Atypical Hemolytic Uremic Syndrome in Patients with Pregnancy Related Renal Cortical Necrosis: An Observational Study From Western Part of India

Dear Editor,

Renal cortical necrosis (RCN) is the most catastrophic form of AKI, associated with increasing maternal morbidity and mortality. Prolonged low renal perfusion causes ischemic cortical injury via spasm, clotting, and capillary damage. Obstetric RCN is an important sequela of pregnancy-related AKI, particularly in developing countries. and is most linked to massive blood loss from conditions such as placenta previa, abruptio placentae, post-partum hemorrhage, amniotic fluid embolism, and septic abortion.¹

Of late, complement-mediated thrombotic microangiopathy (CM-TMA) or atypical hemolytic uremic syndrome (aHUS) are distinct causes of AKI occurring in late pregnancy or postpartum.² In this study, we describe the clinico-epidemiological profile and outcomes of pregnancy-related RCN, emphasizing the potential contribution of aHUS, diagnosed clinically or through renal histology, and its impact on renal recovery in postpartum RCN patients from the western part of India. Materials and methods of the study have been provided in the Supplementary File.

A total of 20 patients with pregnancy-related AKI and biopsy-proven RCN were followed. The mean age at presentation was 28.1 (range: 19-42) years. Preeclampsia was seen in four patients (20%). Post-partum hemorrhage occurred in six patients (30%). A majority of patients (17/20) had an institutional delivery. The time from first medical contact to referral to our centre, as well as the delay in referral, were associated with an adverse outcome [Supplementary Table S1]. All patients presented in an anuric state after delivery and were initiated on hemodialysis. About 65% had sepsis; 17 (85%) exhibited classical microangiopathic hemolytic anemia (MAHA). Of these, 13 had histological changes of TMA on kidney biopsy. Five patients had low C3 levels, while five had normal C3 levels [Supplementary Table S2]. Nine patients were treated with plasma exchange. Patients with diffuse RCN with or without TMA on biopsy remained dialysis-dependent at 3 months. No deaths were observed during follow-up; one patient was lost to follow-up. Neonatal outcomes included intrauterine death (9), molar pregnancy (1), and live birth (10).

We assessed the relationship of various clinical and laboratory parameters with dialysis dependency at 3 months [Table 1]. In multivariate regression analysis, diffuse RCN was a statistically significant independent predictor (p= 0.006) of dialysis dependency at 3 months. Among the factors associated with the diffuse RCN, only age > 30 years had a significant association (p=0.01) [Supplementary Table S3]. Both clinical HUS and histological TMA were not associated with diffuse cortical necrosis (p=1.00 and p=0.16, respectively).

The median age at presentation was 28 years, similar to the findings from the systematic review by Gupta et al.³ Despite 65% (13/20) of patients presenting with sepsis, none had derangement of coagulation profile to suggest Disseminated Intravascular Coagulation. A few patients (20%) were diagnosed with preeclampsia, but none had transaminitis or evidence of endothelial damage. Six patients had postpartum hemorrhage and septic abortion, with 5/6 exhibiting the aHUS triad.^4,5 We could not identify a possible triggering factor for atypical HUS; however, an underlying genetic defect of complement dysregulation remains a possible etiology. Patients not being followed in their antenatal period in our institution leave the possibility of any antenatal events predisposing to the condition unanswered. The onset occurred at a gestational age of 34 weeks or beyond, primarily in the postpartum period, except for two cases that occurred within 28 weeks similar to the findings of the Spanish aHUS registry by Huerta et al.⁶ which reported an 88% postpartum onset and the French cohort of aHUS patients, which reported a postpartum incidence of 79%.⁷ About 43% had low C3 levels, highlighting a probable pathophysiological role involving complement dysregulation at the cell surface.

In resource-limited setting, plasma exchange (PLEX) serves as a mainstay treatment for aHUS, where dysfunctional complement-regulating proteins are replaced by fresh frozen plasma.⁸ Anti-Complement Factor H antibodies, which cause 5-10% of aHUS cases, tend to respond well to PLEX when combined with immunosuppression.⁹ Only nine (45%) of our patients received PLEX [Supplementary Table 4], though effectiveness has been reported in only a few case studies of pregnancy-related TMA. In our study, PLEX did not appear to affect renal outcomes at 3 months, in contrast to a study where 50% patients had improvement. Age, multiparity, baseline hemoglobin level, and diffuse RCN were significantly associated with dialysis dependency at 3 months, with diffuse RCN being independently associated.

Diffuse RCN is a key predictor of dialysis dependency at 3 months. Larger studies with diverse populations could clarify the roles of gestational age, parity, and PLEX in preventing cortical necrosis. The limited sample size and follow-up, along with the unavailability of a comprehensive genetic workup, have restricted deeper pathogenic insights.