Iliocaval Anomaly With Resulting Congestive Nephropathy: A Rare Etiology of Allograft Dysfunction Following Kidney Transplantation

ABSTRACT

Background

Renal allograft dysfunction warrants prompt investigation as the differential diagnosis is often broad. Here, we present a pediatric kidney transplant recipient who experienced suboptimal allograft function due to previously undiagnosed inferior vena cava stenosis with resultant chronic congestive nephropathy.

Methods

We retrospectively reviewed a pediatric kidney transplant case at our own institution, and a literature review of congestive nephropathy was performed.

Results

The patient, a 13‐year‐old male with end‐stage renal disease secondary to congenital renal dysplasia, underwent a preemptive living‐related‐donor kidney transplant. His postoperative course was complicated by the development of a lymphocele on posttransplant day 9, necessitating percutaneous drainage and the subsequent creation of a peritoneal window. Despite successful treatment of mild acute cellular rejection (as established by biopsy) and comprehensive evaluation to exclude alternative etiologies, his posttransplant kidney function remained suboptimal (calculated glomerular filtration rate around 40 mL/min/1.73 m²). Approximately 93 weeks posttransplant, he was found to have extensive venous thrombosis involving the iliocaval system and bilateral lower extremity deep veins. The patient underwent successful chemical thrombolysis and serial thrombectomy, resulting in a marked improvement in allograft function. Following thrombolysis, allograft function stabilized, suggesting that the underlying cause of persistent allograft dysfunction was chronic congestive nephropathy due to significant infrarenal inferior vena cava stenosis.

Conclusions

Iliocaval anomalies can contribute to unexplained kidney allograft dysfunction by causing chronic congestive nephropathy. Failure to recognize and address these anomalies may jeopardize graft function and heighten the risk of graft failure.

Abbreviations

BSA

body surface area

DSAs

donor specific antibodies

DVT

deep vein thrombosis

FSGS

focal segmental glomerulosclerosis

GFR

glomerular filtration rate

HLA

human leukocyte antigen

IVC

inferior vena cava

POD

postoperative day

1. Introduction

Allograft dysfunction is a common complication after kidney transplant, with an estimated incidence of 40% to 50% in the pediatric population [1, 2, 3]. Timely and accurate diagnosis is often challenging due to a broad differential [4]. Here we report a case of a pediatric kidney transplant recipient with suboptimal allograft function who was later found to have inferior vena cava (IVC) stenosis, leading to chronic congestive nephropathy and extensive venous thrombosis.

2. Case Representation

A 13‐year‐old male was referred for evaluation of preemptive kidney transplantation. His kidney disease was initially diagnosed at the age of 4, following symptoms of increased urinary frequency and nephrotic‐range proteinuria with normal serum albumin. Renal ultrasound revealed congenital renal dysplasia, and subsequent biopsy demonstrated secondary focal segmental glomerulosclerosis (FSGS). Genetic testing, including the Renasight Panel, did not identify any known pathogenic variants associated with congenital FSGS or other inherited kidney diseases. The patient was never treated for primary FSGS, as the pathologic changes were presumed to be secondary to congenital renal dysplasia.

At the time of transplant evaluation, the patient's calculated glomerular filtration rate (GFR) was 22 mL/min based on a nuclear renal function scan, with body surface area (BSA) correction yielding 27 mL/min/1.73 m². The urine protein‐to‐creatinine ratio was elevated at 7.56. The donor was the recipient's healthy, 50‐year‐old biological mother. The donor's nuclear renal function scan demonstrated a GFR of 128 mL/min, with BSA correction yielding 127.3 mL/min/1.73 m². There was no known family history of thrombosis.

Pre‐transplant tissue typing revealed 0% calculated panel reactive antibody but detected the presence of low‐risk human leukocyte antigen (HLA) DP6 antibody. The final crossmatch was negative. The recipient underwent induction therapy with anti‐thymocyte globulin and Solu‐MEDROL. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil, and a rapid steroid taper. The post‐operative creatinine nadir was 1.2 mg/dL.

At the time of the first outpatient follow‐up on postoperative day (POD) 9, the recipient's creatinine increased to 1.4 mg/dL. A renal ultrasound was performed and showed the development of a lymphocele. It was initially treated with percutaneous catheter drainage, but its persistently high output necessitated the creation of a laparoscopic peritoneal window on POD 24. Although the peri‐transplant fluid collection resolved, renal function remained suboptimal and intermittent nephrotic‐range proteinuria (urine protein‐to‐creatinine ratio of greater than 2 mg/mg) was observed (Figure 1). Extensive diagnostic evaluations were performed but were unrevealing throughout the first posttransplant year, as summarized in Table 1. Multiple biopsies were performed with evidence of borderline to Banff1A acute cellular rejection at POD 163, 194, and 339, with the absence of significant foot process effacement. Steroid therapy provided transient improvement in serum creatinine levels but failed to achieve complete normalization of renal function or resolution of proteinuria.

FIGURE 1.

Trends of posttransplant serum creatinine and urine protein/creatinine ratio. No urine sample was collected during the time period denoted by the dashed line. POD, postoperative day.

TABLE 1.

Timeline of post‐transplant treatment events.

Timeline	Events
Operative day	Kidney transplantation; living relative as the donor
+9 days	US: 16 × 9 × 9 cm peri‐transplant fluid collection, lymphocele
+21 days	Renal biopsy: No evidence of rejection. Absence of DSA
+24 days	Laparoscopic peritoneal window
+32 days	US: Small amount ascites. Normal transplant kidney
+42 days	Renal biopsy: Moderate epithelial foot process effacement. No evidence of rejection. Absence of DSA Treated with steroids
+60 days	NM MAG3 scan: Negative for obstruction
+72 days	Renal biopsy: Intact epithelial foot process. No evidence of rejection VCUG: Normal Tacrolimus pharmacokinetic study: Normal
+163 days	Renal biopsy: ACR, Banff 1A. Negative C4d. Absence of DSA. Treated with ATG (1 mg/kg) and steroids
+194 days	Renal biopsy: Borderline for ACR. Tubular injury was characterized by isometric vacuoles and Tamm‐Horsfall (uromodulin) protein extravasation. Absence of DSA. dd‐cfDNA < 0.18% NM MAG3 scan: Prolonged cortical uptake in transplant kidney Cystogram and retrograde pyelogram: No evidence of obstruction Tacrolimus was switched to envarsus and everolimus, due to concern of CNI toxicity
+235 days	Renal biopsy: Acute tubular injury, which might be secondary to hypoperfusion or nephrotoxic etiologies
+285 days	COVID test: Positive.
+311 days	Absence of DSA. dd‐cfDNA < 0.08%
+339 days	Renal biopsy: borderline ACR Treated with steroids
+396 days	Conversion to Belatacept
+408 days	Urodynamic study: Normal VCUG: Normal
+410 days	Right ankle swelling. Lower extremity duplex US was negative for superficial or deep vein thrombosis
+444 days	Renal biopsy: ACR, Banff 1A Treated with steroids
+469 days	Influenza A infection
+479 days	Left leg swelling. Left popliteal, posterior tibial, peroneal and soleal vein thrombosis on Lower extremity duplex US Hypercoagulation panel: negative Treated with apixaban for 3 months
+542 days	Right inguinal hydrocele was diagnosed at outside hospital US: normal transplant kidney with patent vasculature
+573 days	Worsened proteinuria with development lower extremity edema despite normal albumin (4 g/dL) Treated with rituximab and IVIG infusion. Belatacept stopped. Converted to cyclosporine and mycophenolate mofetil
+651 days	Significant back pain with right groin and right leg swelling Outside doppler US: questionable lower extremity thrombosis and unremarkable allograft study CT venogram: extensive clot burden in the inferior iliac vein, bilateral iliac veins and transplant renal vein Thrombolysis with serial mechanical thrombectomy
+711 days	MRA: patent inferior vena cava, bilateral common iliac veins, bilateral external iliac veins, bilateral internal iliac veins and right transplant renal vein

Abbreviations: ACR, acute cellular rejection; ATG, Anti‐thymocyte globulin; CNI, calcineurin inhibitor; CT, Computed tomography; dd‐cfDNA, donor‐derived cell‐free deoxyribonucleic acid; DSA, donor specific antibody; IVIG, intravenous immunoglobulin; MRA, Magnetic resonance angiography; NM MAG3 scan, Nuclear medicine renal flow and function mercaptoacetyltriglycine scan; US, ultrasound; VCUG, voiding cystourethrogram.

On POD 469, the patient developed significant cough and congestion secondary to influenza A but remained well‐hydrated. Renal‐dosed oseltamivir was initiated. Due to the acute illness, the patient was sedentary for several days. On POD 479, the patient presented to an outside emergency department with left calf pain. Ultrasound revealed extensive infra‐femoral deep vein thrombosis (DVT) in the left lower extremity. A transplant renal ultrasound was performed and was unremarkable. A thrombophilia panel was sent and returned negative. The patient was initiated on apixaban therapy for 3 months, after which repeat ultrasound demonstrated complete resolution of the left lower extremity DVT. On POD 542, the patient developed right groin pain and ultrasound showed a right inguinal hydrocele extending to the scrotum.

On POD 651, the patient presented to an outside emergency department with significant swelling in the right thigh and calf. A lower extremity Doppler ultrasound revealed abnormal flow but was inconclusive for DVT. His serum creatinine had risen to 4.48 mg/dL. Outside transplant kidney doppler ultrasound was overall unremarkable. Due to concerns for potential iliac vein or IVC thrombosis, the patient was transferred to our center. A CT venogram revealed an extensive clot burden involving the iliac veins (right greater than left), extending superiorly into the IVC up to just below the level of the native renal veins, with associated lumbar vein collateralization (Figure 2a,b). Additionally, the transplant renal vein was thrombosed from the hilum to its anastomosis with the right external iliac vein (Figure 2c).

FIGURE 2.

(a–f) Representative images before and after treatment of extensive venous thrombosis. (a) pretreatment CT coronal view showing extensive venous clot burden in the IVC and iliac veins (black arrows) and IVC narrowing at the level right below the native renal veins (white arrow); (b) 3D reconstruction of the vasculature prior to treatment, in which the IVC is absent but showing the entire right external iliac vein and proximal left external iliac vein with extensive lumbar vein collaterals (white arrows) and a patent distal left external iliac vein (white triangles); (c) pretreatment CT coronal view showing transplant renal vein thrombosis extending from hilum to the iliac vein anastomosis (black arrows); (d) patent IVC on venogram, post‐thrombolysis; (e) patent transplant kidney venous vasculature, post‐thrombolysis; (f) patent pelvic vasculatures on follow up magnetic resonance angiography 2 months post‐treatment. CT, computed tomography; IVC, inferior vena cava.

Urgent thrombolysis was performed, accompanied by serial aspirational and mechanical thrombectomy. Post‐procedural venography confirmed patency of the transplant renal vein, iliac veins, and IVC (Figure 2d,e) with brisk flow. A magnetic resonance angiogram conducted 2 months after thrombolysis demonstrated patent IVC, bilateral common and external iliac veins, visualized internal iliac veins, and the right transplant renal vein, with contrast opacification and lumbar collaterals (Figure 2f). His creatinine improved to the 2.0 mg/dL range, and proteinuria resolved at the 3‐month follow‐up check.

The patient and the family were understandably frustrated by the challenging clinical course but remained patient and maintained a positive attitude throughout the process. They expressed hope that this case presentation will help others in a similar situation in the future.

3. Discussion

Pediatric transplant candidates may present with congenital (e.g., venous occlusion, renovascular disease with midaortic syndrome) or iatrogenic (e.g., post‐cannulation) vascular anomalies [5, 6, 7]. While the population‐based incidence is unknown, successful pediatric kidney transplantation in recipients with known iliocaval anomalies has been reported, though such cases can pose significant technical challenges [8, 9, 10]. Accurate preoperative diagnosis and careful surgical planning are required, and the operation may require modification to use the native renal vein, portal vein, or collateral vessels for renovenous anastomosis. Undiagnosed iliocaval stenosis, which could lead to posttransplant venous outflow obstruction and thrombosis, has been described as a rare cause of delayed graft function in the adult kidney transplant literature [11, 12]. Here we present the first reported pediatric case of kidney allograft dysfunction secondary to IVC stenosis and chronic congestive nephropathy.

Our patient had a complicated posttransplant course with an early lymphocele that required percutaneous drainage. He also developed a significant right‐sided hydrocele at 18 months post‐transplant. Of note, the latter resolved spontaneously following intervention for the iliocaval abnormalities described above. It is conceivable that both the lymphocele and hydrocele occurred due to elevated venous pressures within the iliocaval system. Furthermore, it is plausible that the history of borderline/Banff 1A ACR may have contributed to his allograft dysfunction; however, his suboptimal creatinine level and proteinuria persisted despite follow‐up biopsies showing the absence of rejection and suggested an alternative, additive etiology. An extensive evaluation process was performed to rule out other causes of allograft dysfunction and was negative, as detailed in Table 1. The possibility of venous outflow obstruction was not on our differential initially due to features of a normal pretransplant vascular exam with strong femoral pulses bilaterally (in the absence of preoperative imaging), lack of clinical evidence for venous collateralization, and absence of hypercoagulability based on laboratory evaluation and clinical history.

Congestive nephropathy has been increasingly recognized as an underappreciated cause of renal insufficiency, which is characterized by a potentially reversible process caused by venous congestion and raised renal interstitial hydrostatic pressure [13]. Animal models have demonstrated the association between increased renal venous pressure and reduced sodium excretion, reduced GFR, and reduced renal blood flow [14]. Such findings have also been recently shown in patients with decompensated heart failure, where venous congestion is considered to be a more important hemodynamic factor driving renal dysfunction than impaired preload/perfusion [15, 16, 17]. Reversal of kidney function following the restoration of venous pressure to baseline levels has been observed in animal models; however, the results remain inconclusive in complex clinical settings. The extent of recovery may depend on the duration and severity of venous congestion [18]. Anatomical anomalies such as IVC stenosis/occlusion and deep vein thrombosis, which share an analogous pathophysiology to congestive nephropathy, are not uncommon among pediatric patients, especially among those with prior central venous cannulations [19, 20]. Unexplained allograft dysfunction after kidney transplant should prompt further imaging investigation to facilitate early treatment. In retrospect, venous outflow obstruction and impaired venous drainage may have contributed to the persistent high lymphocele output of our patient, which ultimately required the creation of a peritoneal window.

The acute thrombosis involving the iliocaval and lower extremity deep venous system is likely multifactorial. It is unclear whether the patient had congenital IVC stenosis or iatrogenic injury from prior central line insertion. His prior abdominal images were reviewed by radiologists, and there was no image or study that allowed satisfactory evaluation of the IVC, as all the studies were done without intravenous contrast. Examining the vena cava during routine graft Doppler ultrasound in cases of unexplained allograft dysfunction may provide additional diagnostic value and aid in identifying underlying vascular anomalies. We also reviewed his nuclear medicine renal flow and function mercaptoacetyltriglycine scan, which was more consistent with tubular injury, not outflow issues. But his immediate posttransplant computed tomography for lymphocele evaluation did show dilated azygous veins, which could be secondary to IVC anomaly. In addition, there was no history of central catheterization. However, several factors may have contributed to the thrombotic episodes: central vein stenosis with proximal turbulent flow, chronic inflammatory status in the setting of kidney transplant and immunosuppressive therapy, medication interactions, upper respiratory tract infections, and a moderately sedentary lifestyle. The patient had a COVID infection (POD 285), which is associated with an increased thrombotic risk. A procoagulant state following COVID infection has been identified in 75% of the patients at 3 months follow‐up, 50% at 6 months, and 30% at 12–18 months [21]. Influenza virus infection also increases thrombotic risk [22]. Our patient was not on anticoagulation medication before the first thrombotic event. Belatacept conversion (POD 396) was considered a potential triggering event, but this in isolation is unlikely to be solely responsible and, to our knowledge, has not been previously reported in the pediatric literature as a triggering event.

Proteinuria is another stronger predictor of allograft dysfunction and/or failure [23, 24]. As shown in Figure 1, the patient had persistent and gradually worsening proteinuria throughout his posttransplant course. This proteinuria was associated with new onset bilateral lower extremity edema but without hypoalbuminemia or conclusive histological data to support the degree of proteinuria observed. Given ongoing allograft dysfunction of unclear etiology, the care team gave one dose of rituximab (375 mg/m2) followed by intravenous immunoglobulin (1 g/kg) on POD 573–574 in case there was an underlying immune‐mediated cause of his allograft dysfunction that had not been revealed by biopsy or the many other evaluations performed during his clinical course. Notably, rituximab has been reported as a rare cause of thrombotic events [25]. However, the causality has not been well established in larger trials [26].

Our study is limited by the absence of pretransplant contrast imaging, as previously discussed, and the retrospective design of the case review.

4. Conclusion

Thorough evaluation of allograft dysfunction is crucial to timely and appropriate treatment after kidney transplantation. Although rejection is always a concern, the differential is broad. In this report, we present a pediatric renal transplant recipient with suboptimal renal allograft function secondary to IVC stenosis and congestive nephropathy. In this case report, none of the interventions prior to thrombolysis resulted in the resolution of his proteinuria and stability of the patient's allograft function to a creatinine of ~2.0 mg/dL. Congestive nephropathy in a transplant recipient is a rare disease entity but should be considered for refractory allograft dysfunction.

Consent

Informed consent for publication has been obtained from the legal guardian.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.