Diabetic nephropathy (DN) reﬂects renal injury in response to chronic long-standing hyperglycemia. It may occur in patients with type I or II diabetes mellitus, and it manifests as progressive albuminuria followed by a decline in the glomerular ﬁltration rate (GFR).
Recent data from the Centers for Disease Control and Prevention estimate that 23.6 million individuals in the United States, or roughly 7.8% of the population, suffer from diabetes mellitus. Because of this rising epidemic, DN is now the leading cause of chronic kidney disease and end stage renal disease (ESRD) in the United States and other countries (both developed and developing).
Among those with type 1 diabetes, the incidence of overt nephropathy (deﬁned as dipstick-positive proteinuria) has declined over recent years, from approximately 30% to 10% at 25 years. Among those with type 2 diabetes, approximately 12% develop overt nephropathy over the same timeframe.
The risk of nephropathy increases with patient age, duration of diabetic disease, hypertension, and poorer glycemic control. Genetic factors also play an important role, insofar as a patient with diabetes mellitus is more likely to develop nephropathy if a sibling or parent has this complication as well. In addition, blacks and certain minority populations (such as Pima Indians) are more likely to develop DN than Caucasians.
The sequence of events that leads to DN is largely unknown. Proposed mechanisms include hyperglycemia-induced hyperﬁltration, accumulation of advanced glycation end products, and activation of proinﬂammatory/proﬁbrotic pathways.
An increase in the glomerular ﬁltration rate is the earliest demonstrable abnormality, reﬂecting afferent arteriolar vasodilation and efferent arteriolar vasoconstriction. The exact link between hyperglycemia and hyperﬁltration, however, is not fully understood and probably reﬂects multiple mechanisms, including abnormalities in tubuloglomerular feedback induced by increased proximal reabsorption of glucose and sodium, effects of advanced glycation end products, and changes in hormonal input (such as from the renin-angiotensin axis). In the long term, increased intraglomerular pressure can lead to glomerulosclerosis. Systemic hypertension can accelerate this process by further increasing intraglomerular pressure.
Meanwhile, hyperglycemia causes increased production of mesangial matrix proteins, leading to mesangial expansion. Angiotensin II and transforming growth factor-(TGF-) are important factors in this process, and variations in the genes encoding angiotensin II and its receptors have been found to account for some of the inherited risk for nephropathy. It appears that hyperglycemia stimulates angiotensin II synthesis, which in turn stimulates TGF- secretion. TGF-then increases the synthesis and decreases the degradation of matrix proteins, leading to their accumulation. Another hormone known to be involved in this process is vascular endothelial growth factor (VEGF). In animal models of diabetic nephropathy, blockade of TGF- and VEGF has been shown to have beneﬁcial effects.
Advanced glycation end products (AGEs) also play an important role in promoting mesangial matrix accumulation. These compounds are formed nonenzymatically when proteins are exposed to glucose. They then cross link with normal matrix proteins, such as collagen, and render them resistant to proteolysis. Binding of AGEs to a speciﬁc receptor (RAGE) triggers production of reactive oxygen species and subsequent inﬂammation.
In type 1 diabetes, the pathologic changes to the glomerulus occur in a somewhat predictable sequence, with hypertrophy of the glomeruli and thickening of the basement membrane seen early in the disease course. Expansion of the mesangium then follows and leads to the clinical manifestation of proteinuria. As the disease progresses, there is progressive glomerular damage and increasing amounts of albuminuria, with eventual reduction of the GFR and, ultimately, ESRD.
In type 2 diabetes, these events may be temporally compressed, with impaired renal function appearing as an early manifestation. To some extent this difference may reﬂect the fact that diagnosis often does not occur until later in the disease course; however, it may also reﬂect increased patient age in this population and the frequent presence of comorbid hypertension.
PRESENTATION AND DIAGNOSIS
The earliest clinical manifestation of diabetic nephropathy is known as microalbuminuria, deﬁned as 30 to 300 mg of albumin per gram of creatinine in a spot urine sample, a quantity of protein that cannot reliably be detected on a urine dipstick. As the disease progresses, macroalbuminuria ensues ( 300 mg/g of creatinine in a spot sample), which can be detected on a dipstick and is a marker of overt nephropathy. In some cases, proteinuria may be severe enough to cause the full nephrotic syndrome. The ﬁnal stages of DN are characterized by a progressive decline in renal function, which can lead to ESRD.
To assess for the presence and degree of proteinuria, all patients with known diabetes mellitus should be evaluated on an annual basis with a quantitive spot urine albumin to creatinine ratio. Such testing should begin 5 years from diagnosis in patients with type 1 diabetes, and at the time of diagnosis in patients with type 2 diabetes. The screening should also include a serum creatinine concentration to evaluate for renal insufﬁciency and, in patients with overt nephropathy, measurement of serum albumin and lipid concentrations. Monitoring blood pressure is also essential.
In patients with overt nephropathy, other renal diseases should always be ruled out before diabetes is assumed to be the cause. A renal ultrasound should be performed as part of the workup. Although most renal diseases cause the kidneys to appear shrunken, DN causes them to appear normal-sized or even enlarged. (This ﬁnding is not speciﬁc, however, because a small number of other diseases such as amyloidosis, also cause enlarged kidneys.)
Renal biopsy is not routinely indicated, but it may be performed if another diagnosis is suspected on clinical or serologic grounds, or if the rate of progression is atypical. For example, a biopsy would be indicated in a patient with an active, cellular urine sediment or a rapid decline in ﬁltration function over the course of weeks or months. Conversely, a diabetic patient with retinopathy, long-standing proteinuria, a bland urine sediment, and a slow decline in renal function can be reasonably assumed to have diabetic nephropathy without a biopsyproven diagnosis.
Upon biopsy, the pathologic lesion of DN may be classiﬁed into one of four classes. Class I features isolated thickening of the glomerular basement membrane; class II features mesangial expansion; class III (also known as nodular glomerulosclerosis or the “Kimmelstiel-Wilson” lesion) features intercapillary nodules resulting from severe mesangial expansion, with compression of adjacent capillary lumina; and class IV features advanced glomerulosclerosis ( 50% of glomeruli have global sclerosis). The correlation between clinical and pathologic ﬁndings is often weak, however, and patients with minimal clinical manifestations may undergo biopsies that reveal established diabetic lesions, or vice versa.
DN is both prevented and treated by rigorously controlling serum glucose concentrations (goal hemoglobin A1C 7.0) and lowering blood pressure. In the United Kingdom Prospective Diabetes Study, for example, each 10 mm Hg reduction in systolic pressure was associated with a 12% reduction in the risk for diabetic complications, with the lowest risk occurring in patients with a systolic blood pressure under 120 mm Hg.
ACE inhibitors and angiotensin receptor blockers (ARBs) are the preferred antihypertensive agents because they also reduce proteinuria and slow the inﬂammatory processes that drive further renal dysfunction. They should be offered to all diabetics with hypertension, as well as to all normotensive diabetics with microalbuminuria or macroalbuminuria. Available evidence indicates that these agents may also be effective for delaying the onset of microalbuminuria in patients with no albuminuria.
It is unclear if dietary protein restriction has any role in retarding progression of renal insufﬁciency. Renal replacement therapy, including dialysis or renal trans- plantation, is indicated once patients approach ESRD.
A large study of type 2 diabetics found that the annual risk of progression from no albuminuria to microalbuminuria was 2.0%, from microalbuminuria to macroalbuminuria was 2.8%, and from macroalbuminuria to impaired ﬁltration function was 2.3%. Overall, at 10 years after diagnosis, 25% had microalbuminuria or worse, 5% had macroalbuminuria or worse, and 1% had elevated plasma creatinine or were undergoing renal replacement therapy.