Cardiac transplantation and cyclosporine nephrotoxicity

Transcription

1 & 2007 International Society of Nephrology the renal consult Cardiac transplantation and cyclosporine SB Ahmed 1, SS Waikar 2, HG Rennke 2,3 and AK Singh 2 1 Department of Medicine, Foothills Medical Centre, University of Calgary, Calgary, Alberta, Canada; 2 Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts, USA and 3 Department of Pathology, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts, USA CASE PRESENTATION A 26-year-old Caucasian man with a history of viral myocarditis and subsequent heart transplant at age 13 underwent a kidney biopsy for rapidly deteriorating renal function. The patient s baseline serum creatinine was mg/dl ( mmol/l) with 3 þ albuminuria by dipstick, but had recently increased to 4.8 mg/dl (422 mmol/l) over a 5-month period. His immunosuppressive regimen included azathioprine, prednisone, and cyclosporine (CsA); the latter was changed to sirolimus 6 months before presentation without improvement in renal function. Treatment with sirolimus led to the development of acne, which was treated with a 5-month course of cephalexin. Empiric therapy with prednisone for presumed allergic interstitial nephritis was ineffective after 2 weeks of therapy. Past history was otherwise remarkable for hypertension and hyperlipidemia. Physical examination revealed a well-appearing man. His blood pressure was 156/96, heart rate was 92, and he was afebrile. His jugular venous pressure was not elevated and there was trace peripheral edema. The remainder of the examination was unremarkable. Laboratory values are shown in Table 1. The serological work-up for a secondary cause for his nephrotic-range proteinuria was negative. He subsequently underwent renal biopsy to guide therapy. Correspondence: SB Ahmed, th St NW, C201D, Calgary, Alberta, T2N 2T9 Canada. sofia.ahmed@calgaryhealthregion.ca Kidney International (2007) 72, ; doi: /sj.ki ; published online 16 May 2007 Received 1 February 2007; revised 3 April 2007; accepted 17 April 2007; published online 16 May 2007 RENAL BIOPSY FINDINGS Light microscopic examination revealed extensive cortical atrophy, with focal glomerular and tubular changes present suggestive of a collapsing glomerulopathy and possibly secondary to superimposed structural and functional adaptations. Extensive glomerular sclerosis, tubular atrophy, and interstitial fibrosis were present affecting approximately 70% of the kidney parenchyma, in addition to prominent arterial sclerosis and arteriolar hyalinosis. Immunofluorescence revealed no significant immune deposits in the glomeruli. Segmental, irregular granular deposition of IgM and C3 was present in the mesangial areas, and the tubules contained reabsorbed proteins (albumin, IgG, and C3) in the form of diffuse cytoplasmic granules. Electron microscopy showed extensive injury of the visceral epithelium characterized by focal effacement of foot processes and prominent vacuolization of the epithelial cell cytoplasm. Focal and segmental collapse of capillaries with entrapment of hyaline was noted. DIAGNOSIS Collapsing glomerulopathy with extensive cortical atrophy and focal global and segmental glomerulosclerosis. Arterial sclerosis and arteriolar hyalinosis, possibly related to CsA therapy. CLINICAL FOLLOW-UP After the diagnosis of collapsing glomerulopathy, the patient was started on captopril 6.25 mg po t.i.d., which was subsequently discontinued as his serum creatinine increased from 4.8 mg/dl (424 mmol/l) to 7.3 mg/dl (645 mmol/l) over a 6-day period. He progressed to end-stage renal disease (ESRD) over the next 7 months and initiated peritoneal dialysis before undergoing living-unrelated renal transplantation 12 months after renal biopsy. At last follow-up, 6 months after renal transplantation, the serum creatinine was 1.4 mg/dl (124 mmol/l) with no proteinuria on urinalysis (Figure 1). DISCUSSION Collapsing glomerulopathy (CG) is a morphologic variant of focal segmental glomerulosclerosis (FSGS), characterized by segmental and global collapse of the glomerular capillaries, marked hypertrophy and hyperplasia of podocytes, and severe tubulointerstitial disease, 1 and presents with heavy proteinuria, renal insufficiency, and rapid progression to ESRD. 2 The cause of this podocyte disorder is unknown, and CG has been reported as an immunological, viral, toxinrelated or inherited disease with similar renal survival Kidney International (2007) 72,

2 t h e r e n a l c o n s u l t SB Ahmed et al.: Cardiac transplantation and cyclosporine outcomes, 3 suggesting that the characteristic renal pathology may simply be the final common pathway to glomerular obsolescence. The patient s previous exposure to parvovirus B19 may have contributed to the development of CG; 4 although this virus is also commonly found in the general population. Long-term CsA use has been associated with FSGS and, at least in renal transplant patients, 5 the development of CG. In the absence of other secondary causes of CG in our patient, we concluded that the renal pathology primarily reflected longstanding damage consistent with calcineurin-inhibitor. Clearly, however, we could not rule out the possibility that an undetected viral infection was playing a causative role or that this was simply a primary FSGS, although given the tendency of Table 1 Laboratory values Serum/blood (reference range) Blood urea nitrogen (mg/dl) 64 (7 22) (29 mmol/l ( )) Creatinine (mg/dl) 4.8 ( ) (424 mmol/l (62 115)) Urine (reference range) Urinalysis ph 6, specific gravity 1.020, 1+blood, 3+protein, all else negative Microscopy Nondysmorphic red blood cells, white blood cells, and hyaline casts Protein/creatinine (mg/mg) 4.59 (o0.15) Serologic tests (reference range) Hepatitis B antigen Hepatitis B and C antibodies HIV antibody ANA Complement CH 50 (U/ml) 226 ( ) C3 (mg/dl) 116 (90 180) C4 (mg/dl) 33 (10 40) ANCA Anti-glomerular basement membrane antibody Parvovirus B19 IgG 3.11 (positive41.10) Parvovirus B19 IgM 0.11 (negativeo0.9) ANCA, anti-neutrophil cytoplasmic antibody. idiopathic FSGS to recur post-renal transplant, the latter diagnosis is less likely. 6 CYCLOSPORINE NEPHROTOXICITY AFTER CARDIAC TRANSPLANT CsA is considered to be the main cause of renal dysfunction post-cardiac transplant. Features of CsA-associated are outlined in Table 2. Irreversible CsA has been reported after heart, liver, lung, pancreas, and bone marrow transplantation as well as in patients with uveitis, diabetes mellitus, rheumatoid arthritis, and psoriasis. 7 In the heart transplant population, chronic CsA toxicity is responsible for a 10% prevalence of ESRD occurring by 10 years post-heart transplantation, 8 whereas results are even more dismal after heart lung transplantation, with a 10% prevalence of ESRD within 5 years. 9 After heart transplantation, there is loss of renal function within 3 6 months which is both CsA dose-dependent 10 and progressive. 11 CsA-induced is characterized by an initially reversible decline in glomerular filtration rate (GFR), which is likely caused by a direct drug-induced afferent arteriolar vasoconstriction, leading to renal hypoperfusion and salt and water retention associated with hypertension. 7 The mechanisms underlying renal vasoconstriction and hypofiltration are unclear, but abnormalities in endogenous Table 2 Clinical and pathological spectrum of CsA-associated Sodium retention and edema Electrolyte disorders (hyperkalemia, hypomagnesemia, hyperchloremic metabolic acidosis, hyperuricemia) Hypertension Proteinuria (nonnephrotic or nephrotic range) Acute reversible, chronic nonprogressive, and chronic progressive decrease in GFR ESRD Acute thrombotic microangiopathy Isometric tubular vacuolization Hyaline arteriolopathy Interstitial fibrosis (typically patchy or striped ) Segmental to global glomerulosclerosis with hypertrophy of remaining glomeruli CsA, cyclosporine; ESRD, end-stage renal disease; GFR, glomerular filtration rate. Figure 1 Renal histology (light microscopy). (a) The cortex reveals extensive tubular atrophy, marked sclerosis of the arterial walls and hyaline degeneration of arterioles (arrows). Two glomeruli reveal global sclerosis, and one glomerulus in the upper right corner shows a collapsing lesion. There is also widespread tubular atrophy present (periodic acid-schiff stain). (b) The glomerular tuft shows extensive collapse of capillaries, early hyaline entrapment, and prominence and crowding of glomerular epithelial cells (periodic acid-schiff stain). (c) Three tubules to the left side reveal microcystic changes and contain weak periodic acid-schiff -positive cast material. Two proximal tubules (right side of the photomicrograph) contain prominent protein reabsorption granules. The interstitium is expanded by connective tissue and mild inflammation (periodic acid-schiff stain) Kidney International (2007) 72,

3 SB Ahmed et al.: Cardiac transplantation and cyclosporine t h e r e n a l c o n s u l t vasoconstrictor and vasodilator mechanisms may be responsible. 7 Predictive factors in the development of cyclosporine Identification of risk factors in the development of CsA has proven to be difficult, and somewhat controversial (Table 3). There appears to be general agreement that physicians should prescribe the lowest possible dose that still provides therapeutic benefit, although the optimal dosing regimen remains unclear. High CsA levels early in the post-transplant period may contribute kidney failure: in a study of pediatric cardiac transplant recipients, Hornung et al. 12 demonstrated that decline in renal function after heart transplantation correlates with early CsA exposure, and that renal dysfunction persisted even after reduction in CsA dose. However, two large studies by Zietse et al. 11 and Lindelow et al. 13 demonstrated no relationship between the CsA concentration and the decline in renal function measured as the slope of serum creatinine as a function of time or by serial GFR measurements. A case control study by van Gelder et al. 14 showed that CsA doses and trough levels in the 24 heart transplant patients who developed ESRD were not different from the patients maintaining stable renal function, suggesting that CsA is the result of an individually determined susceptibility to the calcineurin inhibitor. Certainly, some of the variability in interindividual CsA side-effect profile disposition has been attributed to differences in the expression of the metabolizing enzymes cytochrome P450 3A4 and 3A5, and in the expression of the drug transporter P-glycoprotein encoded by the ABCB1 gene. 15 In addition, the method of CsA administration is likely relevant because GFR has been reported to improve if CsA is given once rather than twice daily in stable heart transplant patients. 16 Age plays a controversial role in the development of renal failure after heart transplantation, with some studies showing that kidney disease was not limited to elderly patients with ischemic heart disease, but also occurred in young patients Table 3 Potential risk factors for development of CsA Risk factor Older age at time of transplant Ischemic cardiomyopathy in native heart Female gender Elevated CsA trough levels in early post-transplant period Hypertension + Preoperative renal dysfunction Diabetes mellitus Hyperlipidemia + No calcium channel blocker use + Urinary retinol-binding protein 40.4 mg/l Unknown Cytochrome P450 3A4 and 3A5, drug Unknown transporter P-glycoprotein expression CsA, cyclosporine. Presence or absence of risk factor in current case having dilated cardiomyopathy, 11,14 whereas others show age to be an independent predictor of post-cardiac transplant renal dysfunction. 13,17,18 Male gender may be protective, 19 and it is postulated that this is secondary to the increased nephron endowment in men compared to women. Blood pressure has been negatively correlated with rate of GFR decrease in cardiac transplant recipients. 18,20 Although some groups have reported no correlation between preoperative renal function and post-transplant risk of chronic kidney disease, 13 others have found that an impaired preoperative GFR increased the risk of renal failure. 18,19 Risk factors for cardiovascular disease, such as hyperlipidemia 21 and diabetes, 18,19 have been reported to contribute to progression of renal dysfunction in this population, although it is difficult to know if the presence of these risk factors accelerates progression of CsA specifically, as most studies do not include renal biopsy data. Retinol-binding protein is a small globular protein that is filtered by glomeruli and almost totally reabsorbed by the proximal tubules. Urinary excretion increases in the presence of proximal tubule dysfunction. 22 CsA is associated with irreversible tubular injury, and Câmara et al. 23 found that high urinary retinol-binding protein concentrations predicted those heart transplant recipients who were at highest risk of progressive renal failure, suggesting that such patients may benefit from a reduction in CsA dose to limit renal damage. Renal histology Renal histology from native kidneys exposed to long-term CsA shows a variable amount of both global and segmental glomerular sclerosis with a tendency for remaining functional glomeruli to be larger, consistent with glomerular hyperfiltration and increasing proteinuria. 10,24 In contrast to native kidneys, the glomerular collapse in renal allografts is associated with obliterative vascular changes with a zonal distribution, possibly related to uneven distribution of the blood supply. 25 These changes are possibly secondary to progressive arteriolar vasculopathy leading to glomerular ischemia and tubular atrophy, changes which are seen as early as after 2 years of low-dose CsA therapy. 24 The pattern of loss initially results in a characteristic appearance of striped tubular atrophy and fibrosis which begins in the medulla and progresses to the medullary rays of the cortex. In a study examining the renal pathology of heart lung transplant recipients, changes were noted in both the endothelial and vascular smooth muscle cells. 26 Interestingly, although cardiac transplant patients treated with low doses of CsA had slightly lower mean serum creatinine concentrations, similar pathological changes were seen on renal biopsy when compared to those treated with higher doses, 27 suggesting that low versus high dosage of CsA confers only marginal protection against this serious microvascular injury. Pathogenesis The pathophysiology of CsA is unclear. There appears to be dissociation between progressive tubulointer- Kidney International (2007) 72,

4 t h e r e n a l c o n s u l t SB Ahmed et al.: Cardiac transplantation and cyclosporine stitial and arteriolar disease and renal function with use of CsA. In a study of uninephrectomized rats on either low- or high-salt diets treated with CsA or placebo, Elzinga et al. 28 found that although GFR was similarly depressed in CsAtreated animals on either diet, tubulointerstitial injury was largely confined to salt-depleted CsA-treated rats. Long-term CsA treatment reduces the salinity/tonicity of the renal medullary interstitium as a result of inhibition of active sodium transporters, leading to downregulation of tonicityresponsive enhancer binding proteins, which protect the renal medulla from the deleterious effects of hyperosmolality; 29 it is thus plausible that salt deficiency accelerates this process. In contrast, Mervaala et al. 30 reported a detrimental interaction between increased sodium intake and CsA treatment in spontaneously hypertensive rats. Interestingly, both the models of high-sodium intake and extreme salt deficiency are associated with activation of the reninangiotensin system. 28,30 Animal models of CsA have shown that blockade of the renin-angiotensin system protects the kidneys from morphological vascular and tubulointerstitial injury, but without any effect on the decline of GFR, 31 whereas endothelin antagonism prevented the decrease in GFR without protecting against morphological injury. 32 Certainly, rat models exposed to CsA have demonstrated increased amounts of renin in the juxtaglomerular apparatus and in hilar arterioles, with increased expression of AT1 receptors. 33 These reports suggest that angiotensin II, but not endothelin, is involved in the development of CsA-induced renal fibrosis. Calcineurin-inhibitor-induced renal vasoconstriction and chronic ischemia are also associated with upregulated intrarenal expression of the transforming growth factor-b1 in a dose-dependent manner, which is known to cause irreversible glomerulosclerosis and tubulointerstitial fibrosis. 34 Although the use of ACE inhibitors has not been shown to date to impact long-term renal function in cardiac transplant recipients, 13 there are reports of calcium channel blockers having a favorable effect on post-heart transplant renal function. 35 Of note, there is evidence that use of tacrolimus, a newer calcineurin inhibitor (CNI) with similar pharmacologic characteristics as CsA, may have a better side-effect profile with respect to renal function compared to CsA. 36 STRATEGIES TO PREVENT CYCLOSPORINE NEPHROTOXICITY In terms of strategies to reduce the risk of CsA-induced, it is generally agreed that close monitoring of CsA levels is imperative in limiting the degree of kidney damage. As there are numerous drugs affecting the metabolism of CsA, the initiation or withdrawal of new medications should be followed by careful follow-up of CsA levels. CNI-free immunosuppressive regimens in cardiac transplantation are currently being explored, and newer agents, such as the targets of rapamycin protein inhibitors sirolimus and everolimus, may play a significant role in care of the heart transplant patient. 37 However, caution should be exercised with the use of sirolimus in the treatment of FSGS, as it been associated with and significant increases in proteinuria; withdrawal of the drug appears to reverse the proteinuria. 38 Attempts to prevent renal dysfunction should occur at an early stage post-transplant; therapy may include calcium channel blockers and probably renin-angiotensin system blockade, prevention of rejection episodes, avoidance of nephrotoxins, and treatment of risk factors for kidney disease, such as diabetes mellitus and hypertension. CONCLUSION Nephrologists caring for patients with cardiac transplants should be aware of the nephrotoxic effects of CsA, as longterm renal failure is a major contributor to poor prognosis after heart transplantation, with calcineurin-inhibitor being the leading pathogenic cause of renal impairment. There is unfortunately no universally accepted accurate marker or predictor of the development of kidney disease in patients exposed to CsA, although there is increased interest in the impact of genetic polymorphisms and hence individual susceptibility to CsA-associated. The literature suggests that an immunosuppressive regimen that lowers or even avoids calcineurin inhibitors with the addition of new anti-rejection agents such as mycophenolate mofetil or sirolimus may be of benefit, although this must be balanced with the risk of rejection and possible worsening of, outlining the need for a close clinical relationship between the cardiologist and the nephrologist caring for the heart transplant patient. REFERENCES 1. Schwimmer JA, Markowitz GS, Valeri A et al. Collapsing glomerulopathy. Semin Nephrol 2003; 23: Weiss MA, Daquioag E, Margolin EG et al. Nephrotic syndrome, progressive irreversible renal failure, and glomerular collapse : a new clinicopathologic entity? Am J Kidney Dis 1986; 7: Laurinavicius A, Hurwitz S, Rennke HG. Collapsing glomerulopathy in HIV and non-hiv patients: a clinicopathological and follow-up study. Kidney Int 1999; 56: Moudgil A, Nast CC, Bagga A et al. 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