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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).

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

hypertension. 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 . • • • • • Hypertension Peripheral vascular occlusive disease (decreased peripheral pulses. The converse is not true. Symptoms Early stage diabetic nephropathy has no symptoms. and in these patients the condition typically precedes the onset of overt nephropathy. or coronary artery disease Physical Generally. 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. while those persons who do not have retinopathy frequently exhibit nondiabetic glomerular disease. the kidney's ability to function starts to decline. Over time. diabetic nephropathy is considered after a routine urinalysis and screening for microalbuminuria in the setting of diabetes. and most have little or no renal disease (as assessed by renal biopsy and protein excretion). 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. Patients usually have physical findings associated with long-standing diabetes mellitus.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. Patients with type 2 diabetes who have marked proteinuria and retinopathy typically have diabetic nephropathy. 2 Clinical detection of the retinopathy is easy.

are helpful in monitoring for the progression of kidney disease and in assessing its stage. o Perform echogenicity studies for chronic renal disease. at which stage the disease may be potentially reversible (ie. usually around the eyes in the mornings. which may lead to a workup to rule out other primary glomerulopathies. Nephrotic syndrome Nephrotic syndrome is a group of symptoms including protein in the urine (more than 3. high cholesterol levels. Typically. high triglyceride levels. later. 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). glucosuria. creatinine. and swelling. such as the MDRD formula). o Microalbuminuria is defined as albumin excretion of more than 20 mcg/min. This phase indicates incipient diabetic nephropathy and calls for aggressive management. microalbuminuria can regress). including calculation of GFR (by various formulas. decreased or shrunken with chronic renal disease. o Perform microscopic urinalysis to help rule out a potentially nephritic picture. o Rule out obstruction.• • • • • Nausea and vomiting Poor appetite Swelling of the legs Swelling. o A 24-hour urinalysis for urea. and protein is extremely useful in quantifying protein losses and estimating the GFR. Blood tests . . • Imaging Studies • Renal ultrasound o Observe for kidney size.Blood tests. which is usually normal to increased in the initial stages and.5 grams per day). low blood protein levels. rapidly progressive glomerulonephritis). the urinalysis results from a patient with established diabetic nephropathy show proteinuria varying from 150 mg/dL to greater than 300 mg/dL. especially in the setting of rapidly deteriorating renal function (eg. and occasional hyaline casts.

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. and amyloidosis.may be low Urinalysis . or mononucleosis). In children. Symptoms Swelling (edema) is the most common symptom. This condition can also occur as a result of infection (such as strep throat. genetic disorders. This disorder occurs slightly more often in males than females. hepatitis. it is most common from age 2 to 6. and mesangiocapillary glomerulonephritis. Nephrotic syndrome can affect all age groups. They include: • • • • • Creatine . cancer. It can accompany kidney disorders such as glomerulonephritis. systemic lupus erythematosus. focal and segmental glomerulosclerosis. or diseases that affect multiple body systems including diabetes. It may occur: • • • In the face and around the eyes (facial swelling) In the arms and legs. immune disorders.reveals large amounts of urine protein . while membranous glomerulonephritis is the most common cause in adults.blood test Blood urea nitrogen (BUN) Creatinine clearance Albumin blood test . Laboratory tests will be done to see how well the kidneys are working.Causes Nephrotic syndrome is caused by various disorders that damage the kidneys. use of certain drugs. The most common cause in children is minimal change disease. particularly the basement membrane of the glomerulus. multiple myeloma. This immediately causes abnormal excretion of protein in the urine.