Successful term pregnancy after renal transplant in end-stage renal disease with complement factor H-related mutation: A case report

Abstract

BACKGROUND

Complement-mediated thrombotic microangiopathy (TMA) is a rare endothelial injury syndrome caused by dysregulated activation of the alternative complement pathway, often linked to genetic abnormalities in complement factor H (CFH), complement factor I, or complement factor H-related (CFHR) proteins. Both renal transplantation and pregnancy are independent triggers for recurrence. This case highlights a genetically high-risk patient who achieved a successful term pregnancy after renal transplantation without complement inhibition, emphasizing individualized risk stratification, close surveillance, and multidisciplinary management for favourable maternal and graft outcomes.

CASE SUMMARY

A 32-year-old woman with end-stage renal disease secondary to genetically confirmed complement-mediated TMA—homozygous CFH exon 17 deletion and CFHR3-CFHR1 duplication—was maintained on dialysis for 2.5 years before undergoing a successful live-donor kidney transplant from her mother. Post-transplant immunosuppression included tacrolimus, mycophenolate mofetil, and prednisolone, later modified to azathioprine during pregnancy planning. One-year post-transplant, she conceived spontaneously. Pregnancy was complicated by transient gestational hypertension, controlled with nifedipine, labetalol, and amlodipine. Proteinuria remained < 150 mg/day; white blood cell counts 5.8-7.2 × 10⁹/L without cytopenia. Serum creatinine ranged 0.9-1.1 mg/dL, and tacrolimus trough levels 5-7 ng/mL. At 36 weeks, she delivered a healthy 3 kg infant by elective caesarean section. Postpartum follow-up at three months confirmed stable maternal and graft function.

CONCLUSION

High-risk complement-mediated TMA patients can achieve successful pregnancy post-transplant through individualized care without mandatory complement blockade.

Core Tip: This case highlights a rare instance of successful term pregnancy in a renal transplant recipient with genetically confirmed complement-mediated thrombotic microangiopathy—homozygous complement factor H exon 17 deletion and complement factor H-related (CFHR3-CFHR1) duplication—managed without complement blockade. Despite the dual risk posed by transplantation and pregnancy, careful preconception counseling, immunosuppressive modification, and vigilant multidisciplinary surveillance ensured stable graft function and favorable maternal-fetal outcomes. This report emphasizes individualized, genotype-informed management and adds valuable evidence to guide pregnancy counseling in women with complement dysregulation post-transplant.

INTRODUCTION

Thrombotic microangiopathy (TMA) is a group of disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury, most commonly affecting the renal microvasculature[1,2]. Among its subtypes, atypical hemolytic uremic syndrome (aHUS) is primarily driven by dysregulated activation of the alternative complement pathway, often linked to mutations in complement factor H (CFH), complement factor I, membrane cofactor protein, or C3, as well as to anti-factor H antibodies[3,4]. Although aHUS accounts for a small fraction of TMA cases, it carries a high risk of progression to end-stage renal disease (ESRD) and recurrence after transplantation.

Genetic rearrangements involving the CFH-CFHR gene cluster, such as CFH exon deletions and CFHR3-CFHR1 duplications, are rare but increasingly recognized as contributors to complement dysregulation[5]. These abnormalities may remain subclinical until triggered by immune or endothelial stressors, notably transplantation or gestation[6-8]. In transplant recipients with complement gene mutations, the risk of disease relapse is substantial, and pregnancy may further amplify complement activation, rendering this combination particularly precarious and clinically challenging[9,10].

Compared with CFH point mutations, the clinical significance of CFHR3-CFHR1 structural variants is less clearly defined, yet emerging data suggest that these rearrangements act as important genetic modifiers of disease severity. Although their penetrance is incomplete, these variants can predispose to endothelial injury and TMA recurrence, underscoring the need for vigilant monitoring in genetically high-risk patients. Published reports of pregnancy in renal transplant recipients with CFHR3-CFHR1 abnormalities are exceedingly scarce, and when described, most have reported adverse maternal or graft outcomes[11-13].

Recent genetic and clinical evidence indicates that hybrid CFHR1/CFH fusion genes can directly antagonize factor H activity, worsening complement dysregulation, while pregnancies in kidney transplant recipients with complement gene variant-mediated TMA are predominantly associated with adverse outcomes[14,15].

We report a rare case of a woman with ESRD due to genetically confirmed CFH exon 17 deletion and CFHR3-CFHR1 duplication who achieved an uneventful term pregnancy after living-donor kidney transplantation, without prophylactic complement inhibition. This case underscores the importance of individualized management strategies in genetically high-risk patients confronting the dual challenges of transplantation and pregnancy.

CASE PRESENTATION

Chief complaints

A 32-year-old woman with ESRD presented for evaluation and management of fertility planning after a successful live-donor kidney transplant.

History of present illness

She had been on maintenance hemodialysis for 2.5 years before undergoing transplantation. Her initial illness was characterized by TMA, with microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury requiring dialysis. ADAMTS13 activity was normal, and no secondary triggers of TMA were identified. Autoimmune evaluation showed normal anti-factor H antibody titres. Genetic testing revealed a homozygous deletion in exon 17 of the CFH gene (variant of uncertain significance) and a duplication of CFHR3-CFHR1, suggestive of complement-mediated TMA of uncertain penetrance related to CFHR dysregulation.

One-year post-transplant, after modification of her immunosuppressive regimen, she conceived spontaneously. During the second trimester, blood pressures ranged from 138-150/88-96 mmHg, consistent with transient gestational hypertension, which was well controlled with oral nifedipine, labetalol, and amlodipine. Pregnancy progressed without recurrence of TMA or graft dysfunction.

History of past illness

She had no history of hypertension, diabetes, autoimmune disorders, thromboembolic events, or other systemic illnesses prior to her TMA presentation. There was no prior exposure to nephrotoxic drugs, no prior pregnancies, and no significant infectious disease history.

Personal and family history

She denied a family history of kidney disease, TMA, or other complement-mediated disorders. She was a non-smoker, non-alcoholic, and denied recreational drug use.

Physical examination

On initial post-transplant follow-up, her vital signs were within normal range: Blood pressure 118/74 mmHg, heart rate 78 beats/minute, respiratory rate 18 breaths/minute, temperature 36.6 °C. Systemic examination was unremarkable. No edema or skin rash was noted. During pregnancy follow-up, physical examinations were consistently within normal limits apart from the elevated blood pressure.

Laboratory examinations

Baseline post-transplant laboratory results showed stable graft function (serum creatinine approximately 0.8-1.0 mg/dL) (Normal: 0.6-1.2). Doppler ultrasonography confirmed good renal perfusion. Tacrolimus trough levels during the first month ranged from 8.95 ng/mL to 9.43 ng/mL (target: 8-12 early post-transplant); the dose was increased from 2.5 mg/day to 3.5 mg/day to maintain target levels. At four months, she developed secondary polycythemia, managed with therapeutic phlebotomy and telmisartan. From months 5-12, tacrolimus was maintained at 1.5 mg twice daily (trough 6.2-7.6 ng/mL). During pregnancy, tacrolimus levels ranged from 4.3 ng/mL to 7.0 ng/mL, with stable hemoglobin, platelet count, and renal function. Cytomegalovirus (CMV) polymerase chain reaction and toxoplasma testing remained negative. No hemolysis parameters suggested TMA recurrence. Serial urinalyses confirmed urine protein excretion < 150 mg/day throughout pregnancy, excluding preeclampsia. White blood cell counts remained between 5.8-7.2 × 10⁹/L, with no cytopenia. Thiopurine methyltransferase (TPMT) genotyping confirmed a wild-type genotype, consistent with high enzymatic activity, supporting safe substitution of mycophenolate mofetil with azathioprine.

Imaging examinations

Post-transplant Doppler ultrasound demonstrated adequate graft perfusion without vascular or urological complications. Antenatal obstetric ultrasonography showed appropriate fetal growth, amniotic fluid index within normal limits, and no structural anomalies.

FINAL DIAGNOSIS

Based on clinical presentation, laboratory findings, genetic analysis, and post-transplant course, the final diagnosis was: Complement-mediated TMA associated with homozygous CFH exon 17 deletion and CFHR3-CFHR1 duplication. End-stage renal disease secondary to complement-mediated TMA. Successful live-donor kidney transplantation. Uncomplicated singleton pregnancy following renal transplantation.

TREATMENT

Transplant phase: Live-donor kidney transplantation (mother as donor) with induction using anti-thymocyte globulin (50 mg) and maintenance immunosuppression with tacrolimus, mycophenolate mofetil (MMF), and prednisolone.

Post-transplant modification: At 12 months, in preparation for conception, MMF was replaced with azathioprine following TPMT genotyping, which confirmed safe metabolism. Telmisartan was switched to nifedipine and labetalol.

Pregnancy phase: Tacrolimus levels maintained within target (4.3-7.0 ng/mL); gestational hypertension managed with nifedipine, labetalol, and amlodipine.

Polycythemia management: Therapeutic phlebotomy and telmisartan (later discontinued before conception).

OUTCOME AND FOLLOW-UP

Delivered a healthy female infant weighing 3 kg via elective lower segment caesarean section at 36 weeks of gestation.

Postpartum period complicated by transient hypertension, managed conservatively without need for medication escalation.

At six weeks and three months postpartum, both mother and infant remained clinically stable.

No evidence of graft dysfunction, recurrence of TMA, or infectious complications was observed.

Graft function preserved with stable serum creatinine, and both maternal and neonatal outcomes remained favorable at last follow-up.

Her post-transplant immunosuppressive regimen, fertility planning, antenatal surveillance, and maternal-neonatal outcomes are summarized in Table 1.

Table 1.

Clinical timeline and management course of the patient from renal transplantation to postpartum follow-up

Timepoint	Event	Details
Month 0	Renal transplantation	Underwent live-donor renal transplantation with her mother as the donor. Induction with anti-thymocyte globulin (50 mg) was administered; maintenance included tacrolimus, MMF, and prednisolone. Postoperative recovery was uneventful
Month 1	Graft stabilization	Serum creatinine remained stable. Doppler ultrasonography confirmed adequate perfusion. Tacrolimus trough levels rose from 8.95 ng/mL to 9.43 ng/mL (dose adjusted from 2.5 mg/day to 3.5 mg/day)
Month 4	Polycythemia	Developed secondary polycythemia, managed with therapeutic phlebotomy and telmisartan
Months 5-12	Maintenance phase	Graft function remained stable with no recurrence of TMA. Maintained on tacrolimus 1.5 mg twice daily (trough: 6.2-7.6 ng/mL)
Month 12	Pregnancy planning	Patient expressed desire for conception. MMF was replaced by azathioprine after TPMT genotyping confirmed high enzyme activity. Telmisartan was switched to nifedipine and labetalol. CMV and toxoplasma serologies were negative
Month 15	Conception	Spontaneous conception occurred within three months of immunosuppressive modification
2nd Trimester	Antenatal hypertension	Developed transient gestational hypertension, controlled with nifedipine, labetalol, and amlodipine. Tacrolimus levels ranged from 4.3 ng/mL to 7.0 ng/mL. No recurrence of TMA was observed
3rd trimester	Stable course	Laboratory parameters remained within normal limits. CMV PCR and toxoplasma results were negative. Experienced a mild self-limited upper respiratory tract infection
Week 36	Delivery	Delivered a healthy female infant (3.0 kg) via elective lower segment caesarean section
Postpartum	Recovery and follow-up	Experienced transient postpartum hypertension, managed conservatively. At six weeks and three months postpartum, both mother and infant were clinically stable; no graft dysfunction or relapse was noted

CMV: Cytomegalovirus; MMF: Mycophenolate mofetil; TPMT: Thiopurine methyltransferase; TMA: Thrombotic microangiopathy; PCR: Polymerase chain reaction.

DISCUSSION

Complement-mediated TMA encompasses a heterogenous group of disorders marked by overactivation of the alternative complement pathway and endothelial damage[1]. While aHUS is the best-characterized phenotype, structural variants within the CFH-CFHR gene cluster—particularly CFH exon deletions and CFHR1-CFHR3 duplications—represent a distinct subgroup[2].

These genetic changes may impair complement regulation through competitive binding or disruption of factor H function, placing carriers at latent risk that becomes clinically manifest only when triggered by immune stressors such as infection, pregnancy, or transplantation, consistent with the “second-hit” hypothesis[3-6]. Despite not fulfilling all aHUS diagnostic criteria, these patients remain at appreciable risk of complement-mediated injury, particularly in the post-transplant setting where endothelial stress and complement amplification co-exist.

Recurrence of complement-mediated TMA following renal transplantation is highly dependent on the specific complement abnormality. In patients with CFH mutations and anti-FH antibodies, recurrence rates may exceed 60%-80% in the absence of complement blockade[4]. In contrast, the risk in patients with CFHR1-CFHR3 duplications or deletions is not well defined, owing to their incomplete penetrance and heterogeneous expression. Valoti et al[14] provided mechanistic evidence that hybrid CFHR1/CFH fusion proteins antagonize factor H, thereby aggravating complement dysregulation and explaining variability in post-transplant clinical expression.

Nevertheless, these rearrangements are increasingly recognized as predisposing factors, especially in the setting of immune activation. The introduction of eculizumab has significantly altered the landscape of transplant outcomes in high-risk aHUS, with multiple studies, including those by Duval et al[5] and George et al[6], demonstrating a marked reduction in post-transplant recurrence when C5 inhibition is used prophylactically or at first signs of relapse.

Pregnancy further complicates management in complement-mediated disorders due to physiologic activation of the complement cascade, driven by hormonal shifts, placental development, and immune adaptation[10]. It is therefore regarded as a complement-amplifying condition, predisposing to new-onset or recurrent aHUS, as demonstrated by Michael et al[1] and Tarr et al[10]. Even in renal transplant recipients with previously stable grafts, the risk of pregnancy-related complications such as preeclampsia, preterm birth, and graft dysfunction remains significant[8,9,11]. Haninger-Vacariu et al[15] documented pregnancies in kidney transplant recipients with complement gene variant-mediated TMA, most of which were complicated by adverse maternal or graft outcomes, underscoring the rarity of favorable term pregnancies in this high-risk subgroup.

The patient achieved both successful renal transplantation and an uneventful term pregnancy in the absence of eculizumab, despite carrying a high-risk CFH-CFHR rearrangement. This outcome should be interpreted with caution: While it highlights the importance of risk stratification, immunologic stability, and meticulous follow-up, it remains exceptional and cannot be generalized to other contexts.

Duval et al[5] described a pregnant renal transplant recipient with aHUS maintained on lifelong eculizumab, illustrating the effectiveness of sustained complement inhibition in preventing relapse. By contrast, the present case adds to the limited literature on post-transplant pregnancies managed without eculizumab in high-risk genotypes, suggesting that relapse is not inevitable and may reflect individual complement dynamics[1,3,4].

Immunosuppressive management was a key determinant of this patient's favorable trajectory. MMF was replaced with azathioprine in accordance with reproductive guidelines and after confirming high TPMT activity and tacrolimus levels were maintained within target range[7]. These choices align with the American Society of Transplantation and KDIGO recommendations favouring azathioprine and CNIs in pregnancy[8,12]. Blood pressure was controlled with safe antihypertensives, even during transient gestational hypertension.

Importantly, the absence of preeclampsia in this case is striking. The reported incidence of preeclampsia in Renal transplant recipients ranges from 20% to 30%, significantly higher than in the general population (6%-8%)[8,9]. Despite complement dysregulation, she had an uneventful antenatal course, affirming that high-risk pregnancies can succeed with vigilant care[13].

Fertility restoration following transplantation, due to reactivation of the hypothalamic-pituitary-gonadal axis, is well documented[7]. However, conception should be deferred until at least one-year post-transplant and until graft function stabilizes — criteria strictly observed in this case[7]. Negative CMV and toxoplasma tests excluded other endothelial triggers[3]. A coordinated multidisciplinary team ensured structured monitoring.

This case has limitations that must be acknowledged. The follow-up period was limited to three months postpartum, preventing assessment of longer-term maternal, neonatal, and graft outcomes. In addition, the rarity of such favorable outcomes in patients with CFHR rearrangements emphasizes that this report should not be generalized to all contexts, particularly in resource-limited settings where access to complement inhibitors is constrained.

CONCLUSION

This case report underscores that favorable maternal and graft outcomes can be achieved in renal transplant recipients with genetically confirmed CFH-CFHR structural rearrangements, even in the absence of complement inhibition. The patient remained in sustained clinical remission and carried an uneventful term pregnancy, despite harboring a high-risk homozygous CFH exon 17 deletion with CFHR3-CFHR1 duplication. Such outcomes underscore the importance of genotype-informed counseling, immunosuppressive optimization, and rigorous multidisciplinary surveillance. Nevertheless, given the incomplete penetrance and heterogeneous clinical expression of CFHR variants, this experience must be regarded as exceptional. Broader validation through longer follow-up and larger cohorts is essential before generalizing these findings, but the present case adds valuable evidence to the sparse literature on pregnancy outcomes in transplant recipients with CFH-CFHR-mediated complement dysregulation.