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Nephrotic syndrome: Clinical Presentation and Biochemical Diagnosis

Case Presentation
A 62-year-old man with a 10-year history of type 2 diabetes mellitus visited the hospital with complaints of swelling in his lower extremities. The patients' had a co-incidence of diabetes mellitus and hypertension. The clinical laboratory report showed the following observations:

Biochemical Parameters
Results
Serum Glucose
250 mg/dL
Serum Albumin
2.5g/dL
Serum Creatinine
1.5 mg/dL
Blood Urea itrogen
25mg/dL
Serum Sodium
130 mEq/L
Serum Potassium
4.3 mEq/L
Serum Total Cholesterol
275 mg/dL
Serum Anti-ANA antibodies
Negative
Serum Rheumatoid factors
Negative
Serum Cryoglobulins
Negative

Urine examinations
Urinary proteins: 5.0 gm/dL
Urinary glucose: ++

Provisional diagnosis: Diabetic kidney disease with hypoalbuminemia, massive protein loss( nephrotic syndrome), hypercholesterolemia.

Nephrotic Syndrome
Nephrotic syndrome is a clinical disorder characterized by proteinuria (>3.5g per day) which results from altered permeability of the glomerular filtration barrier for protein, namely the GBM and the podocytes and their slit diaphragms. Other metabolic complications include hypoalbuminemia, edema, hyperlipidemia, lipiduria, and hypercoagulability co-exist with massive proteinuria.

Biochemical basis of diabetic kidney disease
Diabetic kidney disease or nephropathy is the leading cause of end-stage renal disease (ESRD). The earliest abnormalities in diabetic nephropathy are the thickening of the glomerular basement membrane and expansion of the mesangium due to the accumulation of the extracellular matrix. The expansion and injury of mesangial cells may occur by an increase in the mesangial cell glucose concentration. 
The high blood glucose and glomerular hypertension in the mesangial cells lead to cell proliferation, hypertrophy and stimulate the expansion of these cells. Glucose may bind reversibly and eventually irreversibly to proteins in the kidneys and circulation to form advanced glycosylation end products (AGEs). AGEs can form complex cross-links over years of hyperglycemia and can contribute to renal damage by stimulation of growth and fibrotic factors via receptors for AGEs. In addition. The cytokines and mediators of proliferation and expansion such as PDGF, TGF-beta, VEGF contribute to further renal and microvascular complications.

Biochemical basis of other metabolic complications
In nephrotic syndrome, hypoalbuminemia occurs due to increased renal loss and inadequate but increased hepatic synthesis of albumin. The hypoalbuminemia results in decreased intravascular oncotic pressure, leading to leakage of extracellular fluid from the blood to the interstitium. Intravascular volume falls, thereby stimulating the activation of the renin-angiotensin-aldosterone axis and the sympathetic nervous system and release of vasopressin (ADH), and suppressing arterial natriuretic peptide release. These neural and hormonal responses promote renal salt and water retention thereby restoring intravascular volume and triggering further leakage of fluid to the interstitium.

Increased hepatic lipoprotein synthesis occurs in response to reduced oncotic pressure and may be compounded by increased urinary loss of proteins that regulate lipid homeostasis. Low-density lipoproteins and cholesterol are increased in the majority of patients whereas very-low-density lipoproteins and triglycerides tend to rise in a patient with severe disease.

Hypercoagulability is multifactorial in origin and is caused by the increased loss of antithrombin III, altered levels and or activity of protein C and S, hyperfibrinogenemia due to increased hepatic synthesis, impaired fibrinolysis, and increased platelets aggregation.

Other metabolic complications of nephrotic syndrome include protein malnutrition and iron-resistant microcytic hypochromic anemia due to transferrin loss. Hypocalcemia and secondary hyperparathyroidism can occur as a consequence of vitamin D deficiency due to enhanced urinary excretion of cholecalciferol binding proteins.




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