Renal Disease in Cryoglobulinemia

BACKGROUND: Renal disease in cryoglobulinemia is difficult to grasp and diagnose because it is rare, serological testing is challenging and prone to artifacts, and its morphology is shared by other renal diseases resulting in a spectrum of differential diagnoses. On occasion, a definitive diagnosis cannot even be rendered after immunofluorescence and electron microscopic studies. SUMMARY: Based on kidney biopsies seen in our routine diagnostic and referral practice, we discuss and illustrate various morphological patterns of renal injury associated with cryoglobulins. We outline key pathophysiologic and clinical aspects associated with cryoglobulinemia induced renal disease and describe morphologic changes with a focus on electron microscopy. We present our practical, morphology-based approach to diagnostic decision-making with special consideration of differential diagnoses and disease mimickers. Since cryoglobulins are rarely tested for prior to kidney biopsy, pathologists and clinicians alike must have a high level of suspicion when interpreting renal biopsies and managing patients. KEY MESSAGES: Cryoglobulinemia-associated glomerulonephritis (GN) is a multifactorial disease which is important to recognize for clinical practice. Morphological features suggestive of cryoglobulinemia-associated GN include a pattern of membranoproliferative GN with abundance of monocytes and the presence of (pseudo)thrombi. By electron microscopy, the main diagnostic features are a prominent infiltration of monocytes/macrophages and the presence of mesangial and subendothelial deposits with frequently curved microtubular/cylindrical and annular substructures.