Abstract
Introduction
Since 2016, kidney transplantation in patients with atypical hemolytic uremic syndrome (aHUS) in the Netherlands is performed without eculizumab prophylaxis. Eculizumab is given in case of posttransplant aHUS recurrence. Eculizumab therapy is monitored in the CUREiHUS study.
Methods
All participating kidney transplant patients who received eculizumab therapy for a suspected posttransplant aHUS recurrence were evaluated. Overall recurrence rate was monitored prospectively at Radboud University Medical Center.
Results
In the period from January 2016 until October 2020, we included 15 (12 females, 3 males; median age 42 years, range 24−66 years) patients with suspected aHUS recurrence after kidney transplantation in this study. The time interval to recurrence showed a bimodal distribution. Seven patients presented early after transplantation (median 3 months, range 0.3−8.8 months), with typical aHUS features: rapid loss of estimated glomerular filtration rate (eGFR) and laboratory signs of thrombotic microangiopathy (TMA). Eight patients presented late (median 46 months, range 18−69 months) after transplantation. Of these, only 3 patients had systemic TMA, whereas 5 patients presented with slowly deteriorating eGFR without systemic TMA. Treatment with eculizumab resulted in improvement or stabilization of eGFR in 14 patients. Eculizumab discontinuation was tried in 7 patients; however, it was successful only in 3. At the end of the follow-up (median 29 months, range 3–54 months after start of eculizumab), 6 patients had eGFR <30 ml/min per 1.73 m2. Graft loss had occurred in 3 of them. Overall, aHUS recurrence rate without eculizumab prophylaxis was 23%.
Conclusions
Rescue treatment of posttransplant aHUS recurrence is effective; however, some patients suffer from irreversible loss of kidney function, likely caused by delayed diagnosis and treatment and/or too aggressive discontinuation of eculizumab. Physicians should be aware that recurrence of aHUS can present without evidence of systemic TMA.
Keywords: atypical hemolytic uremic syndrome, eculizumab, kidney transplantation, thrombotic microangiopathy
Graphical abstract
In the pre-eculizumab era, approximately two-thirds of adult patients with aHUS progressed to end-stage renal disease after the first aHUS episode despite plasma therapy.1 Kidney transplantation was not considered an option because of high recurrence rate, often resulting in graft loss.2 The discovery of the role of complement in aHUS pathogenesis, and subsequently, the development of the complement C5 blocker, eculizumab, greatly improved the prospects for aHUS patients. Because of the expected risk of relapse, eculizumab was initially introduced as lifelong therapy. Currently, data suggest that therapy can be safely discontinued in selected patients with aHUS in native kidneys.3, 4, 5, 6 The optimal treatment strategy in patients with aHUS, who receive a kidney transplant, is debated. A Kidney Disease: Improving Global Outcomes consensus statement recommends prophylactic eculizumab therapy in aHUS patients with an estimated moderate or high risk of recurrence, and lifelong continuation of therapy.7 However, this advice is not based on evidence from randomized clinical trials. Retrospective studies have shown that eculizumab prophylaxis is safe, prevents aHUS relapse during treatment duration, and may improve allograft survival compared to posttransplant eculizumab therapy.8, 9, 10 We previously reported a low recurrence risk in patients with aHUS who were transplanted without eculizumab prophylaxis with a regimen that preferred the use of living donor kidneys and treatment directed at minimizing endothelial damage.11,12 In the Netherlands, the Dutch Health Care Institute conditionally approved eculizumab therapy, provided treatment was restrictive according a protocol developed by a Dutch national working group. According to the protocol, kidney transplant recipients are not routinely treated with eculizumab prophylaxis, but are administered eculizumab rescue therapy only when recurrent aHUS is suspected. Withdrawal of eculizumab should be considered after 3 months of therapy. Here, we report the outcome of patients who received eculizumab as treatment for posttransplant aHUS recurrence. Formal comparisons between strategies that are based on rescue therapy or on prophylactic therapy are lacking. When discussing risks and benefits of these strategies, recurrence rate is an important variable. Therefore, we analyzed recurrence rate in our ongoing cohort of patients with aHUS who are transplanted without eculizumab prophylaxis.11,12
Methods
CUREiHUS Study
Since 2016, patients with aHUS in the Netherlands are being treated with eculizumab according a restrictive strategy.3 aHUS recipients of a kidney transplant are not routinely treated with prophylactic eculizumab. Patients are preferably transplanted with a living donor kidney. A transplantation protocol aimed at reducing triggers of endothelial injury is advised.11 This includes induction therapy with anti-interleukin-2 antibodies, use of low-dose tacrolimus, use of mycophenolate mofetil with therapeutic drug monitoring, strict blood pressure control, with early introduction of an angiotensin-converting-enzyme inhibitor, and routine use of statins. After kidney transplantation, patients are closely monitored for aHUS recurrence. In patients with a suspected aHUS recurrence, treatment with eculizumab is started (rescue therapy). From 2016 to 2019, the standard eculizumab induction scheme was used (in all patients weighing ≥40 kg, 900 mg eculizumab weekly in weeks 1–4).13 From 2020 onwards, a weight-based dosing eculizumab induction regimen is being used.14 Maintenance therapy consists of biweekly 1200 mg of eculizumab. Meningococcal vaccination is advised in all aHUS patients before kidney transplantation. Patients who are unvaccinated receive meningococcal vaccination at start of eculizumab and are treated with antibiotic therapy for the first 2 weeks after vaccination.3
The CUREiHUS study was designed to monitor this treatment protocol. This national multicenter observational study was approved by the Medical Research Ethics Committee of Oost-Nederland (NL52817.091.15) in 2016. After written informed consent, all adult and pediatric patients who started treatment with eculizumab because of suspected aHUS (first episode or relapse) were included. Of note, the treatment protocol was based on the algorithm developed by a Dutch working group, and required to receive conditional approval from the Dutch Health Care Institute. Patients thus consented to data acquisition, no consent was needed for the treatment schedule. Because the study was observational, thus evaluating the outcome of patients treated according the protocol, there was no requirement for a data safety monitoring board.
We evaluated all patients who started eculizumab therapy because of suspected aHUS recurrence after kidney transplantation. The diagnosis of aHUS recurrence was made by the treating physician in consultation with members of the national aHUS working group. Eculizumab withdrawal was considered after at least 3 months in patients with stable or improved eGFR, in the absence of laboratory evidence of TMA and without concurrent active triggers of endothelial injury (e.g., calcineurin inhibitor [CNI] toxicity, ongoing rejection, and hypertension). Restart of eculizumab therapy by the treating physician was defined as suspected aHUS relapse. eGFR was calculated with the creatinine-based 2009 CKD-EPI formula. Laboratory evidence of TMA was defined by the presence of at least 2 of the following 3 criteria: (i) thrombocytopenia (platelet count <150 × 109/l), (ii) lactate dehydrogenase greater than the upper limit of normal (>250 U/l), and (iii) low haptoglobin (<0.3 mg/l). All reports of the kidney biopsies, which were performed after kidney transplantation, were blinded and reviewed by one of the researchers (JW) for signs of TMA and other etiologies of kidney injury. Histologic evidence of active TMA was defined as the presence of glomerular capillary, arterial, and/or arteriolar thrombosis. For all patients, the interval between first laboratory evidence of TMA and start of eculizumab was evaluated (if applicable). In addition, we evaluated the interval between the last stable serum creatinine (before decline of eGFR) and the start of eculizumab. In all patients, the rate of kidney function loss at the time of suspected recurrence and/or relapse was determined. Acute kidney disease was defined as increase in serum creatinine of ≥50%, which is known to have occurred within 3 months.
Values were expressed as absolute numbers and percentages for categorical variables, and as mean and SD or median and range for continuous variables. Statistical analyses were performed with SPSS version 25 (Armonk, NY) and figures were drawn using GraphPad Prism version 8 (Boston, MA).
Genetic analysis was routinely performed to screen for variants in complement genes.6 Genetic variants were classified as benign, likely benign, variant of uncertain significance, likely pathogenic, or pathogenic, following guidelines.15, 16
Recurrence Risk After Kidney Transplantation in aHUS Patients Without Eculizumab Prophylaxis
The CUREiHUS study did not include patients with aHUS without recurrence after kidney transplantation. Therefore, the risk of aHUS recurrence after kidney transplantation could not be assessed from CUREiHUS data. To estimate recurrence risk, a retrospective analysis of patients with aHUS who were transplanted between 2011 and 2020 at the Radboud University Medical Center was performed. Relevant data were obtained from medical records. Primary outcome was the incidence of aHUS recurrence after kidney transplantation. Similar definitions were used as described above. The need for informed consent for collection of data was waived by the local medical ethics committee for retrospective and anonymized data collection.
Results
During the period from January 2016 to October 2020, 15 kidney transplant recipients who received eculizumab because of a suspected aHUS recurrence were included in the CURiHUS study. The clinical characteristics are presented in Table 1. We observed a bimodal distribution of the time interval from transplantation until aHUS recurrence Table 3). In 7 patients, aHUS recurrence occurred early after kidney transplantation (median 3 months, range 0.3–8.8 months). This early onset of recurrent aHUS is in agreement with data from literature.2 In contrast, recurrence was diagnosed late after kidney transplantation in 8 patients (median time interval, 46 months; range 18–69 months). In view of these differences, the groups are described separately. The patient distribution and course after eculizumab therapy are illustrated in Supplementary Figure S1.
Table 1.
Clinical characteristics of the transplanted patients
| Patient | Age at Ktx / Gender | Previous history aHUS | Previous KTx | Type of kidney donor | Trigger before aHUS recurrence | CNI at aHUS recurrence |
|---|---|---|---|---|---|---|
| P1 | 66/F | No | No | LR | CNI toxicity | Discontinued before start of ECU |
| P2 | 50/F | Yes | Yes (1×), early recurrence of aHUS (1 wk), graft loss | LU | Type II TCMR (MPS) CMV reactivation Urosepsis |
Low-dose CNIa |
| P3 | 40/F | Yes | Yes (1×), early recurrence of aHUS (3.4 mo), graft loss | LU | n.a. | Low-dose CNI |
| P4 | 42/M | Yes | No | LU | Type IA TCMR (MPS, alemtuzumab) | Switched before start of ECU to mTOR |
| P5 | 41/F | Nob | No | DCD | ABMR (MPS, TPE, bortezomib, IVIG) | Low-dose CNI |
| P6 | 58/F | Yes | No | DBD | Pancreatitis | Low-dose CNI |
| P7 | 30/F | Yes | Yes (1×), early recurrence of aHUS (1 yr), graft loss | DBD | n.a. | Switched before start of ECU to belatacept |
| P8 | 54/M | Yes | No | LU | BKN TCMR (MPS) |
Low-dose CNI |
| P9 | 44/F | Nob | No | LR | n.a. | Switched before start of ECU to belatacept |
| P10 | 38/F | Nob | Yes (3×), no aHUS recurrence, graft loss | DBD | IVF treatment | Low-dose CNI |
| P11 | 30/M | Yes | No | LU | ABMR (MPS) | Low-dose CNI |
| P12 | 43/F | Yes | Yes (1×), early recurrence of aHUS (10.2 mo), graft loss | LU | ABMR | Low-dose CNI |
| P13 | 22/F | Nob | No | LR | Hypertension after discontinuation of ACEi | Discontinued before start of ECU |
| P14 | 24/F | Yes | No | LU | Pregnancy Norovirus infection |
Low-dose CNI |
| P15 | 46/F | Yes | Yes (1×), dubious recurrence of aHUS (19 yr), graft loss | LU | Influenza A infection | Low-dose CNI |
ABMR, antibody mediated rejection; ACEi, angiotensin-converting enzyme inhibitors; aHUS, atypical hemolytic uremic syndrome; CMV, cytomegalovirus; CNI, calcineurin inhibitors; DBD, donation after brain death; DCD, donation after circulatory death; ECU, eculizumab; F, female; IVIG, intravenous immunoglobulins; Ktx, kidney transplantation; LR, living related donor; LU, living unrelated donor; M, male; MPS, methylprednisolone; mTOR, mechanistic target of rapamycine inhibitors; n.a., not applicable; TCMR, T-cell mediated rejection; TPE, therapeutic plasma exchange.
Low dose CNI’s was defined as tacrolimus levels between 3 and 7 μg/l.
these patients presented at relative young age with hypertensive kidney disease, but were not formally diagnosed with aHUS before kidney transplantation.
Table 3.
Laboratory values and outcome of recurrence
| Patient | Interval Ktx–start ECU (mo) | Stable eGFR after Ktx (ml/min per 1.73 m2) | eGFR at start ECU (ml/min per 1.73 m2) | UPCR at recurrence (gr/10 mmol creatinine) | Hematuria at recurrence | Trombocytes (×10ꝰ/l) / LDH (U/l) / haptoglobin (g/l) at start ECU | Relapse | FU after Ktx/after recurrence (mo) | eGFR at end of study (ml/min per 1.73 m2) | UPCR at end of study (gr/10 mmol creatinine) | ECU therapy at end of study |
|---|---|---|---|---|---|---|---|---|---|---|---|
| P1 | 3.0 | 23.1 | 18.6 | Unknown | Trace | 184/324/0.87 | NRa | 9.6/6.7 | Graft loss. RRT | n.a. | No |
| P2 | 3.1 | 58.5 | 36.6 | 0.45 | None | 190/379/<0.20 | No | 39.9/36.9 | 46.6 | 0.29 | No |
| P3 | 2.2 | 70.3 | 33.4 | 0.31 | Trace | 124/427/<0.10 | Yes, restart ECU | 55.7/53.5 | 30.7 | 0.14 | Yes |
| P4 | 4.5 | 53.0 | 29.3 | 2.05 | Positive, not quantified | 86/410/2.18 | No | 35.2/30.7 | 40.2 | 0.17 | No |
| P5 | 0.6 | 21.7 | 22.4 | 2.27 | Unknown | 67/440/<0.10 | NRa | 33.4/32.8 | 12.1 | 4.09 | Yes |
| P6 | 0.3 | 46.1 | 23.2 | 2.40 | Unknown | 87/1767/<0.10 | n.a.b | 3.3/3.1 | 50.8 | 0.26 | Yes |
| P7 | 8.8 | 88.9 | 39.0 | 11.94 | 3+ | 209/351/<0.20 | Yes, restart ECU | 62.0/53.2 | 41.1 | 0.06 | Yes |
| P8 | 20.7 | 83.2 | 24.0 | 2.99 | None | 456/148/0.78 | n.a.b | 30.0/9.4 | 44.5 | 0.20 | No |
| P9 | 65.5 | 46.5 | 32.8 | Unknown | None | 257/206/1.10 | n.a.b | 82.1/16.6 | 42.7 | 0.27 | Yes |
| P10 | 46.3 | 37.4 | 18.3 | 0.96 | Trace | 261/344/1.75 | n.a.b | 49.3/2.9 | 20.3 | 0.78 | Yes |
| P11 | 45.6 | 54.3 | 39.7 | 0.91 | Unknown | 127/163/0.31 | n.a.b | 48.7/3.2 | 32.0 | 0.76 | No |
| P12 | 48.4 | 49.9 | 29.4 | Unknown | None | 310/213/1.60 | n.a.b | 71.6/23.2 | 28.4 | 0.45 | Yes |
| P13 | 69.0 | 47.1 | 3.8 | 0.50 | Unknown | 46/1688/<0.10 | Yes, restart ECU | 121.1/52.2 | Graft loss. second kidney transplant | n.a. | Yes |
| P14 | 43.5 | 81.5 | 60.1 | 6.63 | Trace | 108/210/<0.10 | No | 72.8/29.2 | 80.1 | 0.28 | No |
| P15 | 17.6 | 46.1 | 4.3 | 11.77 | None | 71/835/1.20 | Yes, intensivation ECUc | 62.3/44.7 | Graft loss. RRT | n.a. | No |
ECU, eculizumab; eGFR, estimated glomerular filtration rate (CKD-EPI); Ktx, kidney transplantation; n.a., not applicable; NR, nonresponder to eculizumab treatment; RRT, renal replacement therapy; UPCR, urine protein-creatinine ratio.
These patients did not respond to eculizumab therapy with recovery or stabilization of eGFR (nonresponders).
In these patients eculizumab was not tapered/withdrawn during the study duration or follow-up duration after tapering/withdrawal was insufficient (<3 months).
In this patient a relapse was observed during ongoing therapy with eculizumab at a prolonged dosing interval of 4 weeks. Free eculizumab levels were <50 ug/ml and CH50 was >10%. At diagnosis of relapse eculizumab therapy was intensified (dosing interval every 2 weeks, 1200 mg), resulting in adequate complement blockade.
Patients With Early aHUS Recurrence (Patient 1 to Patient 7)
There were 7 patients (P1−7; 6 females, 1 male) with early aHUS recurrence. Median age at transplantation was 42 years (range 30–66 years [Table 1]). All patients were at moderate or high risk of aHUS recurrence according Kidney Disease: Improving Global Outcomes guidelines. A genetic variant was detected in 6 patients, 5 patients had a diagnosis of aHUS at the time of kidney transplantation, and 3 patients had received a previous kidney transplant, all failed because of aHUS recurrence (Table 2). Possible triggers for aHUS recurrence was observed in 5 patients (Table 1) as follows: rejection (type II T-cell-mediated rejection in P2, type IA T-cell-mediated rejection in P4, antibody mediated rejection [ABMR] in P5), pancreatitis in P6, infection (cytomegalovirus reactivation and urosepsis) in P2, and CNI toxicity in P1.
Table 2.
Genetics of the transplanted patients
| Patient | Genetic variant | cDNA level (prot level) | Classification of genetic variant (class) | Homozygous MCP and/or CFH haplotypea | KDIGO risk stratification for recurrence after Tx |
|---|---|---|---|---|---|
| P1 | CFH | Het c.2872A>G (p.Lys958Glu) | VUS (III) | No | Moderate |
| P2 | CFI | Het c.454G>A (p.Val152Met) | Likely benign (II) | CFH haplotype | High |
| P3 | CFH | Het c.2034G>T (p.Trp678Cys) | Likely pathogenic (IV) | No | High |
| P4 | C3 | Het c.481C>T (p.Arg161Trp) | Pathogenic (V) | No | High |
| P5 | Negative | n.a. | n.a. | No | Moderate |
| P6 | CFH CFB |
Het c.1520-1G>A Het c.1697A>G (p.Glu566Ala) |
Likely pathogenic (IV) Likely benign (II) |
No | High |
| P7 | CFH-CFHR1 hybrid geneb | Likely pathogenic (V)b | No | High | |
| P8 | C3 CFB Homozygous CFHR3-1 deletion (FH AB negative) |
Het c.1774C>T (p.Arg592Trp) Het c.2024T>C (p.Val675Ala) |
Pathogenic (V) VUS (III) |
MCP haplotype | High |
| P9 | Negative | n.a. | n.a. | Noc | Moderate |
| P10 | Negative | n.a. | n.a. | No | Moderate |
| P11 | C3 | Het c.481C>T (p.Arg161Trp) | Pathogenic (V) | MCP haplotype | High |
| P12 | Negative | n.a. | n.a. | MCP haplotype | High |
| P13 | CFH | Het c.1548T>A (p.Asn516Lys) | VUS (III) | CFH haplotype | Moderate |
| P14 | CFH | Het c.1423T>C (p.Tyr475His) | VUS (III) | CFH haplotype | Moderate |
| P15 | C3 CFH |
Het c.26T>C (p.Leu9Pro) Het c.388G>A (p.Asp130Asn) |
VUS (III) VUS (III) |
No | Moderate |
C3, complement 3; cDNA, copyDNA; CFB, complement factor B; CFH, complement factor H; CFHR1, complement factor H-related protein 1; CFI, complement factor I; Het, heterozygous; MCP, membrane cofactor protein; n.a., not applicable; prot level, protein level; VUS, variant of uncertain significance.
The risk haplotype MCPggaac consists of homozygosity for c.−652A>G (rs2796267), c.−366A>G (rs2796268), c.IVS9−78G>A (rs1962149), c.IVS12+638G>A (rs859705), and c.4070T>C (rs7144). The risk haplotype CFH-H3 consist of homozygosity for c.-331C>T (rs3753394), c.2016A>G (rs3753396), and c.2808G>T (rs1065489).
Genomic analysis using MLPA identified a a heterozygous deletion of CFH-E23 up to and including CFHR1-E5 (official HGVS nomenclature): NC_000001.10:g.(196715167_196716320)_(196799888_196801005)del). This description is based on the last normal probe position (CFH-E22 probe: g.196715167), the first altered probe position (CFH-E23 probe: g.196716320), the last altered probe position (CFHR1-E5 probe: g.196799888) and the first normal probe position (CFHR1-E6 probe: g.196801005)16.
In this patient the MCP haplotype was not tested.
The eGFR course after kidney transplantation in the individual patients is illustrated in Supplementary Figure S2: 1 to 7. Five of 7 patients reached an eGFR of ≥45 ml/min per 1.73 m2 after transplantation. Two patients (P1 and P5) had poor recovery of graft function, with eGFR of 23 ml/min per 1.73 m2 and 22 ml/min per 1.73 m2, respectively. P1 was diagnosed with TMA because of CNI toxicity, CNI withdrawal resulted in apparent TMA response, however eGFR loss continued; P5 was diagnosed with severe ABMR, with persistent kidney dysfunction despite treatment with methylprednisolone, plasmapheresis, intravenous immunoglobulins (IVIG), and bortezomib.
At the time of diagnosis of aHUS recurrence, 6 patients presented with laboratory evidence of TMA (Table 3). In all 5 patients with eGFR >45 ml/min per 1.73 m2 after transplantation, serum creatinine increased ≥50% in a period of 2 to 59 days. A kidney biopsy was performed in 6 patients and showed evidence of TMA in all.
Eculizumab was started within 1 day (range 0−4 days) after detection of TMA parameters in the blood, and 14 days (range 2−59 days) after the last stable eGFR. In 6 patients (P2−P7), start of eculizumab was followed by resolution of TMA and improvement of eGFR (Supplementary Figure S2: 2–7). In P1, eculizumab therapy did not result in improvement of kidney function. In this patient, laboratory signs of TMA improved after withdrawal of CNI, without improvement of eGFR. A repeat biopsy taken after discontinuation of CNI, showed active TMA, without evidence of rejection. Eculizumab therapy (trough levels 66−211 μg/ml) was not successful. A third biopsy showed glomerulitis and peritubular capillaritis. Progressive kidney failure under eculizumab therapy was also seen in P5, explained by concomitant treatment resistant ABMR (Supplementary Figure S2: 1 and 5).
Eculizumab was discontinued in 4 patients (Table 3). In 2 patients (P2 and P4), eGFR has remained stable without evidence of relapse, with a follow-up of 27 and 23 months after withdrawal, respectively. Two patients (P3 and P7) developed a relapse of aHUS after withdrawal of eculizumab. Their clinical course is notable (Figure 1). In both patients, eGFR slowly decreased over a period of 10 to 16 months without obvious laboratory signs of TMA. A kidney biopsy performed because of this “creeping creatinine” disclosed subtle signs of TMA without rejection or other causes of eGFR decline. Reintroduction of eculizumab resulted in improvement (P7) or stabilization (P3) of eGFR, supporting underlying aHUS as cause of kidney function deterioration (Figure 1).
Figure 1.
eGFR course of patient 3 and 7. Eculizumab was administered at a dose of 1200 mg biweekly (gray bar), or at a dose of 1200 mg with an extended interval (hatched bar). P3 (previously known with aHUS) received a second kidney transplant from a living unrelated donor at the age of 40 years. The transplantation protocol consisted of TAC, MMF, prednisolone, and induction therapy with basiliximab. On day (d) 68 laboratory signs of TMA were seen (T 124 × 10ꝰ/l, haptoglobin <0.10 g/l, LDH 427 U/l). A biopsy (d68) showed active TMA without signs of rejection (C4d negative) and eculizumab was started. After 8.8 months, eculizumab was discontinued. Two months after withdrawal, a slow loss of eGFR was seen (1.7 ml/min per 1.73 m2 per month, over a period of 10 months). A kidney biopsy (d491) showed no abnormalities on light microscopy, but with electron microscopy (EM), a widened subendothelial lucent zone with platelet adhesion was seen. Despite discontinuation of tacrolimus, eGFR loss continued. A repeated kidney biopsy (d692) showed double contour formation of the GBM, with mild hyalinosis, and remnants of arteriolar thrombosis in the arterioles. C4d staining was negative. With EM, widening of the subendothelial zone with electron-lucent material was seen. Laboratory evaluation did not reveal consistent TMA signs. No increase in proteinuria (0.16 g/10 mmol) and no hematuria was observed. On d694 eculizumab was restarted, resulting in stabilization of eGFR. Treatment with eculizumab at extended dose interval targeting drug levels of 50−100 μg/ml was ongoing at last follow-up.
P7 (previously known with aHUS) received a second DBD kidney transplant at the age of 30 years. The transplantation protocol consisted of TAC, MMF, prednisolone, and induction therapy with alemtuzumab. On d209, a biopsy was performed because of proteinuria (urine protein-creatinine ratio 3.3 g/10 mmol). The biopsy showed no abnormalities but was relatively small. A second biopsy (d212) showed active TMA, without signs of rejection (C4d negative). Tacrolimus was switched to belatacept. Because of eGFR loss and ongoing proteinuria, a third biopsy (d265) was performed, showing again active TMA. On d267 laboratory signs of TMA were observed (T 209 × 10ꝰ/l, haptoglobin <0.20 g/l, LDH 351 U/l) and eculizumab was started. A reduction in proteinuria was seen (urine protein-creatinine ratio <0.20 g/10 mmol). After 9.1 months, eculizumab was discontinued. After withdrawal of eculizumab, a slow loss of eGFR was observed (1.9 ml/min per 1.73 m2 per month, over a period of 16 months). A biopsy (d1013) showed endothelial swelling without thrombi. C4d staining was negative. No EM was performed. There were no clinical signs of TMA, and no increase of proteinuria (0.07 g/l) or significant hematuria (1+). Eculizumab was restarted (d1030), resulting in improvement of eGFR. At last follow-up, the patient was still receiving treatment with eculizumab with an extended dose interval targeting drug levels of 50 to 100 μg/ml. eGFR, estimated glomerular filtration rate.
Patients With Late aHUS Recurrence (Patient 8 to Patient 15)
There were 8 patients (P8 to P15) with late aHUS recurrence (6 females and 2 males). Median age at transplantation was 41 years (range 24−55 years) (Table 1). All patients were considered to be at moderate or high risk for aHUS recurrence. A genetic variant was found in 5 patients. Five patients had a diagnosis of aHUS at the time of transplantation. Three patients had received a previous kidney transplantation, which had failed because of definite recurrence in one (Table 2).
All but one patient had eGFR >45 ml/min per 1.73 m2 after transplantation. In 1 patient, eGFR stabilized at 37 ml/min per 1.73 m2, which was considered acceptable in view of the donor characteristics (old age, donation after brainstem death donor). The clinical course of eGFR is illustrated in Supplementary Figure S3: 8 to 15.
Three patients (P13, P14, and P15) presented with typical “aHUS” features, characterized by acute kidney disease and laboratory evidence of TMA (confirmed by biopsy in P13, P15) (Table 3). Possible triggers for aHUS recurrence in these patients were pregnancy (P14, TMA starting in week 25), hypertension (P13, after withdrawal of enalapril while preparing for pregnancy), and severe heart failure with concurrent influenza A infection (P15) (Table 1). Eculizumab was started 0 to 5 days after detection of TMA in the blood, and resulted in disappearance of TMA and improvement in eGFR. In P14, eculizumab was stopped after child birth, with no evidence of recurrent disease during a follow-up of 29 months. In the other 2 patients, eculizumab was stopped or tapered (with incomplete complement blockade). In both, eculizumab was restarted because of suspected relapse, however eGFR deteriorated (details in Supplementary Figure S3: 13 and 15).
Five patients (P8−P12) presented without laboratory signs of TMA (Table 3). Three patients (P8, P9, and P10) had evidence of TMA in the kidney biopsy. A gradual deterioration of eGFR (0.7−1 ml/min per 1.73 m2 per month during a period of 19−26 months) was noted in 2 of them (P9 and P10). In the third patient (P8) aHUS recurrence was preceded by BK nephropathy and a rejection (for details, see Supplementary Appendix) and faster loss of eGFR was seen. These 3 patients responded to eculizumab therapy, with at least partial recovery of eGFR. In 2 patients (P11 and P12), the kidney biopsy showed evidence of ABMR and no signs of active TMA but some features of chronic TMA (thickening of capillary wall and subendothelial lucent zone). In these patients also, a gradual deterioration of eGFR was observed (2−3 ml/min per 1.73 m2 per month during a period of 5 to 11 months). In view of the original disease history, eculizumab was started and eGFR stabilized (details in Supplementary Figure S3: 11 and 12). At the time of database closure, eculizumab was discontinued in 2 patients (P8 and P11) with insufficient follow-up to draw conclusions on safety of withdrawal.
End of Follow-Up
At the end of follow-up (median 49 months, range 3−121 months after transplantation; and median 29 months, range 3–54 months after start of eculizumab), 3 of 15 patients had lost their graft (P1, P13, and P15) (Table 3). Median eGFR in patients with functioning grafts (n = 12) was 40.7 ml/min per 1.73 m2 (range 12−80), and urine protein-creatinine ratio was 0.28 g/10 mmol creatinine (range 0.06−4.1). Eculizumab was withdrawn in 7 patients, however, at last follow-up, only 3 patients (P2, P4, and P14) with preserved graft function and follow-up >12 months after eculizumab withdrawal were still off anticomplement therapy (27, 23, and 29 months of follow-up after discontinuation of eculizumab, respectively). No meningococcal infections were observed during the study period. Eculizumab therapy was associated with infusion related side effects (e.g., fatigue, malaise, and gastrointestinal complaints) in 3 patients.
Recurrence Risk After Kidney Transplantation in aHUS Patients Without Eculizumab Prophylaxis
During the period from 2011 to 2020, 26 patients with aHUS were transplanted in Radboud University Medical Center using a transplantation protocol aimed at reducing endothelial injury. Nineteen patients received a living donor kidney. Clinical characteristics are given in Supplementary Table S2. Four patients (4/19; 21%) developed aHUS recurrence and were treated with eculizumab (see above, P3, P4, P11, and P14). Of note, aHUS recurrence occurred early after transplantation in 2 patients (2/19, 11%). Seven patients received a deceased donor kidney. Of these, 2 (2/7; 29%) developed a recurrence, both early after kidney transplantation, for which eculizumab therapy was started (see above, P6; the second patient developed recurrence and was treated with eculizumab before the start of the CUREiHUS study). The overall 5 year graft survival in this cohort was 89%.
Discussion
The optimal treatment strategy of patients with aHUS after kidney transplantation is unknown. One option is the use of prophylactic therapy, in which eculizumab is started before kidney implantation and continued lifelong. Targeted rescue therapy is the alternative, in which eculizumab is started in patients who develop aHUS recurrence after transplantation. Evidence-based recommendations are lacking because of the absence of randomized controlled trials. Variables that should affect decision making include efficacy of rescue therapy (is TMA-induced kidney injury reversed and graft failure prevented?), risks of lifelong exposure to eculizumab (infections), and costs (eculizumab is very expensive, and is not affordable in some countries; kidney replacement therapy is expensive too; cost comparison will depend on the number-needed-to-treat).
A Kidney Disease: Improving Global Outcomes consensus report advises prophylactic therapy in patients at moderate or high risk of recurrence, which preferably should be continued lifelong.7 This advice is based on the expected high recurrence rate, which in the older literature averaged 60%.17 Lifelong therapy is proposed in view of the possibility of relapse after drug withdrawal.
We confirm our preliminary observations that recurrence rates are lower nowadays.12 In our cohort, including 26 patients with a median follow-up of 65.0 months (range 8−121 months), recurrence rate was 23%. Admittedly, we preferably performed living donor kidney transplantation, and the majority of the patients had a pathogenic variant in C3. Recurrence rate may be higher in patients with complement factor H mutations. Still, good outcome in deceased donor kidney transplantation was also reported by Noris and Remuzzi: no aHUS recurrence was seen in 7 patients (2 complement factor H variants, 2 CFI variants and 1 MCP variant), followed-up for a median of 28 months (range 4−41 months).18 The authors suggested that the lower recurrence rate may be explained by the transplantation protocol, which emphasizes low CNI dose, AUC-targeted mycophenolate mofetil dosing, and endothelial protection.18 Recurrence rate dictates the number-needed-to-treat. Using our data, 4 patients need lifelong eculizumab prophylaxis to prevent 1 recurrence; if prophylaxis was limited to 12 months, the number-needed-to-treat would be 6.5.
Our study provides data on the efficacy of targeted rescue therapy in 15 patients who started eculizumab at the time of suspected relapse. At first sight, one could draw conclusions that are seemingly contradictory, as follows: on one hand rescue treatment was effective, with disappearance of TMA and improvement of stabilization of eGFR in 14 patients; on the other hand, many patients had persistent kidney injury, at the end of follow-up 3 patients had developed kidney failure, and another 3 had severe kidney insufficiency with eGFR < 30 ml/min per 1.73 m2.
A more detailed analysis of the data may provide some explanation for these discrepancies. Ten patients had aHUS recurrence characterized by systemic TMA, developing either early after transplantation (n = 7) or late (n = 3), in the latter preceded by a well-known aHUS trigger. These patients mirror the typical presentation of aHUS recurrence as reported in literature, because in most studies, the presence of systemic TMA was required as inclusion criterium.10,19, 20, 21 In all but 1 of these patients (P1), an early diagnosis of recurrent aHUS was made and eculizumab was started within 0 to 5 days. TMA signs disappeared in all patients, and kidney function improved in 9 of 10 patients.
The short-term outcome in these patients confirms case reports and uncontrolled cohort studies, which provided evidence that rescue treatment is effective, with overall good outcome, provided treatment is started early after diagnosis.22, 23, 24, 25, 26, 27, 28, 29, 30, 31 Indeed, renal survival was good (5 year graft survival of 84%) in patients in a French cohort, in which eculizumab was started <7 days after aHUS recurrence, whereas survival was 70% in patient with eculizumab started >7 days, and 30% in patients not treated with eculizumab.10 Inferiority of rescue therapy was suggested in only 1 report, based on data derived from the industry-sponsored global aHUS registry.8 On comparing 88 patients treated with eculizumab prophylaxis and 52 patients treated with eculizumab posttransplant, there was no significant difference in graft survival (7.0% vs. 2.9%). However, eGFR at 2 year follow-up was markedly lower in patients who received eculizumab as rescue therapy (45 vs. 70 ml/min per 1.73 m2).8 The registry does not capture consecutive patients because inclusion in the aHUS registry is on the basis of physician preference and selection. In addition, no information is available on donor type, use of immunosuppressive drugs, rejection, or cause of graft failure. Detailed information on aHUS diagnosis, time to start of eculizumab therapy, concomitant rejections, and CNI toxicity is also lacking.8 Therefore, firm conclusions cannot be drawn.
In our cohort, there were 5 patients with a suspected relapse, occurring late after kidney transplantation and characterized by a rather indolent course without systemic signs of TMA and a slow deterioration of eGFR. Obviously, it can be questioned if these patients indeed suffered from recurrence of aHUS. The presentation may be rather unusual; however, we must realize that literature is skewed because many studies, by definition, only included patients with systemic TMA. We suggest that recurrent aHUS may present almost subclinically, merely manifested by a creeping creatinine, and histologic evidence of often chronic TMA. The best evidence is provided by patients 3 and 7. These patients were diagnosed with recurrent aHUS (with systemic TMA), successfully treated with eculizumab, but after eculizumab withdrawal, there was a slow but progressive increase in serum creatinine without laboratory evidence of TMA. Kidney biopsy showed subtle evidence of chronic TMA, and restart of eculizumab clearly reversed kidney injury. Similar cases can be found in literature.26,32, 33, 34 Treatment with eculizumab in the 5 patients with “localized” aHUS recurrence improved or stabilized eGFR, thus supporting the role of complement dysregulation in causing graft function loss. Still, we cannot prove that in our 5 patients, progressive kidney injury was the result of activity of aHUS. Most doubts may be raised in the 2 patients who were not diagnosed with aHUS before transplantation and thus presented with de novo TMA. According to a literature review by Garg et al. de novo TMA is observed in 3.5% of patients after kidney transplantation.317 Many causes can be discerned, such as ABMR, CNI toxicity, mTOR inhibitor toxicity, infections (e.g., cytomegalovirus), and anti-VEGF therapy. The authors conclude that TMA is often renal limited (“localized TMA”) without systemic manifestations. They suggest that in any patient with acute or chronic TMA, an underlying complement abnormality should be considered and complement studies should performed, especially in patients who are young, with unknown cause of end-stage renal disease, and/or evidence of TMA in a prior graft. Notably, whereas in 29% of patients with de novo systemic TMA after kidney transplantation mutations in complement regulatory proteins can be found,35 we are unaware of such information in a cohort of patients with late onset, localized TMA. In the patients with late onset of recurrent aHUS and “localized” TMA, the diagnosis of recurrent aHUS was often made late. Therefore, these patients already had kidney insufficiency at start of eculizumab therapy. In view of the severe kidney injury, early withdrawal of eculizumab was not attempted. Although our study lacks power, we suggest that late recurrence, longer period of eGFR loss before start of eculizumab and low eGFR at start of eculizumab are associated with eGFR <30 ml/min per 1.73 m2 at last follow-up (Supplementary Table S1).
Admittedly, although initial response to eculizumab rescue therapy was considered good, long term outcome in our patients was not acceptable. Three patients have lost the graft, and another 3 patients experienced severe loss of eGFR. Although in some patients, other factors contributed to kidney injury (e.g., ABMR, CNI toxicity, and recurrent pyelonephritis), in most patients, progressive kidney injury likely resulted from late diagnosis and/or early withdrawal of eculizumab. Although data are limited, we suggest that eculizumab withdrawal is associated with a higher relapse rate in patients after kidney transplantation when compared to patients with aHUS in native kidneys.6 We also caution that normal laboratory values do not exclude recurrence of aHUS (as described for patients 3 and 7).
Our study has limitations. The CUREiHUS study is not a randomized clinical trial, but an observational study designed to monitor daily practice of aHUS treatment in the Netherlands. The number of patients is small, and average follow-up after eculizumab withdrawal is <3 years. The diagnosis of recurrent aHUS was suspected, but cannot be considered proven in all patients.
It is evident that there is an unmet need for biomarkers that would guide diagnosis and treatment as follows: pretransplant predictors of recurrence, biomarkers that allow differentiation between recurrent aHUS and de novo TMA because of other causes, biomarkers that allow to predict relapse in patients treated without prophylaxis, and biomarkers that allow to suspect TMA as the cause of kidney injury in patients with creeping creatinine.
In conclusion, we cannot prove that a strategy of rescue therapy is noninferior to prophylactic therapy in patients with aHUS who receive a kidney transplant. However, our data suggest that rescue therapy is feasible, and able to maintain graft function in the majority of patients. As such, rescue therapy reduces health care costs. When considering rescue therapy, the following should be taken into account: eculizumab therapy should start whenever a recurrence aHUS is suspected; a recurrence of aHUS can present “subclinically,” only characterized by a slowly increasing serum creatinine, thus we suggest an aggressive kidney biopsy policy; in patients with suspected aHUS recurrence, alternative causes of “de novo TMA” must be excluded or treated, however this should not delay start of eculizumab; withdrawal of eculizumab should be considered very cautiously, if at all.
Disclosure
NvdK and JW received grant support from the Dutch Board of Health Insurance Companies to conduct the CUREiHUS study. NvdK received consultancy fees from Roche Pharmaceuticals and Novartis and is subinvestigator in APL2-C3G trial, Apellis. JW received consultancy fees from Alexion and Novartis. AB received consultancy fees from Novartis, is a member of the DSMB Zoster-047 trial, GSK, and a subinvestigator in the Belatacept study, BMS. VG and CD are subinvestigator in the APL2-G3G trial, Apellis. JW, NvdK, VG, MK, AB, SB, ED, JvdW, and AvZ are members of the European Reference Network for Rare Kidney Diseases (ERKNet)-Project No 739532. All other authors declare no conflict of (financial) interest.
Acknowledgments
We would like to thank all members of the Dutch aHUS working group for their participation and collaboration in the CUREiHUS study. We would like to thank Laura Baas and Andrei Sarlea for performing all laboratory analysis and dr. Elena Volokhina for supervision and interpretation of the laboratory data. At last, we thank all research nurses and database managers for their important local management and data collection: Yvet Kroeze, Nienke Sonneveld, Dorien Standaar, Marja van Dijk, Judith Veen, Helma Dolmans, Katinka van Linschoten-Schinkel, Caro Fonkert, Maud van den Brocke, Inger Kunnekes.
Funding
This work was supported by research grants from the Netherlands Organization for Health Research and Development(ZonMw), “Goed Gebruik Geneesmiddelen” (projectnumber: 836031008) and the Dutch Board of Health Insurance Companies (Zorgverzekeraars Nederland). They did not have any role in data collection, analysis, or submission of this manuscript.
Author Contributions
NvdK, JW, and KW designed the study. All data were collected and monitored by CD and RB. Laboratory and genetic results were evaluated by LvdH. All remaining data were analyzed, and the manuscript drafted by CD, under critical supervision and review of JW. Recruitment and inclusion of patients and local study and clinical management were done by all members of the national aHUS working group. All authors read, commented on, and revised the manuscript before approval.
Footnotes
Figure S1. Patient distribution and course after eculizumab.
Figure S2. eGFR course of patients with early aHUS recurrence.
Figure S3. eGFR course of patients with late aHUS recurrence.
Table S1. Characteristics of patients (N = 15) with CKD stage ≤3 and stage ≥4 at end of the CUREiHUS study.
Table S2. Clinical characteristics of patients transplanted at Radboud University Medical Center (2011−2020) without the use of eculizumab prophylaxis.
Contributor Information
Caroline Duineveld, Email: caroline.duineveld@radboudumc.nl.
the Dutch aHUS Working Group:
A.D. van Zuijlen, Dr.SP. Berger, F.J. Bemelman, J.W. van der Heijden, J. van de Wetering, A.P.J. de Vries, J.F.M. Wetzels, J.A.E. van Wijk, A.H.M. Bouts, E.M. Dorresteijn, V. Gracchi, F.A.P.T. Horuz-Engels, M.G. Keijzer-Veen, R.W.G. van Rooij, N.C.A.J. van de Kar, and L.P. van den Heuvel
Appendix
Dutch aHUS Working Group Collaborators
Members of the Dutch aHUS working group are: Dr. AD van Zuijlen, Department of Nephrology, University Medical Center Utrecht, Utrecht; Dr. SP Berger, Department of Nephrology, University Medical Center Groningen, Groningen; Prof. Dr. FJ Bemelman, Department of Nephrology, Amsterdam University Medical Center, Amsterdam; Dr. JW van der Heijden, Department of Nephrology, Amsterdam University Medical Center, Amsterdam; Dr. J. van de Wetering, Department of Nephrology, Erasmus Medical Center, Rotterdam; Dr. APJ de Vries, Department of Nephrology, Leiden University Medical Center, Leiden; Prof. Dr. JFM Wetzels, Department of Nephrology, Radboud University Medical Center, Nijmegen; Dr. JAE van Wijk, Department of Pediatric Nephrology, Amsterdam University Medical Center, Amsterdam; Dr. AHM Bouts, Department of Pediatric Nephrology, Amsterdam University Medical Center, Amsterdam; Drs. EM Dorresteijn, Department of Pediatric Nephrology, Sophia Children’s Hospital, Erasmus Medical Center, Rotterdam; Drs. V Gracchi, Department of Pediatric Nephrology, University Medical Center Groningen, Groningen; Dr. FAPT Horuz-Engels, Department of Pediatric Nephrology, Maastricht University Medical Center, Maastricht; Dr. MG Keijzer-Veen, Department of Pediatric Nephrology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht; Dr. RWG van Rooij, Department of Pediatric Nephrology, Leiden University Medical Center, Leiden; Prof. Dr. NCAJ van de Kar, Department of Pediatric Nephrology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, and Prof. Dr. LP van den Heuvel, Department of Laboratory Medicine, Department of Pediatric Nephrology, Amalia Children’s Hospital, Radboud University Medical Center.
Supplementary Material
Figure S1. Patient distribution and course after eculizumab.
Figure S2. eGFR course of patients with early aHUS recurrence.
Figure S3. eGFR course of patients with late aHUS recurrence.
Table S1. Characteristics of patients (N = 15) with CKD stage ≤3 and stage ≥4 at end of the CUREiHUS study.
Table S2. Clinical characteristics of patients transplanted at Radboud University Medical Center (2011−2020) without the use of eculizumab prophylaxis.
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