Pediatric Nephrology

, Volume 21, Issue 10, pp 1476–1479

Recurrence of proteinuria 10 years post-transplant in NPHS2-associated focal segmental glomerulosclerosis after conversion from cyclosporin A to sirolimus


    • Division of Pediatric NephrologyUniversity Children’s Hospital
  • Tanja Knüppel
    • Division of Pediatric NephrologyUniversity Children’s Hospital
  • Rüdiger Waldherr
    • Group Practice of Pathology
  • Franz Schaefer
    • Division of Pediatric NephrologyUniversity Children’s Hospital
  • Stefanie Weber
    • Division of Pediatric NephrologyUniversity Children’s Hospital
  • Burkhard Tönshoff
    • Division of Pediatric NephrologyUniversity Children’s Hospital
Brief Report

DOI: 10.1007/s00467-006-0148-9

Cite this article as:
Höcker, B., Knüppel, T., Waldherr, R. et al. Pediatr Nephrol (2006) 21: 1476. doi:10.1007/s00467-006-0148-9


Mutations in the NPHS2 gene, which encodes podocin, are associated with steroid-resistant nephrotic syndrome in childhood. Renal histology frequently presents focal segmental glomerulosclerosis (FSGS). Post-transplant recurrence of proteinuria in patients affected by homozygous or compound heterozygous NPHS2 mutation is encountered rarely (1–2%) compared to 30% recurrence in nonhereditary FSGS. We report on a pediatric kidney transplant recipient with NPHS2-associated nephrotic syndrome and FSGS, who developed biopsy-proven recurrence of FSGS 10 years post-transplant in temporal association with conversion from cyclosporin A (CsA)- to sirolimus (SRL)-based immunosuppression, due to histological evidence of severe CsA-induced nephrotoxicity. Reswitch of the immunosuppressive regimen from SRL to CsA led to a noticeable decrease of proteinuria and to stabilization of graft function. We conclude that patients with hereditary FSGS are not entirely protected from post-transplant recurrence of proteinuria, even in the long term. The close temporal relationship of FSGS recurrence with CsA withdrawal and conversion to SRL suggests that caution should be exercised in the use of CsA-free immunosuppression also in patients with NPHS2-associated FSGS.


Focal segmental glomerulosclerosisNPHS2 geneCyclosporin ASirolimusPodocinNephrotic syndromeProteinuria


Focal segmental glomerulosclerosis (FSGS) constitutes the underlying primary renal disease in approximately one-tenth of pediatric patients receiving kidney transplants. Recurrence of FSGS in renal allografts is observed in 20–30% of children and adolescents. The onset of proteinuria frequently falls into the first weeks after kidney transplantation [1]. Various pathogenic causes for recurrence of proteinuria have been discussed, especially an as yet unidentified proteinuric circulating factor, the production of which might follow T-cell dysfunction (reviewed in [2]). In the last decade, mutations in genes encoding podocyte proteins have been identified in different forms of hereditary FSGS. Large-scale multicenter studies demonstrated that patients with two pathogenic NPHS2 mutations bear a very low risk of recurring FSGS after renal transplantation, whereas those with only one mutation presumably run a risk comparable to non-NPHS2 FSGS patients (reviewed in [2]). The impact of different immunosuppressive regimens on the risk of post-transplant recurrence of proteinuria has been defined incompletely.

Case report

We report on an 18-year-old female patient who developed infantile steroid-resistant nephrotic syndrome at the age of 2 months. The initial renal biopsy showed minimal change glomerulonephritis in a total of 50 glomeruli. The patient was steroid-resistant to a 4-week course of prednisone [60 mg/m2 body surface area (BSA) per day] and responded only partially to cyclosporin A (CsA) over a 27-month period; however, renal function declined progressively. At that point in time, a second renal biopsy showed FSGS in 1 of 22 glomeruli. A recently performed NPHS2 mutation analysis revealed a frequently observed heterozygous mutation of exon 3 (R138Q) of NPHS2 and a heterozygous pathogenic splice-site mutation (IVS 4–1, G>T) before exon 5, proving genetically defined NPHS2-associated FSGS [2].

As a consequence of progressive renal failure, our patient had to undergo peritoneal dialysis for approximately 1 year. At the age of 7 years, she received a kidney allograft, her mother acting as living donor. Up to the present time her mother suffers neither from proteinuria nor renal dysfunction.

Initial immunosuppression consisted of antilymphocyte globulin, CsA, azathioprine, and methylprednisolone. Aside from one steroid-sensitive acute rejection episode, the post-transplant period passed uneventfully. In the ensuing years, her graft function remained stable with a glomerular filtration rate (GFR; estimated creatinine clearance according to the Schwartz formula [3]) of 90 ml/min per 1.73 m2 BSA, in the absence of proteinuria. Administering a mean CsA dose of 4.1±0.6 mg/kg per day enabled a trough level of 124±44 ng/ml to be achieved.

Ten years after renal transplantation, her GFR slowly dropped by nearly 35% to 58 ml/min per 1.73 m2, indicating graft function deterioration. Moreover, the patient developed progressive proteinuria of up to 1.3 g/m2 BSA per day (Fig. 1). Kidney allograft biopsy revealed severe arteriolar hyalinosis as well as focal interstitial fibrosis and tubular atrophy, indicative of calcineurin inhibitor (CNI)-induced nephrotoxicity. There was no existence of vascular or interstitial rejection, and C4d was negative along peritubular capillaries (Fig. 2a and b). Furthermore, no segmental glomerular sclerosis was detected in 15 glomeruli altogether. Since conversion from CNI- to sirolimus (SRL)-based immunosuppression is currently favored as a promising approach to treat renal transplant recipients with CNI-induced nephrotoxicity [4], the immunosuppressive regimen was switched from CsA to SRL, combined with mycophenolate mofetil (600 mg/m2 BSA daily) and methylprednisolone (4 mg/m2 BSA per day). A mean SRL dose of 2.4±0.5 mg/m2 per day was given to aim at SRL trough levels within the target range of 5–10 μg/l (mean 9.9±2.7 μg/l).
Fig. 1

Post-transplant course of GFR according to Schwartz (closed symbols) and urinary protein excretion (open triangles) in our patient in relation to different immunosuppressive regimens. Cyclosporin A doses and trough levels are expressed as mean values±standard deviation
Fig. 2

First renal allograft biopsy with severe nodular (transmural) hyaline arteriolopathy (a, Masson trichrome stain) and arteriolar deposits of IgM (b) on immunohistology. Original magnification ×160

After an initial increase to 72 ml/min per 1.73 m2, GFR dropped again to 50 ml/min per 1.73 m2 4 months after switch from CsA to SRL (Fig. 1). In addition, the patient developed recurrence of nephrotic syndrome, as indicated by pronounced proteinuria (10.7 g/m2 BSA per day) and hypoalbuminemia. A second kidney allograft biopsy showed segmental glomerular sclerosis in one of nine glomeruli, along with persisting lesions of chronic CNI-induced nephrotoxicity. There were no signs of rejection and C4d was still negative (Fig. 3a and b). Reswitch of the immunosuppressive regimen from SRL to CsA, 4 months after conversion to SRL, caused a remarkable decrease of proteinuria to 1.3 g/m2 BSA per day and an improvement of graft function (GFR 67 ml/min per 1.73 m2) (Fig. 1). At that point in time the permeability factor in our patient’s serum, measured by the method described in [5], turned out to be negative. During the depicted observation period the patient received no angiotensin-converting enzyme inhibitor. After reswitch of the immunosuppressive regimen from SRL to CsA, the patient was administered a mean CsA dose of 3.4±0.3 mg/kg per day; the mean CsA trough level amounted to 86±44 ng/ml.
Fig. 3

Second renal allograft biopsy with segmental hilar sclerosing lesion (a, PAS stain) and segmental nonspecific deposits of C3 on immunohistology (b). Original magnification ×160


The pathophysiology of FSGS recurrence in our patient is still unclear to date. One possible mechanism at work may be that increasing proteinuria as a sign of recurrent FSGS is a reflection of CsA withdrawal. On the one hand, CsA influences the immunologic system directly. It thus can be speculated that, in our particular case, SRL was insufficient to suppress immune activation and glomerular injury, leading to FSGS recurrence. This hypothesis is supported by a report from Skhiri et al. on an unusual post-transplant recurrence of unclassified FSGS in a 35-year-old kidney recipient of a living-related allograft, which resolved after CsA introduction, but did not respond to SRL [6]. On the other hand, CsA also leads to a reduction of proteinuria in nonimmunologic renal disease, such as Alport’s syndrome [7]. This has been attributed variably to the vasoconstrictive effect of CsA, an inhibition of vascular permeability factor production, and a modulation of lymphokine secretion [8]. Furthermore, recent experimental data indicate that podocytes are a direct target of CsA, implying that the beneficial effect of CsA on proteinuria results, at least in part, from the increased expression of synaptopodin, which in turn stabilizes the contractile apparatus of podocyte foot processes [9]. Therefore, the decline of proteinuria after reconversion of the immunosuppressive regimen to CsA in our patient may have resulted in part from nonimmunologic mechanisms such as vasoconstriction and/or stabilization of glomerular permeability secondary to CsA.

One might argue that CsA itself is responsible for the histological findings we gained in the second renal biopsy, since it is reported that a FSGS lesion can occur in the context of CsA administration [1012]. However, we feel that, while CsA nephrotoxicity is sometimes associated with morphological features of FSGS, the pronounced increase of proteinuria into the nephritic range, in temporal connection with CsA withdrawal and introduction of SRL, is consistent with the notion that the observed clinical results are not merely a consequence of CsA nephrotoxicity.

Interestingly, our patient shows two proven pathogenic NPHS2 mutations. The R138Q missense mutation constitutes a hotspot mutation that involves approximately 30% of all disease-associated alleles. The second mutation affects a 100% conserved splice site residue and therefore disturbs correct splicing mechanisms and subsequently protein synthesis. Recurrence of proteinuria post-transplant in patients with two pathogenic NPHS2 mutations happens rarely (approximately 1–2%) in contrast to 30% recurrence of proteinuria in non-genetically defined FSGS [2]. Hence, an additional immunological mechanism appears to be operative at least in some patients with NPHS2-associated FSGS. This hypothesis is supported by the report of Carraro et al., who observed the presence of a circulating factor enhancing glomerular permeability also in a few NPHS2-associated FSGS patients with post-transplant recurrence of proteinuria [5]. In our patient, the occurrence of nephrotic-range proteinuria in temporal association with CsA withdrawal speaks strongly for an immunological mechanism. However, the concentration of the permeability factor in our patient did not turn out to be elevated. Unfortunately, the measurement took place only after reintroduction of CsA. Hence, we cannot exclude that the circulating factor in our patient’s serum was positive during SRL treatment. We conclude that patients with hereditary FSGS are not entirely protected from post-transplant recurrence of proteinuria, also in the long run. Caution should be taken in hereditary FSGS when a CsA-free, SRL-based immunosuppressive regimen is considered. Although the temporally related response of proteinuria to reintroduction of CsA in our patient suggests an immune-mediated glomerular disease, the exact underlying mechanism at work remains to be clarified.

Copyright information

© IPNA 2006