We report 2 cases of posttransplant renal lymphangiectasia, a rare and poorly understood lymphatic disease associated with lymphatic vessel dilation and extracapsular lymphatic fluid leakage. Approximately 50 cases of renal lymphangiectasia have been reported in the literature.1 However, to our knowledge, no cases have been described in the context of a transplanted kidney or any other transplanted solid organ. The clinical presentation of renal lymphangiectasia includes ascites, abdominal pain, renal dysfunction, hypertension, hematuria, and proteinuria.2 Both our cases presented with severe, symptomatic ascites ultimately requiring allograft nephrectomy. The study followed the Declaration of Helsinki guidelines and was approved by the Institutional Ethics Committee.
METHODS AND RESULTS: CASE SERIES
A 12-year-old boy with end-stage renal disease secondary to cystinosis received a 4-year-old neurologic brain death donor renal transplant. After induction with basiliximab (Novartis, Basel, Switzerland), immunosuppression was maintained with tacrolimus, mycophenolate mofetil, and prednisone. Within the first 6 months, he had 2 episodes of Banff Grade I cellular rejection, both of which resolved with pulse steroids. He subsequently developed acute antibody-mediated rejection, requiring anti-CD20 monoclonal antibody in addition to intravenous immunoglobulin and plasmapheresis. His serum creatinine returned to baseline at 40 µmol/L. His comorbidities otherwise included hypertension, and central hypogonadism with arrested pubertal development.
Two years following his transplant, a perinephric fluid accumulation was incidentally identified on ultrasound. The allograft kidney appeared diffusely echogenic with poor corticomedullary differentiation and numerous subcapsular cysts, the largest of which was 2.5 × 2.0 cm. Contrast enhanced computed tomography of the abdomen was performed, which demonstrated a multitude of hypoattenuating peripheral cortical lesions and subcapsular fluid collections (Figure 1). He subsequently developed symptomatic abdominal ascites. On laparoscopic exploration, the subcapsular cysts were decorticated and marsupialized into the peritoneum. He was monitored closely and followed with serial ultrasounds.
During the next months, his ascites recurred and became increasingly symptomatic, requiring therapeutic paracentesis. Ascites fluid was transudative, nonchylous, and negative for both culture and cytology (creatinine 69 µmol/L, ERC 0.492, cell count: neutrophils 40% and lymphocytes 9%). Echocardiogram and hepatic ultrasound showed normal ventricular function and no portal hypertension, respectively. An MRI was negative for occult malignancy and there was no lymphadenopathy suggestive of posttransplant lymphoproliferative disease. The renal allograft was again shown to be enlarged (11.8 × 7.7 cm), with abnormal signal intensity pattern and perinephric and subcapsular fluid collections. A nuclear lymphangiogram was performed, which demonstrated allograft lymphatic tracer uptake and intraperitoneal tracer dispersion, but no specific site of leakage was identified. There was no evidence of leakage from the iliac lymphatics. The patient’s serum creatinine remained 60 µmol/L. It was concluded that the fluid was lymph originating from the allograft, in keeping with renal lymphangiectasia.
Frequent, high-volume paracentesis led to dehydration from inadequate fluid replacement. A peritoneal dialysis catheter was eventually placed to facilitate daily draining. The patient was transferred to our center and in 3 subsequent laparoscopic and open operative procedures, active secretion of fluid could be seen coming from open punctate areas on the surface of the allograft. Interconnection of the lymphatic spaces could be seen by direct methylene blue injection into one of the open holes (Figure 2). With all the open surfaces on the renal capsule identified, the exposed subcapsular tissue was ablated with the argon beam coagulator, and Tisseel (Baxter, Deerfield, IL) and BioGlue (CryoLife, Kennesaw, GA) were liberally applied to the kidney surface to seal leaks. These measures were successful in temporarily reducing fluid accumulation. However, these manoeuvres were only effective for 3–4 weeks, until symptomatic ascites would recur.
With worsening quality of life, the patient elected for allograft nephrectomy. Intraoperatively, there was a marked decrease in lymphatic fluid accumulation within the iliac fossa once the kidney was removed. Pathologic examination of the explanted kidney demonstrated diffuse subcapsular cystic changes (Figure 3). Postoperatively, there was complete and immediate resolution of his ascites. After 6 weeks of hemodialysis, he was eventually transitioned to peritoneal dialysis, and he has been reassessed and relisted for renal transplantation.
A 55-year-old female with end-stage renal disease secondary to microscopic polyangiitis received a pediatric en bloc renal transplant from a 4-month-old donation after circulatory death donor. No significant structural abnormality was noted at the time of surgery and the kidneys were transplanted into the retroperitoneal space. After induction with Thymoglobulin (Sanofi, Paris, France), immunosuppression was maintained with tacrolimus, mycophenolate mofetil, and prednisone. Serum creatinine stabilized at 70 µmol/L. She did subsequently develop ganciclovir-resistant cytomegalovirus viremia, managed with foscarnet, as well as Banff Grade II cellular rejection, controlled with Thymoglobulin and pulse steroids. Her total dose of Thymoglobulin in the first year was 8 mg/kg. Her comorbidities otherwise included hypothyroidism, hypertension, and hyperlipidemia.
Four years posttransplant, the patient presented with new onset ascites. There were no associated symptoms at the time and physical examination was otherwise unremarkable. Echocardiogram demonstrated normal ventricular function and hepatic ultrasound was negative for portal hypertension. Her CA-125 was mildly elevated at 95 U/mL; however, cytology from paracentesis was negative for ovarian malignancy. Renal function was stable with serum creatinine of 120–140 µmol/L. Renal ultrasound demonstrated diffuse, heterogeneous increased echogenicity of the renal parenchyma, as well as unusual curvilinear medullary fluid densities in both transplanted kidneys (Figure 4). Renal biopsy demonstrated chronic vasculopathy, but no evidence of acute rejection or polyoma infection.
The patient was taken for diagnostic laparoscopy. Small “punctate” fluid leaks were found around the transplanted kidneys, and intraoperative ultrasound identified multiple subcapsular pockets of fluid. The liver and ovaries appeared normal and there was no evidence of disease in the omentum or peritoneal surface. The appearance was consistent with that seen in case 1, and the leaks were ablated and sealed with Tisseel and BioGlue. Postoperatively, ascites recurred within 2 weeks and was managed with furosemide and by switching tacrolimus to sirolimus to decrease lymph production from the kidneys, as there had been a report of successful treatment of intestinal lymphangiectasia with mechanistic target of rapamycin (mTOR).3 Ultrasound-guided therapeutic paracentesis was also attempted to reduce ascites. Despite these efforts, the ascites continued to gradually worsen. She subsequently developed umbilical and incisional hernias from her laparoscopic ports secondary to accumulation of ascites.
Given the significant impact on the patient’s quality of life, she underwent an allograft nephrectomy with concurrent hernia repairs. The 2 transplant kidneys were soft, with a “sponge-like” texture. After allograft nephrectomy, without ligation of perivascular lymphatics, the lymphatic leaks resolved. Histologically, large cystic spaces were seen in the renal cortex (Figure 5). As her preoperative percent panel-reactive antibody was 70%, intravenous immune globulin was administered perioperatively to decrease the risk of further sensitization and facilitate potential retransplantation. She resumed hemodialysis and her ascites resolved immediately. Her percent panel-reactive antibody remains under 90%.
The development of lymphatic endothelial cell markers has elucidated lymphatic biology.4 Renal lymphatic capillaries are predominantly distributed around the interlobular and arcuate arteries of the cortex and drain into hilar collector vessels, while the medulla is generally devoid of lymphatics.5 The embryonal development of renal lymphatics is mediated by the dominant vascular endothelial growth factor receptor (VEGFR)-3/vascular endothelial growth factor (VEGF)-C axis, among other pathways.6 Lymphatic vessels are normally quiescent but de novo lymphangiogenesis may occur and is similarly driven by VEGFR-3/VEGF-C axis.7 In the context of renal transplantation, lymphatics are dissected without reanastomosis and the allograft has no immediate lymphatic drainage postoperatively. Lymphangiogenesis subsequently begins regenerating lymphatic connections within 3 days, approaching physiologic state at 2 weeks postoperatively.8
Lymphoceles, lymph-filled pseudocystic collections, are the most common lymphatic complication in renal transplantation, with reported incidences between 1% and 26% (mean 5.2%).9 The chief risk factor for lymphocele formation is dissection of large lymph vessels, donor or recipient, causing lymphatic leak.10 Acute rejection, which increases renal lymphatic flow, and mTOR inhibitors, which have an anti-lymphangiogenic effect, are also known to contribute to the development of lymphoceles.10
In contrast, renal lymphangiectasia is a rare disease whose precise pathophysiology is unknown, though it is thought to arise from miscommunication between the renal and retroperitoneal lymphatics. This results in an accumulation of lymphatic fluid, making the lymphatic vessels ectatic, dissecting the interstitium, and forming both parenchymal and perinephric collections.1 The miscommunication may be a congenital abnormality causing lymphatic malformation, or acquired secondary to trauma, infection, inflammation, scarring, or malignancy.1
Although the literature suggests that there may be a genetic predisposition to develop lymphangiectasia,11 we do not have any follow-up of the paired kidney from our first case, since these organs came from a different center and the fate of the second kidney is unknown. Interestingly, both our patients had pediatric donor kidneys and had severe rejection episodes requiring biologic therapy. Pediatric donor kidneys might be inherently more susceptible to developing lymphangiectasia following lymphatic dissection, because of interruption of ongoing lymphatic development. Currently, there is insufficient knowledge of the postnatal maturation of renal lymphatics to speculate specific mechanisms. Since early acute rejection has been associated with decreased lymph vessel density, a reduction of efferent lymphatic outflow tract may give rise to lymphangiectasia.12
In both our patients, the dominant clinical finding was severe, transudative, nonchylous ascites. Ultrasound findings included enlarged kidney size, increased renal echogenicity, altered corticomedullary differentiation, and anechoic multiseptated thin-walled fluid collections.13 Contrast-enhanced computed tomography further delineated the presence of hypodense (0–10 HU) parenchymal and perinephric cysts.2 These findings are well demonstrated in Figures 1 and 4. Histologically renal lymphangiectasia is characterized by cortical dilated endothelial-lined spaces, without glomerular or tubular abnormalities, as demonstrated in Figures 3 and 5.1 The spaces have been characterized to be positive for lymphatic endothelial immunomarkers, including D2-40.4 The medulla is spared, consistent with known renal lymphatic distribution.4 Histologically, this can be differentiated from autosomal dominant polycystic kidney disease, in which the cysts are lined by cuboidal or flattened epithelium (staining positive for cytokeratin markers) and simple cysts (cysts lined by a single layer of cuboidal, flattened, or atrophic epithelium).1
There is little precedent to guide the management of renal lymphangiectasia—most strategies are similar to those used for lymphoceles.10 Asymptomatic cases in native kidneys may simply be followed to monitor renal function. Small collections may similarly be amenable to percutaneous drainage. Areas of leaking and recurrent collections in the retroperitoneum may be marsupialized into the peritoneum, where fluid is better reabsorbed.13 This was attempted in our first case, but the high output overwhelmed the absorptive capacity of the peritoneum.14 Although ascites can be controlled with diuretics, both patients progressed to severe recalcitrant ascites, with significant impact on quality of life within 1 year of onset. We, therefore, further adopted a strategy of sclerosing and sealing the renal capsule and surface, which was found to be temporarily effective. However, we believe the volume and pressure of lymphatic leak precluded the long-term success with this strategy in these cases. Nephrectomy had been described for significant symptoms which are recurring or refractory13 and did completely resolve ascites in both our cases. Importantly, this indicates that lymphangiectasia is limited to the renal parenchyma and does not affect perinephric or retroperitoneal lymphatics.
Renal lymphangiectasia is a rare disease, even more so in the context of renal transplantation. Nonetheless, being a quaternary referral center, we have had experience with 2 such cases. The diagnosis of lymphangiectasia should be considered in renal transplant patients with ascites, after all other sources have been ruled out. Radiographic findings of subcapsular cystic collections in the kidney may help confirm the diagnosis. Renal lymphangiectasia with high output ascites may ultimately require treatment with allograft nephrectomy.
1. Bazari H, Attar EC, Dahl DM, et al. Case records of the massachusetts general hospital. Case 23-2010. A 49-year-old man with erythrocytosis, perinephric fluid collections, and renal failure. N Engl J Med. 2010; 363:463–475
2. Pandya VK, Shah MK, Gandhi SP, et al. Bilateral renal lymphangiectasia. J Clin Diagn Res. 2016; 10:TD01–TD02
3. Pollack SF, Geffrey AL, Thiele EA, et al. Primary intestinal lymphangiectasia treated with rapamycin in a child with tuberous sclerosis complex (TSC). Am J Med Genet A. 2015; 167A:2209–2212
4. Ishikawa Y, Akasaka Y, Kiguchi H, et al. The human renal lymphatics under normal and pathological conditions. Histopathology. 2006; 49:265–273
5. Wong BW, Zecchin A, García-Caballero M, et al. Emerging concepts in organ-specific lymphatic vessels and metabolic regulation of lymphatic development. Dev Cell. 2018; 45:289–301
6. Schulte-Merker S, Sabine A, Petrova TV. Lymphatic vascular morphogenesis in development, physiology, and disease. J Cell Biol. 2011; 193:607–618
7. Mäkinen T, Veikkola T, Mustjoki S, et al. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J. 2001; 20:4762–4773
8. Mobley JE, O’Dell RM. The role of lymphatics in renal transplantation. Renal lymphatic regeneration. J Surg Res. 1967; 7:231–233
9. Lucewicz A, Wong G, Lam VW, et al. Management of primary symptomatic lymphocele after kidney transplantation: a systematic review. Transplantation. 2011; 92:663–673
10. Ranghino A, Segoloni GP, Lasaponara F, et al. Lymphatic disorders after renal transplantation: new insights for an old complication. Clin Kidney J. 2015; 8:615–622
11. Meredith WT, Levine E, Ahlstrom NG, et al. Exacerbation of familial renal lymphangiomatosis during pregnancy. AJR Am J Roentgenol. 1988; 151:965–966
12. Stuht S, Gwinner W, Franz I, et al. Lymphatic neoangiogenesis in human renal allografts: results from sequential protocol biopsies. Am J Transplant. 2007; 7:377–384
13. Wani NA, Kosar T, Gojwari T, et al. Perinephric fluid collections due to renal lymphangiectasia. Am J Kidney Dis. 2011; 57:347–351
14. Flessner MF. Peritoneal transport physiology: insights from basic research. J Am Soc Nephrol. 1991; 2:122–135