Report Describes Patient with aHUS, Alport, Subset of Kidney Inflammation

A rare case report described a woman with genetic and clinical evidence of atypical hemolytic uremic syndrome (aHUS), along with Alport syndrome and pauci-immune crescentic glomerulonephritis (PCGN), suggesting a shared disease mechanism among the three renal conditions.

The study, “A rare case of Alport syndrome, atypical hemolytic uremic syndrome and Pauci-immune crescentic glomerulonephritis,” was published in the journal BMC Nephrology.

Unlike people with aHUS, those with PCGN do not typically show dysfunction of the complement system — a set of more than 20 blood proteins that work with the body’s immune system. PCGN is the most common cause of primary rapidly progressive GN — inflammation of the glomeruli, the kidney’s small filtering units — and is characterized by necrotizing (dead tissue) and crescentic GN, defined by two or more layers of proliferating cells in the kidney’s Bowman’s capsule.

The team from Stanford University presented a case of a 26-year-old woman with Alport syndrome, crescentic GN and thrombotic microangiopathy (TMA, blood clots in the kidney’s small blood vessels).

The patient presented with progressive shortness of breath. She had had a diagnosis of asthma at age 3, hearing loss at age 23 and hypertension at age 24. Ten months prior to admission, her urinary samples showed high levels of protein and blood.

On admission, her blood pressure was very high — 191/125 mmHg — and her urine had numerous “muddy brown casts.” Her level of haptoglobin — a protein that clears free hemoglobin from circulation — was 10 mg/dl (low), and LDH cholesterol was 2,331 u/L (very high).

A chest x-ray revealed pulmonary congestion and kidneys were echogenic on ultrasound — an indication of renal disease. The patient was then started on hemodialysis.

The first kidney biopsy revealed crescentic glomeruli, marked tubular atrophy (shrinkage), interstitial fibrosis — destruction of renal tubules and tiny blood vessels, and buildup of proteins of the extracellular matrix, which provides support to cells — and sparse interstitial inflammation.

One arteriole, a small artery, showed swelling in the endothelium, which lines the interior of blood vessels, and a fibrin clot. In electron microscopy examinations, the team found endothelial cell damage with basement cell membrane rupture, suggesting Alport syndrome.

Overall, these findings were consistent with crescentic GN without extra-renal manifestations. Because of the insufficient samples and concerns for systemic TMA and AS, the patient underwent a second biopsy three weeks after admission.

Its findings included three globally sclerosed and eight crescentic glomeruli. Also, two glomeruli showed fibrin clots. The previously observed tubular atrophy and interstitial fibrosis involved more than 80% of the kidney’s cortex. Arteries and arterioles revealed edema, or swelling, cell death and wall thickening.

Subsequent ultrastructural examination of the glomeruli demonstrated extensive endothelial cell injury and prominent mesangiolysis, a process characterized by swelling, loosening and dissolution of the glomeruli’s mesangial cells, which interact closely with endothelial cells.

On immunofluorescence, a different imaging technique, the alpha3 chain of the protein collagen IV was absent in both glomeruli and tubules, while the alpha5 chain was absent along the glomerular basement membranes. According to the team, these findings “support a diagnosis of [Alport syndrome] that likely contributed to the underlying chronic kidney disease.”

Also, the C5b-9 protein complex was found in capillaries around renal tubules, as well as in crescentic and sclerosed glomeruli, indicating complement system activation.

Then, 12 aHUS-related genes were sequenced. This revealed heterozygous missense variants — changes in the building blocks of DNA, called nucleotides, leading to a different amino acid (the proteins’ building blocks) — in exons 11 and 2 of the CFI and CFHR5 genes, respectively. Of note, exons are the DNA bits containing information to make proteins.

The patient also had a variant within an intron — normally taken out before RNA is converted to proteins — in MCP/CD46. All these alterations were heterozygous, which means that they only occurred in one gene copy of these complement system-associated genes.

Five additional single nucleotide polymorphisms — differences in a single nucleotide — were found near and within MCP/CD46.

“The clinical, laboratory, and genetic findings indicate a diagnosis of aHUS coexistent with glomerular crescents seen on biopsy,” the researchers stated.

On admission, the patient was treated with pulse methylprednisolone followed by oral prednisone. Daily plasma exchange was started but soon discontinued. Cytoxan (cyclophosphamide) was given after the biopsies, while treatment with Soliris (eculizumab, by Alexion) was initiated after the second biopsy and continued every two weeks over the eight-month follow-up. However, her kidney function remained poor, necessitating hemodialysis.

Overall, the investigators suggested that “abnormal activation in complement pathway” might underlie the patient’s clinical manifestations.