Case 5 -
Chronic Transplant Glomerulopathy
Lillian W. Gaber
The Methodist Hospital
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A 63-year-old female, with past medical history of arthritis, elevated uric acid, anemia, HTN, anxiety
and panic attacks was first seen in 1987, at age 40 for renal dysfunction ( Scr 1.7mg/dl), Proteinuria
(700 mg/24 hr), and hematuria.
The patient had slow progression to end stage kidney disease. At the time when transplant work up was
initiated in 2002 her 24 hour urine collection had 7.0 gm of protein.
She underwent a kidney transplant from a living unrelated donor in 2002. Post transplant Immune
suppression consisted of prednisone, Cellcept and Neoral, which was later switched to Prograf in 2003.
Post transplant renal function was generally stable (baseline serum creatinine around 1.3 mg/dl). She
had fluctuations in renal function attributed to calcineurin nephrotoxicity that responded to adjustments
of immune suppression medications.
Proteinuria (urine protein/creatinine ratio of 1) was first detected in 2002, and slowly progressed
over the following 7 years to nephrotic range proteinuria. The patient refused to undergo diagnostic
Finally, the patient consented to a kidney biopsy to investigate nephrotic range proteinuria in 2009.
The entire biopsy was submitted for light microscopy evaluation. A priority to light microscopic
evaluation for this biopsy was decided because the primary diagnosis given was to rule out rejection and
adequacy of the renal cortical sample could not be determined on the gross evaluation of the biopsy.
Up to 20 glomeruli were present in the sample. The most prominent finding in the biopsy was
thickening of the wall of blood vessels. Blood vessel wall thickening was observed in both the large and
the small arteries and was related to the deposition of strongly PAS-positive material. This material
was rather pale eosinophilic and amorphous in H&E stained sections. Focal expansion of the
peri-hilar mesangium by these deposits was noted in two glomeruli. There was marked sclerosis of the
large intra renal arteries. Congo-red staining revealed a wide spread positive reaction for amyloid
protein in the blood vessels. It was characterized by salmon colored tissue deposits that gave an apple
green birefringent signal upon polarization. In contrast to the diffuse vascular deposition, glomerular
involvement was patchy and mild. Global glomerulosclerosis was severe. One glomerulus exhibited focal
sclerosis with localized accumulation of foam cells in the glomerular capillaries. The few open or
partially open glomeruli showed mesangial matrix expansion, an increase in cellularity, and focal double
contours. Interstitial fibrosis was patchy and of moderate grade, which appeared disproportionately
attenuated compared to the extent of glomerulosclerosis
Immunostaining for Kappa and Lambda light chains showed the intra-renal amyloid deposits to be
monoclonal for Kappa light chain Immunostaining for C4d and BK virus was negative.
Immunofluorescence evaluation was not preformed.
A portion of the paraffin-embedded biopsy material was re-processed for evaluation by electron
microscopy. Despite artifacts caused by suboptimal processing, there was a notable and widespread
expansion of the lamina interna rara of the glomerular basement membrane associated with frequent
mesangial interposition and with matrix increase. Mesangial matrix was enlarged and replaced in many
areas by a very coarsely granular material. Non branching fibers characteristic of amyloid could not be
found in the examined glomerulus. Electron dense deposits were not seen.
The renal biopsy results triggered aggressive evaluation of the patient for multiple myeloma. While
the SPEP and UPEP were initially negative, she had an abnormal free Kappa/Lambda ratio of 6.2. A bone
marrow biopsy revealed 15% plasma cells and the serum Beta 2 microglobulin level was 20 mg/dl.
Accordingly the patient was diagnosed with stage III multiple myeloma, and received chemotherapy.
The serum creatinine remained stable over a follow up period of 7 month. The urinary protein
excretion had decreased from the time of biopsy, but remained in the nephrotic range.
This patient presented with post transplant proteinuria which started by the end of the first year
post transplantation, reached nephrotic range by year 3, and continued to slowly progress over the
following 4 years when, finally, a biopsy was obtained.
The etiology of proteinuria in this patient is probably multifactorial. Proteinuria could have been
caused initially by a slowly progressive chronic transplant glomerulopathy, and then accentuated by the
involvement of the transplanted kidney by novo light chain deposition nephropathy secondary to multiple
myeloma. The patient had no evidence of antibody mediated renal injury i.e. Biopsy was C4d negative and
patient had no DSA.
Post transplant proteinuria is frequent among kidney transplant recipients, with varied prevalence
rates depending on the cut off values used to define the condition. The etiology of post transplant
proteinuria is influenced by whether proteinuria is persistent or transient, and by the time of its
onset. Early and mild proteinuria, with protein excretion rates less than 500 mg/24 hours, is a frequent
finding that occurs in about 45% of the kidney transplant recipients. A large number of these patients
have defective tubular absorption or podocyte dysfunctions, which result in protein leakage. These
abnormalities are usually caused by ischemic acute tubular injury or by drug induced nephrotoxicity e.g.
calcineurin inhibitors and sirolimus use. This type of Proteinuia is transient, and is usually reversed
by treatment of the cause. In contrast, persistent nephrotic or subnephrotic- range proteinuria is
usually a manifestation of glomerular pathology. Persistent post transplant proteinuria has low
prevalence estimated at about 7% to 13%, and is associated with high rates of graft loss. The major
pathological findings in kidney transplant recipients that develop nephrotic range proteinuria can be
grouped into two large categories; one is chronic allograft nephropathy/injury and the second is
glomerulonephritis. In one series of 73 patients with post transplant nephrotic syndrome, 31 (42%)
patients had biopsy proven chronic allograft nephropathy with most of these 31 biopsies demonstrating
associated non specific chronic injury and glomerulosclerosis. Lesions of chronic transplant
glomerulopathy (CTG) were additionally seen in one fourth of the patients with chronic allograft
nephropathy. In that same series, 43 patients were diagnosed with glomerulonephritis as the cause for
nephrotic syndrome, 36% of whom had recurrent glomerular disease, 43% had de novo glomerular disease, and
in 21% the etiology of the glomerulonephritis was undetermined.
Chronic transplant glomerulopathy is a histopathological entity with distinctive light microscopic and
ultra structural features. Central to the pathology of CTG is the duplication of the glomerular basement
membranes, which is best illustrated by PAS or silver staining of histological sections. Electron
microscopy shows a characteristic expansion of the sub endothelial layer by flocculent material.
Mesangial interposition contributes, to a lesser extent, to the capillary wall double contour. Along
with capillary wall thickening there is a variable increase in glomerular matrix, an increase or decrease
in glomerular cellularity, glomerular tuft enlargement and hypertrophy of the podocytes with
intra-cytoplasmic packing of protein transport droplets. All of these changes ultimately lead to
progressive sclerosis of the glomerular tuft. Clinically CTG is characterized by severe proteinuria and
progressive deterioration of graft function. Antibody mediated graft injury plays a major role in the
pathogenesis of CTG in a subset of patients. These patients show evidence of antibody mediated
micorvascular injury such as; multilayering of the basal lamina of the peritubular capillaries and GBM
thickening, capillaritis, glomerulitis, intragraft C4d deposition, the presence of DSA, and of a history
of previous antibody mediated rejection. Emerging studies indicate the association of conditions that
induce endothelial damage and a thrombotic microangiopathy with CTG. A List of these conditions now
includes; HCV infection, CMV infection, and nephrotoxicity induced by use of calcineurin inhibitors or
Similar to CTG, chronic allograft injury is clinically characterized by progressive deterioration of
graft function, proteinuria and hypertension. The elimination of the generic term chronic allograft
nephropathy (CAN) and its replacement by the description of chronic allograft injury was recommended at
the Banff 2005 conference. The recommendation was based on the lack of specificity of the pathologic
lesions and the ambiguity in defining this syndrome. The pathogenesis of chronic allograft injury could
be related to immune mediated or non immune-dependent mechanisms. Chronic antibody mediated rejection is
diagnosed when interstitial fibrosis and tubular atrophy are associated with one or more of these
features: CTG, chronic micorvascular injury, C4d intragraft deposition, and the presence of DSA.
Chronic T cell mediated rejection is suspected in grafts that display evidence of tubulitis along with
thickening of the elastic layer of the blood vessels, fibrous intimal hyperplasia and variable
inflammation in the intima all features of chronic transplant Vasculopathy. A long list of non-immune
mediated conditions can also cause chronic allograft injury or exacerbate an immune injury. Causes of
non immune chronic allograft injury include donor factors such as senescence, nephrosclerosis, donor
vasculopathy, or recipient diseases such as hypertension, diabetes, hyperlipidemia, and the metabolic
syndrome. Other non immune causes of chronic injury include insults unique to the allografts such as
exposure to nephrotoxins, viral infections, and reflux nephropathy.
In the patient presented here with chronic graft injury and chronic transplant glomerulopathy the
etiology is unlikely to be immunologic due to lack of specific features of either an antibody induced
micorvascular injury or an inflammatory pathology. The patient had several events of renal dysfunction
in the early post transplant courses that were felt clinically to be due to calcineurin inhibitor
nephrotoxicity. Based on the case history, the possibility of recurrent glomerulonephritis could not be
completely discarded, but in the meantime is difficult to prove because of the absence of tissue
diagnosis of the primary glomerulonephritis in the native kidney, the advanced stage of glomerular
scarring, and the absence of immunofluorescence studies in the transplant biopsy.
Monotypic Kappa amyloid nephropathy in renal allograft is a rare event, with only a handful of cases
reported in the literature. The pattern of histopathological abnormalities in this case was also unusual
as the arterial involvement was dominant to the glomerular involvement and the patient had no apparent
monoclonal gammopathy by traditional urine and serum testing. Tissue biopsy in the work of proteinuria ,
even as late a biopsy as this case was, are quiet important and may provide results that benefit the
practicing physician. In this case, the biopsy results initiated a comprehensive diagnostic and staging
- Kidney biopsies should be pursued for comprehensive
evaluation of patients with persistent nephrotic range proteinuria. A diagnosis of chronic allograft
nephropathy should not be assumed for patients with progressive deterioration of renal function and
- Pertinent clinical history and a differential
clinical diagnosis should be provided at the time of biopsy in order to direct tissue allocation for the
different renal biopsy studies
- This case demonstrates the complexity of the
pathogenesis of chronic allograft nephropathy, and the diagnostic importance of renal allograft biopsies
even during late episodes of graft dysfunction
- There is a potential discrepancy between measured
renal functional parameters and structural findings, this again points to the need to investigate
functional alterations by histological correlation.
- While, in this patient, chronic allograft injury
was advanced and irreversible, the diagnosis of amyloidosis triggered a hematologic evaluation and
offered the patient an early chance for treatment
- Early low-grade proteinuria: causes, short-term evolution and long-term consequences in renal transplantation. Halimi JM, Laouad I, Buchler M, Al-Najjar A, Chatelet V, Houssaini TS, Nivet H, Lebranchu Y. Am J Transplant. 2005 Sep;5(9):2281-8.
- Proteinuria in kidney transplant recipients: prevalence, prognosis, and evidence-based management. Knoll GA. Am J Kidney Dis. 2009 Dec;54(6):1131-44. Epub 2009 Sep 2
- Post-transplant nephrotic syndrome: A comprehensive clinicopathologic study. Yakupoglu U, Baranowska-Daca E, Rosen D, Barrios R, Suki WN, Truong LD . Kidney International, Vol. 65 (2004), pp. 2360–2370
- Transplant Glomerulopathy, Late Antibody-Mediated Rejection and the ABCD Tetrad in Kidney Allograft Biopsies for Cause. B. Sis, , P. M. Campbell, T. Mueller, C. Hunter, S. M. Cockfield, J. Cruz, C. Meng, D. Wishart, K. Solez and P. F. Halloran, American Journal of Transplantation 2007; 7: 1743–1752
- Transplant Glomerulopathy May Occur in the Absence of Donor-Specific Antibody and C4d Staining. Enver Akalin, Rajani Dinavahi, Steven Dikman,Graciela de Boccardo, Rex Friedlander,Bernd Schroppel,Vinita Sehgal, Jonathan S. Bromberg,Peter Heeger,and Barbara Murphy. Clin J Am Soc Nephrol 2: 1261–1267, 2007.
- Monoclonal immunoglobulin deposition disease in a renal allograft: probable recurrent disease in a patient without myeloma. Alpers CE, Marchioro TL, Johnson RJ. Am J Kidney Dis. 1989 May;13(5):418-23.
- C4d deposition without rejection correlates with reduced early scarring in ABO-incompatible renal allografts. Haas M, Segev DL, Racusen LC, Bagnasco SM, Locke JE, Warren DS, Simpkins CE, Lepley D, King KE, Kraus ES, Montgomery RA. J Am Soc Nephrol. 2009 Jan;20(1):197-204. Epub 2008 Sep 5
- Chronic Transplant Glomerulopathy: Need for Further Assessment. Lorraine Racusen. Clin J Am Soc Nephrol 2: 1108–1109, 2007.