Case 3

1. Case 3 nephrOticsydnrome

2. Glenda is a 48 year-old woman who presents to you (her GP) saying that her legs have been swollen for a month. On examination you find that she has pitting oedema in both legs up to her knees. • Q 1. How do you define oedema? Think of the fluid compartments in the body, and what must happen in order for oedema to develop, and try to come up with the most basic explanation of the development of oedema (one sentence.)

3. Definition of oedema: • palpable swelling produced by expansion of the interstitial fluid volume (UptoDate) • An abnormal increase in interstitial fluid within tissues (Robbins) • Development of oedema (UptoDate): • An alteration in capillary hemodynamics that favours the movement of fluid from the vascular space into the interstitium OR • The development of edema requires an alteration in one or more of Starling's forces in a direction that favors an increase in net filtration.

4. Revision slide • Starling forces determine fluid movement by osmosis through capillary membranes: • 1. Pc = capillary pressure––moves fluid out of capillary • 2. Pi = interstitial fluid pressure––moves fluid into capillary • 3. πc = plasma colloid osmotic pressure––moves fluid into capillary • 4. πi = interstitial fluid colloid osmotic pressure––moves fluid out of capillary

5. Q 2. What four physiological processes affect trans-capillary fluid exchange? Which of these are affected by chronic kidney disease?

6. Overview • Edema––excess fluid outflow into interstitium commonly caused by: • 1. ↑ capillary pressure (↑ Pc; heart failure) • 2. ↓ plasma proteins (↓ πc; nephrotic syndrome, liver failure) • 3. ↑ capillary permeability (↑ Kf; toxins, infections, burns) • 4. ↑ interstitial fluid colloid osmotic pressure (↑ πi; lymphatic blockage) • 227

7. In more detail… • Increased hydrostatic pressure – • Regional increases in hydrostatic pressure can result from a focal impairment in venous return. Thus, deep venous thrombosis in a lower extremity may cause localized edema in the affected leg. • On the other hand, generalized increases in venous pressure, with resulting systemic edema, occur most commonly in congestive heart failure, where compromised right ventricular function leads to pooling of blood on the venous side of the circulation.

8. Reduced plasma osmotic pressure occurs when albumin, the major plasma protein, is not synthesized in adequate amounts or is lost from the circulation. An important cause of albumin loss is the nephrotic syndrome. • reduced plasma osmotic pressure leads to a net movement of fluid into the interstitial tissues with subsequent plasma volume contraction. • The reduced intravascular volume leads to decreased renal perfusion increased production of renin, angiotensin, and aldosterone, but the resulting salt and water retention cannot correct the plasma volume deficit because the primary defect of low serum protein persists.

9. Salt and water retention can also be a primary cause of edema. Increased salt retention—with associated water—causes both increased hydrostatic pressure (due to intravascular fluid volume expansion) and diminished vascular colloid osmotic pressure (due to dilution). • Salt retention occurs whenever renal function is compromised, such as in primary disorders of the kidney and disorders that decrease renal perfusion.

10. Impaired lymphatic drainage results in lymphedema that is typically localized; causes include chronic inflammation with fibrosis, invasive malignant tumors, physical disruption, radiation damage, and certain infectious agents.

11. Further examination findings are: • T 37; BP 115/70; pulse 72 reg; • no abnormalities found on examination of the heart; • JVP not elevated; • peripheries are well perfused. • Abdominal examination is normal, as is the remainder of the examination. • Urine dipstick shows protein 4+

12. Q 3. You consider that your patient has nephrotic syndrome, on account of her heavy proteinuria and oedema. (i) What quantity of protein in the urine constitutes ‘nephrotic range’ proteinuria? (ii) What is the third feature (in addition to proteinuria and oedema) that makes up the classic triad of nephrotic syndrome? (iii) what other classical features of the syndrome will you seek?

13. What quantity of protein in the urine constitutes ‘nephrotic range’ proteinuria? • 3.5g/day • What is the third feature (in addition to proteinuria and oedema) that makes up the classic triad of nephrotic syndrome? • Hypoalbuminemia • Hyperlipidemia (Hyperlipidemia and lipiduria: An increase in serum cholesterol and phospholipid levels and lipiduria are typically components of the nephrotic syndrome. This is due to increased hepatic synthesis, which may be triggered by the decrease in plasma oncotic pressure)

14. Proteinuria: due to increased permeability of the glomerular basement membrane to albumin and arises in response to alterations in both the size and charge barriers of the glomerular filtration apparatus. Albumin is the predominant protein excreted. • Hypoalbuminemia seems to be due to failure of hepatic synthesis of albumin to compensate for the albumin lost in urine. Release of cytokines may also suppress hepatic albumin synthesis • Edema: Plasma oncotic pressure decreases because of proteinuria and a decrease in serum albumin concentration. • What other classical features of the syndrome will you seek?

15. Hypertension, and hyponatremia • Other metabolic derangements: • Ahypercoagulable state, possibly due to urinary loss of antithrombin III and decreased activity of proteins S and C. • Loss of vitamin D-binding globulin may result in vitamin D deficiency, hypocalcemia, osteomalacia, and secondary hyperparathyroidism. • Loss of immunoglobulins may result in impaired immunity and increased rates of infections.

16. Causes: • Minimal change glomerulopathy • In children • Disease is immunologically mediated and related to abnormal T-cell function rather than immune-complex deposition • Membranous nephropathy: • Most common clinicopathologic entity associated with idiopathic nephrotic syndrome in adults • May be primary or secondary to a wide range of diseases. Its pathogenesis is unknown, and treatment is controversial • Focal segmental glomerulosclerosis • Membranoproliferativeglomerulonephritis

17. Secondary causes • Type 1 and 2 DM • SLE • Amyloid • Myeloma Rare causes • Syphilis, sickle cell disease, Hep B, malaria, cancer, reflux nephropathy, NSAIDs