Kidney disease is common in candidates awaiting heart transplantation. Preexisting renal insufficiency is a risk factor for posttransplant chronic renal failure; the latter is associated with increased morbidity and mortality. Abnormal kidney function in patients with heart failure can be secondary to poor renal perfusion and reversible hemodynamic factors or secondary to intrinsic parenchymal disease. Many of these patients have underlying conditions that are common risk factors for both ischemic heart disease and chronic kidney disease, most notably hypertension and diabetes mellitus.
In the past, renal insufficiency was considered a contraindication to heart transplantation (1, 2) and was associated with decreased posttransplant survival (3). In 2006, two thirds of US centers indicated that a serum creatinine of more than 3 mg/dL was an absolute contraindication for heart transplantation (1).
With advances in operative techniques and perioperative management, combined heart and kidney transplantation (HKT) is being performed in growing numbers. However, given the scarcity of organs, it is important to determine which patients will benefit from combined HKT versus heart transplantation (OHT) alone. For this purpose, it is necessary to distinguish reversible renal hypoperfusion from irreversible parenchymal disease. Patients with hemodynamically mediated renal failure are likely to recover their kidney function once they receive a heart transplant and adequate renal perfusion is restored (4).
In patients with end-stage heart failure, differentiating abnormal kidney function due to renal parenchymal disease from that due to hypoperfusion can be exceedingly difficult through noninvasive means. The medical history and previous laboratory results are helpful in determining the likelihood of intrinsic disease, especially if prolonged prior elevation in serum creatinine is present, but they cannot prove irreversibility. Renal imaging is helpful only if small or severely echogenic kidneys are seen on ultrasound, indicating chronic disease. Hence, in many patients, the cause of renal failure and the degree of reversibility will remain unclear. A renal biopsy may help identify those patients with significant underlying renal pathologic condition who would benefit from combined HKT. A similar approach has been successfully used in liver transplant recipients (5).
The objective of this study was to examine the utility of kidney biopsy in patients with renal insufficiency awaiting heart transplantation.
Thirty consecutive heart failure patients being evaluated for heart transplant who had significant renal disease received kidney biopsies at Columbia Presbyterian Medical Center between June 2001 and April 2009. Significant renal disease was defined arbitrarily by an estimated glomerular filtration rate (eGFR) by modification of diet in renal disease (MDRD) of less than 40 mL/min/1.73m2, proteinuria greater than 500 mg/day (as determined by 24-hr urine protein or spot protein to creatinine ratio) or history of amyloidosis irrespective of eGFR. There were 27 male and 3 female patients, with age ranging from 48 to 70 years. The causative factor of cardiomyopathy was ischemic in 13 patients, nonischemic in 10 patients, amyloid in 5 patients, and congenital heart disease in 1 patient. One patient had amyloid and ischemic heart disease. The nonischemic subset included patients with cardiomyopathy secondary to hypertension, adriamycin therapy and substance abuse, with the remaining having idiopathic dilated cardiomyopathy.
One patient experienced significant bleeding after kidney biopsy (defined by a need for blood transfusion or a procedure to stop bleeding). This occurred in the setting of low molecular weight heparin that was restarted 24 hr after the biopsy.
In evaluating the biopsies, we assessed the renal pathologic diagnosis, as well as the percent tubular atrophy and interstitial fibrosis (TA/IF) as a specific indicator of intrinsic renal disease severity and chronicity. Mild TA/IF was defined as involving less than or equal to 25% of the sampled cortex, moderate 26% to 50%, and severe more than 50%. Combined HKT was recommended for moderate and severe TA/IF, or mild TA/IF with significant glomerular pathologic condition.
The primary outcome was active listing for heart transplant and, where applicable, active listing for a dual cardiac/renal transplant. Secondary outcomes in patients transplanted included patient survival, need for postoperative hemodialysis, and serum creatinine 3 months after the transplant.
Table 1 summarizes the findings for all 30 patients at the time of transplant evaluation including the cause of heart failure, baseline creatinine and eGFR, degree of proteinuria, kidney size at the time of biopsy, and the renal histopathology findings.
Eight patients had proteinuria greater than 1500 mg/day at the time of biopsy (there were no patients with urine protein between 500 mg and 1500 mg). Their pathology included diabetic glomerulosclerosis (n=3), fibrillary glomerulonephritis (n=1), secondary/AA amyloidosis (n=1), membranous glomerulonephritis (n=1), ischemic nephropathy with IgA (n=1), and focal segmental glomerulosclerosis (n=1) secondary to obesity and hypertension. The degree of fibrosis varied from mild to moderate (20%–50%).
For the 19 patients with eGFR less than 40 mL/min and proteinuria less than 500 mg, the extent of fibrosis ranged from 5% to 60%. Etiologies included diabetic glomerulosclerosis (n=3), ischemic nephropathy (n=7), focal global glomerulosclerosis (n=3), calcineurin inhibitor (CNI) nephrotoxicity (n=1), hypertensive arterionephrosclerosis (n=2), renal amyloidosis (n=1), diffuse global glomerulosclerosis (n=1), and renal atheroembolic (n=1) disease.
Of the eight patients with ischemic nephropathy, four patients had significant tubular atrophy/interstitial fibrosis. All eight patients had comparable eGFR by MDRD ranging from 22.0 to 35.0 mL/min. Seven of them had less than 500 mg proteinuria/day. Kidney size ranged from 9.4 to 12.6 cm. These pathologic findings confirm that chronic hypoperfusion alone can lead to progressive structural lesions, which would not be expected to improve with heart transplantation alone. It also demonstrates that the degree of reversibility cannot be predicted based on the serum creatinine or the eGFR. For example, patient 5 in Table 1 had 5% TA/IF but his serum creatinine and eGFR on evaluation were 2.4 and 29.0 mL/min, respectively.
Of the five patients with cardiac amyloidosis, only one patient (patient 10) had extensive renal amyloidosis (secondary AA type) on biopsy and was recommended for a dual transplant. This patient had nephrotic range proteinuria (12.0 g/day) at baseline. The other four patients had a GFR ranging from 32.0 to 42.0 mL/min and proteinuria of less than 400 mg/day. Their pathologic conditions included renal vascular amyloid, ischemic nephropathy, hypertensive nephrosclerosis, and focal global glomerulosclerosis. All patients had minimal interstitial atrophy and therefore were listed for heart transplant alone. All five patients had kidney size ranging from 10.1 to 11.3 cm on ultrasound.
Based on the biopsy findings, OHT alone was recommended in 14 patients of whom 8 ultimately received a heart transplant. One patient (patient 3) with 20% fibrosis on biopsy was subsequently listed for combined HKT because of worsening renal function (creatinine increased from 2.1 to 2.4 mg/dL). Three patients were not listed because they were considered high risk by the heart transplant committee. One patient refused further evaluation and one patient was delisted due to severe comorbidities. The median follow-up was 18 months (range, 2–65 months; Table 2). None of the patients required renal replacement therapy (RRT) after OHT. The mean eGFR was 47.0 mL/min (range, 35.0–79.0 mL/min) 3 months after transplant. Of note, patient 12 had transthyretin amyloidosis and received combined liver and kidney transplant 1 year after heart transplant, as the patient's renal insufficiency had worsened after two bouts of urosepsis. The patient's nadir serum creatinine after OHT was 1.3 mg/dL and before the kidney transplant was 2.6 mg/dL.
Combined HKT was recommended for 16 patients based on their kidney biopsy results. One patient died before listing and six patients were deemed noncandidates (reasons included obesity, psychosocial barriers, and multiple comorbidities.). Of the nine patients who were eventually listed for HKT, two patients died while on the waiting list and three patients received combined HKT (Table 3). The remaining two patients were too hemodynamically unstable immediately after heart transplant to proceed with renal transplantation. One patient (20) subsequently received a successful living donor renal transplant 6 months later, his creatinine was 3.5 before the kidney transplant. The other patient (24) was initiated on dialysis 1 month before receiving the heart transplant, he remained dialysis-dependent posttransplant and died 2 years later of humoral rejection. No other deaths were reported to date in all the other patients who received OHT alone. Of the four patients who received combined HKT, one patient died, 29 months posttransplant, due to multiorgan failure in the setting of bowel obstruction.
Renal insufficiency is common in candidates being evaluated for heart transplant—many risk factors for renal disease and ischemic heart disease overlap and reduced glomerular filtration is a frequent consequence of severely reduced cardiac output. Mild renal dysfunction is also virtually universal after heart transplantation, with more severe disease present in 10.9% of patients (6). Acute renal failure is common in the perioperative period, frequently requiring RRT and alterations in immunosuppression regimens (7).
In a study of 370 patients who received heart transplant, the estimated mean GFR decreased by 24% within the first posttransplant year (8). Twenty-three percent of patients developed a 50% reduction in GFR by the third year, and 20% developed end-stage renal disease by the 10th year of follow-up. Low preoperative GFR was found to be a significant predictor of eventual end-stage renal disease. Furthermore, heart transplant patients with preexisting intrinsic renal disease were particularly vulnerable to posttransplant worsening of renal function in the setting of CNI toxicity.
Both pretransplant and posttransplant renal failure are associated with increased mortality (3, 9–12). In a retrospective review of 622 patients who underwent 628 heart transplants, Odim et al. found that a preoperative GFR (Cockroft-Gault formula) of less than 40 mL/min was associated with an early mortality of 17% compared with 7% mortality when GFR was greater than 40 mL/min. Patients with a preoperative GFR of less than 40 mL/min were also more likely to require postoperative dialysis than patients with a preoperative GFR of more than 40 mL/min (32% vs. 9%). In addition, recipients who required postoperative dialysis had greatly increased mortality regardless of preoperative creatinine clearance (CrCl). Early mortality was 41% for patients requiring dialysis postoperative versus 3% for patients not requiring dialysis. Ouseph et al. studied 52 patients who underwent heart transplant between 1995 and 1996 and found that the 1-year survival in patients who required postoperative continuous RRT was 36.5%, whereas those who did not had a 1-year survival of 91%.
Although renal insufficiency for many years was a contraindication to cardiac transplant, a variety of studies have shown that a combined HKT is a reasonable alternative to heart transplant alone (13) and that posttransplant mortality is similar in both procedures (14–16). Based on the Organ Procurement and Transplantation Network data as of January 21, 2009, patients who underwent combined HKT, between 2002 and 2007, had survival rates of 87.92% and 78.77% at 1 and 5 years, respectively. Infections (specifically bacterial septicemia) followed by cardiovascular disease accounted for most of the causes of death among the reported cases. Patients who received heart transplants alone had a similar 1-year survival of 87.74% and a 5-year survival of 73.11%. Cardiovascular complications including graft failure from acute rejection and cardiac arrest were more common than infectious complications.
Many studies also showed that when transplanted simultaneously, heart and kidney allografts are themselves protected from rejection and protect the other organ (16–18).
Given the inadequate supply of deceased donor organs, achieving adequate allocation of organs is crucial. Patients with no evidence of intrinsic renal disease are likely to recover renal function post-heart transplant while patients with any significant degree of intrinsic disease are more likely to experience progressive renal failure once started on CNIs. Hence, the optimal goal would be to allocate combined HKT to patients who would fare better with combined transplants and avoid kidney transplants in patients who would otherwise do well with heart transplant alone. This requires accurate assessment of the level of renal function and distinguishing patients with reversible kidney disease from patients with irreversible renal failure that is significant enough to compromise transplantation outcomes. Bergler-Klein et al. analyzed the renal plasma flow and GFR of the native and transplant kidneys in eight patients after a simultaneous HKT using a radioisotope scan. All subjects had been hemodialysis dependent before transplant. Radioisotopic scanning showed nonfunctioning of the native kidneys in patients with intrinsic renal disease but exhibited normal function of both native and transplant kidneys in patients without preexisting intrinsic renal disease (4). As such, it is critical to determine the cause and degree of kidney disease, during heart transplant evaluation, which can be exceedingly difficult.
The determination of renal function may itself be problematic. Many patients with severe congestive heart failure (CHF) are malnourished and have muscle wasting in which case normal serum creatinine levels may be misleading. Measurement of CrCl by 24-hr urine collection may be instructive. Smilde et al. compared [125I]-iothalamate clearance. Cockcroft-Gault (GFR), MDRD, simplified MDRD equations, and 24-hr CrCl in 110 patients with CHF. CrCl and GFR Cockcroft-Gault were the most accurate, whereas MDRD was the most precise formula. All formulas overestimated renal function at low GFR and underestimated renal function at high GFR. The predictive performance of the formulas was best in severe CHF (New York Heart Association classes III and IV) (19).
The medical history and previous laboratory results are also helpful. Recent normal serum creatinine levels suggest that renal function will recover once renal perfusion is improved after transplantation, whereas prolonged prior elevations in serum creatinine suggest but do not prove irreversibility. Many patients with heart failure are treated with increasing doses of diuretics and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, resulting in chronic, progressive elevations in serum creatinine level in the absence of structural renal damage. In patients with decreased eGFR, renal ultrasound to assess renal size and chronicity (small and echogenic kidneys indicate chronic disease), urinalysis to look for proteinuria or persistent microscopic hematuria (suggestive of underlying glomerular disease) and screening for renal artery stenosis in hypertensive patients are recommended diagnostic tests.
Russo et al. analyzed United Network for Organ Sharing data on 19,373 heart transplant recipients between January 1, 1995, and December 31, 2005. They created a risk score based on pretransplant characteristics that are associated with diminished survival. These included peripheral vascular disease, recipient age older than 65 years, nonischemic cause of heart failure, dialysis dependence at the time of transplantation, and bridge to transplantation using a ventricular assist device. Regression analysis was performed and weights were assigned for each risk factor. Further stratification by eGFR was performed based on a previous analysis of the United Network for Organ Sharing data where they found that an eGFR less than 33 mL/min served as the threshold for worse outcomes after heart transplantation alone. They noted that only patients with a low-risk score (<4) and an eGFR of less than 33 mL/min gained a survival benefit from HKT. There was a trend toward better survival in the moderate-risk group, but the difference was not significant. There was no survival benefit in the high-risk group. There was no benefit for HKT in patients with an eGFR greater than 33 mL/min irrespective of their risk score. They concluded that the use of the eGFR and their risk profile can guide the allocation of heart and kidney organs (20).
Tanriover et al. (5) created an algorithm to appropriately allocate organs for combined liver/kidney transplants. They used the duration of renal failure, GFR measured by the [125I]-iothalamate test and renal biopsy findings in their algorithms. The records of 196 patients who underwent liver transplant between March 2003 and December 2007 were reviewed. A cohort of 20 patients who underwent liver transplant evaluation under the proposed algorithm was identified. The 20 patients who underwent kidney biopsy had chronic kidney disease stage III (GFR <60 mL/min and >30 mL/min) for more than 3 months or had acute renal failure requiring dialysis for more than 1 month. Two patients had major bleeding episodes postbiopsy. Six patients underwent liver transplant alone (OLT) and four patients underwent combined liver kidney transplants. The average 12-month renal outcome was favorable in the OLT group (mean serum creatinine 1.3 mg/dL) and combined liver kidney transplant groups (mean serum creatinine 1.1 mg/dL). Among the six patients who underwent OLT alone, five had a GFR of less than 40 mL/min with minimal fibrosis on biopsy. On follow-up, their creatinine ranged between 0.9 and 1.5 mg/dL.
Our study suggests that kidney biopsy does in fact provide useful information regarding the cause and severity of kidney disease. When comparing the prebiopsy clinical data with the biopsy results, neither the cause of heart failure nor the GFR or the degree of proteinuria could reliably predict the renal pathologic diagnosis or the degree of TA/IF. For example, two patients with ischemic cardiomyopathy (patients 1 and 5 in Table 1), minimal proteinuria (<100 mg/24 hr) and eGFR of 27.0 and 29.0 mL/min had TA/IF of 50% and 5%, respectively. Patient 19 with eGFR of 24.0 mL/min and 4606.6 mg proteinuria had diabetic nephropathy on biopsy with 25% TA/IF, whereas patient 18 with eGFR of 28.0 mL/min and 1848.0 mg proteinuria had also diabetic nephropathy on biopsy but with 50% TA/IF. The lack of correlation between eGFR or creatinine and findings on biopsy was confirmed when plotting the data and finding the big splay in the serum creatinine and eGFR at different levels of TA/IF (Fig. 1). Patients with amyloid cardiomyopathy had different pathology findings on biopsy and four of five had minimal interstitial fibrosis and were recommended for heart transplant listing alone. In eight patients with ischemic nephropathy, the percentage TA/IF was a major determinant in the patient's transplant disposition. One patient, however, with 20% TA/IF was initially cleared for heart transplant alone but was subsequently listed for combined HKT in the setting of worsening renal function. Of note, patients with more than 1.5 g/24 hr proteinuria were more likely to have glomerular disease and moderate to severe fibrosis. In examining the outcome of patients who received OHT alone based on biopsy findings, none required RRT postoperatively or on further follow-up. One of seven patients subsequently underwent kidney transplant for worsening renal function.
There are a number of limitations to this study mainly the small sample size and retrospective design. The criteria of selecting patients were arbitrary and predate the criteria laid out by the study of Russo et al. However, using the GFR criteria used in that study would have led to an unnecessary renal transplant in patients 5, 11, 14, and 16 and would not have transplanted patients 2, 3, 17, and 28 who had moderate degrees of fibrosis or significant glomerular disease with an eGFR more than 33 mL/min. Other limitations relate to the fact that several patients died while awaiting organ transplant, some are still on the waiting list and the remaining were not felt to be suitable candidates by the heart transplant committee for other nonrenal comorbidities; their outcome using our criteria cannot be determined. Finally, the inclusion criteria for a renal biopsy were arbitrary but felt to represent a fair balance between risk and benefit. The study by Odim et al. (9) confirmed that a GFR less than 40 mL/min was associated with worse outcome.
In patients with heart failure who are being evaluated for cardiac transplant and who have concomitant renal insufficiency or proteinuria, a renal biopsy can provide useful diagnostic information to help differentiate intrinsic renal disease from renal hypoperfusion. This distinction can be valuable in guiding the decision for heart transplant alone versus combined HKT. We propose performing a kidney biopsy in OHT candidates with significant renal impairment or proteinuria to clarify these issues.
1. Mehra MR, Kobashigawa J, Starling R, et al. Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates—2006. J Heart Lung Transplant
2006; 25: 1024.
2. Miller LW. Listing criteria for cardiac transplantation: Results of an American Society of Transplant Physicians—National Institutes of Health Conference. Transplantation
1998; 66: 947.
3. Anguita M, Arizón JM, Vallés F, et al. Influence on survival after heart transplantation of contraindications seen in transplant recipients. J Heart Lung Transplant
1992; 11(4 Pt 1): 708.
4. Bergler-Klein J, Pirich C, Laufer G, et al. The long-term effect of simultaneous heart and kidney transplantation on native renal function. Transplantation
2001; 71: 1597.
5. Tanriover B, Mejia A, Weinstein J, et al. Analysis of kidney function and biopsy results in liver failure patients with renal dysfunction: A new look to combined liver kidney allocation in the post-MELD era. Transplantation
2008; 86: 1548.
6. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med
2003; 349: 931.
7. Stevens LM, el Hamamsy I, Leblanc M, et al. Continuous renal replacement therapy after heart transplantation. Can J Cardiol
2004; 20: 619.
8. Rubel JR, Milford EL, McKay DB, et al. Renal insufficiency and end-stage renal disease in the heart transplant
population. J Heart Lung Transplant
2004; 23: 289.
9. Odim J, Wheat J, Laks H, et al. Peri-operative renal function and outcome after orthotopic heart transplantation. J Heart Lung Transplant
2006; 25: 162.
10. Cipullo R, Finger MA, Ponce F, et al. Renal failure as a determinant of mortality after cardiac transplantation. Transplant Proc
2004; 36: 989.
11. Ouseph R, Brier ME, Jacobs AA, et al. Continuous venovenous hemofiltration and hemodialysis after orthotopic heart transplantation. Am J Kidney Dis
1998; 32: 290.
12. Canver CC, Heisey DM, Nichols RD. Acute renal failure requiring hemodialysis immediately after heart transplantation portends a poor outcome. J Cardiovasc Surg (Torino)
2000; 41: 203.
13. Leese DB, Jeevanandam V, Furukawa S, et al. Simultaneous heart and kidney transplantation in patients with end-stage heart and renal failure. Am J Transplant
2001; 1: 89.
14. Bruschi G, Busnach G, Colombo T, et al. Long-term follow-up of simultaneous heart and kidney transplantation with single donor allografts: Report of nine cases. Ann Thorac Surg
2007; 84: 522.
15. Blanche C, Kamlot A, Blanche DA, et al. Combined heart-kidney transplantation with single-donor allografts. J Thorac Cardiovasc Surg
2001; 122: 495.
16. Hermsen JL, Nath DS, Munoz del Rio A, et al. Combined heart-kidney transplantation: The university of Wisconsin experience. J Heart Lung Transplant
2007; 26: 1119.
17. Narula J, Bennett L, DiSalvo T, et al. Outcomes in survival of combined heart-kidney transplantation: Multiorgan, Same-Donor Transplant Study of the International Society of Heart and Lung Transplantation/United Network for Organ Sharing Scientific Registry. Transplantation
1997; 63: 861.
18. Rana A, Robles S, Russo MJ, et al. The combined organ effect: Protection against rejection? Ann Surg
2008; 248: 871.
19. Smilde TD, Van Veldhuisen DJ, Navis G, et al. Drawbacks and prognostic value of formulas estimating renal function in patients with chronic heart failure and systolic dysfunction. Circulation
2006; 114: 1572.
20. Russo MJ, Rana A, Chen JM, et al. Pretransplantation patient characteristics and survival following combined heart and kidney transplantation. Arch Surg
2009; 144: 241.