Figure 1134

Pathogenesis of the different types of renal lesions in dysproteinemias. Paraproteins can deposit in the glomerular basement membrane (GBM) (and tubular basement membrane [TBM]) either as light or heavy chains, unmodified immunoglobulins, amyloids, or cryoglobulins. Because of their size of 22 kD, light chains are freely filtered through the GBM. These light chains are then reabsorbed by proximal tubular cells. This process can induce a cascade of events. Because some of these light chains are relatively resistant to proteolysis, they can induce lysosomal damage. This damage can give rise to functional impairment of the proximal tubular cell, leading to a decreased resorptive capacity (eg, for sodium and light chains) and thereby increasing the distal delivery. When this lysosomal overload leads to intracellular crystal formation, Fanconi's syndrome may ensue. Increased distal delivery of light chains can then induce precipitation of light chains together with Tamm-Horsfall protein (THP) that is secreted in the loop of Henle. This precipitation is enhanced by an increased tubular fluid sodium chloride concentration. Other factors that enhance cast formation are listed in Figure 11-43. This intratubular cast formation leads to obstruction, tubular damage, and an interstitial inflammatory response with leakage of THP in the interstitium, inducing macrophage influx and giant cell formation. This entity is known as myeloma cast nephropathy. Finally, interstitial plasma cell invasion may occur in patients with myeloma, although this rarely leads to clinical symptoms and most often is only diagnosed by kidney biopsy specimen or is seen at autopsy. CCT—cortical collecting tubule; DT—distal tubule; LC—light chains; PCT—proximal convoluted tubule; PR—pars recta; TAL—thin ascending limb. (Adapted from Winearls [69].)

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