Pathophysiology and Pathogenesis of Diabetic Nephropathy

Genetic Risk Factors

The risk of nephropathy is strongly determined by genetic factors and only approximately 30% of patients with type 1 or type 2 diabetes will ultimately develop nephropathy. Genetic factors may directly influence the development of diabetic nephropathy and/or be clustered with genes influencing cardiovascular diseases. One support for genetic transmission is an experimental study showing that bone marrow–derived mesangial cell progenitors transmit diabetic nephropathy from donors with type 2 diabetes ( db/db mice) to naive, normoglycemic recipients. There is ongoing research through genomic screening and candidate gene approaches to better identify genetic loci for diabetic nephropathy susceptibility. Although some potential genes have been identified, linkage was only present in defined ethnic subpopulations and not in the majority of patients. An incomplete list of previously implicated genes is shown in Table 78.1 . The major problem with such studies is that diabetic nephropathy is a complex disease trait, meaning that several genes are likely involved and the inheritance patterns do not follow simple Mendelian rules. For example, a potential association between polymorphisms in candidate genes and the development and progression of nephropathy has been widely studied. These case-control studies are often problematic and clear guidelines for such polymorphism studies have been provided. The complexity of this genetic linkage analysis is exemplified by studies with controversial results investigating the insertion or deletion polymorphism of the angiotensin-converting enzyme (ACE) gene. Discrepancies could be explained by genetic heterogeneity and by small effects in limited cases in most studies (often <200 cases). The current opinion about the role of ACE gene polymorphism is that it may be associated with progression of disease in certain ethnic populations, but it is not a predictor of the development of diabetic nephropathy.

The introduction of Genome-Wide Association Studies (GWAS) is projected to bring new insights into the genetics of diabetic nephropathy. After scanning the entire genome, this method tries to identify single nucleotide polymorphisms (SNPs) associated with a particular disease, and thus can pinpoint areas of the genome involved in renal disease for example. So far, 2 GWAS have been conducted on patient populations with diabetic nephropathy. Pezzolesi et al. identified two loci that are significantly associated with renal disease in patients with type 1 diabetes: the FRMD3 (4.1 protein ezrin, radixin, moesin [FERM] domain containing 3) and CARS (cysteinyl-tRNA synthetase). These findings were replicated using samples from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. On the other hand, using a Japanese cohort, Maeda et al. suggest that ELMO1 (engulfment and cell motility 1 gene) and SLC12A3 (solute carrier family 12, member 3) may be associated with type 2 diabetic nephropathy. This was later confirmed by studies on African-American cohorts with type 2 diabetes as well as data from the GoKinD collection which includes Caucasians with type 1 diabetes. Because it casts a wide net, GWAS should increase our understanding of the pathology of diabetic nephropathy, and help identify novel therapeutic targets. This powerful method also promises to give clinicians and researchers a better understanding of the differences in disease progression and therapeutic responsiveness, paving the way towards a personalized medical practice.

More recently, the tools of genome-wide association studies have been applied to diabetic nephropathy. This method allows for a comprehensive genetic survey of the entire genome for chromosomal regions that are linked with a specific trait, in this case diabetic nephropathy. A genome scan for diabetic nephropathy in African-Americans identified susceptibility loci on chromosomes 3q, 7p, and 18q. Another scan in Pima Indians, a native American tribe with an alarmingly high incidence of early-onset type 2 diabetes, also identified linkage to diabetic nephropathy on chromosome 7. This powerful method, or its derivative technologies, may in the future more clearly identify the genetic risk for developing diabetic nephropathy. However, the genetic findings still need to be sussed out for their functional significance and explained in the larger pathophysiological context.

Stage I

The earliest renal manifestations in type 1 diabetes are nephromegaly and glomerular hypertrophy, which are accompanied by afferent arteriolar vasodilation, renal hyperperfusion (although some find that renal blood flow is reduced ), and glomerular hyperfiltration ( Fig. 78.1 ). Microscopically, there is thickening of the glomerular and tubular basement membranes. All these early functional and structural manifestations appear even if the patient is not destined to develop overt diabetic nephropathy. The UAE in this stage is normal (<30 mg/d or <20 µg/min) ( Fig. 78.1 ) but occasionally a transient increase in UAE (“transient microalbuminuria”) is present secondary to poor glycemic control or infection. Typically the blood pressure is below the hypertensive range (<140/90 mm Hg). The GFR is increased by 20 to 40% above normal values, with higher levels being frequently achieved when glycemic control is poor. Some studies suggest that patients with more renal hypertrophy or higher degrees of hyperfiltration (GFR >150 ml/min) are at increased risk for the future development of overt nephropathy. In patients with type 2 diabetes, this early stage is not readily discernible owing to the increased age but there may be modest degrees of nephromegaly and hyperfiltration.

Stage II

Incipient or latent nephropathy is defined by the appearance of microalbuminuria (UAE of 30–300 mg/day or 20–200 µg/min). Without intervention, UAE increases at the rate of 10% to 20% per year and is almost always accompanied by a steady rise in blood pressure. Hypertension (>140/90 mm Hg) is typically diagnosed one to two years after the appearance of microalbuminuria in type 1 diabetes. Microalbuminuria rarely develops before five years of disease duration (median, 10 years) in type 1 diabetes, but in type 2 diabetes microalbuminuria may be present at the time of diagnosis of hyperglycemia in up to 20% of patients with as many as 40% of patients having elevated blood pressure as well. This may be due to the fact that many of these patients have had impaired glucose tolerance for years before actually being diagnosed with diabetes, or it may reflect another disease causing increased UAE as part of the metabolic syndrome, most notably essential hypertension. Other possible causes of increased UAE in this population include renovascular hypertension, morbid obesity, and sleep apnea. Even during this clinically “silent” phase of the disease, there may be significant mesangial matrix expansion or diffuse glomerulosclerosis, further thickening of the glomerular and tubular basement membranes, and some degree of podocyte loss. The GFR may remain elevated or may decrease to within the “normal” range (100–120 ml/min) ( Fig. 78.1 ). Longitudinal studies have shown that the patient with microalbuminuria is at greater risk for the development of overt proteinuria (UAE >300 mg/d) compared with patients with normoalbuminuria. For example, type 1 diabetic patients with persistent microalbuminuria have approximately an 80% chance of developing established nephropathy within the ensuing five to seven years. In contrast, the percentage of patients with type 2 diabetes who progress to overt proteinuria is significantly lower, in part because of excess mortality due to cardiovascular events. Thus, the predictive value of microalbuminuria in patients with type 2 diabetes is much less clear than in type 1 patients.

Stage III

This stage is characterized by the development of overt proteinuria (total protein excretion >500 mg/day) or macroalbuminuria (UAE >300 mg/d) ( Fig. 78.1 ). In type 1 patients this occurs after an average of 15 years of diabetes. Hypertension is almost always present, and the worse the blood pressure control is, the more rapidly the GFR declines ( Fig. 78.4 ). If a renal biopsy were to be performed, the glomeruli would typically demonstrate diffuse glomerulosclerosis and/or nodular glomerulosclerosis, further podocyte loss with focal areas of foot process effacement, arteriolar hyalinosis in both the afferent and efferent arterioles, and variable degrees of tubulointerstitial fibrosis. Structure–function correlations indicate a highly significant inverse correlation between declining GFR and mesangial expansion. The progressive expansion of the glomerular mesangium causes a reduction in the glomerular filtering surface area. Nephron loss due to tubulointerstitial fibrosis is another major cause of the reduction in GFR. In the untreated patient, the GFR falls at a rate of about 1 ml/min/month, but this rate of fall can vary significantly from patient to patient. As the GFR falls from previously supernormal levels, the serum creatinine may remain in the normal range or be slightly elevated and is therefore not a reliable indicator of the magnitude of disease progression.

Stage IV

After approximately five years of overt nephropathy, untreated patients progress to advanced nephropathy, as characterized by nephrotic-range proteinuria (>3.5 g/d), worsened hypertension that becomes difficult to control, and a progressive decline in GFR ( Fig. 78.1 ). In fact, diabetic nephropathy is the most common cause of the nephrotic syndrome in the adult population. Parenchymal and vascular lesions become more severe. The rate of decline in GFR is steady over a period of months but is variable from patient to patient and depends on the degree of elevation of blood pressure as well as the amount of UAE.

Stage V

The final stage is progressive renal failure reaching ESRD, with the GFR declining to 15 ml/min or lower. The patient may soon need renal replacement therapy to control uremic symptoms or excessive volume expansion. The average time for progression to ESRD from the time of diagnosis of diabetes is about 20 to 25 years, with a more rapid course developing in patients with uncontrolled hypertension and/or heavy proteinuria. Many patients, especially those with type 2 diabetes, never reach ESRD because of the severely increased risk of cardiovascular mortality in this population.