Clinical

History
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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.
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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.

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

Large acellular accumulations also may be observed within these areas. thus distinguishing diabetic nephropathy from most other forms of chronic renal insufficiency. most frequently observed as coarse branching of solid (positive periodic-acid Schiff reaction) material (diffuse diabetic glomerulopathy). The renal vasculature typically displays evidence of atherosclerosis. The image below is a simple schema for the pathogenesis of diabetic nephropathy. usually due to concomitant hyperlipidemia and hypertensive arteriosclerosis. The glomeruli and kidneys are typically normal or increased in size initially. but this is not immunopathogenetic or diagnostic. Immunofluorescence microscopy may reveal deposition of immunoglobulin G along the GBM in a linear pattern. These are circular on section and are known as the Kimmelstiel-Wilson lesions/nodules. Simple schema for the pathogenesis of diabetic nephropathy. Light microscopy findings show an increase in the solid spaces of the tuft. Immune deposits are not observed. . wherein renal size is reduced (except renal amyloidosis and polycystic kidney disease).extracellular matrix.

Hyperglycemia increases the expression of transforming growth factor-beta (TGF-beta) in the glomeruli and of matrix proteins specifically stimulated by this cytokine. matrix/mesangium. Hypertension is an adverse factor in all progressive renal diseases and seems especially so in diabetic nephropathy. or matrix/glomerulus). particularly African Americans. First.1 Hyperglycemia also may activate protein kinase C. with prominent matrix content. In addition to the renal hemodynamic alterations. These different histologic patterns appear to have similar prognostic significance.Electron microscopy provides a more detailed definition of the structures involved. and activation of cytokines. persons of Hispanic origin. patients with overt diabetic nephropathy (dipstick-positive proteinuria and decreasing GFR) generally develop systemic hypertension. which may contribute to renal disease and other vascular complications of diabetes. the peripheral basement membrane) is thicker than normal. Third. the basement membrane in the capillary walls (ie. definitive genetic markers have yet to be identified. volume fraction of mesangium/glomerulus. The exact cause of diabetic nephropathy is unknown. . perhaps via increased matrix production or glycosylation of matrix proteins. and American Indians. 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). Second. Certain ethnic groups. mesangial expansion is directly induced by hyperglycemia. Three major histologic changes occur in the glomeruli of persons with diabetic nephropathy. Familial or perhaps even genetic factors also play a role. The deleterious effects of hypertension are likely directed at the vasculature and microvasculature. may be particularly disposed to renal disease as a complication of diabetes. GBM thickening occurs. the mesangial regions occupy a large proportion of the tuft. advanced glycosylation products. In advanced disease. TGF-beta may contribute to the cellular hypertrophy and enhanced collagen synthesis observed in persons with diabetic nephropathy. Further. 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. However. Some evidence has accrued for a polymorphism in the gene for angiotensin-converting enzyme (ACE) in either predisposing to nephropathy or accelerating its course. but various postulated mechanisms are hyperglycemia (causing hyperfiltration and renal injury).

the urinalysis results from a patient with established diabetic nephropathy show proteinuria varying from 150 mg/dL to greater than 300 mg/dL. glucosuria. Typically.  . and occasional hyaline casts.Workup Laboratory Studies Urinalysis  Regular annual urinalysis is recommended for screening for microalbuminuria (see image below).

creatinine. and protein is extremely useful in quantifying protein losses and estimating the GFR. microalbuminuria can regress). (ACE-I stands for angiotensin-converting enzyme inhibitor)   Microalbuminuria is defined as albumin excretion of more than 20 mcg/min. A 24-hour urinalysis for urea.Screening for and prevention of the progression of microalbuminuria in diabetes mellitus. . This phase indicates incipient diabetic nephropathy and calls for aggressive management. at which stage the disease may be potentially reversible (ie.

Imaging Studies Renal ultrasound    Observe for kidney size. decreased or shrunken with chronic renal disease. Rule out obstruction. Blood tests . Perform microscopic urinalysis to help rule out a potentially nephritic picture. Perform echogenicity studies for chronic renal disease. Renal biopsy is not routinely indicated in all cases of diabetic nephropathy. including calculation of GFR (by various formulas. are helpful in monitoring for the progression of kidney disease and in assessing its stage. especially in the setting of rapidly deteriorating renal function (eg. Pathologic features are described in Pathophysiology. especially in persons with a typical history and a progression typical of the disease. Histologic Findings Staging . later. It is indicated if the diagnosis is in doubt. rapidly progressive glomerulonephritis). if other kidney disease is suggested. which may lead to a workup to rule out other primary glomerulopathies. or if atypical features are present. which is usually normal to increased in the initial stages and.Blood tests. Procedures Serum and urinary electrophoresis is performed mainly to help exclude multiple myeloma (in the appropriate setting) and to classify the proteinuria (which is predominantly glomerular in diabetic nephropathy). such as the MDRD formula).

.Stages in the development of diabetic nephropathy.

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