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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2011  |  Volume : 22  |  Issue : 5  |  Page : 1030-1032
Nitric oxide production as an indicator of recurrence of focal and segmental glomerulosclerosis following kidney transplantation

1 2nd Department of Propaedeutic Surgery, Athens University, Medical School, "Laiko" Hospital, Athens, Greece
2 Laboratory for Experimental Surgery and Surgical Research, Medical School, Athens University, Athens, Greece
3 Department of Nephrology, "Laiko" Hospital, Athens, Greece

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Date of Web Publication6-Sep-2011

How to cite this article:
Bellos JK, Perrea DN, Theodotopoulou E, Vlachos I, Kostakis AI. Nitric oxide production as an indicator of recurrence of focal and segmental glomerulosclerosis following kidney transplantation. Saudi J Kidney Dis Transpl 2011;22:1030-2

How to cite this URL:
Bellos JK, Perrea DN, Theodotopoulou E, Vlachos I, Kostakis AI. Nitric oxide production as an indicator of recurrence of focal and segmental glomerulosclerosis following kidney transplantation. Saudi J Kidney Dis Transpl [serial online] 2011 [cited 2022 May 25];22:1030-2. Available from: https://www.sjkdt.org/text.asp?2011/22/5/1030/84560
To the Editor,

Primary focal and segmental glomerulosclerosis (FSGS) is a clinicopathological syndrome that usually has an abrupt onset, with moderate to severe proteinuria, hypertension, steroid resistance, typical glomerular lesions and steady progress to end-stage renal disease. [1] FSGS is identified to be a disease associated with injury to glomerular podocytes. The etiology of the podocyte damage has not been clearly established. A circulating factor called the FSGS factor has been recognized as a possible etiologic factor. Moreover, it appears to be associated with recurrence of FSGS (rFSGS) after kidney transplantation (Tx) [2] , and the estimated frequency of recurrence varies from 20 to 30%. Nitric oxide (NO) is an important effector molecule of the inflammatory response. It is synthesized by mesangial cells and has been proposed to contribute to glomerular injury in various disease states. Accumulating evidence suggests that the induction of inducible isoform of NO synthase (iNOS) expression is likely to be mediated by cytokines, and local NO production might be involved in the initiation and/or progression of mesangial proliferative glomerulonephritis. [3] Also, studies have been conducted to investigate renal NO production in patients with the nephrotic syndrome. [4],[5] However, to our knowledge, there is no data correlating rFSGS and serum NO production after kidney Tx. Herewith, we report a patient with rFSGS who presented elevated NO serum levels a few days before the onset of proteinuria.

We studied the serum nitrite and nitrate (NOx) levels in 50 consecutive patients who had undergone living related kidney transplantation. The study was approved by the Ethical Committee and written informed consent was obtained from all patients. For the assay, whole blood was obtained from the peripheral vein in all subjects as follows: one day before surgery immediately after the hemodialysis session (NOx0), 30 minutes after kidney graft reperfusion (NOx1) and on days one (NOx2), five (NOx3) and 10 (NOx4) post-operatively. To measure NOx levels, the serum was separated by centrifugation at 5000 g for 10 minutes and was kept frozen at -80°C until analysis. Urinary cultures were also performed along with the NOx assays. Of the 50 patients who were enrolled in our study, six patients presented with acute rejection in the first post-Tx month and were excluded from further analysis. One female patient aged 41 years, whose primary disease was FSGS, presented with severe proteinuria (10.4 g/24 hours) on the 13 th post-Tx day. Even though the patient's NOx levels exhibited a progressive reduction during the first five days post-operatively (NOx1, NOx2, NOx3), a two-fold increase was observed on the 10 th (NOx4) post-Tx day (201.7%) ([Table 1], [Figure 1]). On the 15 th day after Tx, the patient underwent an allograft biopsy that contained 12 glomeruli with no apparent lesions, except for one globally sclerotic glomerulus. Immunofluorescence showed minimal staining for IgM globulin and C3 in tubular basement membranes. Electron microscopy was not available. The patient's immunosuppressive regimen consisted of sirolimus (SIR), tacrolimus (TAC) and methylprednisolone (MP). Based on our clinical protocol, the doses were: SIR 3 mg/day and TAC 0.05 mg/kg/day. A single shot of 500 mg of MP was given intra-operatively followed by 20 mg/day on day one and then gradually tapered. The TAC and SIR levels at regular measurements were within the normal range. The patient was treated with a course of multiple sessions of plasmapheresis, and showed partial response.
Figure 1: Serum NOx levels (μmol/L) (left vertical axis) in all uncomplicated patients and in the patient with recurrence of focal and segmental glomerulosclerosis during the first 10th days post-operatively.

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Table 1: Serial NOx measurements (μmol/L) in the study patient and the controls.

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Recurrence of severe FSGS in the renal allograft presents a major challenge to transplant physicians. The risk factors and characteristics of recurrence include a rapid progression of the primary disease to end-stage renal failure, early onset of nephrotic range proteinuria after renal transplantation, frequent loss of the allograft, a high frequency of recurrence in subsequent allografts and children less than 15 years of age. [6]

Although there are studies relating NOx levels with FSGS or the nephrotic syndrome, there is no data correlating rFSGS and serum NO production after kidney Tx. Fascinatingly, the serum NOx levels in the patient with rFSGS before Tx (NOx0) were higher than the mean levels of uncomplicated patients who had other causes of renal failure. This may reflect the NO status of the FSGS disease during the period before the Tx.

There are factors that are known to influence NO production in a transplant patient. Infections and surgical stress play a role in stimulating NO production, while some drugs (glucocorticoids, tacrolimus) inhibit NO production. None of our patients had a clinically apparent infection. Furthermore, urinary cultures, which were obtained at the time of NO measurement, were negative. All patients sustained the same amount of surgical stress, with no intra-operative complications. In addition, the post-operative course was uneventful. All patients received a living related kidney transplant. Ischemia time was practically the same between patients, as well as the operative time. All patients received the same immunosuppressive regimen. All blood samples were obtained after an overnight fast to ensure that NOx levels accurately reflect total body NO synthesis.

It has been suggested that proteinuria is the result of alteration of the glomerular permeability barrier by a circulating plasma factor. This factor, which has been partially identified as a protein, induces redistribution and loss of nephrin and podocin in podocytes. The removal of the circulating protein by plasmapheresis seems to have a favorable effect in reducing proteinuria. [2],[7] Also, it has been speculated that this factor, which is called the FSGS-factor, inhibits the synthesis of NO from L-arginine by blocking NO synthase (NOS). Thus, it antagonizes the anti-fibrotic effect of NO within the mesangium, resulting in progressive glomerulosclerosis. [7] A recent study in children suffering from sporadic FSGS showed elevated plasma levels of asymmetric dimethyl-arginine, [8] which is an endogenous inhibitor of all types of NOS. [9] However, our data shows elevated NO levels very early in the disease course before the clinical and laboratory findings of rFSGS. Therefore, the above data may suggest a different evolution of natural history of recurrence of the disease.

In conclusion, we found increased serum levels of NOx in rFSGS at least three days before the onset of proteinuria. This finding could be helpful in preventing the recurrence and early initiation of therapy with plasmapheresis, which has been shown to be effective in achieving remission of proteinuria and maintaining good graft function. [10] However, further studies are needed to establish the measurement of NOx serum levels as a routine post-transplant screening test for patients with FSGS.

   References Top

1.Schwartz MM, Korbet SM. Primary focal segmental glomerulosclerosis: pathology, histological variants, and pathogenesis. Am J Kidney Dis 1993;22(6):874-83.  Back to cited text no. 1
2.Savin VJ, Sharma R, Sharma M, et al. Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N Engl J Med 1996; 334(14):878-83.  Back to cited text no. 2
3.Kashem A, Endoh M, Yano N, Yamauchi F, Nomoto Y, Sakai H. Expression of inducible-NOS in human glomerulonephritis: the possible source is infiltrating monocytes/macro-phages. Kidney Int 1996;50:392-9.  Back to cited text no. 3
4.Trachtman H, Gauthier B, Frank R, Futterweit S, Goldstein A, Tomczak J. Increased urinary nitrite excretion in children with minimal change nephritic syndrome. J Pediatr 1996;128(2):173-6.  Back to cited text no. 4
5.Kawashima H, Kashiwagi Y, Watanabe C, et al. NOx (nitrite/nitrate) in patients with pediatric nephrotic syndrome. Pediatr Nephrol 2007;6:840-3.  Back to cited text no. 5
6.Crosson JC. Focal segmental glomerulosclerosis and renal transplantation. Transplant Proc 2007; 39:737-43.  Back to cited text no. 6
7.Trachtman H, Futterweit S, Singhal PC, et al. Circulating factor in patients with recurrent focal segmental glomerulosclerosis postrenal transplantation inhibits expression of inducible nitric oxide synthase and nitric oxide production by cultured rat mesangial cells. J Investig Med 1999; 47(3):114-20.  Back to cited text no. 7
8.Lücke T, Kanzelmeyer N, Chobanyan K, et al. Elevated asymmetric dimethylarginine (ADMA) and inverse correlation between circulating ADMA and glomerular filtration rate in children with sporadic focal segmental glomerulosclerosis (FSGS). Nephrol Dial Transplant 2008; 23(2):734-40.  Back to cited text no. 8
9.Tsikas D, Böger RH, Sandmann J, Bode-Böger SM, Frölich JC. Endogenous nitric oxide synthase inhibitors are responsible for the L-arginine paradox. FEBS Lett 2000;478(1-2):1-3.  Back to cited text no. 9
10.Pradhan M, Petro J, Palmer J, Meyers K, Baluarte HJ. Early use of plasmapheresis for recurrent post-transplant FSGS. Pediatr Nephrol 2003;9:934-8.  Back to cited text no. 10

Correspondence Address:
John K Bellos
2nd Department of Propaedeutic Surgery, Athens University, Medical School, "Laiko" Hospital, Athens
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Source of Support: None, Conflict of Interest: None

PMID: 21912042

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