The 2020 ERA-EDTA first fully virtual conference provided an opportunity to share the latest expert views on the pathophysiological mechanisms and novel treatment strategies in aHUS from leading experts in the field – professor Jean-Michel Halimi and professor Alberto Ortiz, in a virtual panel meeting chaired by professor Eric Rondeau.
Acute kidney injury to chronic kidney disease in aHUS: a progression link?
According to the current KDIGO guidelines, acute kidney injury (AKI) is defined by the presence of either one of the following criteria: an increase in serum creatinine by ≥0.3 mg/dl (≥26.5 µmol/l) within 48 h; an increase in serum creatinine to ≥1.5 times baseline within the previous 7 days; and/or urine volume ≤0.5 ml/kg/h for 6 h (4). The diagnosis is often made late, i.e. after the organ has already been affected and, possibly, irreversibly damaged. The histopathologocal substrate is characterized by necrotic tubular cell death and inflammation, with an additional component of microvascular injury, specific for AKI in TMA (5). The outcome can range from resolution to progression to chronic kidney disease (CKD), eventually leading to end-stage renal disease (ESRD) (6). The cells of the renal vasculature have a poor capacity for repair, resulting in the reduction in vascular density, i.e. ‘capillary rarefaction’ which promotes hypoxia, impairs hemodynamic responses, predisposes to CKD progression and hypertension development ( 7, 8).
CKD is defined as an abnormality of kidney structure, detected by pathohistological analysis; or function, manifested by persistent albuminuria >30mg/g creatinine and/or decrease in glomerular filtration rate <60ml/min/1.73m2; that is present for > 3 months (9). CKD is one the fastest-growing cause of mortality worldwide, with the current incidence of the disease estimated to double by 2040 (10). While mortality of the ESRD patients on renal replacement therapy is affected by a combination of socioeconomic factors, pre-existing medical disorders, renal replacement treatment modalities, and kidney failure itself, a very recent observation that albuminuria per se directly suppresses the production of anti-aging factor Klotho by kidney tubular cells may be the missing link explaining the association between albuminuria, CKD progression and premature death in predialysis patients (11-13). Recent investigations also confirmed that Shiga toxin, responsible for triggering classical HUS, also down-regulates renal klotho expression, thus contributing to renal tissue injury (14).
Before the introduction of the complement inhibitors therapies, the outcome and dialysis-free survival of patients with aHUS largely depended on their genetic background (15). The introduction of eculizmab largely modified the outcomes in adults with AKI caused by aHUS, increasing the prevalence of patients with recovered kidney function, and virtually eradicating the need for dialysis (Figure 2), (16, 17). To achieve such results, appropriate timing of the therapy is of major importance. It appears that introducing eculizumab ≤7 days after first signs of the last aHUS manifestation provides a significantly greater mean improvement in eGFR from month 1 onwards, thus calling for early initiation of therapy to achieve the optimum results (18).