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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2006  |  Volume : 17  |  Issue : 3  |  Page : 420-424
Chronic Allograft Nephropathy


King Fahad National Guard Hospital, Riyadh, Saudi Arabia

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How to cite this article:
Jumani AQ. Chronic Allograft Nephropathy. Saudi J Kidney Dis Transpl 2006;17:420-4

How to cite this URL:
Jumani AQ. Chronic Allograft Nephropathy. Saudi J Kidney Dis Transpl [serial online] 2006 [cited 2021 Mar 6];17:420-4. Available from: https://www.sjkdt.org/text.asp?2006/17/3/420/35779

   Case presentation Top


A 50-year old female with a history of chronic kidney disease secondary to polycystic kidney disease underwent a living unrelated renal transplant on 8th March, 2001 after a short period on hemodialysis. Initial immuno­supressive regimen included prednisone, cyclosporine and mycophenolate mofetil (MMF).

The course of the patient was complicated by acute rejection one week after transplantation, which was treated with intravenous methyl prednisolone and a short course of anti­thymocyte globulin followed by modification of the immunosuppressive regimen to pre­dnisone, tacrolimus and MMF. Serum creatinine levels decreased to a nadir of 70 µmol/L.

After discharge from the hospital, the patient's follow-up as an outpatient was uneventful until June 2003 when she started to gradually develop renal allograft dysfunction; serum creatinine levels increased from 90 to 140 µmol/L and a 24-hour urine collection test revealed proteinuria at 1.1 gm/day. The patient was readmitted to the hospital for evaluation of the deteriorated renal function in December 2003.

The ultrasound and Doppler of the allograft revealed normal sized allograft without detectable distension of urinary passages. The renal allograft biopsy revealed chronic changes such as sclerosed glomeruli, arteriolar thickening, and tubular atrophy besides inter­stitial fibrosis; all of these signs are compatible with chronic allograft nephropathy (CAN), which was diagnosed by light microscopy, [Figure - 1],[Figure - 2],[Figure - 3].

Electron microscopy of the biopsy specimen revealed focal effacement of the cell foot processes. The visceral epithelial cells showed focal microvillus degeneration and a number of lipid droplets. The capillary loops illustrated prominent widening of the subendothelial spaces with accumulation of finely granular electron lucent material bound in some places by a multilayered basement membrane (double contours), which resulted in the narrowing of capillary lumens. Few scattered electron dense deposits were noted in the subendothelial area. Glomerular endo­thelial cells demonstrated focal loss of fenestrae. The mesangial areas showed increased matrix. The final result of the biopsy labeled the CAN in this patient as grade II (CI2, CT2, MM2, CV2, AH0) according to the Banff 97 classification. The patient was continued on the same immunosuppressive regimen. Tacrolimus was administered at the lower limit of the normal therapeutic range. In addition, the patient was initiated on an angiotensin receptor inhibitor. The patient had a stable serum creatinine ranging between 150-160 µmol/L with minimal proteinuria at 0.4 gm/day.


   Discussion Top


Chronic allograft nephropathy (CAN) is the most prevalent cause of renal transplant failure in the first post-transplant decade, but its pathogenesis has remained elusive.[1]

The clinical diagnosis is usually suggested by gradual deterioration of graft function as manifested by slowly increasing plasma creatinine concentration, progressive proteinuria, and hypertension. [2]

The pathologic changes of CAN involve all parts of the renal parenchyma including the blood vessels, glomeruli, interstitium, and tubules.[2] The vessel walls are usually thickened by the subintimal accumulation of loose and then organized connective tissue, variable mononuclear cellular infiltration, proliferation of myofibroblasts, and disruption and duplication of the internal elastic lamina. [3] The glomerular capillary walls are also thickened with an occasional double-contour appearance resembling that detected in membranoproliferative glomerulonephritis (MPGN). The presence of this double contour is considered the most specific finding in CAN within the Banff classification system. [4] Moreover, the interstitium generally demon­strates variable degrees of patchy fibrosis and focal cellular infiltrates with lymphocytes and plasma cells, associated with a variable degree of tubular atrophy and tubular cell dropout.[4]

The distinction between CAN and MPGN can be illustrated on electron microscopy, which typically reveals thickening and dupli­cation of the glomerular basement membrane devoid of immune deposits in the CAN relative to MPGN in which the prominent subepithelial immune deposits predominate.

However, it is frequently difficult to dis­tinguish between CAN and the nephropathy associated with the calcineurin inhibitors (CNI) based upon the results of microscopy alone.

The pathogenesis of the CAN includes immuno­logical and non- immunological factors.

The immunological factors comprise both cell mediated and humeral immunity. CAN likely develops secondary to acute reje­ction.[5],[6] The incidence of CAN is < 1% in those patients with no episodes of acute rejection, while it increases to 20% in the living related and 36% of cadaveric allografts if acute rejection occurred within 60 days after transplantation and increases to 43% in the living related and 60% in the cadaveric allografts if acute rejection occurred beyond 60 days post transplantation.

Moreover, the positive complement, C4d, deposits in the peritubular capillaries as detected by immunoflourescence microscopy. Regardless of the history of rejection, C4d is associated with the development of CAN. In a study by Sijpkens et al. of 1111 kidney transplants which had at least 6 months of graft function, 18 cases were identified with chronic transplant glomerulopathy (1.6%); glomerular C4d deposits were detected in 10/11 biopsies.[7]

Non-immunological factors may play a role in the development and progression of CAN such as hypertension, glomerular hyper­filtration and hypertrophy, delayed graft function, and hyperlipidemia.

The hyperfiltration hypothesis proposes that kidneys with reduced renal mass will progress toward failure due to hypertrophy of the remaining nephron to endure the excess load, eventually resulting in nephron exhaustion. Several conditions may be asso­ciated with probable hyperfiltration such as small kidneys from aged donors, allografts transplanted into large recipients (over 100 kg), allografts from females to males compared with males to females, kidneys that experience rejection episodes, and cadaveric grafts com­pared with living-unrelated donor grafts.[8]

Management of CAN may include strategies such as minimization of incidence of acute rejection; reduction, withdrawal or avoidance of CNI, and aggressive control of non­immunological mechanisms.

Minimizing the incidence of acute rejection, especially during the first year post transplant­ation reduces the probability of developing CAN. Careful follow-up including serial allograft biopsies have been advocated.

A study of 118 patients with biopsy-proven CAN evaluated the efficacy of reducing or withdrawing cyclosporine or tacrolimus, and adding or continuing mycophenolate. It concluded that renal function could be stabilized in many patients. The outcomes were significantly better when CNI was dis­continued. [9] In another study, 84 consecutive patients who had biopsy-proven CAN were randomized into two groups; group 1 included 50 patients who received a 40% CNI reduction plus mycophenolate mofetil, and group 2 included 34 patients immediate switch of CNI to sirolimus. Graft survival was signi­ficantly better in group 2 (P = 0.038). CAN grading worsened significantly in group 1, whereas it remained stable in group 2.[10]

Finally, controlling the non-immunological factors such as hypertension (including the use of angiotensin inhibitors and/or angiotensin receptor blockers), hyperlipidemia, obesity, and smoking may help in slowing the pro­gression of CAN.


   Questions Top


Dr. Moh. Chihabeddin Kerchid (Security Forces Hospital) chairman of the club: Now the presentation is open for discussion.

Dr. Dujana Moosa (Armed Forces Hospital): Did you repeat the biopsy after the initial management of the acute renal rejection?

Dr. Jumani: No, since there was a good response to therapy and s. creatinine improved to normal. Dr. Faissal Shaheen (King Fahad Hospital, Jeddah, SCOT): I have two questions, first, what is the role of delayed graft function in the development of CAN? Second, do we have evidence from literature that MMF has impact on the long-term outcome of CAN?

Dr. Jumani: for the first question, the delayed graft function has been shown to affect the allograft survival and the development of CAN. This is mostly due to the damage to the allograft from the ischemia and also the predisposition to acute rejection. For the second question, we have evidence about the MMF reducing the incidence of acute rejection. However, for the CAN, we have some evidence from the registries about the benefit of MMF combined with CNI but there are no prospective studies to address this issue yet as far as I know. There are some attempts to give MMF with steroids alone or with sirolimus without CNI (CNI avoidance or withdrawal) but the long-term studies are not available yet.

Dr. Ahmad Shabaloot (King Faissal Hospital, Riyadh): Can we say that the return of the serum creatinine to normal is enough evidence to the resolution of the acute allograft dysfunction and that the patient may not be predisposed to the development of CAN?

Dr. Jumani: Though we use the clinical improvement as a satisfying evidence to the improvement of the allograft, but it may not be accurate in the assessment of what is going on really with the allograft. Serum creatinine does not tell the whole story. There is still subclinical process that may result in the development of CAN despite the clinical improvement. S. Creatinine is not the ideal marker of complete restoration of allograft function.

Dr. Numan Turaif (King Khaled University Hospital, Riyyadh): Is there any role for sirolimus to treat the proteinuria in CAN? Dr. Jumani: There are some reports that advocate the protective role of sirolimus and it is a consideration, but there is no compulsory evidence to use this drug routinely for this indication.

Dr. Dujana Moosa: I believe there is evidence in the literature for the effect of partial response of the acute rejection to therapy on the development of CAN, but not the complete response.

Dr. Jumani: Not every clinical response judged by the return of s. creatinine to normal means complete response of the allograft. In any inflammatory process such as the acute rejection, there is residual damage to the allograft that may have a role in the development of CAN.

Chairman: I believe the studies of the serial protocol biopsies may answer this question about he residual renal injury. Do you believe this is true?

Dr. Jumani: there are studies that address this issue, but the evidence do not support performing serial protocol biopsies to document recovery of the allograft post acute rejection at present.

Audience: I believe that the severity of proteinuria is an independent risk factor and a marker in the progress of CAN and graft loss.

Audience: Is there any evidence that cyclo­sporine is more nephrotoxic and results in the development of CAN than tacrolimus?

Dr. Jumani: Both belong to the same family and can result in long-term nephrotoxicity. I agree with the notion that we require less nephrotoxic drugs with better adverse effect profile, but we do not have the ideal solution yet.

 
   References Top

1.Paul LC. Chronic allograft nephropathy: An update. Kidney Int 1999;56(3):783-93.  Back to cited text no. 1    
2.Monaco AP, Burke JF Jr, Ferguson RM, et al. Current thinking on chronic renal allograft rejection: issues, concerns, and recommendations from a 1997 roundtable discussion. Am J Kidney Dis 1999;33(1): 150-60.  Back to cited text no. 2    
3.Gouldesbrough DR, Axelsen RA. Arterial endothelialitis in chronic renal allograft rejection: a histopathological and immunocytochemical study. Nephrol DialTransplant 1994;9(1):35-40.  Back to cited text no. 3    
4.Gough J, Yilmaz A, Miskulin D, et al. Peritubular capillary basement membrane reduplication in allografts and native kidney disease: a clinicopathologic study of 278 consecutive renal specimens. Transplant­ation 2001;71(10):1390-3.  Back to cited text no. 4    
5.Basadonna GP, Matas AJ, Gillingham KJ, et al. Early versus late acute renal allograft rejection: impact on chronic rejection. Transplantation 1993;55(5):993-5.  Back to cited text no. 5    
6.Matas AJ, Gillingham KJ, Payne WD, Najarian JS. The impact of an acute rejection episode on long-term renal allograft survival (t1/2). Transplantation 1994;57(6):857-9.  Back to cited text no. 6    
7.Sijpkens YW, Joosten SA, Wong MC, et al. Immunologic risk factors and glomerular C4d deposits in chronic transplant glome­rulopathy. Kidney Int 2004;65(6): 2409-18.  Back to cited text no. 7    
8.Terasaki PI, Koyama H, Ceeka JM, Gjertson DW. The hyperfiltration hypothesis in human renal transplantation. Transplantation 1994;57(10):1450-4.  Back to cited text no. 8    
9.Weir MR, Ward MT, Blahut SA, et al. Long-term impact of discontinued or reduced calcineurin inhibitor in patients with chronic allograft nephropathy. Kidney Int 2001;59:1567-73.  Back to cited text no. 9    
10.Stallone G, Infante B, Schena, et al. Rapamycin for treatment of chronic allograft nephropathy in renal transplant patients. J Am Soc Nephrol 2005;16(12): 3755-62.  Back to cited text no. 10    

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Correspondence Address:
Abdul Qadir Jumani
King Fahad National Guard Hospital, P.O. Box 22490, Riyadh 11426
Saudi Arabia
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PMID: 16970267

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