Authors: David Brooker, Kalathil Sureshkumar, Khaled Nashar, Reem Daloul
Categories: Case Report, Kidney transplant, transplant kidney artery stenosis, nephrotic proteinuria, nephrotic syndrome, kidney artery stenosis
Source: Kidney Medicine
Authors: David Brooker, Kalathil Sureshkumar, Khaled Nashar, Reem Daloul
Transplant renal artery stenosis (TRAS) is a common vascular complication after kidney transplantation. It usually presents with worsening hypertension, fluid retention, and renal allograft dysfunction. Nephrotic range proteinuria has not been reported as a manifestation of TRAS, although renal artery stenosis (RAS) in native kidneys can cause heavy proteinuria. Here, we present the case of a 73-year-old female with history of chronic kidney disease from diabetic nephropathy. She developed renal allograft dysfunction associated with nephrotic range proteinuria of about 7 g/day 4 months after deceased donor kidney transplantation. Work-up for renal allograft dysfunction, including 2 kidney allograft biopsies and extensive serological evaluation was negative. Renal allograft Doppler ultrasonography revealed TRAS. The patient underwent percutaneous angioplasty with subsequent normalization of kidney function and improved proteinuria to 0.5 g/day. Three months later, the patient developed recurrent TRAS with worsening kidney function and increased proteinuria to 1.5 g/day. After repeat angioplasty, the proteinuria subsided to a level of about 0.2 g/day. She continued to have stable kidney function with serum creatinine in the 1.2-1.3 mg/dL and proteinuria in the 0.2-0.3 g/day range since then. We believe our case demonstrates that nephrotic range proteinuria could be a rare and unusual presentation of TRAS.
Nephrotic range proteinuria, defined as urinary protein excretion greater than 3.5 g/day, is usually a manifestation of a disease entity involving the renal glomeruli. It can be isolated or in the context of nephrotic syndrome (NS). Several primary kidney and systemic diseases can cause nephrotic range proteinuria with or without NS. In kidney transplant recipients, proteinuria decreases by 3 weeks after transplantation. Persistent or new proteinuria >3 g/day is associated with glomerular pathology, including chronic transplant glomerulopathy, recurrence of native glomerulonephritis, or de novo glomerulonephritis.1, 2, 3 Renal artery stenosis (RAS) is an unusual cause of heavy proteinuria and NS in native kidneys.4, 5, 6, 7 However, transplant renal artery stenosis (TRAS) has not been previously reported to cause nephrotic range proteinuria or NS. Here we present the case of a kidney transplant recipient who developed renal allograft dysfunction and nephrotic proteinuria after transplantation as a result of clinically significant TRAS.
A 73-year-old White female with a history of chronic kidney disease stage- IV presumed because of diabetic nephropathy, prolonged history of insulin dependent diabetes mellitus type 2 with diabetic retinopathy, and hypertension, underwent a preemptive deceased donor kidney transplantation. The donor was a 51-year-old female who died after cardiac death. The kidney donor profile index was 70%. Terminal donor serum creatinine (Scr) was 0.47 mg/dL. The donor had a history of hypertension but no diabetes. Procurement biopsy was not performed. The patient received induction with thymoglobulin followed by maintenance therapy with tacrolimus/mycophenolate mofetil and early steroid withdrawal. Her immediate posttransplant course was uncomplicated. Serum creatinine ranged 1.3-1.5 mg/dL. She had pretransplant sub-nephrotic proteinuria of 1.4 g, which improved to 0.37 g by 3 weeks posttransplant. Her blood pressure was well controlled on amlodipine 10 mg daily and carvedilol 12.5 mg twice a day.
Four months after transplant, she developed acute kidney injury with Scr peak of 5.2 mg/dL, significant peripheral edema, and worsening hypertension. Work-up showed a bland urinalysis with new nephrotic range proteinuria of 6.9 g/day. Her serum albumin was 2.5 g/dl consistent with nephrotic syndrome. Evaluation was negative for donor-specific antibodies, infections, and monoclonal gammopathy. Serologies were negative for ANA, ANCA, double-stranded DNA, and PLA2R antibodies with normal complement levels. Kidney allograft biopsy revealed acute tubular injury but no rejection, Fig 1. Immunofluorescence was negative. Electron microscopy was negative for transplant glomerulopathy and immune deposits with minimal segmental epithelial foot process effacement. Kidney transplant ultrasound (U/S) showed normal grayscale appearance of the renal allograft and increased peak systolic velocity (PSV) of 240 cm/second at the arterial anastomosis without significant gradient across the anastomosis. The echocardiogram revealed normal left and right ventricle size and function with normal pulmonary pressure.Figure 1First kidney biopsy. Trichrome stain shows acute tubular injury, minimal IFTA, no tubulointerstitial inflammation or rejection, and severe atherosclerosis.
The patient was initially treated with diuretics without improvement in renal allograft function. Elevated Scr in the 5-6 mg/dL range prevented therapy with renin-angiotensin-aldosterone system (RAAS) blockers. A repeat kidney allograft biopsy 2 weeks later showed persistent acute tubular injury without rejection, along with negative immunofluorescence and electron microscopy. Repeat renal transplant U/S showed worsening PSV to 314 cm/second. The finding of TRAS was initially deemed noncontributory to the patient’s condition due to clinical picture with nephrotic syndrome. However, because of persistent allograft dysfunction despite 2 negative allograft biopsies, the patient was referred to interventional radiology. She underwent carbon dioxide (CO2) angiogram, which revealed severe stenosis of the kidney transplant artery at the anastomosis with the external iliac artery, Fig 2A and B. Patient was treated with balloon angioplasty. Within weeks after treatment, renal allograft function improved back to a nadir Scr of 1.3 mg/dL, proteinuria decreased to 0.5 g/day, and blood pressure improved. Blood pressure medications decreased to low dose atenolol 25 mg daily only. Three months later, the patient developed worsening hypertension with systolic blood pressure in the 200s mm Hg, worsening proteinuria up to 1.5 g/day, and increased Scr to 2.3 mg/dL. Transplant kidney U/S was unremarkable aside from elevated PSV in the transplant artery with parvus tardus waveforms concerning for recurrent TRAS. The patient underwent a repeat CO2 angiogram with balloon angioplasty. After the intervention, proteinuria subsided to a level of 0.2-0.3 g/day, and Scr improved to 1.2-1.3 mg/dL. She continued to require 2 agents for blood pressure control. The patient has been stable with no further episodes of TRAS recurrence.Figure 2(A) Angiography demonstrating transplant renal artery stenosis (arrow). (B) Angiography demonstrating transplant renal artery after angioplasty (arrow).
Nephrotic range proteinuria is seen in up to 13% of kidney transplant recipients.^1^^,^^3^ Posttransplant proteinuria is associated with worse kidney allograft survival,^8^ and nephrotic range proteinuria carry even a worse prognosis. Common etiologies of nephrotic range proteinuria in kidney transplant recipients are chronic allograft glomerulopathy, recurrent native glomerular disease, and recurrence of diabetic nephropathy.^2^^,^^3^ Native kidneys’ RAS has been associated with nephrotic range proteinuria in case reports.4, 5, 6, 7 However, nephrotic range proteinuria as a manifestation of TRAS has not been previously reported.
TRAS is a well-recognized vascular complication post kidney transplantation with an incidence of 1% to 12%.^9^ This wide variation in incidence reflects the variable diagnostic criteria and imaging modalities used by different studies. TRAS is associated with 3 times higher risk for allograft loss.^10^ It can happen any time after kidney transplantation, but most commonly in the first 6 months posttransplant. The causes include donor derived atherosclerotic vascular disease, surgical technique, and trauma to the donor or recipient artery during procurement or transplantation. TRAS that happens years after kidney transplant most likely reflects recipient atherosclerotic disease involving either the kidney transplant artery or the adjacent iliac artery. Risk factors to TRAS include older recipient and donor age, delayed graft function, diabetes, and ischemic heart disease.^9^^,^^10^
Similar to RAS in native kidneys, TRAS usually results in the activation of the RAAS system, leading to sodium and fluid retention. Clinical manifestations include worsening or refractory hypertension, fluid retention, pulmonary edema, or allograft dysfunction.^11^ Our patient presented with the classical symptoms of worsening hypertension, edema, and renal allograft dysfunction without evidence of rejection or other pathologies on kidney transplant biopsy. However, the nephrotic range proteinuria muddled the clinical picture and delayed the correct diagnosis and management. The strong association between TRAS treatment and resolution of the nephrotic range proteinuria, followed by recurrence of proteinuria in the setting of recurrent TRAS, confirms the direct cause-effect relationship between TRAS and heavy proteinuria in our patient. The mechanism of how renal artery stenosis can induce heavy proteinuria is not entirely understood. In vitro mechanistic and animal studies have demonstrated that Angiotensin II (Ang II) can alter the permeability of the basement membrane and weaken the structural integrity of the slit diaphragm by multiple mechanisms, including direct podocyte injury, increased nephrin endocytosis, and increased glomerular capillary pressure.12, 13, 14, 15 These changes to the basement membrane result in glomerular proteinuria. Indeed, Ang II infusion in rat models leads to significant proteinuria.^16^^,^^17^ TRAS is a high renin-high angiotensin condition. The rapid resolution of proteinuria following deactivation of the RAAS system in our case report and other reports in native kidnyes,5, 6, 7 suggest that proteinuria in humans might also be mediated by Ang II effects on the glomerular basement membrane. However, Ang II-induced proteinuria appears related to changes to the glomerular basement membrane permeability and glomerular hemodynamics rather than permanent structural changes given normalization of proteinuria after treatment. In our patient, the kidney biopsy, including electron microscopy evaluation, did not show any histological changes such as secondary focal segmental glomerulosclerosis or diffuse foot process effacement.
Doppler ultrasonography is frequently the initial imaging modality in patients with clinical suspicion for TRAS giving its availability, low cost, and noninvasive nature. The definition and diagnostic criteria for TRAS per Doppler ultrasound vary widely among studies and institutions.^9^ A PSV > 250 cm/second is the most used criteria.^9^ Computed tomography angiogram or magnetic resonance angiograms are other screening techniques that could be deployed. Digital subtraction angiography (DSA) is considered the gold standard diagnostic test.^18^ Carbon dioxide digital subtraction angiography (CO2-DSA) has been suggested as a useful tool for the diagnosis of TRAS in patients with significant renal impairment.^19^^,^^20^ Indication for TRAS treatment depends mostly on clinical presentation. An incidental finding of TRAS on renal Doppler ultrasound without associated clinical symptoms such as renal allograft dysfunction or hypertension does not warrant an intervention and should be managed conservatively.^18^ On the contrary, patients with ultrasound findings suggestive of TRAS and consistent clinical presentation should undergo percutaneous transluminal angioplasty. In our patient, blood pressure control and allograft function improved following CO2-DSA and percutaneous transluminal angioplasty.
In summary, TRAS is a common vascular complication following kidney transplantation. Classical clinical presentation includes worsening hypertension, fluid retention, and renal allograft dysfunction. Nephrotic range proteinuria with or without NS could be a rare and unusual presentation. It is important to be aware of nephrotic proteinuria as a manifestation of TRAS to avoid delaying therapy or exposing the patient to unnecessary additional invasive procedures.