Diabetic Nephropathy
George Jarad
General Principles
Diabetic nephropathy (DN) is the most common cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in diabetic patients. Early recognition, diagnosis, and institution of appropriate treatment are necessary to prevent the disease or slow disease progression.
Definition
DN is a clinical syndrome characterized by progressive loss of kidney function that develops as a direct consequence of diabetes mellitus. The hallmark of DN is the development of glomerular hyperfiltration and albuminuria. Definitive diagnosis of DN requires a kidney biopsy. However, in most cases, careful analysis of patient clinical characteristics is sufficient to make the diagnosis.
Epidemiology
DN is the most common cause of ESRD in the United States and the world.
DN develops secondary to either type 1 or type 2 diabetes. However, most cases are secondary to type 2 diabetes considering its higher prevalence.
The risk of DN is equivalent in both types of diabetes, although the prevalence might be higher among patients with type 1 diabetes.
The development of DN imparts a significant increase in morbidity and mortality, before and after the development of ESRD. After starting dialysis, the mortality of diabetic patients is more than 50% higher than nondiabetic ESRD population.
Pathophysiology
The pathophysiology of DN is not fully understood, although hyperglycemia, hyperinsulinemia, and hemodynamic changes appear to play important role.
Hyperglycemia plays the central role in the development of DN by mediating hemodynamic and structural changes in the kidney through multiple mechanisms.
Prolonged hyperglycemia might induce production or glycosylation of mesangial proteins, leading to mesangial expansion and injury to kidney epithelial cells.
The accompanied increase in advanced glycation end products (AGEs) has been linked to microvascular diabetic complications, including DN.
Hyperglycemia and AGEs induce multiple signaling pathways that are injurious to kidney cells. These include the generation of advanced glycosylation end products, reactive oxygen species, changes in cellular microRNA, stimulation of transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), and other proinflammatory cytokines.
Impaired insulin signaling in podocytes may also play a role in podocyte injury, glomerular basement membrane (GBM) thickening, and glomerular hyperfiltration.
Intraglomerular hypertension and glomerular hyperfiltration eventually lead to the development of microalbuminuria and proteinuria.
Albuminuria may play a direct role in the progression of DN.
Risk Factors
Modifiable Risk Factors
Hyperglycemia: Among modifiable risk factors, control of blood glucose level is the most obvious and most important.
DN is rare if A1C is maintained below 7.0% throughout life.
The risk is increased for all A1C levels above the nondiabetic range, and is greatest at levels >12%.
Large clinical studies, including the United Kingdom Prospective Diabetes Study (UKPDS) and the Diabetes Control and Complications Trial, have shown that poor glycemic control is associated with increased risk of microalbuminuria and other microvascular complications of diabetes, such as nephropathy, retinopathy, and neuropathy.1,2
Hypertension: Hypertension may precede or follow the development of DN. Poor hypertension control plays an important role in the development and the progression of disease.
Hyperinsulinemia and increased arterial stiffness contribute to the development of hypertension.
The development of nephropathy exacerbates hypertension due to sodium and fluid retention.
Blood pressures higher than 130/80 mm Hg increase the risk of development and progression of DN.
Obesity: Further increases this risk, although it is uncertain whether this effect is independent of diabetic and glycemic control.
Nonmodifiable Risk Factors
Genetic factors:
The risk of developing microalbuminuria and proteinuria increases in the presence of a family history of DN.
Variation of the gene encoding the angiotensin-converting enzyme (ACE) has been suggested as a risk factor, although this has not been confirmed.
In African American, high-risk APOL1 genetic variants do not appear to play an important role.
Race: Patients of African-American, Mexican-American, Pima Indian and Australian Aboriginal descent are at increased risk. Whether the increased risk is the result of genetic or socioeconomic factors or a combination of the two is not clear.
Age: Older age and longer duration of diabetes are associated with increased risk of albuminuria in type 2 diabetes. In type 1 diabetes, the age at diagnosis is more important than duration. The development of diabetes before the age of 20 carries increased risk, however, if the diagnosis is made before 5 years of age, the risk is reduced.
Prevention
Before the development of microalbuminuria, diabetes should be controlled with goal A1C below 7%. Tighter control of diabetes should be weighed against the increased risk of hypoglycemia.
It is empirical to control coexisting hypertension. The use of ACE inhibitors or ARB for primary prevention of DN and microalbuminuria is controversial.
All diabetic patients should be screened for DN at regular intervals.
Screening
Microalbuminuria is the earliest sign of DN. Microalbuminuria refers to a small increase in urinary protein excretion that is not detectable using urinary dipstick (please see Table 13-1).
TABLE 13-1 CLASSIFICATION OF PROTEINURIA
24-hr Collection (mg/24 hr)
Adjusted for Urine Cr (mg/g creatinine)
Normal
<30
<30
Microalbuminuria
30–300
30–300
Albuminuria
>300
>300
Albuminuria (sometimes called macroalbuminuria) is the excretion of >300 mg of protein in a 24-hour period. Progression from microalbuminuria to proteinuria is an important event as it is the hallmark progression of the DN.
Tests for microalbuminuria:
A 24-hour urine collection, while accurate, can be cumbersome and difficult to interpret because of improper sampling and the logistical difficulties of saving urine through 24 hours. Adequacy of the collection should be assessed by measuring creatinine excretion (15 to 20 mg/kg in females and 20 to 25 mg/kg in males per day).
A ratio of albumin (or protein)-to-creatinine in a random sample of urine can be used instead. The accuracy increases if the test is performed on first morning urine. This study is often called a spot microalbumin test or protein/creatinine ratio. The ratio of albumin excreted per 1 g of creatinine correlates well with albumin excretion in a 24-hour period.
Screening should be conducted yearly in patients with type 2 diabetes staring at the diagnosis of the disease. Proteinuria assessment can be deferred for the first 5 years in patients with type 1 diabetes.
A routine urinalysis should not be the only test used to screen for DN. Quantifying proteinuria, whether the dipstick test is negative or positive is necessary.
If a routine urine dipstick test result is positive for protein, a spot protein/creatinine test is necessary to quantify albumin excretion, to follow the efficacy of treatment and disease progression.
Diagnosis
Clinical Presentation
The course of DN is better studied in type 1 diabetes because of the accurate correlation between the onset of disease and the time of diagnosis. The natural history and progression of kidney disease is believed to be similar in both types of diabetes.
In type 1 diabetes, the first 5 years are characterized by normal laboratory values for serum creatinine and urinary albumin excretion. Despite normal laboratory values, hyperglycemia leads to glomerular hyperfiltration and early histopathologic changes (glomerular hypertrophy and thick GBM).
Microalbuminuria typically develops between 5 and 10 years from diagnosis of diabetes in 40% of patients.Related posts:
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