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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
CASE REPORT  
Year : 2019  |  Volume : 30  |  Issue : 4  |  Page : 989-994
Everolimus worsening chronic proteinuria in patient with diabetic nephropathy post liver transplantation


1 Department of Medicine, Division of Nephrology, University of California Los Angeles David Geffen School of Medicine, Los Angeles, CA, USA
2 Department of Medicine, Division of Digestive Disease, Hepatology, University of California Los Angeles David Geffen School of Medicine, Los Angeles, CA, USA
3 Department of Pathology, Division of Renal Pathology, University of California Los Angeles David Geffen School of Medicine, Los Angeles, CA, USA
4 Department of Medicine, Division of Digestive Disease, Hepatology, University of California Los Angeles David Geffen School of Medicine; Department of Surgery, University of California Los Angeles David Geffen School of Medicine, Los Angeles, CA, USA

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Date of Submission15-Jul-2018
Date of Decision28-Aug-2018
Date of Acceptance29-Aug-2018
Date of Web Publication27-Aug-2019
 

   Abstract 


Mammalian target of rapamycin (mTOR) inhibitors are used in renal sparing protocols and transplant immunosuppression in patients with solid organ and stem cell transplants. They cause various side effects, including proteinuria, which is mediated by blockade of the vascular endothelial growth factor receptor pathway. There have been various reports of mTOR inhibitors causing proteinuria or worsening proteinuria form preexisting renal glomerulo-pathies. We report a 73-year old male with diabetic glomerulosclerosis, acute liver failure due to Budd-Chiari syndrome, chronic low platelets, and worsening proteinuria from 0.46 g protein/g creatinine to 2.2 g protein/g creatinine. Workup revealed no thrombotic microangiopathy through skin biopsy, and a renal biopsy confirmed only clinically suspected diabetic and hypertensive glomerulosclerosis and possible calcineurin inhibitors. On discontinuation of everolimus urine protein decreased back to 0.6 g/g creatinine. We review the mechanism of mTOR-induced proteinuria and how this may affect diabetic nephropathy secondarily. We also consider the clinical implications of this in transplant patients receiving these agents.

How to cite this article:
Hanna RM, Yanny B, Arman F, Barsoum M, Mikhail M, Al Baghdadi M, Rastogi A, Wallace W, Saab S. Everolimus worsening chronic proteinuria in patient with diabetic nephropathy post liver transplantation. Saudi J Kidney Dis Transpl 2019;30:989-94

How to cite this URL:
Hanna RM, Yanny B, Arman F, Barsoum M, Mikhail M, Al Baghdadi M, Rastogi A, Wallace W, Saab S. Everolimus worsening chronic proteinuria in patient with diabetic nephropathy post liver transplantation. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Sep 21];30:989-94. Available from: http://www.sjkdt.org/text.asp?2019/30/4/989/265481



   Introduction Top


Everolimus is an immunosuppressive agent used in the transplant setting and is classified as a mammalian target of rapamycin (mTOR) inhibitor.[1] These agents have used in onco-logic conditions as well due to the activity of the mTOR pathway in the uncontrolled proliferation seen in malignancies.[2] These agents are useful as immunosuppression in many cases, particularly as a renal sparing protocol in patients with renal disease and in patients with transplants who develop malignancies.[3] There are several concerning side effects attributed to this class of agents including poor wound healing, and proteinuria of some degree in 50% of patients.[4] This proteinuria is generally thought to be glomerular rather than tubular and is thought to be mediated by decreased signaling downstream from the vascular endothelial growth factor (VEGF) receptor pathway. The inhibition of mTOR signaling at the level of the podocytes probably triggers proteinuria.[4] The effect of mTOR inhibitors on the endothelial cells may be even more severe with several cases reporting the development of thrombotic micro-angiopathy (TMA) with the use of mTOR inhibitors.[5] Thus, both of the principal cell types that makeup the glomerulus can experience deleterious effects due to the administration of these agents. [Figure 1] shows a simplified scheme of how of the VEGF signaling pathway links to mTOR signaling and the effects of diabetes and various pharmacological agents on this pathway.
Figure 1: mTOR and VEGF signaling pathways.
DN: Diabetic nephropathy, JAK: Janus kinase, mTOR: Mammalian target of rapamycin, mAB: Monoclonal antibodies, PI3K: Phosphoinositide 3-kinase, Ras: Rat sarcoma protein, Raf: Rapidly accelerated fibrosarcoma protein, STAT: Signal transducer and activator of transcription proteins, TKI: Tyrosine kinase inhibitor, VEGF: Vascular endothelial growth factor, VEGFR: Vascular endothelial growth factor receptor.


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The interplay between diabetic nephropathy and VEGF signaling is not well described at this point. It is known that VEGF signaling can affect podocyte function in murine models of diabetic nephropathy.[6] Some animal studies of mouse models have suggested that VEGF inhibition may have some role in treating diabetic renal disease;[7] however, many case reports suggest that VEGF inhibitors and downstream inhibitors of this pathway clinically worsen proteinuria in human patients.[8],[9] This observation maybe due to the need for a physiologically exact dose of VEGF and downstream mTOR signaling. Pathology appears to occur with low-VEGF pathway signaling[10],[11] and high-VEGF pathway signa-ling,[7] both inducing proteinuria through different mechanisms. Whether VEGF blockade worsens diabetic kidney disease or merely causes an independent VEGF nephropathy is not currently known. Although the finding that long-term excess VEGF-A inhibition can result in podocytes loss may suggest a direct VEGF nephropathy is to blame.[11]

DN: Diabetic nephropathy, JAK: Janus kinase, mTOR: Mammalian target of rapamycin, mAB: Monoclonal antibodies, PI3K: Phosphoinositide 3-kinase, Ras: Rat sarcoma protein, Raf: Rapidly accelerated fibrosarcoma protein, STAT: Signal transducer and activator of transcription proteins, TKI: Tyrosine kinase inhibitor, VEGF: Vascular endothelial growth factor, VEGFR: Vascular endothelial growth factor receptor.

The interplay between agents that could affect targets downstream of the VEGF receptor is even less well known. We describe the effect of anti-VEGF agents upstream of mTOR inhibitors for this reason. There is one report,[8] which describes worsening of protei-nuria in a diabetic after the administration of one mTOR inhibitor (sirolimus) with the resolution of that proteinuria after switching to a different agent.[8] It follows from the above discussion that perhaps the “dose” of mTOR signaling can trigger mTOR-induced podo-cytes toxicity if signaling from the trophic VEGF pathway decreases below a minimum amount. We describe a case where a patient was noted to have rising proteinuria from his baseline level due to diabetic nephropathy after he was switched from mycophenolate to everolimus due to renal dysfunction. His proteinuria increased to 2 g/day and reverted to baseline after the patient was switched back to tacrolimus and mycophenolate. The renal biopsy did not demonstrate any evidence of podocyte loss or foot process effacement. Rather his biopsy showed diabetic glomerulo-sclerosis and calcineurin toxicity.


   Case Report Top


We report the case of a 73-year old male with acute hepatic failure due to hepatic vein thrombosis (Budd–Chiari syndrome) that was thought to be due to protein C deficiency. No other cause for the thrombophilia was found including negative testing for paroxysmal nocturnal hemoglobinuria. He had no other factors contributing to his liver failure, including cirrhosis, and his family history was only positive for Henoch–Schonlein purpura in his younger sister. The patient received a liver transplant was started on tacrolimus, myco-phenolic acid, and prednisone. He developed leukopenia and was switched to tacrolimus and everolimus (Dose-ranging from 2.5 mg TDS to 3 mg TDS) along with prednisone to increase his level of immunosuppression in setting of acute cellular rejection (ACR) of the hepatic allograft. The patient’s wife remembered that after this transition, the patient experienced much more swelling and fatigue than on the previous mycophenolate and tacrolimus-based regimen.

He presented to care at the University of California Los Angeles – Health system with worsening serum creatinine and worsening proteinuria. He was admitted to the hospital with anasarca, acute renal injury with serum creatinine rising from 1.6–2 mg/dL (pre- transplant creatinine was 1.18 mg/dL), and worsening proteinuria from a baseline of 0.46 g protein/g creatinine to 2–2.5 g protein/g creatinine (the baseline, pretransplant protei- nuria was around 0.279 g protein/g creatinine). The glycemic control level before switching to everolimus ranged from Hb A1C 5.6–6.7). He was worked up for TMA due to chronically low platelets, and this workup was negative, including a negative skin biopsy with terminal complement staining.[12] The skin biopsy occurred two months after everolimus was started and while the patient was still on the drug. His hepatic allograft remained functioning well, and a repeat liver biopsy was not needed during his episode of worsening renal function due to lack of evidence for ACR or humoral rejection (antibody-mediated rejection). Given that the skin biopsy did not disclose a TMA, and that liver allograft was functioning well, a decision was made by Scripps transplant hepatology to stop everolimus. The patient was then transitioned back to a low dose of mycophenolate with close monitoring for leukopenia, which did not occur.

The serum creatinine remained elevated at 22.5 despite stopping the everolimus, though the patient’s proteinuria decreased by greater than 50% back to the baseline of 0.5–1 g/g creatinine versus its peak of 2–2.5 g/g crea-tinine. [Figure 2] graph shows serum creatinine and urine protein to creatinine ratio after the patient was switched to everolimus and the resolution of the pathology after he was switched back to mycophenolic acid.
Figure 2: Graphs of trends of proteinuria and serum creatinine noted. Black arrow start of everolimus and red arrow stopping of everolimus.
: Skin biopsy, : Kidney biopsy.


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A renal biopsy demonstrated arterial and arteriolar nephrosclerosis with moderate tubulointerstitial scarring and focal segmental glomerulosclerosis plus mild acute tubular injury, no evidence of abnormal basement membranes or IgA deposits. These findings are most consistent with moderately severe hypertension and diabetic renal disease. There is only mild foot process effacement, and the lesion of focal segmental glomerular sclerosis is likely secondary to the hypertensive and diabetic disease. There may be a component of chronic calcineurin inhibitor toxicity; however, the characteristic arteriolar lesions of CNI toxicity are not seen on the biopsy. [Figure 3] shows the renal biopsy results.
Figure 3: (a) Diabetic glomerulosclerosis, focal and segmental sclerosis (black arrow), mild acute tubular injury (circled) without another glomerular disease. LM, H and E, 20, (b) EM: Mesangial expansion (white arrow) and lipid droplets (starred) suggestive of diabetic glomerulosclerosis, (c) EM: mildly thickened basement membrane due to diabetic nephropathy (black arrow), (d) Striped tubular atrophy (circled) (suggestive of chronic calcineurin inhibitor toxicity) and thick tubular basement membranes (suggestive of diabetes mellitus). The mesangium is also mildly expanded pointing to diabetic nephropathy.

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The patient’s proteinuria remained in his baseline range, and eventually, serum crea-tinine decreased down toward 2–2.2 mg/dL and remained in this range. This was elevated relative to his baseline and did not decrease with the withdrawal of mTOR inhibitor therapy. Ongoing workup did not reveal any obstructive etiology, and the renal biopsy was instrumental in determining that no other glomerular disease was going, save for the effect of increasing proteinuria of the mTOR inhibitor. No TMA was found on skin biopsy with terminal complement C5b–C9b staining or on the renal biopsy.


   Discussion Top


Our patient had proteinuria due to mTOR inhibition independent of his diabetic nephro-pathy. In the literature, it is clear that while inhibition of the VEGF pathway may modulate diabetic proteinuria in nonhuman mammals. It appears in humans or the less controlled clinical setting; these agents can induce their own glomerulopathy that results in nephrotic syndrome or TMA.[9],[10],[11] Ultimately, when the offending agent as identified clinically after excluding all other likely factors, it is removal lead to improvement in urine protein loss. This is an important finding as earlier reports discuss everolimus reversing proteinuria due to sirolimus. In this case, this suggests that ultimately the cumulative effect of VEGF and mTOR inhibition if excessive can trigger a nephropathy independent of the process of diabetic nephropathy. The fact that the renal biopsy did not show podocytes effacement or TMA may suggest that the effects on the podocytes maybe easy to miss clinically, especially when the disease is limited and mild (i.e., mild increase in proteinuria). Alternatively, the fact that almost 1 month elapsed between stopping the everolimus and the renal biopsy may have resulted in resolution of any additive renal pathology features that would have been found if the biopsy was performed earlier.

The toxicity of anti-VEGF agents, mTOR inhibitors, and tyrosine kinase inhibitors when given systemically is known but incompletely. The interaction of these agents with diabetic nephropathy clinically is not well known, and it is not known if diabetics are particularly susceptible to toxicity or not. It maybe that controlled in vivo models demonstrate protei-nuria amelioration due to more modest VEGF inhibition; but in cases of greater VEGF and mTOR inhibition podocytes loss, glomerular injury, and nephrotic syndrome results. These risks are also in addition to the known risks of TMA and atypical hemolytic uremic syndrome due to endothelial cell dysfunction caused by systemic VEGF and mTOR blockade. This should be considered in patients who present with proteinuria post initiation of everolimus.



 
   References Top

1.
Saran U, Foti M, Dufour JF. Cellular and molecular effects of the mTOR inhibitor everolimus. Clin Sci (Lond) 2015;129:895-914.  Back to cited text no. 1
    
2.
Xie J, Wang X, Proud CG. MTOR inhibitors in cancer therapy. F1000Res 2016;5(F1000 Faculty): 2078.  Back to cited text no. 2
    
3.
Gatault P, Lebranchu Y. Conversion to mTOR-inhibitor-based immunosuppression: Which patients and when? Transplant Res 2013;2:S3.  Back to cited text no. 3
    
4.
Letavernier E, Legendre C. MToR inhibitors-induced proteinuria: Mechanisms, significance, and management. Transplant Rev (Orlando) 2008;22:125-30.  Back to cited text no. 4
    
5.
Nava F, Cappelli G, Mori G, et al. Everolimus, cyclosporine, and thrombotic microangio-pathy: Clinical role and preventive tools in renal transplantation. Transplant Proc 2014;46: 2263-8.  Back to cited text no. 5
    
6.
Tufro A, Veron D. VEGF and podocytes in diabetic nephropathy. Semin Nephrol 2012;32: 385-93.  Back to cited text no. 6
    
7.
Cheng L, Chen J, Mao X. Everolimus vs. rapamycin for treating diabetic nephropathy in diabetic mouse model. J Huazhong Univ Sci Technolog Med Sci 2011;31:457.  Back to cited text no. 7
    
8.
Neau-Cransac M, Moreau K, Deminière C, Merville P, Saric J. Decrease in sirolimus-induced proteinuria after switch to everolimus in a liver transplant recipient with diabetic nephropathy. Transpl Int 2009;22:586-7.  Back to cited text no. 8
    
9.
Hanna RM, Lopez E, Wilson J, Barathan S, Cohen AH. Minimal change disease onset observed after bevacizumab administration. Clin Kidney J 2016;9:239-44.  Back to cited text no. 9
    
10.
Kim HW, Lim JH, Kim MY, et al. Long-term blockade of vascular endothelial growth factor receptor-2 aggravates the diabetic renal dysfunction associated with inactivation of the Akt/eNOS-NO axis. Nephrol Dial Transplant 2011;26:1173-88.  Back to cited text no. 10
    
11.
Baelde HJ, Eikmans M, Lappin DW, et al. Reduction of VEGF-A and CTGF expression in diabetic nephropathy is associated with podocyte loss. Kidney Int 2007;71:637-45.  Back to cited text no. 11
    
12.
12. Magro CM, Momtahen S, Mulvey JJ, Yassin AH, Kaplan RB, Laurence JC. Role of the skin biopsy in the diagnosis of atypical hemolytic uremic syndrome. Am J Dermatopathol 2015; 37:349-56.  Back to cited text no. 12
    

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Correspondence Address:
Ramy M Hanna
Department of Medicine, Division of Nephrology, University of California Los Angeles David Geffen School of Medicine, Los Angeles, CA 90095
USA
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DOI: 10.4103/1319-2442.265481

PMID: 31464262

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    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

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