In diabetes mellitus, the body is unable to regulate blood glucose levels properly. In type 1 diabetes, the pancreas is unable to produce insulin due to autoimmune destruction of its beta cells, whilst in type 2 diabetes, tissues become insensitive to insulin despite it being produced at normal or even increased amounts.

High blood glucose concentrations can cause widespread damage to the body and the kidneys are particularly susceptible to this. One of the functions of the kidney is to regulate blood pressure, which it does by controlling the level of ions in the plasma. By excreting more ions out in the urine, blood pressure is reduced and vice versa, due to the subsequent osmolarity of the plasma and the degree of fluid shift between the vasculature and the extracellular fluid. The renin-angiotensin-aldosterone system carefully monitors the levels of ions in the plasma and dictates how fast the kidneys filter blood and the degree of sodium absorption into the blood, which thereby affect blood pressure.

Diabetic nephropathy is caused by excessive glucose concentration in the blood. Hyperfiltration of glucose into the PCT leads to increased reabsorption of glucose back into the interstitium by sodium-glucose transporters (SGLT1). This reabsorption drives sodium chloride and water with the glucose, thereby reducing the flow of fluid in the renal tubules. Although blood pressure is initially normal, this “tricks” the kidney into thinking it is low, as the macula densa senses reduced fluid flow. The kidney tries to compensate by increasing blood pressure through various mechanisms, but this exerts further stress on the kidneys. Eventually, this causes renal damage and eventually renal nephropathy, that is, inflammation and scarring to the kidneys which can lead to renal failure if left untreated.

Excessive blood glucose can damage the kidneys through other mechanisms too, through the production of advanced glycation end products (AGE), proteoglycans and sorbitol which cause inflammation, fibrosis and damage to tissues.

For a flowchart on diabetic nephropathy please see below.