng, Bicheng & Jiping, 2001). Now, not only the AGE level is measured, but the concomitant rise in serum creatinine is measured as well (Zilin et al., 2001). This test, however, is far from being available in general medical reference laboratories.

End-stage kidney failure is typically characterized by a glomerular filtration rate (GFR) of 10% or less, gross albuminuria, and elevated blood urea nitrogen/creatinine levels (Parmer, 2002). As devastating as this condition is, the rate of progression to this level of severity is actually very gradual.

Initially, due to an impairment of the afferent arteriolar autoregulatory ability, an increase in glomerular filtration pressure develops (Parmer, 2002). This elevated intraglomerular pressure stimulates several responses within the glomerular capillary bed. Endothelial mesangial cells thicken (Parmer, 2002). This, together with the continual deposition of AGEs, eventually leads to thickening of the glomerular basement membrane and loss of selective permeability (Parmer, 2002). Microalbuminuria develops as well as impairment of nitric oxide transport (Eknoyan et al., 2003). The first appearance of microalbuminuria (urine albumin level greater than 50 mg/L) can precede end stage damage by as much as 20 years (Eknoyan et al., 2003). Though micro-vascular damage is irreversible, early intervention in the management of hyperglycemia has been shown to halt the progression of glomerular damage and stabilize kidney function (National Diabetes Information Clearinghouse [NDIC], n.d.). Tight glucose control normalizes the production of AGEs and stabilizes kidney AGE excretion so intimal deposition is prevented (Hall, 2006). Data confirms that for every 1% reduction in glycosylated hemoglobin there is a 37%-40% reduction in renal failure risk (Hall, 2006). Conversely, at glycosylated hemoglobin level of 8.0% there is a 1.7 +/- 2.3 ml/year decline in glomerular filtration rate (United Kingdom Prospective Diabetes Study, [UKPDS], 1998).

Implications for Nursing Practice

Kidney failure is quite possibly the most patient-education intensive field for nursing today. With the scope of this disease involving every aspect of the patient’s life, constant support and education are essential. Basic education on diabetes should be done for all patients and reinforced at every “possible opportunity. A clear understanding of medications, diet, laboratory values, and basic anatomy and physiology equip the patient to deal with their disease effectively. Access to internet sites and numerous patient education tools put endless resources at the fingertips of all nursing staff and most patients.

Whether in hospitals or outpatient settings, nurses are the primary health care providers that develop patient relationships and ongoing interactions. Patients look to the nurse for information, support, and encouragement. Though much research has been done exploring what factors influence patient compliance with health care regimens, outcomes for health prevention and promotion continue, in many cases, to be dismal.

In a review of the Health Belief Model, Jones, Jones, and Katz (1988) cite several factors that determine patient compliance:

1. The patient must believe he/she is personally at risk for this disease or condition.

2. The patient must internalize that this disease will have a severe impact on his/her life.

3. The patient must believe that the treatments recommended for him/her by medical professionals will actually help the problem.

4. The patient must be willing to invest himself/herself in the effort of implementing the proposed treatment.

However, after all these, no single factor is considered as capable of influencing patients’ decisions and compliance as that of a trusting relationship with the health care provider. In this case, that provider is the nurse (Jones et al., 1988).

As with most diseases, the best way to manage the problem is to prevent it from happening. In the case of diabetic nephropathy, that is especially true. We now realize that many cases of type 2 diabetes can be prevented entirely with early identification of at-risk persons. Known risk factors of obesity, immediate family history of diabetes, gestational diabetes, and advancing age are easily identifiable. The combination of diet, exercise, and medications can effectively prevent the serious consequence of kidney failure in the patient with diabetes.

When that prevention fails and the diabetic state does exist, rigid control of hyperglycemia prevents diabetic nephropathy. In the extreme of kidney failure, the total life change that renal replacement therapy necessitates often requires aggressive emotional support from nursing and other professional staff.

In the case of patients who already face kidney failure and renal replacement therapy, the role of glycemic control continues to be imperative in preventing further end organ damage. Diabetic retinopathy, peripheral vascular disease, and cardiovascular disease may still be mitigated by intensive glycemic control.

In the United States alone, the annual economic burden of kidney failure from all causes is expected to exceed $38 billion dollars by the year 2010 (Eknoyan et al., 2003). Not only is this disease a very “high tech” condition to treat, and therapy is daily and ongoing, economic impact is significant for the patient and the family as well. Job losses, home care, child care, and endless other activities of daily living suddenly cost more. Assisting patients and families in finding and utilizing all available assistive agencies is another key role of nursing personnel.


Diabetic nephropathy is a potentially fatal endpoint of uncontrolled diabetes. As with most negative sequelae of diabetes, nephropathy is largely preventable. Early detection of persons at risk, both before and after the onset of diabetes, aggressive glycemic control, patient education, and close monitoring can largely avert chronic kidney disease or kidney failure due to diabetic nephropathy.


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Eknoyan, G., Hostetter, T., Bakris, G., Hebert, L., Levey, A.S., Parving, H., et al. (2003). Proteinuria and other markers of chronic kidney disease: A position statement of the National Kidney Foundation (NKF) and the National Institutes of Diabetes Digestive and Kidney Diseases (NIDDK). American Journal of Kidney Disease, 42, 617-622. Retrieved November 1, 2007, from http://www. rot.pdf

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National Diabetes Information Clearinghouse (NDIC). (n.d.). Diabetes control and complications trial (DCCT). Retrieved November 1, 2007, from pubs/control/

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Zilin, S., Naffeng, L., Bicheng, L., & Jiping, W. (2001). The determination of AGE-peptides by flow injection assay; a practical marker of diabetic nephropathy. Clinical Chemistry, 313(1-2), 69-75. Retrieved February 2, 2007, from &cpsidt=13393715

Sherril Sego, MSN, FNP-C, is Primary Care Nurse Practitioner, Kansas City VA Medical Center, Kansas City, MO.

Table 1

Steps To Diabetic Nephropathy

1. Hyperglycemia

2. Thickening mesangium

3. Glomerular hyperfiltration

4. Impaired endothelial integrity

5. Onset of microalbuminuria

6. Impairment of nitric oxide


7. Loss of afferent/efferent

auto-regulatory control

8. Continued loss of glomerular

filtration capabilities

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