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A 56-year-old woman with a history of primary pulmonary hypertension and heart and lung transplantation was admitted to the hospital because of renal failure.
When the patient was approximately 43 years old, a diagnosis of primary pulmonary hypertension was made at another institution; progressive hypoxemia and polycythemia developed, and 3 years later (10 years before admission), heart and lung transplantation was performed at another hospital. The patient's symptoms improved, and oxygenation and hemoglobin levels returned to normal. Her medications included prednisone (10 mg daily), cyclosporine (225 mg twice daily), azathioprine (75 mg per day in divided doses), folate, hydralazine, furosemide, nifedipine, potassium sulfate, aluminum hydroxide, and trimethoprim for intermittent urinary tract infections.
During the next 10 years, the patient was followed by specialists in cardiology, pulmonary medicine, transplantation surgery, and nephrology. The levels of urea nitrogen and creatinine gradually rose, and proteinuria developed; urinalyses disclosed no increase in red or white cells or casts (Table 1). Seven months before admission, indirect immunofluorescence testing for antineutrophil cytoplasmic antibodies (ANCA) and an enzyme-linked immunosorbent assay for antibodies to p29 (proteinase 3) and to myeloperoxidase were negative. A test for antinuclear antibodies was positive at 1:160, with a speckled pattern. Ultrasonographic examination of the kidneys showed increased echotexture bilaterally. The right kidney was 10.5 cm in length and the left 8.7 cm. There was no evidence of hydronephrosis. The cyclosporine level was 239 ng per milliliter. Three months before admission, the erythrocyte sedimentation rate was 57 mm per hour (normal range, 1 to 25). The patient was admitted to this hospital for further evaluation.
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The patient's father had had hypertension and coronary artery disease and had died at the age of 78 years, and her mother had diabetes; her 25-year-old daughter was in good health. The patient did not smoke tobacco; she drank alcohol occasionally. On admission, her medications included cyclosporine, azathioprine (75 mg per day in divided doses), prednisone (5 mg per day), nifedipine, thyroxine, calcitriol, trimethoprim, oral clotrimazole, folic acid, calcium carbonate, multivitamins, and vitamin A; pneumococcal vaccine had been administered after her splenectomy.
On examination, the blood pressure was 130/80 mm Hg, the pulse 90 beats per minute, the temperature 36.4°C, and the oxygen saturation 99% when the patient was breathing ambient air. There was a well-healed scar over the sternum. The lungs were clear; there was a grade 2/6 systolic cardiac murmur and 1+ to 2+ edema of the hands and lower legs. Results of the remainder of the examination were normal. The complete blood count and levels of serum electrolytes, liver-function tests, and levels of total protein and albumin were normal. Results of other laboratory tests are shown in Table 1.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Nelson B. Goes: This patient presented with chronic kidney disease 10 years after successful heart–lung transplantation for idiopathic pulmonary hypertension. She had a history of intermittent urinary tract infections and a remote pretransplantation history of glomerulonephritis, with subsequent intermittent, low-grade proteinuria (non-nephrotic range) and normal urea nitrogen and creatinine levels (creatinine, 3.2 mg per deciliter [282.9 µmol per liter], creatinine clearance 21 ml per minute). She had a low positive titer on antinuclear antibody testing, negative results on ANCA testing, and an ultrasound showing asymmetry of the kidneys, increased echogenicity, and no evidence of hydronephrosis. Chronic kidney disease is categorized in five stages that are based on the estimated glomerular filtration rate, with stage 1 representing mild disease, and stage 5 kidney failure. According to this classification, the patient has stage 4 disease, a stage at which dialysis is likely to be required within a year and kidney transplantation needs to be considered.
Chronic Kidney Disease in Nonrenal Solid-Organ Transplantation
Chronic kidney disease is a common complication of nonrenal solid-organ transplantation.1 At 5 years, the cumulative incidence of chronic kidney disease is highest among recipients of intestine allografts (21.3%), followed by recipients of liver (18.1%), lung (15.8%), heart (10.9%), and heart–lung (6.9%) allografts. The risk continues to increase with the interval since transplantation. This patient, who received a heart–lung transplant 10 years ago, is at high risk for the development of chronic kidney disease.
In one study,1 29% of patients with chronic kidney disease after nonrenal solid-organ transplantation required renal replacement therapy. Chronic kidney disease increases the risk of death by a factor of 4 among recipients of nonrenal solid-organ transplants. Several factors are associated with chronic kidney disease in such patients, including female sex, older age, immunosuppressive treatment with calcineurin inhibitors, low glomerular filtration rate, presence of acute renal failure before or at the time of transplantation, and need for dialysis. The presence of underlying chronic renal disease may be missed in patients thought to have renal disease because of the failure of other organs (e.g., patients with very low cardiac output who are awaiting heart transplantation or those with the hepatorenal syndrome who are awaiting liver transplantation). The presence of hypertension and diabetes is associated with an increased risk of chronic kidney disease. More recent recipients of nonrenal solid-organ transplants are less likely to have chronic kidney disease, possibly because of more judicious use of immunosuppressive agents. Although the differential diagnosis in this case includes all causes of chronic kidney disease, I will specifically consider diseases that are common among patients who receive transplants (Table 2).
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Diabetes mellitus is an important complication of transplantation that contributes to chronic kidney disease. Weight gain is probably the most important factor predisposing patients to the development of diabetes mellitus after transplantation.2 The risk is also increased by exposure to corticosteroids and the calcineurin-inhibitor agents (cyclosporine and tacrolimus). Hypertension occurs in 80% of transplant recipients, is also related to the use of calcineurin inhibitors and corticosteroids, and may cause chronic kidney disease, as can some of the underlying disease processes that lead to end-stage organ failure necessitating transplantation, such as hepatitis C and amyloidosis.
Glomerular Disease
Could this patient have had a glomerular disease? At the age of 19 years, she had the nephrotic syndrome, but there was apparently no histologic diagnosis. She could have had minimal-change disease. She also could have had membranous glomerulonephritis, which is the most common cause of the nephrotic syndrome in white adults and can have a very long and indolent course with relatively preserved renal function. Indeed, about 25% of patients with membranous glomerulonephritis have a spontaneous remission.3 Could she have had systemic lupus erythematosus and lupus nephritis? At the age of 34 years, she had systemic and pulmonary hypertension, which can be complications of lupus. However, despite low antinuclear antibody titers on two occasions, she did not have other features of lupus.
Tubulointerstitial Disease
This patient, who was taking multiple medications and had multiple urinary tract infections, is at high risk for the development of chronic tubulointerstitial disease. She could have had undiagnosed episodes of pyelonephritis. She did not have exposure to nonsteroidal antiinflammatory agents. Transplant recipients have close follow-up and are typically compliant, so I would not expect her to have taken over-the-counter medications without her physicians' knowledge. Obstructive nephropathy has to be considered in this patient; she had a history of abdominal operations, but the renal ultrasonographic studies are not consistent with this disorder. Physicians caring for patients with transplants have to consider tumors that can develop in the immunosuppressed state. Both cytomegalovirus and polyomavirus BK (BK virus) nephropathy can also occur in immunosuppressed patients. Although BK-virus nephropathy is almost exclusively found among renal transplant recipients,4 there are reported cases in recipients of heart, lung, and kidney–pancreas allografts.5,6,7
Vascular Disease
In this patient, vascular diseases have to be considered not only because of her exposure to calcineurin inhibitors but also because of her history of pulmonary hypertension. She had no systemic features of scleroderma, and nothing suggested scleroderma in the native lung or allografts. She did not have systemic manifestations of vasculitis, but she could have had vasculitis limited to the kidneys. Hydralazine has been associated with Wegener's granulomatosis, but ANCA test results were negative; since these tests are very reliable, Wegener's granulomatosis is unlikely in this case.8
Thrombotic microangiopathy and the hemolytic–uremic syndrome are well-known complications of calcineurin inhibitors. The normal, stable platelet count in this patient would not support these diagnoses. She could have had isolated renal thrombotic microangiopathy with no systemic features, which is a possibility that I will keep in the differential diagnosis. Anticardiolipin or lupus anticoagulant antibodies can be seen in transplant recipients and contribute to thrombotic microangiopathy. This patient had asymmetrical kidneys and elevated cholesterol levels, and her immunosuppressed state increases the likelihood of renal-artery stenosis. Indeed, vascular complications (myocardial infarcts and strokes) are the main cause of death among transplant recipients.
Complications of Immunosuppressive Drugs
One has to consider immune and nonimmune complications of immunosuppressive drugs in the assessment of chronic kidney disease in patients who have undergone nonrenal solid-organ transplantation.9 The immune complications of immunosuppression include cancer and infections. Among malignant tumors, there is a predisposition to virus-related cancer, such as that in the skin and cervix, and to virus-related lymphoproliferative disorders. Although post-transplantation lymphoproliferative disease can develop in renal allografts, it is unlikely that both native kidneys would be involved after nonrenal transplantation. Finally, this patient's renal disease was indolent, developing over many years. All these factors make renal post-transplantation lymphoproliferative disease unlikely.
Nonimmune side effects occur with most immunosuppressive agents as well. Azathioprine, one of the oldest, is an antimetabolite that has toxic effects on the bone marrow and the liver. The inosine monophosphate dehydrogenase inhibitors, mycophenolate mofetil and mycophenolic acid, target T and B lymphocytes, since in contrast to all other cells in the body, lymphocytes lack an alternative pathway for synthesis of purines. These agents may cause anemia, leukopenia, and diarrhea, but they have not been associated with renal failure.
Calcineurin Inhibitors
The introduction of treatment with the calcineurin inhibitors, cyclosporine and tacrolimus, caused a revolution in the field of transplantation, making transplantation of lungs, heart, pancreas, and liver possible. These prodrugs cross the cytoplasmic membrane; cyclosporine binds cyclophilin and tacrolimus binds FKB12, forming complexes that prevent calcineurin from dephosphorylating the nuclear factor of activated T cells and preventing activation of target genes such as IL2. Both agents can cause hypertension, nephrotoxicity, the hemolytic–uremic syndrome, thrombotic microangiopathy, and diabetes.10,11,12 Calcineurin inhibitors also cause hyperlipidemia, which this patient had (Table 1). Hyperuricemia and neurotoxicity are also seen. The likely mechanisms of action include increasing peripheral vascular resistance5 and up-regulation of profibrogenic genes such as the gene for transforming growth factor 
.8,13
Calcineurin nephrotoxicity may be acute or chronic. Acute nephrotoxicity may be associated with renal thrombotic microangiopathy or the hemolytic–uremic syndrome, and it causes a reduction in the glomerular filtration rate (which is usually reversible) and hyperkalemia. Glomerulosclerosis may occur and is usually associated with high-grade arteriolar hyalinosis and vascular narrowing. Both focal segmental glomerulosclerosis and diffuse glomerulopathy have been associated with long-term use of calcineurin inhibitors.11,12 They are also associated with fibrosis of the renal interstitium. This patient had been taking cyclosporine for 10 years and had evidence of toxicity in the form of hyperlipidemia; the presence of slowly rising creatinine and non–nephrotic-range proteinuria is not typical for a glomerular process, but it does fit well with the course of chronic interstitial nephritis caused by exposure to calcineurin inhibitors.
TOR Inhibitors
Target of rapamycin (TOR) inhibitors block the cell cycle through their action on the intracytoplasmic protein TOR. There are two agents in this class, sirolimus and everolimus. Both are known to cause bone marrow suppression, hyperlipidemia, and delayed wound healing, and in renal-transplant recipients they prolong the period of recovery after episodes of acute tubular injury. Most patients who present with these complications recover shortly after these drugs are stopped. Acne, mouth ulcers, gastrointestinal symptoms, peripheral edema that can be asymmetric and is not associated with the nephrotic syndrome or congestive heart failure, venous thrombosis, and some degree of nephrotoxicity may occur. However, this patient was not taking a TOR inhibitor.
In conclusion, I believe that this patient's chronic kidney disease was induced by calcineurin inhibitors, specifically, cyclosporine. The diagnostic procedure should be a renal biopsy.
Dr. Nancy Lee Harris (Pathology): Dr. Bazari, would you summarize your thinking at the time that you saw this patient?
Dr. Hasan Bazari (Nephrology): She had progressive renal disease characterized by marked but non-nephrotic proteinuria, and like Dr. Goes, I thought that her condition was probably due to cyclosporine toxicity. One could speculate that she had secondary focal sclerosis. The question of whether her primary disease could have recurred is always in the background. We wondered about either membranous or focal and segmental glomerulosclerosis as the underlying preexisting diagnosis, but since her condition had been stable for years and chronic kidney disease occurred in the setting of exposure to a calcineurin inhibitor, we favored the diagnosis of cyclosporine toxicity. We performed a renal biopsy.
Clinical Diagnosis
Chronic kidney disease induced by the calcineurin inhibitor cyclosporine.
Dr. Nelson B. Goes's Diagnosis
Chronic kidney disease induced by the calcineurin inhibitor cyclosporine.
Pathological Discussion
Dr. Robert B. Colvin: A renal biopsy was performed, and 1 year later, after end-stage renal disease had developed, a nephrectomy was performed, with transplantation of a kidney from an unrelated living donor. Examination of the kidney by light microscopy showed widespread collapse of glomeruli and marked hyperplasia of podocytes, with reabsorption droplets, segmental and global scarring, hyalinosis, and adhesions (Figure 1A and 1C). The glomerular basement membrane was normal on periodic acid–Schiff staining (Figure 1C). A geographic distribution of the sclerosis (e.g., by vascular tree or corticomedullary junction) was not evident. Tubules showed marked focal dilatation with proteinaceous casts, reactive epithelial cells, and "anoikis" (or sloughing of epithelium — derived from the Greek word for "homeless") (Figure 1B). Occasional tubules had neutrophils, but there was no other evidence of pyelonephritis, and this is a common finding in end-stage kidney disease. Podocyte proliferation was evident on immunoperoxidase staining for Ki67 (Figure 1D). A nodular interstitial mononuclear infiltrate is present. Arteries are characterized by severe intimal fibrosis, which I would attribute to the long-standing hypertension. There is marked hyalinosis of arterioles, often circumferential and sometimes nodular on the external aspect of the arteriole — a feature of calcineurin-inhibitor toxicity (Figure 1A, 1E, and 1F). Several arterioles are occluded by hyaline and foam cells (Figure 1A and 1F).
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The glomerulonephritis that the patient had at the age of 19 years resolved, and it is not related to the current disease. Instead, the glomerular changes are typical of focal segmental glomerulosclerosis, which has five subtypes: collapsing, tip, cellular, perihilar, and not otherwise specified (or usual).14 The presence of collapsed glomeruli and marked podocyte reaction puts this case into the collapsing category. The collapsing variant of focal segmental glomerulosclerosis (also known as collapsing glomerulopathy)15 is a form of glomerular injury characterized by capillary collapse and visceral epithelial hypercellularity; it is often associated with nephrotic-range proteinuria and a rapid, progressive decline in renal function.14 Collapsing glomerulopathy is a pattern of injury that has several causes, including human immunodeficiency virus, treatment with pamidronate,16 heroin abuse, and parvovirus B-19 infection,17 but in a substantial number of cases there is no known cause. The common pathogenetic mechanisms are obscure, although hemodynamic disturbances, probably at the arteriolar level, are probably important in the pathogenesis of the collapsing lesions.18,19 The pathophysiological process that leads to this variant is believed to be dysregulation of the podocyte.20,21 Podocyte proliferation (not normally detectable) is typical of this disease, illustrated by the positive staining for Ki67 in this and other cases (Figure 1D).20,22
Glomerular Collapse as a Form of Cyclosporine Toxicity
Could the collapsing glomerulopathy in this case be due to cyclosporine toxicity? Glomerular collapse has been noted both at autopsy and on biopsy in more than 50% of native kidneys in patients with nonrenal solid-organ transplants who were treated with cyclosporine.23,24,25 The development of focal segmental glomerulosclerosis (type not otherwise specified) has been reported in up to 30% of renal-transplant recipients taking cyclosporine who have chronic allograft nephropathy 6 months or more after transplantation.26 Finally, collapsing glomerulopathy has been described in renal allografts in patients taking cyclosporine18,19,27 and has been associated with a high rate of renal failure and graft loss.
In this case, I believe that the vascular disease is the probable basis of the glomerular change. The arteriolar lesions are probably due to a combination of chronic cyclosporine toxicity, hyperlipidemia, and hypertension. A component of thrombotic microangiopathy cannot be ruled out.
Cyclosporine-Mediated Arteriolopathy
This case has features that are typical of chronic cyclosporine arteriolopathy, which is characterized by replacement of the degenerated smooth-muscle cells in the tunica media vasorum with hyaline deposits, which typically have a beaded pattern.28 The lesion begins and predominates in the afferent arterioles but may progress to the small arteries and efferent arterioles.24,29 This characteristic arteriolopathy has been found at autopsy in approximately half the native kidneys in patients treated with cyclosporine and in none of the patients who were not.23 Tacrolimus causes similar lesions.30
This is the second case that we have seen at this hospital of collapsing glomerulopathy in the native kidneys of a patient taking calcineurin inhibitors for a nonrenal solid-organ transplant; the other was in a patient with a liver transplant who was taking tacrolimus.
Dr. Harris: Dr. Bazari, how is the patient doing?
Dr. Bazari: As Dr. Colvin mentioned, after the biopsy the patient's renal function continued to deteriorate, necessitating dialysis, and a transplantation was performed 1 year later. Her immunosuppressive regimen includes prednisone, cyclosporine, and mycophenolate mofetil. The doses of antihypertensive medications were increased, and simvastatin was added; her lipid profile improved, and 6 years after the renal transplantation, the cardiac risk ratio was 2.4 (desirable ratio, less than 5) and the serum creatinine level was within the normal range, at 1.3 mg per deciliter (114.9 µmol per liter).
Anatomical Diagnoses
Collapsing glomerulopathy, associated with severe hyaline arteriolopathy, probably caused by chronic cyclosporine toxicity (with other potential factors including hyperlipidemia and hypertension).
Hypertensive arteriosclerosis.
Dr. Goes reports receiving consulting fees from Boehringer Ingelheim and grant support from Fujisawa Healthcare, and Dr. Colvin reports receiving grant support from the Roche Organ Transplant Research Foundation. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Nephrology Division, Department of Medicine (N.B.G.), and the Department of Pathology (R.B.C.), Massachusetts General Hospital; and the Departments of Medicine (N.B.G.) and Pathology (R.B.C.), Harvard Medical School.
References
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