Kidney Biopsy and Type IV Collagen Gene Sequencing Fail to Explain Hematuria in Loin Pain Hematuria Syndrome

Abstract

Introduction: Loin pain hematuria syndrome (LPHS) is a rare clinical syndrome with a reported prevalence of 1 in 10,000. The syndrome is characterized by severe pain localized to the kidney in the absence of identifiable urinary tract disease. Because of an inadequate understanding of the pathophysiology of the disease, the goal of management has been limited to symptomatic pain management. Through detailed phenotype and genotype assessment we sought to identify possible underlying etiologies.

Methods: We completed a chart review, ultrasound imaging, kidney biopsy, and type IV collagen (COL4A3, COL4A4, and COL4A5) gene sequencing in 14 patients with loin pain hematuria recruited from a single center.

Results: Red blood cells and red cell casts were observed within the tubules in 10 of 14 patients. The glomerular basement membrane (GBM) was normal in 11 patients and thickened in 1 patient. Staining for IgA kappa was present in 1 patient. C3 deposition without any inflammation was present in 7 patients. Arteriolar hyalinosis was present in 4 patients and endothelial cell injury was present in 6 patients. No pathogenic COL4A3, COL4A4, or COL4A5 variants were identified.

Conclusion: Conventional histopathology and genetic testing for type IV collagen variants failed to identify the cause of hematuria in 14 patients with LPHS.

Keywords: glomerular basement membrane; kidney biopsy; loin pain hematuria syndrome; rare disease; thin basement membrane disease; type IV collagen.

Graphical abstract

Figure 1

Flow diagram. EM, electron microscopy; GBM, glomerular basement membrane; IF, immunofluorescence.

Figure 2

Alterations of glomerular basement membrane visible with light microscopy. Mesangial deposition of IgA in one patient. (a) IgA deposition in mesangial areas detected by electron microscopy and (b) IgA deposition detected by immunofluorescence studies in the same patient.

Figure 3

Alterations in endothelial cells. Minor alterations in Microvasculature. Subendothelial hyalinosis and enlarged endothelial cells as visualized under periodic acid–Schiff staining at 100× magnification in (a) small arteries/arterioles (arrow) and in (b) hilar arterioles (arrow). Electron microscopy images show (c) expansion of subendothelial spaces and loss of fenestration in endothelium (arrows), and (d) endothelial cell swelling partially obliterating capillary lumen.

Figure 4

Presence of red blood cells and casts. (a) Intact and dysmorphic red blood cells are seen inside tubules (arrow) and glomerular urinary space (arrowhead)-with hematoxylin and eosin staining at 100× (b) acute tubular injury with loss of brush border, simplification, and vacuolar degeneration in epithelial cells with periodic acid–Schiff staining, 200× (c) red cell cast in many tubules with Masson Trichrome stain, 100× (d) Arrow shows dysmorphic and degenerated red blood stains with periodic acid–Schiff staining, 100×.