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Nephrotic-Range Proteinuria and Peripheral Edema in a Child: Not Only Idiopathic Nephrotic Syndrome

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ABSTRACT

Hemolytic uremic syndrome (HUS) is defined by the simultaneous occurrence of hemolytic anemia, thrombocytopenia, and acute kidney injury due to thrombotic microangiopathy (TMA) mainly occurring in renal and cerebral microvessels. Although the most common cause of HUS in children is Shiga toxin-producing Escherichia coli, atypical forms in which Shiga toxin is not the trigger may occur. Research over the last few years has shown that complement dysregulation secondary to mutations of genes coding for proteins involved in the regulation of the alternative pathway of complement account for most forms of atypical HUS (aHUS). Among these, thrombomodulin (THBD) gene mutations, representing 3–5% of all alternative pathway complement component abnormalities, correlate with early disease onset and rapid evolution to end-stage renal failure. aHUS onset is generally sudden, but occasionally the only manifestations of renal TMA are arterial hypertension, proteinuria, and a progressive increase in serum creatinine. Nephrotic syndrome at disease onset is exceptional. We describe the case of an adolescent female who presented with peripheral edema due to nephrotic-range proteinuria with bioptic evidence of TMA. Study of the alternative complement pathway showed a heterozygous missense THBD gene mutation (P501L variant) consistent with aHUS diagnosis. One year later she developed clinical signs of hemolytic anemia. Eculizumab, an anti-C5 monoclonal antibody, was started with rapid improvement. This case report highlights the phenotypic variability in aHUS due to THBD gene mutation. Early diagnosis by renal biopsy followed by genetic screening is required to optimize management in such a rare disease with a severe prognosis.

No MeSH data available.


Related in: MedlinePlus

Electron microscopy (F.D.-C.). Amorphous material deposition in the subendothelial space and multilayering of the glomerular basal membrane (red arrows). Cytoplasmic debris and deformed red blood cells occluding vessel lumina (blue stars).
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Figure 2: Electron microscopy (F.D.-C.). Amorphous material deposition in the subendothelial space and multilayering of the glomerular basal membrane (red arrows). Cytoplasmic debris and deformed red blood cells occluding vessel lumina (blue stars).

Mentions: Renal biopsy demonstrated diffuse thickening and multilayering of glomerular capillaries with entrapment of red blood cell fragments. Hilar arterioles showed intimal fibromucoid hyperplasia; occasional thrombi occluded vascular lumina (fig 1). On ultrastructural examination, glomerular capillaries and arterioles were thickened for subendothelial amorphous material deposition and endothelial cell hyperplasia (fig 2). A routine immunofluorescence panel (IgA, IgG, IgM, C1q, C3, and fibrinogen) was substantially negative in glomeruli; C3 complement fraction stained arteriolar walls (fig 3). These findings were consistent with thrombotic microangiopathy (TMA).


Nephrotic-Range Proteinuria and Peripheral Edema in a Child: Not Only Idiopathic Nephrotic Syndrome
Electron microscopy (F.D.-C.). Amorphous material deposition in the subendothelial space and multilayering of the glomerular basal membrane (red arrows). Cytoplasmic debris and deformed red blood cells occluding vessel lumina (blue stars).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121544&req=5

Figure 2: Electron microscopy (F.D.-C.). Amorphous material deposition in the subendothelial space and multilayering of the glomerular basal membrane (red arrows). Cytoplasmic debris and deformed red blood cells occluding vessel lumina (blue stars).
Mentions: Renal biopsy demonstrated diffuse thickening and multilayering of glomerular capillaries with entrapment of red blood cell fragments. Hilar arterioles showed intimal fibromucoid hyperplasia; occasional thrombi occluded vascular lumina (fig 1). On ultrastructural examination, glomerular capillaries and arterioles were thickened for subendothelial amorphous material deposition and endothelial cell hyperplasia (fig 2). A routine immunofluorescence panel (IgA, IgG, IgM, C1q, C3, and fibrinogen) was substantially negative in glomeruli; C3 complement fraction stained arteriolar walls (fig 3). These findings were consistent with thrombotic microangiopathy (TMA).

View Article: PubMed Central - PubMed

ABSTRACT

Hemolytic uremic syndrome (HUS) is defined by the simultaneous occurrence of hemolytic anemia, thrombocytopenia, and acute kidney injury due to thrombotic microangiopathy (TMA) mainly occurring in renal and cerebral microvessels. Although the most common cause of HUS in children is Shiga toxin-producing Escherichia coli, atypical forms in which Shiga toxin is not the trigger may occur. Research over the last few years has shown that complement dysregulation secondary to mutations of genes coding for proteins involved in the regulation of the alternative pathway of complement account for most forms of atypical HUS (aHUS). Among these, thrombomodulin (THBD) gene mutations, representing 3–5% of all alternative pathway complement component abnormalities, correlate with early disease onset and rapid evolution to end-stage renal failure. aHUS onset is generally sudden, but occasionally the only manifestations of renal TMA are arterial hypertension, proteinuria, and a progressive increase in serum creatinine. Nephrotic syndrome at disease onset is exceptional. We describe the case of an adolescent female who presented with peripheral edema due to nephrotic-range proteinuria with bioptic evidence of TMA. Study of the alternative complement pathway showed a heterozygous missense THBD gene mutation (P501L variant) consistent with aHUS diagnosis. One year later she developed clinical signs of hemolytic anemia. Eculizumab, an anti-C5 monoclonal antibody, was started with rapid improvement. This case report highlights the phenotypic variability in aHUS due to THBD gene mutation. Early diagnosis by renal biopsy followed by genetic screening is required to optimize management in such a rare disease with a severe prognosis.

No MeSH data available.


Related in: MedlinePlus