|Year : 2010 | Volume
| Issue : 4 | Page : 651-657
|Calcineurin inhibitor toxicity in renal allografts: Morphologic clues from protocol biopsies
Alok Sharma1, Sumeet Jain2, Ruchika Gupta1, Sandeep Guleria2, Sanjay Agarwal3, Amit Dinda1
1 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Surgical Disciplines, All India Institute of Medical Sciences, New Delhi, India
3 Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India
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|Date of Web Publication||27-Oct-2010|
| Abstract|| |
Background: Calcineurin inhibitors (cyclosporine and tacrolimus) are important constituents of post renal transplant immunosuppression. However, renal toxicity limits their utility. Histological features of calcineurin inhibitor toxicity (CNIT) have been the subject of few studies using protocol biopsy samples, and consensus on diagnostic criteria is still evolving. Aims: To analyze the spectrum of histological changes in protocol renal allograft biopsies with evidence of CNIT and identify additional features that are likely to help the pathologist in arriving at a diagnosis. Materials and Methods: One hundred and forty protocol allograft biopsies performed at 1, 6 and 12 months post renal transplant were studied. The defining features of CNIT included: isometric vacuolization of proximal tubular cells, arteriolar hyalinosis with medial/peripheral nodules and striped pattern of tubular atrophy/interstitial fibrosis. Other features such as global glomerulosclerosis, vacuolization of smooth muscle cells of arterioles, tubular microcalcinosis, ischemic shrinkage of glomeruli and hyperplasia of juxtaglomerular apparatus (JGA) were also analyzed and graded semiquantitatively. Results: CNIT was seen in 17/140 protocol biopsies (12.1%). In addition to the diagnostic criteria, arteriolar hyalinosis, smooth muscle cell vacuolization of arterioles and hyperplasia of JGA were found to be useful indicators of CNIT. Conclusions: There is a relatively high incidence of CNIT in protocol allograft biopsies. A critical analysis of renal biopsy in adequate number of serial step sections to identify these features is mandatory, as many of these features are subtle and are likely to be missed if not specifically sought.
Keywords: Calcineurin inhibitor toxicity, protocol biopsy, renal biopsy
|How to cite this article:|
Sharma A, Jain S, Gupta R, Guleria S, Agarwal S, Dinda A. Calcineurin inhibitor toxicity in renal allografts: Morphologic clues from protocol biopsies. Indian J Pathol Microbiol 2010;53:651-7
|How to cite this URL:|
Sharma A, Jain S, Gupta R, Guleria S, Agarwal S, Dinda A. Calcineurin inhibitor toxicity in renal allografts: Morphologic clues from protocol biopsies. Indian J Pathol Microbiol [serial online] 2010 [cited 2020 Nov 24];53:651-7. Available from: https://www.ijpmonline.org/text.asp?2010/53/4/651/72015
| Introduction|| |
Calcineurin inhibitors (cyclosporine and tacrolimus) are important constituents of post transplant immunosuppression in most solid organ transplantation protocols. A wide range of toxic effects have been noted with the use of these drugs, among which renal toxicity is perhaps the most clinically relevant. This assumes even greater importance in the setting of renal transplantation where these drugs acting as the proverbial "double edged swords" prevent renal allograft rejections on one hand, and act as potential nephrotoxic agents on the other.
The diagnosis of calcineurin inhibitor toxicity (CNIT), however, remains a challenge. The simultaneous administration of several drugs to the patient, incongruent correlation of serum levels of drugs with clinical toxicity and poorly understood mechanisms of pathogenesis make the diagnosis of CNIT an enigma. In the absence of reliable clinical indicators of toxicity, a renal biopsy remains the most appropriate tool for diagnosis. Although the opinions over histological features that define CNIT are still divided, few recent studies have emphasized some features which are reliable indicators of CNIT. ,
Introduction of protocol renal allograft biopsies has offered an opportunity to investigate the mechanisms of graft function and damage, in the absence of clinical signs of renal dysfunction. , Several studies have demonstrated that events like allograft rejection and CNIT ("background damage") can occur in the absence of clinical evidence of renal dysfunction (rise in serum creatinine) and may be critical for the eventual graft outcome. The diagnosis of these episodes in protocol biopsies and their appropriate management has been shown to favorably alter the long-term graft outcome. ,,
The aim of this study was to analyze the spectrum of histological changes in protocol renal allograft biopsies with evidence of CNIT and identify additional features that are likely to help the pathologist in arriving at a diagnosis.
| Materials and Methods|| |
Protocol renal allograft biopsies were performed in a patient cohort of live related renal transplants between 2006 and 2007 at our institute at 1, 6 and 12 months post transplant periods. Clinical inclusion criteria included serum creatinine < 1.8 mg/dL, normal graft ultrasound and DTPA scans, no clotting abnormalities and CNI (tacrolimus and cyclosporine) levels within therapeutic range. Live unrelated/cadaver allografts and those performed in children <12 years of age and protocol allograft biopsies with a coexistent rejection (cellular or humoral) were excluded from analysis.
A total of 58 patients fulfilling the clinical inclusion criteria underwent the first protocol biopsy (1 month), while 45 and 37 patients reported for second and third biopsies at 6 and 12 months post transplant, respectively (total number of biopsies evaluated: 140). Detailed laboratory data including renal functions and serum trough levels of drugs (cyclosporine or tacrolimus) were recorded. Estimated glomerular filtration rate (GFR) by the modified diet for renal diseases (MDRD) formula was calculated for each patient at the time of biopsy. Only those biopsies with a first diagnosis of CNIT were included ("new diagnosis"); any further/subsequent biopsies with features of CNIT in these patients were excluded from the analysis. The study was designed with an "intent to treat", implying that all the patients were treated by a sui table modification in their drug dose, following a diagnosis of CNIT on protocol biopsy. Age-matched controls were chosen from the same protocol cohort and the included cases which did not show evidence of CNIT or rejection (n = 20).
Light Microscopic Examination
Formalin fixed and paraffin embedded adequate renal biopsies were sectioned at 3 mm and stained with hematoxylin and eosin (H and E), periodic acid Schiff (PAS), silver methenamine (SM) and Masson's trichrome (MT) stains. The adequacy criteria were as per the 2005 update of Banff 1997 guidelines.  At least 20 serial step sections (including the H and E, PAS, SM and MT stained sections) were examined for each biopsy. The defining features of CNIT included at least one of the following: isometric vacuolization of proximal tubular epithelial cells, arteriolar hyalinosis with medial/peripheral nodule formation in at least one arteriole and presence of tubular atrophy and/or interstitial fibrosis (TA/IF) in a characteristic "striped" or "band" like pattern. These were present with or without other features such as global glomerulosclerosis, vacuolization of smooth muscle cells of arterioles, tubular microcalcinosis, ischemic shrinkage of glomeruli and hyperplasia of juxtaglomerular apparatus (JGA). All the histological features were graded semiquantitatively into one of the four grades as described [Table 1]. The subcapsular cortical area of biopsy core was excluded from analysis due to the presence of nonspecific inflammation and tubular atrophy/interstitial fibrosis (TA/IF) in this region. All the biopsies were independently evaluated in coded slides by three renal pathologists and a case was included only when all the three concurred on the diagnosis of CNIT.
All the values are depicted as mean ± SD (standard deviation). One way analysis of variance (ANOVA) and Chi-square test were appropriately used to test the significance of difference between the two groups. The statistical analysis was performed using the SPPS version 13.0 software.
| Results|| |
Overall, mean age of the recipients was 27.2 ± 7.9 years, while that of the corresponding donors was 42.5 ± 12.3 years. Majority of the recipients (80%) were males, while most of the donors (77%) were females. The mean age of the patients with CNIT (n = 17) was 32.4 ± 6.0 years, while that of corresponding controls was 31.5 ± 6.4 years. The clinical parameters including the serum trough levels of cyclosporine/tacrolimus, mean HLA mismatch and estimated glomerular filtration rate (eGFR) did not show a significant difference among cases and controls. Three patients in each group received pre-transplant Dacluzimab induction [Table 2].
Among the 140 protocol renal allograft biopsies performed, 17 (12.1%) showed light microscopic features of CNIT. In the 1-month protocol biopsies (n = 58), six showed histological evidence of CNIT (10.3%). At 6 months (n = 45), six new cases showed CNIT (13.3%), and among the 12-month protocol biopsies (n = 37), five new cases of CNIT were seen (5.4%). Overall, among the 140 biopsies, 97 (69.3%) were from patients on tacrolimus, while 43 (30.7%) were from patients on cyclosporine; 14/97 (14.4%) adequate biopsies from the former group and 3/43 (6.97%) from the latter group showed histological evidence of CNIT (P = 0.24).
Isometric tubular vacuolization, arteriolar hyaline nodules and striped interstitial fibrosis/atrophy were the defining features of CNIT. [Table 3] and [Table 4].
|Table 4 :Details of important histological features in biopsies with CNIT |
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Isometric vacuolization of proximal tubular epithelial cells
This was identified as the presence of nearly equal sized (isometric) small vacuoles in proximal tubular epithelial cytoplasm [Figure 1]a. This finding was noted in only two biopsies with CNIT, both of which were 1 month protocol biopsies and showed grade 1 vacuolization (seen in <25% of proximal tubular cells).
|Figure 1 :Composite photomicrograph showing the defining features of CNIT in this study: (a) proximal tubular epithelial cell showing the fine isometric vacuoles (H and E, ×400); (b) renal biopsy showing the typical striped fibrosis pattern [note the abrupt transition between fibrotic and intact renal cortex (H and E, ×200)]; (c) an afferent arteriole showing the characteristic nodular hyaline arteriosclerosis (H and E, ×400); (d) similar nodule in a non-afferent arteriole (H and E, ×400)|
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Tubular atrophy/interstitial fibrosis
The grades of TA/IF generally correlated with each other and therefore were analyzed together. Also, 7/17 (41.1%) biopsies with CNIT showed grade 2/3 TA/IF compared to 5/20 (25%) control biopsies which showed similar features (P = 0.49). All the seven biopsies with CNIT and grade 2/3 TA/IF were either 6 or 12 month protocol biopsies.
A unique "striped/band" like pattern of TA/IF was among the diagnostic criteria in the present study and was noted in 58.8% (10/17) of biopsies with CNIT [Figure 1]b.
Arteriolar hyalinosis (identified as presence of amorphous pink, PAS positive material replacing the smooth muscle cells of arterioles) was noted in 15/17 (88.23%) of biopsies with CNIT. In 9 of these, at least one arteriole showed a well-defined medial/peripheral hyaline nodule formation , which was a diagnostic criterion in this study [Figure 1]c and d. Among the controls, only 8/20 (40%) biopsies showed arteriolar hyalinosis and this difference was significant when compared to biopsies with CNIT (P = 0.009). Arteriolar hyalinosis with medial/peripheral nodule formation was the sole defining diagnostic feature in 6/17 (35.2%) biopsies with CNIT and coexisted with isometric vacuolization/striped interstitial fibrosis/tubular atrophy in the rest.
The comparative histological findings of other histological parameters are depicted in [Table 3],[Figure 2].
|Figure 2 :Composite photomicrograph showing other histological features analyzed in this study: (a) tubular microcalcinosis (H and E, ×400); (b) hyperplasia of the JGA (H and E, ×400); (c) smooth muscle vacuolization in an arteriole (H and E, ×400); (d) a glomerulus showing ischemic shrinkage of the tuft with increase in the Bowman's space (H and E, ×200)|
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| Discussion|| |
Subsequent to the introduction of cyclosporine in 1970s, followed by tacrolimus in 1984, the practice of renal transplantation has changed in an unprecedented manner. Although the initial enthusiasm associated with the use of these "wonder drugs" has been somewhat offset by the discovery of several systemic side effects (among which nephrotoxicity perhaps has the most profound clinical relevance), these drugs continue to be used in most transplantation programs. It is estimated that currently more than 90% of patients are discharged post transplantation on a CNI-based immunosuppressive regimen.  Protocol biopsies are being used in several transplant centers to closely monitor the grafts, with an "intent to treat" the histological lesions in the absence of overt renal dysfunction. The incidence of CNI toxicity in studies where protocol biopsies were performed show a wide variation and possibly reflect the variability in definition of histological criteria for CNIT ,,,,, [Table 5] and [Table 6].
|Table 5 :Criteria for CNIT in previous studies on protocol biopsy specimen |
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|Table 6 :Comparative analysis and incidence of CNIT in studies on protocol biopsy specimen |
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In spite of advances in our understanding of the mechanisms of action and pathways involved in the pathogenesis of CNIT, the diagnosis in a given case remains a formidable challenge. On one hand, CNIT manifests as a "functional toxicity", wherein signs of renal dysfunction (raised serum creatinine levels) are seen without morphologic evidence of toxicity, and on the other hand, as a "subclinical toxicity" where histological features of toxicity are seen in the absence of overt renal dysfunction. The latter group has been identified using protocol graft biopsies, which in addition to identifying the lesions at a pre-clinical stage, allows us to gain insights into the various pathogenetic mechanisms of development and persistence of CNIT. 
No single histological feature is pathognomonic of CNIT, and this is further compounded by variation in histological features with duration of CNI intake (acute and chronic CNIT). Previous studies have identified isometric tubular vacuolization as an important feature of acute CNIT, while nodular hyaline arteriosclerosis and a striped pattern of TA/IF are considered reliable indicators of chronic CNIT. , These three features have been used as defining criteria in the present study.
Isometric Tubular Vacuoles
These are identified as relatively uniform sized vacuoles in proximal tubular cytoplasm and represent the dilated endoplasmic reticulum and increased numbers of lysosomes at the ultrastructural level.  This is a difficult feature to identify and needs to be differentiated from vacuolization seen in osmotic nephrosis induced by administration of mannitol, glucose, sucrose, radio contrast agents, intravenous immunoglobulins, etc. ,,, These are present in only few proximal tubular profiles in a given case and are most abundant in the straight portion of the proximal tubules. These features may, however, be subtle and it is often difficult to distinguish these features with certainty. We noted this change in two protocol biopsies performed at 1 month post transplant. Isometric vacuolization is believed to be an indicator of acute onset CNIT and is probably reversible. One of the patients with this finding underwent repeat biopsies at 6 and 12 months and none of these showed isometric vacuoles. The other patient did not report for 6 month protocol biopsy, and his 12 month protocol biopsy did not show isometric vacuoles. This finding, therefore, may be a good indicator of acute CNIT, if identified correctly and all other causes of similar vacuoles in tubular epithelial cells are ruled out. Mihatsch et al. in one of the earliest studies on renal biopsies with CNIT found isometric vacuoles in 40% of biopsies in first 2 weeks post transplant, 30% at 6 months, 18% at 1 year and in about 8% at 3 years. Kambham et al.  have described tubular isometric vacuoles in 47% of biopsies with CNIT in a pediatric transplant protocol biopsy series. The overall incidence of this finding was very low in the present series (11.76%) compared to others; however, in the first month post transplant, 33.3% biopsies with CNIT (2/6) did show these vacuoles indicating that this finding may be supportive of an early CNIT.
Although CNI-induced thrombotic microangiopathy (TMA) is also considered to be a manifestation of acute CNIT,  we did not encounter any case of TMA in this protocol biopsy cohort.
This is a very common finding in renal biopsies, commonly occurring in conjunction with diabetes, aging and hypertension.  However, CNIT is associated with a peculiar "nodular" form of hyalinosis that preferentially affects the media/periphery of the arteriolar wall, in contrast to other conditions, where it is predominantly subendothelial (at least in the early stages). In a large series with long follow up, Nankivell et al.  found features of CNIT in 96.8% of biopsies (cumulative percentage) at 10 years post transplant. However, it must be noted that the criteria used for defining CNIT in this series were de novo or progressive arteriolar hyalinosis (not caused by preexisting donor hyalinosis), striped cortical fibrosis or severe tubular microcalcification (in the absence of preceding acute tubular necrosis). The presence of nodularity within the arteriolar hyalinosis was not used as a diagnostic criterion for nephrotoxicity to account for the variations of vascular cross-sectional appearance according to the plane of sectioning. In addition, the authors noted that early, cyclosporine-related arteriolar hyalinosis was circumferential, and nodularity became more apparent with increasing severity of the lesions. However, we noted the nodular pattern of hyalinosis in 9/17 (52.9%) biopsies with CNIT and this may perhaps be related to examining adequate number of serial step sections to identify the nodularity within the arterioles showing hyalinosis. These nodules are thought to represent inspissated proteins in areas of smooth muscle necrosis induced by the CNIs and are generally associated with long-term CNIT administration (chronic CNIT).  However, we noted this finding in 50% (3/6) biopsies with CNIT as early as 1 month post transplant. None of these three biopsies showed a coexistent striped fibrosis, and in the subsequent protocol biopsies of these patients (two patients were biopsied at 6 and 12 months, one patient was lost to follow up after the 1-month biopsy), persistence of hyaline nodules was noted in 6 month biopsies. The 12-month protocol biopsies of both these patients, however, did not reveal these nodules and showed arteriolar hyalinosis of grade 2 along with a similar grade of TA/IF, without a recognizable striped pattern. Therefore, the features of nodular hyalinosis (CNI associated arteriolopathy) may not be irreversible in all the cases and may indeed regress, particularly after stopping or reducing the CNI dosage. , Mihatch et al.  noted these nodules in 5% biopsies at 1 month post transplant, in 9% biopsies at 1 year and in 12% biopsies at 2 years post transplantation. Savoldi et al.,  in a protocol biopsy series of 38 patients, noted cyclosporine-related arteriolopathy in 15% biopsies at 6 months post transplant, which increased to 45% in the 18-month protocol biopsies. Recently, Kambham et al. noted this pattern in 29% of protocol biopsies. All the above studies included the nodular pattern as a diagnostic criterion. It may be noted that we have not emphasized the finding of nodules in the afferent arterioles, as has been suggested earlier.  The arteriolopathy associated with CNIT is a more diffuse process, though the severity of lesions may differ between arterioles in the same biopsy. In the present series, biopsies with CNIT showing nodular hyaline arteriosclerosis involved afferent arteriolar nodules in only half the cases (4/9). Thus, a careful search for nodules even in the non-afferent arterioles should be made in renal allograft biopsies.
The Striped Pattern of Tubular Atrophy and/or Interstitial Fibrosis
Initially considered to be a secondary change in the course of development of CNIT, the striped of band like pattern of TA/IF is now considered an important histological feature of CNIT. This appears as bands of TA/IF surrounded by areas of intact tubule-interstitium and shows an abrupt transition between the fibrotic and intact areas. The pathogenesis of this striped pattern is complex and is probably initiated by the renal vasoconstriction induced by CNIs.  This leads to local hypoxia or ischemia and formation of free radicals and reactive oxygen species, as well as upregulation of the pro-fibrotic Transforming Growth Factor (TGF) beta protein.  These changes eventually lead to TA/IF which is more pronounced in medulla, and ensuing preferential damage to the cortical medullary rays gives rise to the characteristic striped pattern of TA/IF associated with CNIT. This is perhaps the most established histological feature of CNIT and has been used as a defining feature in many studies on this subject. ,,, Like the arteriolar nodular hyalinosis, this feature too, is thought to represent a chronic CNIT and is probably irreversible, though in advanced cases, the characteristic striped pattern may be replaced by a more widespread and diffuse fibrotic picture. This pattern of TA/IF was seen in 10/17 (58.8%) biopsies with CNIT in the present study, of which two were 1 month protocol biopsies and four each were 6 and 12 month biopsies. Subsequently, five of the six patients with CNIT in 1 and 6 month biopsies and showing striped fibrosis underwent all the three protocol biopsies. At 6 months, one patient with CNIT in 1 month biopsy did not show progression in the grade of TA/IF; however, the striped pattern was not evident in this biopsy. This might reflect the focal nature of striped pattern which may be subject to a sampling error as the 12-month biopsy of this patient again showed a well-defined striped pattern of TA/IF. In rest of the biopsies except one (which comprised medullary tissue only), there was persistence of striped pattern. These findings indicate that this pattern is indeed irreversible; however, its focal nature needs to be considered, particularly in biopsies performed early in the post transplant period. Incidence of this finding in studies by other authors has varied with the duration of follow up. Nankivell et al.  reported 1, 5 and 10 year cumulative prevalence rates (for the presence of striped fibrosis) of 35.1, 69.9 and 88%, respectively, in a 10-year follow-up protocol biopsy study. Kambham et al.,  in another pediatric protocol biopsy series, noted this pattern in 61% of biopsies with CNIT.
Among the other histological features, we found vacuolization of smooth muscle cells of arterioles an important indicator of CNIT. This feature was seen in 70.6% biopsies with CNIT compared to only 15% of control group biopsies. This finding has not been systematically analyzed in any of the previous studies on this subject, though early animal studies investigating cyclosporine toxicity noted this finding, which was considered as a precursor to development of arteriolar smooth muscle necrosis and eventually arteriolar hyalinosis.  We noted these vacuoles regardless of the time of biopsy, although these were more prevalent in first month protocol biopsies.
Hyperplasia of the JGA has also been analyzed in a few previous studies.  Increased rennin secretion associated with CNI therapy may lead to hyperplasia of JGA, a phenomenon typically seen in states of chronic rennin stimulation. , This was a frequent finding in biopsies with CNIT in the present study, though its incidence did not reach statistical significance when compared to the control biopsies. Nevertheless, this finding could be used as a "soft marker" for CNIT and its presence should be actively searched for.
The other features such as tubular microcalcinosis, ischemic glomerular shrinkage and degree of global glomerulosclerosis did not differ significantly among the biopsies with CNIT and controls. Although some others have emphasized the importance of these findings and have used tubular microcalcinosis as a defining feature of CNIT,  we feel that these changes are relatively nonspecific and should not be used for either scoring or diagnosing CNIT in renal allograft biopsies.
| Conclusions|| |
To conclude, the findings of the present study indicate that there is a relatively high incidence of CNIT in protocol allograft biopsies and this may form an important mechanism of clinically inapparent "background" damage to the renal allograft. Histological features that aid the pathologist in diagnosing CNIT include the nodular hyaline arteriosclerosis, striped pattern of interstitial fibrosis and tubular atrophy and isometric tubular vacuolization. In addition to these relatively well-recognized features, the presence of variably sized vacuoles in smooth muscle cells of media of arterioles and JGA hyperplasia were also found to be important "soft markers" for the presence of CNIT. A critical analysis of renal biopsy in adequate number of serial step sections to identify these features is mandatory as many of these features are subtle and are likely to be missed if not specifically sought for.
| Acknowledgment|| |
Alok Sharma and Ruchika Gupta acknowledge CSIR, New Delhi, for research grant support.
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Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
Source of Support: CSIR, New Delhi, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
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