Thrombotic Microangiopathy in Childhood Steroid-Resistant Nephrotic Syndrome: Case Series

Abstract

Introduction

Thrombotic microangiopathy (TMA) with associated nephrotic syndrome is a unique and rare condition that is infrequently described in pediatrics.

Case Presentations

Four children with steroid-resistant nephrotic syndrome (SRNS), immune-mediated and of monogenic origin, presented with TMA during late stages of chronic kidney disease. All patients tested negative for Shiga toxin and had normal A Disintegrin-like and Metalloprotease with Thrombospondin type 1 repeats 13 (ADAMTS13) activity. Genetic and functional studies of complement dysregulation were negative. Three of the 4 patients treated with Eculizumab showed good hematologic response but no kidney function recovery. None of the three children who underwent kidney transplantation had recurrent TMA.

Conclusions

TMA may develop in patients with SRNS, manifesting as an unexplained worsening of kidney function, new-onset hypertension, hemolytic anemia, and thrombocytopenia. Eculizumab was effective in improving hemolytic markers without kidney function recovery. TMA did not recur after kidney transplantation in this entity.

Introduction

Pediatric nephrotic syndrome (NS) is mostly idiopathic in nature, with approximately an annual incidence of 1.4–6.7 cases per 100,000 children per year [1]. It is best classified (for prognostic purposes) according to steroid responsiveness [2]. About 85%–95% of children with NS respond to treatment with steroids and are regarded as having steroid sensitive NS (SSNS) [3], indicative of good long-term prognosis. On the other hand, children with steroid-resistant NS (SRNS), defined as failure to achieve remission of symptoms despite a standardized trial (4–6 weeks) of daily steroid medication, have a variable long-term prognosis depending on their response to other immunosuppressive drugs or if a genetic etiology is found [4].

Thrombotic microangiopathy (TMA) is a term used to describe a clinicopathological syndrome characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and target organ damage. TMA is pathologically characterized by endothelial damage leading to microthrombi and tissue ischemia [5].

TMA is a very rare condition that can be the result of various disorders with different pathogenetic mechanisms: (1) thrombotic thrombocytopenic purpura due to low activity of “a disintegrin-like and metalloprotease with thrombospondin type 1 repeats 13” (ADAMTS13); (2) infection associated TMA, most commonly referred to as Hemolytic uremic syndrome (HUS) and usually caused by Shiga toxin producing E. coli (STEC-HUS), which accounts for 90% of HUS cases in childhood, with an annual incidence of approximately 2–3 cases per 100,000 children less than 5 years old [6]; (3) complement-mediated HUS which most commonly is referred to as atypical HUS (aHUS); (4) pregnancy associated TMA; (5) drug associated TMA (e.g., calcineurin inhibitors, chemotherapy); (6) metabolic associated TMA, due to defects of cobalamin metabolism; (7) hypertensive emergency; (8) autoimmune glomerular diseases (e.g., systemic lupus erythematosus, anti-phospholipid syndrome); (9) transplant associated TMA (solid and stem cell); (10) malignancy; (11) coagulation-mediated TMA, e.g., pathogenic variants in thrombomodulin or diacylglycerol kinase epsilon (DGKE) genes; and more [7]. The diagnoses “aHUS” historically described children with MAHA, thrombocytopenia, and kidney failure not associated with diarrhea. The term is often used to describe any patient with a TMA who does not have severe ADAMTS13 deficiency or documented Shiga toxin. For the purposes of this study, the term TMA will be used.

TMA associated with primary glomerular disorders is relatively rare and has been described in few case reports and series. It has been described in concordance with membranoproliferative and C3 glomerulonephritis [8], immunoglobulin A (IgA) nephropathy [9], and post-infectious glomerulonephritis [10, 11].

The occurrence of TMA in children with NS is rare and has been reported in a few case reports and small series, which include patients who vary greatly in terms of their demographic characteristics, clinical course, and outcome [8, 12–18]. In this study, we describe four children with SRNS who presented with systemic TMA during late stages of their original glomerulopathy.

Methods

All children treated for NS during 2012–2021 at Schneider’s Children’s Medical Center of Israel, the largest tertiary medical center for children in Israel, were reviewed for presence of TMA at any time during follow-up. TMA was defined as the appearance of: (1) MAHA including the demonstration of schistocytes on a blood smear and a negative Coombs test; (2) thrombocytopenia (platelet count <15 × 10⁴/microliter); (3) target organ damage, mostly acute kidney injury (AKI) defined by an elevated serum creatinine level (50% increase compared with previous measurement) and decreased urine output [19], or histopathological findings compatible with TMA [7, 20]. The involvement of other target organs, including the central nervous system or cardiovascular system, was also considered target organ damage. All patients had normal ADAMTS13 activity and were negative for stool Shiga toxin (polymerase chain reaction test [PCR]).

Prior to TMA occurrence, none of the patients received calcineurin inhibitors or other medications that were not specified in the text. Medical data were extracted from the patients’ electronic medical records, including demographic characteristics, clinical presentation, laboratory tests and biopsy results, and complement and genetic analysis. Estimated glomerular filtration rate (eGFR) was calculated using the Schwartz formula [21].

Cases Description

Case 1

A 19-month-old male patient presented with NS (edema, hypoalbuminemia, nephrotic range proteinuria, and microhematuria). His past medical and family history was unremarkable. Blood pressure was within normal range at presentation. Laboratory examination revealed an elevated serum creatinine level for age (0.6 mg/dL, eGFR: 53/min/1.73 m²). Complete blood count and C3 and C4 levels were within normal ranges. He was treated with oral prednisone 60 mg/m²/day for 4 weeks and three doses of intravenous methylprednisolone pulse (30 mg/kg) without any response. A kidney biopsy demonstrated minimal change in disease with very mild immunofluorescent staining for mesangial IgM. Electron microscopy (EM) revealed podocyte foot process effacement of more than 90% without electron-dense deposits. Genetic evaluation for NPHS1, NPHS2, and WT1 (Molecular Genetics Lab, Rabin Medical Center, Petach Tikva, Israel) revealed a variant of unknown significance in the NPHS1 gene, which was also present in several asymptomatic siblings.

Six weeks after presentation, he was diagnosed with severe pneumonia and developed acute anuric kidney failure. The patient was treated with peritoneal dialysis for 2 weeks until improvement. In subsequent months, his kidney function gradually deteriorated. Eleven months after diagnosis of NS, he presented with AKI (eGFR decreased from 21 to 8 mL/min/1.73 m²), anuria, anemia (hemoglobin 6.7 g/dL), new-onset thrombocytopenia (53 K/µL), and stage 2 hypertension with decreased cardiac function (Fig. 1a). His medication regimen included furosemide, zaroxolyn, spironolactone, sodium bicarbonate, calcium carbonate, sevelamer, enoxaparin, folic acid, and vitamin D. A blood smear revealed the presence of schistocytes. Serum ADAMTS13 level was normal, and stool antigen test for Shiga toxin was negative. Levels of complement factors 3 and 4 were again normal, haptoglobin was undetectable, and lactate dehydrogenase (LDH) reached a peak of 2,349 units/L. Therefore, the patient was diagnosed with TMA. Complement system gene evaluation (Bioscientia lab, Ingelheim, Germany) detected a novel CFHR3/CFHR4 hybrid gene, which was found to be homozygous for the CFH-H3 risk haplotype. Intravenous Eculizumab was started 7 days after TMA diagnosis, in addition to the initiation of hemodialysis. Three days after the first dose of Eculizumab, a hematologic response was noted and the platelet count increased to 180 K/µL. However, despite hematologic improvement, kidney function did not recover and blood pressure was difficult-to-control despite dialysis and multiple medications, leading to left ventricular hypertrophy and decreased cardiac function noted on echocardiography. He was switched to peritoneal dialysis, and blood pressure gradually improved with medication and volume control.

Fig. 1.

a–d Clinical disease course of patients 1–4, respectively. eGFR, estimated glomerular filtration rate; LDH, lactate dehydrogenase; MAP, mean arterial pressure; NS, nephrotic syndrome; TMA, thrombotic microangiopathy; Tx, transplantation.

At 2 months after TMA presentation, the patient experienced an episode of heart failure associated with severe hypertension. After better control of blood pressure, cardiac function improved. Eculizumab was discontinued after 8 months of treatment because of stable hematologic status and improved cardiac function.

At the age of 4 years and 4 months, the patient underwent a deceased donor kidney transplantation. The patient received a single dose of Eculizumab prior to transplantation to prevent TMA recurrence. Immediately after transplantation, the patient developed recurrence of NS and was treated with plasmapheresis and rituximab, showing a complete response. No evidence of TMA was noted, and the patient did not receive any further treatment with Eculizumab. Plasmapheresis and rituximab were gradually discontinued within 3.5 years following transplantation. At the age of 12 years, 8 years post-transplantation, his serum creatinine level was stable at 1.1 mg/dL (eGFR 50 mL/min/1.73 m²) with mild proteinuria (urine pr/cr ratio 0.35 mg/mg) and normal blood pressure.

Case 2

An 8-month-old female patient presented with NS and stage 2 hypertension (blood pressure of 119/75 mm Hg), with a serum creatinine level of 0.3 mg/dL (eGFR 93 mL/min/1.73 m²). Her medical and family history was unremarkable, apart from remote parental consanguinity. Serum antinuclear antibody and C3 and C4 levels were within normal limits. Treatment with prednisone 60 mg/m²/day was initiated, with no clinical response after 4 weeks. A renal biopsy demonstrated mild diffuse mesangial proliferation with negative immunofluorescence staining. EM demonstrated diffuse foot process effacement with microvillous transformation, mesangial proliferation, and hypertrophy, with few sclerotic lesions. Genetic evaluation for NPHS1, NPHS2, LAMB2, WT1, PLCE, DGKE, and ARHGDIA genes (Molecular Genetics Lab, Rabin Medical Center, Petach Tikva) and whole-exome sequencing (Yale Genetics labs, New Haven, CT, USA) revealed only a NPHS2 variant (R229Q) in a heterozygous state. A presumptive diagnosis of genetic SRNS was made; therefore, the patient did not receive any further immunosuppressive treatment. Her kidney function continued to deteriorate, and peritoneal dialysis was commenced at 2 years of age. At that time, she still had significant urine output, with nephrotic-range proteinuria and serum albumin below 2.5 g/d. Blood pressure values were between 95th and 95th + 12 mm Hg percentiles.

At the age of 2.5 years, she presented with ecchymoses on her lower limbs, which developed over 2–3 weeks, an abrupt increase in blood pressure, and a drop in her previously preserved urine output. Her medications included sodium polystyrene sulfonate, levothyroxine, darbepoetin-alfa, aspirin, and supplements of calcium carbonate with vitamin D, folic acid, iron, and omega-3. Her laboratory work-up revealed acute anemia (hemoglobin 6 g/dL), thrombocytopenia (99 K/µL), schistocytes on blood smear, and elevated LDH (2,029 U/L), all consistent with TMA. ADAMTS13 activity was normal, and stool PCR for Shiga toxin was negative. C3 and C4 levels were normal. Echocardiography revealed left ventricular hypertrophy and decreased cardiac output (shortening fraction of 25%). Multiple blood transfusions were required. Treatment with antihypertensive medications and intensification of dialysis led only to a partial hematologic response, with a slight increase in hemoglobin level and normalization of platelet count; however, blood pressure remained elevated, with decreased cardiac function and active hemolytic markers (Fig. 1b). Owing to ongoing hemolysis at 2 months after TMA onset, treatment with Eculizumab was initiated, leading to a rapid decrease of blood pressure and normalization of hemolytic markers within 2 weeks. Serum urea levels decreased from a maximum of 239 mg/dL to 80 mg/dL while hemoglobin levels increased to 11 g/dL, without the need for further transfusions.

Complement genetic evaluation (Bioscientia lab, Ingelheim, Germany) identified the common CFHR1/CFHR3 deletion in a heterozygous state. Complement factor H antibody tests were negative. She continued treatment with Eculizumab until she had a kidney transplantation at 4 years of age. The last dose of Eculizumab was administered at 5 days prior to transplantation. NS recurrence was diagnosed immediately after transplantation. She was treated with plasmapheresis and rituximab with a partial response. No recurrence of TMA was observed after transplantation, and she did not receive further Eculizumab. At the last follow-up, she was 11 years old, her serum creatinine was 0.43 mg/dL (eGFR 130 mL/min/1.73 m²), serum albumin level was 3.3 g/dL, and urine protein/creatinine ratio 1.62 mg/mg. Blood pressure was controlled using two medications.

Case 3

A female infant was referred for failure to thrive, dysmorphic facial features, and skeletal dysplasia. She was born at a post-conceptional age of 32 weeks. Her birth weight was 1,200 g. The patient’s parents were first-degree cousins. At 3 years of age, she had a brain stroke and was diagnosed with Moya-Moya brain vasculopathy. She continued to experience several brain strokes, which left her severely debilitated. At 4 years of age, she underwent whole-exome sequencing (Molecular genetics laboratory, Hadasah Medical Center, Jerusalem, Israel), which showed a homozygous pathogenic variant in SMARCAL1 gene (c.1682G>A; p.R561Q) inherited from both parents, and was diagnosed with Schimke immune osseous dysplasia. At the time of genetic diagnosis, nephrotic-range proteinuria was discovered, and during the next 4 years, she suffered from deteriorating kidney function as well as difficult-to-control hypertension. At 7 years of age, an acute elevation of serum creatinine level from 2.5 mg/dL to 5 mg/dL was observed, as well as uncontrolled hypertension despite treatment with four antihypertensive medications. Laboratory tests showed an acute decrease in hemoglobin level to a minimum of 4.3 g/dL and new-onset thrombocytopenia (39 K/µL). A blood smear revealed schistocytes and an elevated LDH level of 1,436 U/L, consistent with TMA. Stool PCR for Shiga toxin was negative, and ADAMTS13 function was normal. Peritoneal dialysis was initiated along with antihypertensive treatment with 2–3 medications. However, blood pressure was still elevated at 150/80 mm Hg, and she continued to show active markers of TMA, including thrombocytopenia and decreased hemoglobin levels, despite treatment with recombinant erythropoietin and iron (Fig. 1c). Gradually, over a few months, blood pressure was better controlled with medications and peritoneal dialysis, hemoglobin levels increased, and platelet counts normalized. Serum LDH remained mildly elevated at approximately 700 U/L, and blood smears repeatedly showed schistocytes, which may indicate persistent TMA. Over the following year, she suffered from continued neurologic deterioration and died from sepsis at 8 years of age.

Case 4

A 1-year-old male with a past medical history of intrauterine growth retardation, severe failure to thrive, severe microcephaly, and global developmental delay, presented with an influenza-like illness and severe NS with anasarca. He had a normal serum creatinine (0.18 mg/dL) and a low C3 level (55 mg/dL). Blood pressure was 107/81 mm Hg. Over the next few days, serum creatinine increased to 0.72 mg/dL. A kidney biopsy performed a week after admission showed mild to marked diffuse collapse of the glomerular tuft and prominent podocytes without mesangial proliferation. Two glomeruli showed segmental mesangiolysis, fibrin thrombi, and signs of acute tubular necrosis (Fig. 2). Immunofluorescence was positive for IgM, IgA, C3, C4, and C1q in the mesangial region in a focal-segmental pattern. EM demonstrated diffuse effacement of foot processes, irregular capillary walls, and swollen endothelial cells without electron-dense deposits.

Fig. 2.

a, b Histopathology of the renal biopsy in case 4. a Glomerulus with fibrin thrombi (arrowheads) (Masson-trichrome stain). b Diffuse collapse of the glomerular tuft and prominent podocytes (arrowheads) without mesangial proliferation (PAS stain).

Soon after renal biopsy, he developed laboratory evidence of TMA, including a further rise in serum creatinine to 1.72 mg/dL, new-onset thrombocytopenia, and hemolytic anemia. Blood pressure was stable at approximately 109/75 mm Hg. The maximum LDH was 2,407 U/L. Peripheral blood smear revealed the presence of schistocytes. Stool PCR for Shiga toxin was negative, and ADAMTS13 activity was normal. The patient started hemodialysis and plasmapheresis. After four sessions of plasmapheresis, Eculizumab treatment was initiated (Fig. 1d). A few days after the first Eculizumab dose, his platelet count normalized, hemolytic parameters improved, and he was gradually weaned off dialysis with eGFR reaching 110 mL/min/1.73 m² at 3 months after starting Eculizumab.

Whole-exome sequencing (Molecular genetics laboratory, Hadassah Medical Center, Jerusalem, Israel) identified a pathogenic variant in the LAGE3 gene [c.316(+4) A>G at chrX:153,706,618 position, leading to a donor splice of intron 2], which is compatible with Galloway Mowatt syndrome (GMS). Complement system evaluation for complement gene mutations, complement proteins, antibodies to factor H, and alternative pathway (Molecular Kidney Research Lab, University of Iowa, USA) did not show pathogenic results.

Despite treatment with Eculizumab, the patient experienced deteriorating kidney function and started chronic hemodialysis by the age of 2 years, approximately 9 months after presentation. He continued treatment with Eculizumab for 1 year and 6 months until the age of 3 years. At 6 years of age, the patient underwent kidney transplantation from a deceased donor without recurrence of TMA or proteinuria. At the last follow-up at the age of 9 years, his serum creatinine level was 0.21 mg/dL and urine protein/creatinine ratio 0.38 mg/mg. Patients’ clinical presentation and course are summarized in Table 1.

Table 1.

Clinical and laboratory data at NS and TMA presentation and outcome

Patient no.	1	2	3	4
Age at NS presentation, months	18	8	36	16
Gender	Male	Female	Female	Male
Ethnicity	Jewish	Arab	Arab	Arab
Histological kidney diagnosis	MCD	DMP	N/A	TMA
Genetic diagnosis	Negative	Negative	SIOD	GMS
Treatment for NS	CS	CSs	None	CS
Blood pressure before TMA (mm Hg)	109/70	116/76	115/79	107/81
Time from presentation to TMA, months	11	21	48	0
Last eGFR before TMA, mL/min/1.73 m2	21	4	7	22
Hypertension at TMA presentation	Yes	Yes	No	Yes
Outcome
Time from TMA to ESRD, months	11	16	48	8
Dialysis duration, months	47	25	13	48
Age at Kidney Tx, years	4.4	4.2	N/A	6
Eculizumab prophylaxis before Tx	Yes	Yes	N/A	No
TMA recurrence	No	No	N/A	No
NS recurrence	Yes	Yes	N/A	No
Age at last follow-up, years	12	11	8	9
Last eGFR (mL/min/1.73 m2)	49	106	Dialysis status	157
Last UPCR, mg/mg	0.45	1	N/A	0.38
Hypertension	No	Yes	Yes	No

Data are “N/A” on patient because of death.

CS, corticosteroids; DMP, diffuse mesangial proliferation; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; GMS, Galloway Mowat syndrome; MCD, minimal change disease; N/A, not available; NS, nephrotic syndrome; SIOD, Schimke immuno-osseus dysplasia; TMA, thrombotic microangiopathy; Tx, transplantation; UPCR, urine protein\creatinine ratio.

Discussion

We present four children with SRNS of different etiologies who, when approaching advanced kidney failure, developed TMA. Such a presentation can be explained by a few unique mechanistic processes:

Decreased Kidney Function

All 4 patients developed TMA while having a very low GFR. In patients 1 and 3, the onset of TMA heralded the progression to CKD stage 5, whereas in patient 2, TMA developed 5 months after starting dialysis and was marked by the loss of residual renal function. Patient 4, who had Galloway Mowatt syndrome, was diagnosed with TMA a few days after NS diagnosis, which included AKI and mild hypertension, during a febrile illness. After a short period of improvement, kidney function deteriorated again, reaching end-stage renal disease 9 months after the diagnosis of TMA. This is contrary to previous publications on pathogenic variants of LAGE3 gene, which reported a slower advancement toward kidney failure [22]. Therefore, in this patient TMA may have expedited progression to kidney failure.

Although not mentioned in the list of TMA etiologies, CKD is characterized by a state of chronic low-grade inflammation and the accumulation of reactive oxygen species (ROS) and uremic toxins, which together promote oxidative stress and endothelial dysfunction, decreased nitric oxide (NO) bioavailability, and upregulated procoagulant factors. This resulted in a shift toward a prothrombotic state and impaired endothelial repair, both of which are central to TMA pathogenesis [23]. Moreover, in CKD patients, platelet dysfunction and coagulation abnormalities create a milieu where both thrombosis and bleeding can occur, due to various effects of uremic toxins on platelets and endothelium, in addition to the well-known prothrombotic risks of hemodialysis and active NS. The net effect is often a heightened risk of microvascular thrombosis [24].

Hypertension

Although all of our patients had hypertension during the diagnosis of TMA, none of them had been diagnosed with malignant (emergency) hypertension. While hypertension is a well-recognized component of TMA, establishing a definitive causal relationship between the two can be challenging in certain cases. Notably, malignant (emergency) hypertension-induced TMA – where severe hypertension serves as the primary etiology – is relatively rare [25], and typically manifests only in the setting of extreme blood pressure elevations. Its pathogenesis is considered multifactorial [26], whereby severe hypertension overwhelms the autoregulatory mechanisms of small blood vessels, leading to mechanical shear stress and endothelial injury, the hallmark of TMA. When evaluating the timing of TMA development and associated hypertension, it seems that hypertension was a secondary process following TMA rather than the initiating factor.

Glomerular Disease

All 4 patients had SRNS at baseline but only patient 4 had renal biopsy during TMA. TMA as a complication of glomerular diseases has been reported in few case reports and series, mainly in recent decades. Nevertheless, glomerular disease is mentioned as a possible etiology of TMA in the current guidelines [27]. Most previously reported cases were forms of chronic glomerulopathies, such as membranoproliferative, idiopathic NS, FSGS, membranous nephropathy, post-infectious glomerulonephritis, and IgA nephropathy [8–11, 16, 28].

TMA in children with NS is relatively rare, described in a few case reports. Malignant hypertension was the presumed etiology for three children with NS who developed TMA, two of whom had idiopathic NS [18] and one FSGS [17]. Others described TMA presenting during a flare-up of minimal change disease, which improved with corticosteroids [16], or TMA following infection in a child with FSGS [12]. In 1983, Krensky et al. [14] reported three children with FSGS and/or mesangial proliferation on renal biopsy who developed sudden onset TMA 1–3 years after initial presentation, in association with kidney function deterioration. Two of them never regained kidney function and underwent kidney transplantation, after which their NS recurred but with no indications of clinical or histological TMA. The third patient experienced kidney failure over 10 months following TMA diagnosis [14].

A bidirectional relationship between glomerular diseases and TMA has been suggested. It has been proposed that abnormal complement activation can lead to podocyte damage and dysfunction. The podocyte injury can, in turn, trigger the development of TMA, which further contributes to the imbalanced coagulation system [29] and endothelial dysfunction [20, 30].

In addition to dyslipidemia, hypertension, and infections, which are all part of NS and known risk factors for endothelial dysfunction, few studies have found increased markers of endothelial dysfunction in NS, such as von Willebrand factor, plasminogen activator inhibitor I, thrombomodulin [31], and tissue plasminogen activator [32]. Other factors, such as adhesion molecules [33] and glomerular endothelium-derived microparticles, have been implicated in contributing to a thrombophilic environment [34]. A well-established association is also known between treatment with medications for NS, such as calcineurin inhibitors, and TMA [35].

Complement System Dysregulation

The last proposed mechanism in these children should be complement system dysregulation, which has been reported as a cause of TMA in various kidney disorders, such as AKI [36], diabetes mellitus [37, 38], IgA nephropathy [39], lupus nephritis [40, 41], monoclonal gammopathies [42], membranous nephropathy [43], anti-glomerular basement membrane (GBM) disease [44], post-infectious glomerulonephritis, and anti-neutrophil cytoplasmatic antibody-associated glomerulonephritis [45].

Chan et al. [46] described a patient with recurrent aHUS post kidney transplant due to a CD46 mutation in the setting of SMARCAL1-mediated inherited kidney disease. The patient was treated with plasmapheresis and cessation of tacrolimus. In contrast to patient 3, TMA was not diagnosed before transplantation and may have been related to other factors, e.g., medications, transplantation, etc.

Challis et al. [47] described two families with mutations in INF2 gene in addition to common aHUS risk haplotypes, who presented with aHUS or a post-transplantation TMA. Due to limited functional complement evaluation in 3 out of 4 patients (only patient 4 had functional evaluation) in our study, we cannot conclude about the possible association between complement system dysregulation and TMA.

Eculizumab is a humanized monoclonal antibody that blocks complement factor C5 and prevents the formation of the membrane attack complex C5b-9. Eculizumab has been proven to be effective in secondary forms of TMA, such as hematopoietic stem cell transplantation-associated TMA [48], systemic inflammatory diseases, pregnancy, drugs, and cancer [49], and it has been examined in other forms of glomerulonephritis, such as C3 glomerulonephritis and dense deposit disease, with only moderate efficacy [50, 51].

To the best of our knowledge, our study is the one of few that describes children with NS who developed TMA and were treated with Eculizumab (in 3/4 patients), showing an apparent positive hematologic improvement. In the report on INF2 mutation and TMA [47], Eculizumab was unsuccessful in preventing either ongoing TMA or end-stage renal disease.

None of the 3 patients who underwent kidney transplantation experienced a recurrence of TMA, a clinical course consistent with the absence of genetic variants associated with complement-mediated TMA or complement functional abnormalities. This strongly suggests that TMA in our patients was not a primary disorder, but rather a secondary process triggered by a combination of reduced GFR and CKD, hypertension, and active glomerulopathy, leading to severe endothelial dysfunction and complement activation. Consequently, we hypothesize that the positive hematologic response to Eculizumab likely reflects the blockade of a final common pathway of endothelial dysfunction and injury, rather than a primary complement dysregulation, while the poor immediate renal outcome in patients 1 and 2 probably reflects significant underlying kidney damage.

Limitations

This is a limited report of four cases from a single referral center. In addition, the cases are composed of both immune mediated as well as genetic SRNS. Therefore, the absence of post-transplantation TMA recurrence should be interpreted with caution. In addition, although genetic analysis and serum C3/C4 levels are reported, no functional assessment of complement activation (e.g., alternative pathway activity or terminal complement complex sC5b-9) was performed on patients 1–3. This significantly limits the interpretation of the pathophysiological basis for Eculizumab responsiveness in this context. Furthermore, genetic evaluations were not standardized across patients. Some underwent gene panel testing, others whole-exome sequencing, and complement gene analysis was performed at different centers with varying depth. The lack of uniformity makes comparison and interpretation of underlying predispositions more difficult.

Conclusion

TMA development should be suspected in patients with SRNS showing worsening kidney function, new-onset hypertension, and suggestive hematologic findings. Eculizumab was effective in restoring hemolytic markers without kidney function recovery. TMA recurrence is unlikely to occur after transplantation.

Statement of Ethics

This study was performed in accordance with the Declaration of Helsinki and approved by the Rabin Medical Center’s Institutional Review Board – approval: RMC-20-0924. All parents provided written informed consent for their minor children to participate in this study and for publication of details of their medical cases and any accompanying images. The CARE Checklist for this case report is available as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000552049).

Conflict of Interest Statement

The authors declare that they have no relevant financial interests. Daniel Landau is the Israeli National Coordinator for the Atypical Hemolytic Uremic Syndrome Registry organized by Alexion, AstraZeneca Rare Disease.

Funding Sources

The authors did not receive any financial support for conducting this study.

Author Contributions

D.F.: data extraction and collection, data analysis, and writing and reviewing; H.A.: data analysis, writing, and reviewing; O.H., D.L., Y.B., and C.R.: data analysis and reviewing.

Funding Statement

The authors did not receive any financial support for conducting this study.

Data Availability Statement

Most data exist unidentified and organized in Excel files. The clinical course was extracted and summarized from the personal medical files of the participants. Therefore, the extracted clinical information is not publicly available due to privacy regulations but can be provided upon reasonable request from the corresponding author.