Long term results and complications of renal transplantation: Observations in the third decade

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1 155 ARTICLE Long term results and complications of renal transplantation: Observations in the third decade VK Rao Professor of Medicine, University of Minnesota Medical School, Minneapolis Abstract Approximately one sixth of patients receiving renal transplants have a functioning kidney beyond 20 years. Chronic rejection is the predominant cause of graft loss. Malignancy, cardiovascular disease, hepatic failure and infection are the major causes of late death. Early detection and control of risk factors that contribute to patient death should favourably influence the long-term success of renal transplantation. Although renal transplantation as a treatment for endstage renal failure has been in existence since the early 60 s 1, its impact on long-term outcome to a large extent remains unknown. Very few centers have had a cohort of patients who survived with a functioning kidney into the 3rd decade. The two prior reports that described the experience with renal transplantation in the 3rd decade have addressed it at a superficial level 2,3. Some of the difficulties in generating the long-term data may perhaps be due to the lack of systematic follow up by the original center. Most major transplant programs in the United States are tertiary care referral centers, and the academic faculty practicing at these institutions have multiple other commitments. They may not have the time to provide on going primary care to their transplant recipients. At the Hennepin County Medical Center in Minneapolis, we have committed ourselves to provide comprehensive care to our renal transplant recipients. All post transplant medical and surgical complications are managed under the guidance and direct supervision of faculty physicians on the transplant service. The clinical and laboratory data and medication list of each patient are monitored by trained nurse coordinators and reviewed by the transplant nephrologist at minimum monthly intervals. These data are recorded in the patient s clinic flow sheet and transmitted electronically to the computer files within the Regional Kidney Disease Program (RKDP) database. In addition, all patients with a functioning kidney are routinely seen in the transplant clinic for their annual evaluation, at which time the nephrologist reviews the complications which occurred during the preceding 12 months, and Address for Correspondence: VK Rao, MD Hennepin County Medical Center 701 ParkAvenue Minneapolis, MN 55415, USA raoxx007@tc.umn.edu outlines a plan for the management of existing problems. The systematic follow up of all transplanted patients by the same group of physicians and surgeons helped us to accumulate the data required to analyze the long-term results of renal transplantation.. Methods Between May 2, 1968 and June 30, 1979, 265 patients received consecutive renal transplants at the Hennepin County Medical Center, Minneapolis, MN. For the purpose of this study, patients who received multiple transplants were considered as new patients with each subsequent transplant. The end points for our observation were: a) patient death, b) kidney loss or c) June 30, 1999 which ever came first. Thus, all patients included in this study were exposed to the risk of transplantation and immunosuppression for a minimum period of 20 years. Of the original cohort of 265 patients, 108 (41%) died and 110 (41%) returned to dialysis within 20 years of their transplantation. The remaining 47 patients (18%) who survived with a functioning kidney, and who were followed by us during the 3rd decade of their transplantation, constituted the study population. Table 1 shows the demographic data of these late survivors. Of the total 47 patients, 23 were males, 43 were Caucasians, 42 underwent splenectomy, 45 received ALG for induction therapy and 19 were recipients of live donor transplants. All received pre transplant blood transfusions. Mean age at transplantation was 3 1±10 years. Mean follow up during the third decade was 3.2±2.6 years. Their maintenance immunosuppression consisted of Azathioprine 1.6±0.5 mg/kg/day and prednisone 8±2 mg/day. The etiology of renal disease in these long-term survivors is shown in Table 2. Systemic diseases accounted for renal failure in 7 (15%). of those with a primary renal

2 156 Indian Journal of Nephrology Indian J Nephrol 2001;11: Table 1 : Demographic Data N % Mean±SD Male gender Pre-tx splenectomy Prior renal txs 5 11 High PRA (> 50%) 5 11 Years of tx Years of tx Live donor renal txs A-B antigen mismatches 1.1±0.98 (number) Age at tx (years) 31±10 Azathioprine dose 1.6±0.5 (mg/kg/day) Predinisone dose 8±2 (mg/day) Post-tx followup (years) 23.2±2.6 Tx: transplant PRA: Panel Reactive Antibodies ALG: Anti Lymphocyte Globulin disease, chronic glomerulonephritis was the most frequent, which affected 14 (30%) patients. Our policies regarding recipient selection, immunosuppression therapy and follow up care have been described previously 4,5. At the annual visits, along with medical evaluation, each patient underwent psychosocial assessment by our clinic social worker. The rehabilitation status was classified into 3 categories: 1) full rehabilitation, if the patient is able to perform all routine activities similar to another individual of the same age and sex, 2) partial rehabilitation, when the patient is able to perform most normal activities but has some functional limitations, 3) medically disabled, when the patient has become disabled as a consequence of a severe medical or surgical complication that occurred in the post transplant period. The criteria that we used for the diagnosis of a late rejection and other medical complications were previously described 5,6. Since a particular complication (such as infection) could occur more than once in a given patient, the frequency of each major complication was determined by the number of patients exhibiting that particular problem among the total group of 47 patients. Prior complications that occurred and resolved during the first and second decades were not included in this analysis. Table 2 : Etiology of end stage renal disease N % Chronic glomerulonephritis Hypertension 5 11 Chronic pyelonephritis 6 13 Obstructive uropathy 4 8 Irreversible acute renal failure 2 4 Congenital/hereditary diseases 5 11 Other systemic diseases: 7 15 (Lupus 1, Scleroderma, 1, Diabetes 3, Wegeners 1, Renal vasculitis 1) Etiology unknown 4 8 Total The cumulative patient and graft survival rates were calculated by the standard life table method 7 and the graphs were plotted depicting 100% survival at 20 years. For statistical purposes, patient death with a functioning kidney was considered as graft failure. In addition, we performed multivariate analysis using the Cox regression model to determine the factors with a significant and independent effect on patient and graft survival results of the patients who survived into the third decade 8. Results The frequency of various complications observed in our patients followed during the third decade is depicted in Figure 1. Infection Of the 47 patients followed, 15 (32%) suffered from an infection. There were a total of 30 infectious episodes. Sites of infection were; urinary tract - 7, skin - 3, pulmonary - 7, upper respiratory tract - 3. One patient developed chronic CMV retinitis, requiring both local (intra ocular) and systemic therapy with Ganciclovir. The vision of this patient had stabilized after a period of 6 months of intensive treatment. Another patient developed septic arthritis involving the elbow. One had acute maxillary sinusitis. However, none had bacteremia or CNS infections. Of the different organisms causing infection, gram-positive bacteria were more prevalent; streptococcus - 5, enterococcus - 2, pneumococcus - 1; four infections were from E-coli and one was from salmonella. Others included, Candida in 3 patients, and CMV in one. Varicella pneumonia led to the demise of one of our late survivors.

3 Long term complications in renal transplantation 157 Fig 1: Frequency of complications observed in renal transplant recepients during the third decade of follow up Allograft Rejection Six patients (13%) experienced graft rejection. Histology showed chronic rejection only in 3 patients. The remaining 3 natients had 4 episodes of histologically confirmed acute rejection super imposed on chronic rejection. Following anti-rejection therapy (intravenous methyl prednisolone) partial recovery of renal function occurred on all four occasions. However, one of these patients with superimposed acute rejection and the other three with chronic rejection only eventually suffered graft loss and resumed chronic dialysis. Two of these 4 have subsequently received cadaver renal transplants. Vascular Occlusive Disease Nine patients (19%) showed clinical evidence of vascular occlusive disease. Coronary artery disease associated with angina was noted in two. one of them was treated with angioplasty and the other required 3-vessel coronary bypass. A 70-year-old woman developed a non Q wave anterior wall MI, 21 years after renal transplantation. She underwent a 3-vessel (LAD, circumflex and RCA) coronary artery bypass surgery. Peripheral arterial occlusive disease was responsible for amputation of both legs in a 51-year-old non-diabetic male. This individual also suffered from postoperative pulmonary embolism and was managed successfully with anti-coagulant drugs. Unexplained atrial fibrillation with rapid ventricular rate was noted two patients. One had reversal to normal rhythm following elective cardio version. Rate control in the second patient was achieved with Lanoxin and Diltiazem. One patient had recurrent hospitalizations for congestive heart failure and another man had surgical repair of abdominal aortic aneurysm. Hypertension and Hyperlipidemia Eighteen patients (38%) had clinical hypertension (>150/ 90 mmhg) requiring antihypertensive drug therapy and 12 (25%) had significant hyperlipidemia. Mean cholesterol level was 297 mg%. Nine of the 12 were treated with HMG CoA se inhibitors (Lovastatin, Pravastatin, Simvastatin, Atorvostatin). The average drop in serum cholesterol was 25% and none of them had rhabdomyolysis or significant liver dysfunction during therapy. Blood pressure control in these long-term survivors was achieved with a variety of agents including ACE inhibitors, calcium channel blockers and beta blockers. Diuretics were not routinely used to minimize the risk of hypovolemia and consequent azotemia. Malignancy Five of the 47 (11 %) suffered from malignancy in the 3rd decade. Three had severe skin lesions (squamous cell - 2 and basal cell - 1). Two had visceral malignancies (breast and bladder in 1 and Hepatic carcinoma in the other). Metastatic squamous cell carcinoma, which originated in the left ear, led to the demise of a 51 year old man 24 years after successful renal transplantation. This patient had a series of surgical procedures including excision of the local lesion, and radical neck dissection because of Iymph node involvement. Another 71-year-old woman suffered recurrent papillary carcinomas involving the bladder and needed repeated cystoscopies and fulguration of cancerous lesions within the bladder. Later she developed an infiltrative ductal carcinoma of the breast with lymph node metastasis and underwent radical mastectomy and chemotherapy with Tamoxifen. She is currently doing well with no signs of recurrence. Hepatic carcinoma contributed to the death of a 59-year-old woman, 21 years after cadaveric renal transplantation. Chronic Liver Disease Eight patients (17%) had clinical evidence of chronic liver diseases (abnorrnal liver function tests lasting for 6 months or longer). Three had viral hepatitis B. Three patients had hepatitis C and one had both hepatitis B and C infection. Two of the 8 patients did not have a liver biopsy. Histology in the remaining 6 showed features typical of chronic active hepatitis with piecemeal hepatocyte necrosis, extensive inflammatory cell infiltration and varving degree of fibrosis. A 62-year-old

4 158 Indian Journal of Nephrology Indian J Nephrol 2001;11: male with hepatitis B showed histological progression from chronic persistence hepatitis (CPH) to chronic active hepatitis (CAH) and micro nodular cirrhosis. The patient died eventually from hepatic failure 23 years after renal transplantation. Other gastrointestinal (GI) disorders Four patients (8%) developed gastrointestinal complications. These included diverticulitis of sigmoid colon in one, adenomatous polyp of rectum in one, hiatal hernia with gastro esophageal reflux in one. The fourth patient, a 55-year-old woman, experienced 2 episodes of upper GI bleed, from a pyloric channel ulcer. She also experienced an episode of acute pancreatitis secondary to gall stone disease and subseauentlv underwent elective cholecystectomy. Musculoskeletal problems Musculoskeletal problems were the most prevalent which affected 15 (32%) of our long-term patients. Half of them had bone fractures. Two patients had bone disease secondary to hyperparathyroidism. Two others suffered from prolapsed inter vertebral disc and required laminectomy and surgical removal of the prolapsed fragment. One had torn left knee medial ligament. Another patient has chronic hip pain but showed no evidence of avascular necrosis on imaging study. One patient has severe osteopenia and is presently receiving Fosamax treatment to improve her bone mineral density. Cataracts Six patients (13%) had visual problems secondary to the development of cataracts. Extraction of the cataract followed by lens implantation was carried out in 3 patients. The other 3 have decreased but stable vision. Other medical problems Twelve patients (25%) had suffered form a variety of other medical problems. They included; acute renal insufficiency secondary to hypercalcemia in one patient, mental depression needing psychiatric counseling and antidepressant medication in 3, multiple cutaneous warts needing laser excision in two, sleep apnea in one, extensive lipomatosis involving the thighs and trunk needing surgical resection in one and unexplained anemia in the other. Clinical outcome Of the 47 patients followed in the 3rd decade, eight (17%) died and four others (8%) suffered graft loss. The causes of death were, malignancy in three, liver failure in one, cardiac infarction in one, varicella pneumonia in one and bacterial pneumonia in two. Chronic rejection was the cause of graft loss in all four patients. Two of the four have subsequently received cadaver renal allografts. The cumulative patient and graft survival rates in the 3rd decade are shown in Figure 2. The 5 and 10-year patient survival rates were 75%. The corresponding graft survival rates were 60% and 48% respectively. The mean follow up was years (range years). Mortality rate in these long-term patients was 2.5% per year and graft attrition rate was an additional 2.5% per year. Rehabilitation At the time of their last annual assessment, 32 of the 47 patients (68%) were considered fully rehabilitated. Twelve patients (26%) were partially rehabilitated. Three patients (6%) were medically disabled. Of the 44 rehabilitated patients, 20 were gainfully employed, 16 were homemakers, six were retired and two were unemployed. Functional status of renal allografts Unexplained microscopic hematuria was noted in two of our patients. Four patients had proteinuria (>1gm/24 hrs). Two of them had massive proteinuria in the nephrotic range. The biopsy specimens in three patients showed features typical of chronic rejection with extensive interstitial fibrosis, vascular occlusion and glomerulosclerosis. One had recurrent IgA nephropathy. The mean serum creatinine level in those with functioning renal transplants was 1.6±0.6 mg/dl. Mean GFR as measured by creatinine clearance was 81±20 ml/min. Discussion Our data demonstrate that mortality and graft loss continues to occur in renal transplant recipients even after 20 years of stable allograft function. Eight of our 47 patients died and another four patients suffered graft loss in the 3rd decade of follow up. Malignancy, liver disease and vascular occlusive disease are the major contributors for death. One of our patients died of varicella pneumonia, rather unusual cause of death from an infectious etiology. Chronic allograft rejection led to kidney loss in all four Figure 2 : Patient and graft survival results during the third decade after renal transplantation

5 patients who later had returned to dialysis. Acute cellular rejection superimposed on chronic rejection was detected on four occasions in three patients. After steroid pulse therapy, partial improvement in graft function was noted in all. Acute renal failure from hypercalcemia was observed in one. The biopsy in this patient showed nephrocalcinosis. Following saline hydration, both hypercalcemia and graft dysfunction have resolved. It is obvious from our experience that renal transplant patients should be followed by their physicians at regular intervals even after 20 years of successful kidney transplantation. This will enable us to detect both reversible and non reversible causes of graft dysfunction. In the later situation one should avoid the usage of empiric and potentially toxic anti rejection medications. It is useful to note that partial recovery of renal function was achieved in those with histological features of acute cellular rejection. It is gratifying to know that excellent rehabilitation and preservation of renal function are possible in those with functioning allografts surviving into the 3rd decade. Many of our patients are gainfully employed outside the home. Despite low dose maintenance immunosuppression, many of our patients have experienced serious medical problems, which perhaps is a reflection of the long-term nature of therapy rather than the milligram dose of each drug per day. Although not fatal, these complications do contribute to patient morbidity and require prompt medical and surgical intervention. At this point in time, we can not predict whether the newer immunosuppressive agents, such as cyclosporine, tacrolimus, mycophenalate, or rapamycin, would have more or less complication rates, if their use is continued for 20 years or longer. Long term complications in renal transplantation 159 What measures should one take to lower patient morbidity and mortality in these long-term survivors? 1) Renal allograft recipients should have routine followup visits to the transplant clinic where an experienced team of nurses and physicians will be able to detect and manage the various post-transplant problems before they reach an irreversible stage. 2) Our data on patient morbidity and mortality clearly show that the principal cause of graft loss is not rejection, but death with a functioning kidney. The high mortality rate from causes such as malignancy, vascular occlusive disease, liver failure and infection is probably the result of cumulative long-term immunosuppression over a number of years. 3) Since most patients with impaired renal function remain asymptomatic, we recommend the use of renal allograft biopsy, to aid in the diagnosis and management of graft dysfunction. It is prudent that physicians should not resort to unnecessary and empiric anti rejection therapy with the assumption that renal dysfunction is always from an immunological rejection. 4) Besides the use of lower doses of maintenance immunosuppressive agents, other prophylactic measures such as early resection of cutaneous malignancies, control of blood pressure and serum lipids, vaccination against hepatitis B. and general surveillance to prevent the transmission of hepatitis C, would also aid in delaying the progression of vascular occlusive disease, hepatic failure and malignancies, which are the leading causes of death in long-term survivors of renal transplantation. References 1. Starzl, TE, Results and complications of renal transplantation. In Starzl TE, Ed. Experience in renal transplantation. WB Saunders Co., Philadelphia 1964; Braun, WE, Popowniak, KL, Tifford, RW, et al. The fate of renal allografts functioning for a minimum of 20 years. Am Soc of Transplant, Physicians 13th Annual Meeting, p 51 (Abstract) 3. Candinas, D, Keusch, G. Conrad B. et al. A 20 year follow up of cadaveric kidney allograft transplantation. Transplant Proc 1992; 24: Rao, KV, Andersen, RC, O Brien, TJ. Factors contributing to improved graft survival in recipients of kidney transplants. Kidney Int, 1983; 24: Rao, KV, Andersen, RC. Long-term results and compactions in renal transplant recipients: observations in the second decade. Transplantation, 1988; 45: Rao, KV, Rose JK. Incidence, histological pattern and clinical outcome of rejection episodes occurring in the late post transplant period. Transplantation, 1985: 40: Cutler, SJ, Ederer, F. Maximum utilization of life table method in analysis survival, J Chronic Dis 1965; 8: Cox, DR. Regression models and life tables (with discussion), JRoy Sta B. 1972; 34: