Histopathology of renal failure after heart transplantation: A diverse spectrum

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http://www.jhltonline.org Histopathology of renal failure after heart transplantation: A diverse spectrum Sean P.

Anyanwu, MD, d and Graciela DeBoccardo, MD e From the a Division of Cardiology and b Departments of Medicine, c Pathology and d Cardiothoracic Surgery, Mount Sinai Medical Center, New York, New York;

1 Histopathology of renal failure after heart transplantation: A diverse spectrum Sean P. Pinney, MD, a Revathi Balakrishnan, MD, b Steven Dikman, MD, c Ajith Nair, MD, a Kimmarie Hammond, ANP, a Michael Domanski, MD, a Anelechi C. Anyanwu, MD, d and Graciela DeBoccardo, MD e From the a Division of Cardiology and b Departments of Medicine, c Pathology and d Cardiothoracic Surgery, Mount Sinai Medical Center, New York, New York; and the e Division of Nephrology, Montefiore Medical Center, Bronx, New York. KEYWORDS: heart transplantation; calcineurin inhibitors; chronic kidney disease; diabetes mellitus; hypertension BACKGROUND: Chronic kidney disease occurs frequently after heart transplantation and is associated with significant morbidity and mortality. Herein we describe the histopathology associated with renal failure in a cohort of heart transplant recipients. METHODS: Over a 4-year period all patients with an estimated GFR 30 ml/min/1.73 m 2 or significant proteinuria were referred to the kidney transplant clinic for clinical evaluation. A percutaneous renal biopsy was performed as part of a standardized evaluation. RESULTS: Eighteen patients underwent renal biopsy years after transplantation. Hypertension (88.9%), Type 2 diabetes (55.6%) and allograft vasculopathy (38.9%) were prevalent. All patients were receiving calcineurin inhibitors. Mean creatinine was mg/dl with an estimated GFR ml/min/1.73 m 2. Eight patients (44%) had proteinuria 1 g per 24 hours. The major histologic findings were nephrosclerosis plus diabetic glomerulopathy (50%), nephrosclerosis and focal segmental glomerulosclerosis (22.2%) and nephrosclerosis alone (22.2%). One patient had direct CNI toxicity consisting of nodular sub-adventitial hyalinosis. Eleven patients (61.1%) had glomerular disease and 11 patients (61.1%) had moderate or severe tubular atrophy. During follow-up, 5 patients (27.8%) started hemodialysis, 4 (22.2%) died, and 2 (11.1%) received a renal transplant. CONCLUSIONS: We observed diverse histologic patterns in this series of renal biopsies suggesting that chronic kidney disease after heart transplantation has a complex and varied pathologic basis. Further defining the renal injuries that precede heart transplantation and predispose to the progression of kidney disease after transplant may assist in treating this population. J Heart Lung Transplant 2012;31: International Society for Heart and Lung Transplantation. All rights reserved. Reprint requests: Sean P. Pinney, MD, Advanced Heart Failure and Cardiac Transplantation, Division of Cardiology, Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1030, New York, NY Telephone: Fax: address: sean.pinney@mssm.edu /$ -see front matter 2012 International Society for Heart and Lung Transplantation. All rights reserved. doi: /j.healun Chronic kidney disease (CKD) is a frequent complication after solid-organ transplantation. 1 For heart transplant recipients, the 1-, 5- and 10-year incidence of chronic renal failure, defined as a glomerular filtration rate (GFR) 30 ml/min/1.73 m 2, is 1.9%, 10.9% and 21%, respectively. 2 Predisposing risk factors for CKD in heart transplant candidates include preexisting atherosclerotic vascular disease and ongoing renal ischemia from upregulation of the renin angiotensin aldosterone system (RAAS). Among the more common CKD risk factors shared by all solid-organ types are advanced recipient age, hypertension and diabetes. The most consistent risk factor for kidney dysfunction in the non-renal organ transplant recipient is the level of renal function prior to transplantation. 3,4 For decades, the primary cause of CKD after solid-organ transplantation has been thought to be calcineurin inhibitor (CNI) toxicity CNIs are believed to produce two specific forms of nephrotoxicity: an acute, functional nephrotoxicity and a chronic, structural form. Recently, several emerging lines of evidence suggest that CNIs may not be the primary driver of renal dysfunction after orthotopic heart transplantation (OHT). First, little direct CNI toxicity

2 234 The Journal of Heart and Lung Transplantation, Vol 31, No 3, March 2012 has been identified in renal biopsies of other solid-organ transplant recipients. 11,12 Second, severe pre-existing nephrosclerosis has been identified in heart failure patients. 13 Third, the adoption of CNI-free immunosuppression regimens has failed to significantly reverse CKD. 14 The purpose of this study was to describe the histopathology associated with renal failure in our cohort of heart transplant recipients. Methods Patients Between January 1989 and January 2009, 340 adult heart transplants were performed at Mount Sinai Medical Center. For the period between January 1, 2005 and January 31, 2009, all patients with impaired kidney function and an estimated GFR 30 ml/min/ 1.73 m 2 or significant ( 1 g per 24 hours) proteinuria were referred to our kidney transplant clinic for evaluation. A percutaneous renal biopsy was performed as part of a standardized workup. We conducted a retrospective chart review of the 18 patients who underwent renal biopsy including 17 transplanted at our center and 1 elsewhere. All patients were 18 years of age at the time of transplantation. Patient information was obtained from inpatient and outpatient charts and from the hospital electronic database. This study was approved by our institutional review board. The immunosuppressive protocol at our center has varied over time. For patients transplanted between 1989 and December 31, 1995, it consisted of cyclosporine, azathioprine and corticosteroids. From January 1, 1996 until September 30, 2005, the majority of patients received tacrolimus monotherapy, as previously described. 15 After this strategy, the use of either azathioprine and mycophenolate mofetil was generally avoided and an attempt was made to wean all patients off corticosteroids within the first 12 months after transplantation. The use of anti-metabolites was reserved for patients with CKD to facilitate reducing serum levels of CNIs. From October 1, 2005, patients received triple-drug immunosuppression with tacrolimus, mycophenolate mofetil and prednisone. Most patients were weaned from corticosteroids within the first 6 months after transplant. The therapeutic target trough immunosuppressive drug level for long-term ( 12 months) maintenance was 150 to 200 mg/dl for cyclosporine-treated patients, 7 to 10 mg/dl for tacrolimus monotherapy patients, and 5 to 7 mg/dl for those receiving tacrolimus in combination with other immunosuppressive agents. Induction immunosuppression was not used. As part of our standard clinical practice, all patients with a reduction in GFR 60 ml/min/1.73 m 2 had their CNI dose reduced to achieve a target tacrolimus level of 5 mg/dl or cyclosporine level 150 mg/dl. As much as possible, nephrotoxic medications were eliminated. Patients with proteinuria were treated with an angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB), as tolerated. All patients completed a 24-hour urine collection for protein and creatinine, which was used to assess proteinuria and creatinine clearance. Estimated GFR (egfr) was calculated using the Modified Diet of Renal Disease (MDRD) formula. 16 Hypertension was defined as systolic blood pressure 140 mm Hg and/or diastolic blood pressure 90 mm Hg on any clinic visit, or the use of anti-hypertensive medications. Diabetes was defined as the use of any insulin or oral hypoglycemic agents, or hemoglobin A 1c 7% at the time of consultation or biopsy. Kidney biopsies Standard percutaneous kidney biopsy was performed as an outpatient procedure under ultrasound guidance using an 18G biopsy needle. The number of cores obtained depended on the adequacy of the tissue specimen, which was evaluated by an on-site pathology technician. Biopsy specimens prepared for light microscopy (LM) were formalin-fixed, paraffin-embedded and stained with hematoxylin and eosin, periodic acid Schiff reagents and the Gomori trichome stain. When sufficient renal tissue could be obtained, selected samples were placed in gluteraldehyde for electron microscopy (EM) and immunopathology transport medium. There were no biopsy-related complications. Definition of histologic lesions A single experienced renal pathologist at our institution reviewed all biopsies. Morphologic entities were defined by standard criteria. 17 Lesions classified as due to CNI nephrotoxicity contained adventitial nodular arteriolar hyalinization and occasional degeneration of medial cells. Glomerular, arterial, arteriolar, interstitial and tubular changes were evaluated on a semi-quantitative scale of 0 (normal), 1 (mild), 2 (moderate) or 3 (severe), developed by our group. Statistical analysis Continuous data are expressed as a mean standard deviation and categorical data are described as proportions. Descriptive frequencies were calculated using SPSS software. The primary end-point was the development of specific changes on LM, as previously described. Results Patient characteristics Baseline characteristics of the 18 patients at the time of heart transplantation and at renal biopsy are summarized in Tables 1 and 2. This cohort was comprised predominantly of men with ischemic cardiomyopathy. The mean age at the time of transplant was years. The ethnic composition of this group was 44% Caucasian, 33% African American, 17% Hispanic and 6% Asian. The mean interval between heart transplantation and renal biopsy was years. Hypertension was prevalent in 89% of patients both at the time of transplantation and renal biopsy. The prevalence of Type 2 diabetes increased from 29% to 56% after transplantation. Forty-four percent of patients were being treated with an ACE-I or ARB and all but 2 were receiving an HMG-CoA reductase inhibitor (statin). The mean pre-transplant creatinine was mg/dl, whereas, at the time of renal biopsy, the mean serum creatinine was mg/dl. The mean MDRD-estimated GFR was ml/min/1.73 m 2, whereas mean cre-

3 Pinney et al. Renal Failure After Heart Transplantation 235 Table 1 Baseline Demographics of Patients (n 18) Gender (male) 15 (83%) Age at transplant (years) Race Caucasian 8 (44%) African American 6 (33%) Hispanic 3 (17%) Asian 1 (6%) Etiology of cardiomyopathy Ischemic heart disease 13 (72%) Myocarditis 2 (11%) Hypertrophic cardiomyopathy 2 (11%) Sarcoidosis 1 (6%) Diabetes mellitus (Type 2) 5 (29%) Hypertension 16 (89%) Creatinine (mg/dl) egfr (ml/min/1.73 m 2 ) Data presented as number (%) or mean SD. atinine clearance by 24-hour urine collection was ml/min/1.73 m 2. Eight patients (44%) had 1 g/day of proteinuria. Heavy proteinuria ( 3 g/day) was present in 3 patients. All patients were receiving a CNI at the time of biopsy. Most were receiving tacrolimus (78%), whereas the others were receiving cyclosporine (22%). Four patients were receiving sirolimus for treatment of allograft vasculopathy, which was present in 39% of patients. Three patients remained on tacrolimus monotherapy. Biopsy findings The major histopathologic findings are described in Figure 1. The most common finding was arterial and/or arteriolar nephrosclerosis, which was present in all but 2 patients (Figure 2A and B). Five patients had both arterial nephrosclerosis and focal segmental glomerular sclerosis (FSGS; Figure 2C). Five additional patients had evidence of diabetic glomerulosclerosis in combination with arterial nephrosclerosis (4) or with FSGS (1). One patient had tubulointerstitial disease, perhaps due to a drug reaction, in the absence of any glomerular disease. One patient had adventitial nodular arteriolar hyaline deposits that were diagnostic of chronic CNI toxicity (Figure 2D). Another patient with diabetic glomerulosclerosis had arteriolar adventitial hyaline nodules possibly due to chronic CNI toxicity, but the pattern of hyaline deposition was more suggestive of diabetes. Sixteen patients (89%) had evidence of tubular atrophy, which was moderate to severe in 11 patients. Thrombotic microangiopathy was not seen. Clinical outcomes Patients were followed until July 1, 2009 for clinical outcomes. Four patients (22%) died during this limited follow-up period, 1 each from renal failure, acute respiratory distress syndrome presumably from sepsis, complications of post-transplant lymphoproliferative disorder (PTLD) therapy and sudden cardiac death. Seven patients (39%) required renal replacement therapy. Of these, 4 (22%) started hemodialysis and 3 (17%) received a renal transplant. The remaining 7 patients were alive with Stage 3 or 4 CKD. Discussion In this series of renal biopsies, we identified several distinct histologic patterns that were associated with renal failure in our heart transplant recipients. The most common finding was arterial and/or arteriolar nephrosclerosis, which was moderate or severe in half of those affected. More than 50% of the patients had glomerular disease, frequently in combination with arterial nephrosclerosis, whereas all but 2 patients had tubular disease. Only 1 patient had biopsyproven direct CNI toxicity. These observations would suggest that the development of CKD after heart transplantation has a complex and varied pathologic basis. Looking at our histologic results, a more complex picture of post-transplant renal failure emerges. In these biopsies one can see the sequelae of the several mechanisms by which heart transplant recipients develop CKD, including: acute kidney injury from hypotension, vasoconstrictor use and cardiopulmonary bypass; the long-term effects of hypertension and diabetes; and treatment with certain nephrotoxic medications, including CNIs. Based on our results, it appears reasonable to assume that patient-specific factors are more likely to produce structural (morphologic) kidney changes than CNIs. Certainly, the addition of CNI-induced vasoconstriction onto this background of ischemic, diabetic and hypertensive nephropathy may worsen renal function, but is unlikely to be its sole cause. It is certainly possible that chronic exposure to CNIs, with the attendant risk of renal vasoconstriction, could in time produce a picture similar to that of hypertensive nephrosclerosis. Although serial renal biopsies may help to establish this pattern over time, it is neither practical nor appropriate to do so. Ours is not the first study to cast doubt upon the role of direct CNI toxicity. In reviewing the causes of renal allo- Table 2 Patient Characteristics at Time of Biopsy Age at renal biopsy (years) Interval between OHT and biopsy (years) Diabetes 10 (56%) Hemoglobin A 1c (%) Hypertension 16 (89%) Cardiac allograft vasculopathy 7 (39%) ACE-I/ARB use 8 (44%) Statin use 16 (89%) Creatinine (mg/dl) GFR (ml/min/1.73 m 2 ) egfr (ml/min/1.73 m 2 ) Proteinuria 1 g per 24 h 8 (44%) Data presented as mean SD or number (%).

graft loss, El-Zoghby and colleagues found that CNI toxicity was infrequently the cause of renal allograft failure. 11 In fact, only 1 of 153 patients (0.

4 236 The Journal of Heart and Lung Transplantation, Vol 31, No 3, March 2012 Figure 1 Major histopathologic findings and degree of tubular atrophy. FSGS, focal segmental glomerulosclerosis; DM, diabetes mellitus; CNI, calcineurin inhibitor. graft loss, El-Zoghby and colleagues found that CNI toxicity was infrequently the cause of renal allograft failure. 11 In fact, only 1 of 153 patients (0.7%) with graft failure had direct CNI toxicity. Similarly, low rates of direct CNI toxicity have been reported in liver transplantation. Kim and colleagues reported a series of 81 liver transplant recipients with impaired renal function, among whom direct CNI toxicity could be identified in only 13 (16%). 12 In both renal and liver transplant recipients, the major cause of impaired renal function was attributable to glomerular disease, not CNI toxicity. This alternative view may help explain why renal function deteriorates early after OHT and why CNI reduction or withdrawal fails to fully reverse CKD. For example, in one large case series, withdrawal of CNIs resulted in an overall increase in GFR from 46 to 61 ml/min at 12 months. 14 When one looks at the patients that those investigators described as having established CNI toxicity, the improvement in GFR is more modest, increasing from 40 to 50 Figure 2 Photomicrographs of representative renal biopsy slides showing common histologic patterns seen in our series. (A) Arterial nephrosclerosis (arrow) with mild scarring. (B) Arterial nephrosclerosis with severe scarring. (C) Two glomeruli, one with focal segmental glomerulosclerosis. (D) Nodular hyaline deposits (arrow) involving the adventitia of a renal arteriole consistent with calcineurin inhibitor nephrotoxicity. ml/min. Furthermore, after switching to sirolimus-based therapy, nearly 30% of patients had a worsening of renal function, particularly diabetic patients with established proteinuria. Other predictors of a poor response included pretransplant ischemic cardiomyopathy or diabetes, lower GFR, higher creatinine and a greater degree of proteinuria prior to conversion. This suggests that the benefit of CNI withdrawal comes from reducing vasoconstriction, but fails to reverse established structural renal disease. The substitution of sirolimus in patients with glomerular disease, particularly diabetics, may be harmful. Regardless of its etiology, the presence of CKD in our series was associated with poor clinical outcomes. Over 60% of the patients required renal replacement therapy or died in a short follow-up period. The 1 patient we identified with direct CNI toxicity underwent a successful living related kidney transplant 2 years after his biopsy was performed. We recognize that this study has several limitations that preclude our ability to draw firm conclusions about the etiology of post-transplant renal dysfunction. The first limitation is that a single renal biopsy allows us to see only one snapshot in time. If we performed serial biopsies, we may have been better able to describe the long-term structural changes occurring in the kidney after heart transplantation. A second limitation is the potential for referral bias. The patients in our series were sent for renal biopsy after developing CKD of a severity that warranted further evaluation. It is possible that there were patients with CNI nephrotoxicity who responded to CNI reduction and were never referred for biopsy. Our series also included several patients with significant proteinuria. Thus, the cohort of patients we biopsied may not necessarily be representative of the larger group of patients who develop CKD. Third, because we were not able to capture the total number of patients in our center with Stage 3 to 5 CKD followed during this time period, our data analysis does not allow us to accurately define the total population at risk. Nonetheless, we have published our earlier experience with CKD, and discovered that the incidence of chronic renal failure was 4.5% after 5 years. 18 Finally, ours is a small cohort, but represents the largest series of heart transplant recipients to have diagnostic renal biopsies reported. Many centers may be reluctant to

5 Pinney et al. Renal Failure After Heart Transplantation 237 perform percutaneous renal biopsies, but we were able to do so without complication. In conclusion, post-transplant CKD is a complex disorder with a varied pathologic basis. Further understanding of the renal injuries that precede heart transplantation and predispose to the progression of kidney disease after transplant is important to properly treat this population. Early evaluation and monitoring of kidney disease remain critical in transplant recipients and consideration should be given to performing a renal biopsy to define the pathology underlying renal failure. Furthermore, management should be directed at the underlying cause, namely by targeting lower blood pressure, achieving good glycemic control and correcting anemia, rather than by obligatorily changing immunosuppressive regimens. Disclosure statement The authors have no conflicts of interest to disclose. References 1. Ojo AO. Renal disease in recipients of nonrenal solid organ transplantation. Semin Nephrol 27: Ojo AO, Held PJ, Port KF, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003;349: Norman SP, Ojo AO. Trends Transplant 2009;3: Jokinen JJ, Tikkanen J, Kukkonen S, et al. Natural course and risk factors for impaired renal function during the first year after heart transplantation. J Heart Lung Transplant 2010;29: Greenberg A, Egel JW, Thompson ME, et al. Early and late forms of cyclosporine nephrotoxicity: studies in cardiac transplant recipients. Am J Kidney Dis 1987;9: Myers BD, Newton L. Cyclosporine-induced chronic nephropathy: an obliterative microvascular renal injury. J Am Soc Nephrol 1991; 2(suppl 1):S Griffiths MH, Crowe AV, Papdaki L, et al. Cyclosporin nephrotoxicity in heart and lung transplant patients. Q J Med 1996;89: Campistol JM, Sacks SH. Mechanisms of nephrotoxicity. Transplantation 2000;69(suppl):SS Davies DR, Bittman I, Pardo J. Histopathology of calcineurin inhibitor-induced nephrotoxicity. Transplantation 2000;69(suppl):SS Olyaei AJ, de Mattos AM, Bennett WM. Nephrotoxicity of immunosuppressive drugs: new insight and preventive strategies. Curr Opin Crit Care 2001;7: El-Zoghby ZM, Stegall MD, Lager DJ, et al. Identifying specific causes of kidney allograft loss. Am J Transplant 2009;9: Kim JY, Akalin E, Dikman S, et al. The variable pathology of kidney disease after liver transplantation. Transplantation 2010;89: Lewis RM, Verani RR, Vo C, et al. Evaluation of chronic renal disease in heart transplant recipients: importance of pretransplantation native kidney histologic evaluation. J Heart Lung Transplant 1994;13: Raichlin E, Khalpey Z, Kremers W, et al. Replacement of calcineurininhibitors with sirolimus as primary immunosuppression in stable cardiac transplant recipients. Transplantation 2007;84: Baran DA, Segura L, Kushwaha S, et al. Tacrolimus monotherapy in adult cardiac transplant recipients: intermediate term results. J Heart Lung Transplant 2001;20: Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999;130: Churg J, Bernstein J, Glassock RJ, eds. Renal disease: Classification and atlas of glomerular disease [ed. 2]. Tokyo, Igaku-Shoin Lubitz SA, Pinney S, Wisnivesky JP, et al. Statin therapy associated with a reduced risk of chronic renal failure after cardiac transplantation. J Heart Lung Transplant 2007;26:

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