PMC7843372_01
Timeline of treatment of aHUS in this patient, starting with the onset of disease at the age of 5 months until 18 years. Normal values of laboratory parameters indicated between parentheses. 1 After onset: chronic PT, including periods with plasma infusion. Every attempt to withdrawal in his first 4 years initiated a relapse. Number of relapses during PT period, n=7, 2 eGFR 65-70 ml/min/1.73m2, UPCR 0.18-0.53 g/10 mmol, 3 No thrombocytopenia, no signs of hemolysis; kidney biopsy right kidney: chronic TMA, no signs of interstitial nephritis or acute TMA,25% IFTA but diffuse small cysts eci, 4 Date of onset unknown, 5 AKI defined by a sudden increase in proteinuria and serum creatinine; kidney biopsy; similar to previous biopsy, 6 A traumatically obtained, extremely painful, and non-healing ulceration was considered as a (trigger of) an extra-renal manifestation of TMA, 7 aHUS relapse defined by AKI, thrombocytopenia and signs of hemolysis. 8 Haptoglobin decreased from 1.89 to 0,26 g/L. aHUS, atypical Hemolytic Uremic Syndrome; AKI, Acute Kidney Injury; eGFR, estimated Glomerular Filtration Rate (Schwartz formula); IFTA interstitial fibrosis and tubular atrophy; PT, Plasmatherapy; TMA, Thrombotic Microangiopathy; UPCR, Urine Protein-to-Creatinine Ratio.
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At the age of 5 months, our patient presented with TMA and nephrotic range proteinuria ( Figure 1 ). Despite a mild, chronic kidney failure (eGFR 65-70 ml/min/1.73m2, urine protein-to-creatinine ratio (UPCR) 0.18-0.53 g/10mmol), overall clinical situation remained stable ( Figure 1 ). Hemoglobin-, thrombocytes, and haptoglobin levels were not decreased, LDH not elevated and schistocytes absent ( Figure 1 ). Lactate dehydrogenase (LDH) was slightly elevated and thrombocytes and hemoglobin levels mildly decreased, whereas haptoglobin was normal and schistocytes were absent ( Figure 1 ). Although a skin biopsy was inconclusive for the presence of TMA, this ulcerative lesion was considered an extra-renal manifestation of TMA, especially taking into account the subsequent development of hematological signs of TMA several weeks later ( Figure 1 ).
Overview of eGFR, proteinuria and ratio of predicted eculizumab concentrations related to the eculizumab treatment in time. (A) Estimated eGFR (Schwartz formula) indicated with dark grey line, and the various interval treatment periods of eculizumab, indicated by the legends: white bar: eculizumab 1200 mg weekly middle grey colored bar: four-weekly 1200 mg eculizumab; light-grey colored bar 6-weekly 1200 mg eculizumab; dark grey colored bar: two-weekly 1200 mg eculizumab. Dotted line indicates the annual eGFR decline of 22.9 ml/min/1.73m2 (baseline eGFR 68 ml/min/1.73m2). (B) Urine Protein-to-Creatine ratio (g/10 mmol) in time indicated with dark grey line. Ratios of predicted eculizumab concentrations of our patient and a standardized patient of same weight indicated with dots. Ratio =1 (horizontal dotted line), normal clearance; Ratio >1, decreased clearance in our patient (eculizumab concentrations higher than expected); Ratio <1; increased clearance in our patient (eculizumab concentrations lower than expected.
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After six months, an unexplained decrease in kidney function was observed (eGFR 43 ml/min/1.73m2), with a mild increase in proteinuria (UPCR 0.80 g/10 mmol) ( Figure 2 ). Despite a temporary improvement in kidney function (eGFR 61 ml/min/1.73m2), an ongoing trend in CKD deterioration was observed ( Figure 2A ). Six months later, at the age of 15 years, a sudden increase in proteinuria (UPCR 5.28 g/10mmol) and decrease in kidney function (eGFR 18 ml/min/1.73m2) were observed without a triggering event ( Figure 2 ). Although hematological values improved rapidly, kidney function and proteinuria only partly recovered and the gradual progression of CKD continued ( Figure 2 ). A ratio >1 implies decreased clearance of eculizumab in our patient (eculizumab concentrations are higher than expected) and a ratio <1 implies increased clearance in our patient (eculizumab concentrations are lower than expected).  Figure 2B  shows that when the UPCR increases, the ratio of predicted eculizumab concentrations is lower than 1, implying faster clearance of eculizumab, probably due to urinary eculizumab loss. However, no improvement in kidney function was observed, and administrations were continued on a 4-weekly interval ( Figure 2A ). In addition, kidney function and proteinuria severely worsened (eGFR 14 ml/min/1.73m2, UCPR 4.50 g/10mmol), and hemodialysis was started for acute on chronic kidney injury ( Figure 2 ).