Diabetic Nephropathy

Background
Diabetes is a metabolic disorder of multiple causes characterized by chronic hyperglycemia and disorders of carbohydrate, fat, and protein metabolism. It results from defects in insulin secretion (type 1), insulin action (type 2), or a combination of these factors. Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria (>300 mg/d or >200 mcg/min) that is confirmed on at least 2 occasions 3-6 months apart, a relentless decline in the glomerular filtration rate (GFR), and elevated arterial blood pressure. The rate of decline in the GFR in various stages of type 1 and type 2 diabetes is shown in the image below. Diabetes is responsible for 30-40% of all end-stage renal disease (ESRD) cases in the United States. Although type 1 and type 2 diabetes mellitus (insulin-dependent diabetes mellitus [IDDM] and non insulin-dependent diabetes mellitus [NIDDM], respectively) lead to ESRD, the great majority of patients are those with NIDDM. In a prospective study in Germany, the 5-year survival rate was less than 10% in the elderly population with type 2 diabetes, and no more than 40% in the younger population with type 1 diabetes. There is good evidence that early treatment delays or prevents the onset of diabetic nephropathy or diabetic kidney disease. World Health Organization and American Diabetes Association diagnostic criteria are as follows: Fasting plasma glucose >126 mg/dL (>7.0 mmol/L) or fasting whole-blood glucose level >110 mg/dL (>6.1 mmol/L), or a 2-hour post-glucose-load plasma glucose >200 mg/dL (>11.1 mmol/L; 180 mg/dL [10.0 mmol/L] if whole blood), or a random plasma glucose >200 mg/dL (>11.1 mmol/L) on more than 1 occasion Prediabetic stage - Fasting plasma glucose 100-126 mg/dL (5.6-7.0 mmol/L) increasingly recognized as a risk factor for end-organ complications; evidence supports lifestyle interventions to prevent or delay onset of diabetes

Pathophysiology
The key change in diabetic glomerulopathy is augmentation of extracellular material. The earliest morphologic abnormality in diabetic nephropathy is the thickening of the glomerular basement membrane (GBM) and expansion of the mesangium due to accumulation of extracellular matrix. The image below is a simple schema for the pathogenesis of diabetic nephropathy. Light microscopy findings show an increase in the solid spaces of the tuft, most frequently observed as coarse branching of solid (positive periodic-acid Schiff reaction) material (diffuse diabetic glomerulopathy). Large acellular accumulations also may be observed within these areas. These are circular on section and are known as the Kimmelstiel-Wilson lesions/nodules. The glomeruli and kidneys are typically normal or increased in size initially, thus distinguishing diabetic nephropathy from most other forms of chronic renal insufficiency, wherein renal size is reduced (except renal amyloidosis and polycystic kidney disease).

Immunofluorescence microscopy may reveal deposition of immunoglobulin G along the GBM in a linear pattern, but this is not immunopathogenetic or diagnostic. Immune deposits are not observed. The renal vasculature typically displays evidence of atherosclerosis, usually due to concomitant hyperlipidemia and hypertensive arteriosclerosis. Electron microscopy provides a more detailed definition of the structures involved. In advanced disease, the mesangial regions occupy a large proportion of the tuft, with prominent matrix content. Further, the basement membrane in the capillary walls (ie, the peripheral basement membrane) is thicker than normal. The severity of diabetic glomerulopathy is estimated by the thickness of the peripheral basement membrane and mesangium and matrix expressed as a fraction of appropriate spaces (eg, volume fraction of mesangium/glomerulus, matrix/mesangium, or matrix/glomerulus). Three major histologic changes occur in the glomeruli of persons with diabetic nephropathy. First, mesangial expansion is directly induced by hyperglycemia, perhaps via increased matrix production or glycosylation of matrix proteins. Second, GBM thickening occurs. Third, glomerular sclerosis is caused by intraglomerular hypertension (induced by renal vasodilatation or from ischemic injury induced by hyaline narrowing of the vessels supplying the glomeruli). These different histologic patterns appear to have similar prognostic significance. The exact cause of diabetic nephropathy is unknown, but various postulated mechanisms are hyperglycemia (causing hyperfiltration and renal injury), advanced glycosylation products, and activation of cytokines. Hyperglycemia increases the expression of transforming growth factor-beta (TGF-beta) in the glomeruli and of matrix proteins specifically stimulated by this cytokine. TGF-beta may contribute to the cellular hypertrophy and enhanced collagen synthesis observed in persons with diabetic nephropathy.1 Hyperglycemia also may activate protein kinase C, which may contribute to renal disease and other vascular complications of diabetes. In addition to the renal hemodynamic alterations, patients with overt diabetic nephropathy (dipstick-positive proteinuria and decreasing GFR) generally develop systemic hypertension. Hypertension is an adverse factor in all progressive renal diseases and seems especially so in diabetic nephropathy. The deleterious effects of hypertension are likely directed at the vasculature and microvasculature. Familial or perhaps even genetic factors also play a role. Certain ethnic groups, particularly African Americans, persons of Hispanic origin, and American Indians, may be particularly disposed to renal disease as a complication of diabetes. Some evidence has accrued for a polymorphism in the gene for angiotensin-converting enzyme (ACE) in either predisposing to nephropathy or accelerating its course. However, definitive genetic markers have yet to be identified.

Clinical
History
Diabetes Passing of foamy urine Otherwise unexplained proteinuria in a patient with diabetes Diabetic retinopathy Fatigue and foot edema secondary to hypoalbuminemia (if nephrotic syndrome is present) Other associated disorders such as peripheral vascular occlusive disease, hypertension, or coronary artery disease

Physical
Generally, diabetic nephropathy is considered after a routine urinalysis and screening for microalbuminuria in the setting of diabetes. Patients usually have physical findings associated with long-standing diabetes mellitus. Hypertension Peripheral vascular occlusive disease (decreased peripheral pulses, carotid bruits) Evidence of diabetic neuropathy in the form of decreased fine sensations and diminished tendon reflexes Evidence of fourth heart sound during cardiac auscultation Nonhealing skin ulcers/osteomyelitis

Almost all patients with nephropathy and type 1 diabetes demonstrate signs of diabetic microvascular disease, such as retinopathy and neuropathy. 2 Clinical detection of the retinopathy is easy, and in these patients the condition typically precedes the onset of overt nephropathy. The converse is not true. Only a minority of patients with advanced retinopathy have histologic changes in the glomeruli and increased protein excretion that is at least in the microalbuminuric range, and most have little or no renal disease (as assessed by renal biopsy and protein excretion). Patients with type 2 diabetes who have marked proteinuria and retinopathy typically have diabetic nephropathy, while those persons who do not have retinopathy frequently exhibit nondiabetic glomerular disease. Symptoms Early stage diabetic nephropathy has no symptoms. Over time, the kidney's ability to function starts to decline. Symptoms develop late in the disease and may include: Fatigue Foamy appearance or excessive frothing of the urine Frequent hiccups General ill feeling Generalized itching Headache

Nausea and vomiting Poor appetite Swelling of the legs Swelling, usually around the eyes in the mornings; general body swelling may occur with late-stage disease Unintentional weight gain (from fluid buildup)

Laboratory Studies
Urinalysis o Regular annual urinalysis is recommended for screening for microalbuminuria (see image below). Typically, the urinalysis results from a patient with established diabetic nephropathy show proteinuria varying from 150 mg/dL to greater than 300 mg/dL, glucosuria, and occasional hyaline casts. o Microalbuminuria is defined as albumin excretion of more than 20 mcg/min. This phase indicates incipient diabetic nephropathy and calls for aggressive management, at which stage the disease may be potentially reversible (ie, microalbuminuria can regress). o A 24-hour urinalysis for urea, creatinine, and protein is extremely useful in quantifying protein losses and estimating the GFR. o Perform microscopic urinalysis to help rule out a potentially nephritic picture, which may lead to a workup to rule out other primary glomerulopathies, especially in the setting of rapidly deteriorating renal function (eg, rapidly progressive glomerulonephritis). Blood tests - Blood tests, including calculation of GFR (by various formulas, such as the MDRD formula), are helpful in monitoring for the progression of kidney disease and in assessing its stage.

Imaging Studies
Renal ultrasound o Observe for kidney size, which is usually normal to increased in the initial stages and, later, decreased or shrunken with chronic renal disease. o Rule out obstruction. o Perform echogenicity studies for chronic renal disease.

Nephrotic syndrome
Nephrotic syndrome is a group of symptoms including protein in the urine (more than 3.5 grams per day), low blood protein levels, high cholesterol levels, high triglyceride levels, and swelling.

Causes Nephrotic syndrome is caused by various disorders that damage the kidneys, particularly the basement membrane of the glomerulus. This immediately causes abnormal excretion of protein in the urine. The most common cause in children is minimal change disease, while membranous glomerulonephritis is the most common cause in adults. This condition can also occur as a result of infection (such as strep throat, hepatitis, or mononucleosis), use of certain drugs, cancer, genetic disorders, immune disorders, or diseases that affect multiple body systems including diabetes, systemic lupus erythematosus, multiple myeloma, and amyloidosis. It can accompany kidney disorders such as glomerulonephritis, focal and segmental glomerulosclerosis, and mesangiocapillary glomerulonephritis. Nephrotic syndrome can affect all age groups. In children, it is most common from age 2 to 6. This disorder occurs slightly more often in males than females. Symptoms Swelling (edema) is the most common symptom. It may occur: In the face and around the eyes (facial swelling) In the arms and legs, especially in the feet and ankles In the belly area (swollen abdomen)

Other symptoms include: Foamy appearance of the urine Weight gain (unintentional) from fluid retention Poor appetite High blood pressure

Exams and Tests The doctor will perform a physical exam. Laboratory tests will be done to see how well the kidneys are working. They include: Creatine - blood test Blood urea nitrogen (BUN) Creatinine clearance Albumin blood test - may be low Urinalysis - reveals large amounts of urine protein