Recurrent and De Novo Renal Disease After Kidney Transplantation With or Without Cyclosporine A Anke Schwarz, MD, Peter-H. Krause, MD, Gerd Offermann, MD, and Frieder Keller, MD • We evaluated the clinical course of 700 renal transplantations, including 1,305 transplant histologies performed in 611 patients between 1970 and 1988, to estimate the influence of cyclosporine A (CsA) after kidney transplantation on the incidence of recurrent or de novo renal disease. Primary renal disease recurred In 11 of 583 functioning transplants (1.9%) with transplant loss in seven patients (1.2%): focal segmental glomerulosclerosis (FSGS, three patients); membranous glomerulonephritis (GN, one patient); mesangiocapillary GN (one patient); rapidly progressive IgA nephropathy (one patient); hemolytic-uremic syndrome (HUS, three patients); and oxalosis in two transplants (one patient). De novo renal disease occurred In six patients (1.0%), including mesanglocapillary GN type I (three patients); nonpurulent focal GN in septicemia (one patient); HUS (one patient); and nodular glomerulosclerosis In steroid diabetes (one patient). De novo membranous GN was seen in 14 additional cases (2.4%). No statistically significant difference could be established between the treatment groups without (n = 225) and with (n = 358) CsA in recurrent and de novo renal disease (n = 7/225 v 10/358, NS); in recurrent and de novo GN (n = 41 225 v 6/358, NS); in recurrent FSGS (n = 1/7 v 2/8, NS); in recurrent and de novo HUS (n - 111 v 2/7, NS); and in de novo membranous GN (n = 7/225 v 7/358, NS). Transplant loss by recurrent and de novo GN was higher without than with CsA (n = 4/4 v 1/6, P = 0.004). On the basis of our Investigation, we conclude that recurrent and de novo renal disease in the transplant occur rarely and are not prevented by CsA. However, even If the incidence of transplant GN is unchanged by CsA treatment, its clinical course seems to be mitigated. CsA treatment also does not Increase the incidence of HUS. © 1991 by the National Kidney Foundation, Inc. INDEX WORDS: Recurrent renal disease; recurrent focal segmental glomerulosclerosis; recurrent hemolytic uremic syndrome; de novo membranous glomerulonephritis; cyclosporine A.
R
ECURRENT renal disease in the transplant was a major problem in the early days of kidney transplantations in identical twins (65 %). 1 The lesion is rare now that mainly unrelated kidneys are transplanted. The immunosuppressive effect of renal replacement therapy before transplantation and subsequent routine prophylactic immunosupression may also playa role. However, in some renal diseases like focal glomerulosclerosis (FSGS) and hemolytic uremic syndrome (HUS), recurrent disease is still a frequent and serious complication, which is often associated with transplant loss.2-6 Our aim was to investigate whether the superior immunosuppressive effect of cyclosporine A (CsA) alters the incidence and clinical course of recurrent or de novo kidney disease in renal transplants.
From the Department ofNephrology, Free University, and the Department of Pathology, NeukOlln Hospital, Berlin, Germany. Address reprint requests to Anke Schwarz, MD, Department of Nephrology, Klinikum Steglitz, Hindenburgdamm 30, 1000 Berlin 45, Germany. © 1991 by the National Kidney Foundntion, Inc. 0272-6386/9111705-0004$3.0010
524
METHODS The clinical course of 700 transplantations in a total of 611 patients was evaluated by reviewing the medical records. Long-term immunosuppressive treatment was performed either with azathioprine and methylprednisolone (1970 to 1982) or with CsA alone or in combination with methylprednisolone or azathioprine (1982 to 1988). CsA was routinely introduced into the treatment in December 1982. These two treatment groups , ie, with or without CsA, were compared with respect to the incidence of recurrent or de novo kidney disease. Details of the immunsuppression protocol have been published elsewhere. 7 •s The graft was considered "functioning" if urine excretion was more than 750 mUd and serum creatinine less than 450 p.mollL (5.0 mg/dL) for at least 14 days. We reviewed the histology of 1,305 transplant specimens from 522 of 700 transplants in 488 of 611 patients. Tissue specimens were obtained by percutaneous biopsy or from explanted organs. Indication for biopsy was the lack of function of a transplant shortly after transplantation or a creatinine increase of at least 10 %; or high proteinuria of more than 1. 5 gIL. Additionally, routine biopsies were performed from 1983 to 1986 in 100 CsA-treated patients 7 to 9 months after transplantation befnre discontinuation of steroid medication. 7 Tissue was fixed in formalin, embedded in paraffin, cut in 3- to 4-p.m thick sections, and stained by hematoxylin and eosin, periodic acidSchiff (PAS), acid fuchsin orange-G (AFOG), silver stain (MOVAT), chromotrope-aniline blue (CAB), and Kossa for light microscopic evaluation. Immunofluorescent studies were performed on formalin-fixed and paraffin-embedded tissue after pretreatment by pronase digestion using fluorescein isothiocynate (FITC)-Iabeled antibody to IgG, IgM, IgA, com-
American Journal of Kidney Diseases, Vol XVII, No 5 (May), 1991: pp 524-531
525
RECURRENT RENAL DISEASE AFTER TRANSPLANT
plement (e3), and fibrinogen according to the method of Huang.' The transplant histologies were evaluated nearly exclusively by one investigator (P.-H.K.). Rejection was diagnosed as described elsewhere lO ; the diagnosis of glomerulonepritis (GN) was made according to the classification of ehurg and Sobin l l and Zollinger and Mihatsch.'2 Values are given as arithmetic mean (± SD). Statistical significance was determined by the Student's t test (absolute quantities), Fisher's exact test (relative quantities), or log-rank analysis (graft survival). A P value of less than 0.05 was regarded as statistically significant. \3
Patients Seven hundred kidney transplantations were performed in 611 patients at the Klinikum Steglitz in Berlin between June 1960 and November 1988; 73 patients received two transplants, and II patients received three transplants. Living-related transplantation was performed in 34 cases (5%) and was done significantly less often in the group treated without esA than in the group treated with it (1 % v 8%, P = 10- 5). Graft survival in living-related transplantations was significantly better than in others (under esA treatment, 81.1 % ± 13.3 % v 48.1 % ± 5.6% after 5 years, P = 0.005). The mean age of the recipients at the time of transplantation was 41 ± 11 years; 27 recipients were under 18 (4%). Five patients were lost to observation after 3 to 5 years. Long-term immunosuppression Table 1.
was obtained by azathioprine and steroids in 288 cases and by esA, alone or combined with steroids or azathioprine, in 412 cases. No transplant function was seen in 117 cases (17%), ie, 22 % of nonfunctioning grafts in patients treated without esA and 13% in those treated with esA (P = 0.002). The observation time was significantly longer in patients treated without esA than in those treated with esA (4.2 ± 4 v 2.8 ± 2 years, P = 0.0001). The cumulative number of patient years with a functioning graft was comparable in both groups (1,182.2 v 1,113.8 years). The incidence of biopsies was higher in the group treated without esA than in that treated with it (2.1 ± 2.0 v 1.7 ± 1.5 biopsies per transplant, P = 0.01). High proteinuria (> 1.5 gIL) was the main reason for biopsy in 38 transplants (20 without and 18 with esA) with 55 biopsies (27 without and 28 with esA) without significant difference between the two treatment groups (27/603 v 281702 biopsies, NS). Graft survival was 61 % after 1 year and 42 % after 5 years in patients treated without esA and 80% after 1 year and 57% after 5 years in those treated with esA (P = 0.001).
Recurrence of FSGS Nephrotic syndrome and FSGS recurred in three of 15 functioning transplants in patients with FSGS (20%). The three transplantations with recurrence were performed in September 1979, January 1986, and November 1986. One patient had been treated without esA and two with esA (Table 1). 1\\'0 of
Incidence of Recurrent and De Novo Renal Disease With or Without CsA Incidence All
Recurrent disease GN (histologically confirmed) Idiopathic RPGN Goodpasture's syndrome Anti-GBM nephritis Schonlein-Henoch RPGN Wegener's disease FSGS Mesangiocapillary GN Mesangioproliferative GN IgA nephropathy Membranous GN Postinfectious GN GN with lupus erythematosus GN unclarified HUS
11/583 6/108 0/7 0/7 0/1 0/2 0/3 3/15 1117 0/9 1/8 1/10 0/3 0/3 0/23 2/7
(2%) (6%)
(20%) (6%) (13%) (10%)
GsA
Non..csA
GsA
5/225 2/44 0/2 0/1
3/5 2/2
3/6 1/4
111
6/358 4/64 0/5 0/6 0/1 0/1 0/2 2/8 1/12 0/3 1/6 0/5 0/2 0/2 0/11 2/7
2/2 2/225
4/358
3/4 2/2 1/1 1/1 1/7 1/1 0/1
0/1 0/1 117 0/5 0/6 0/2
115 0/1 0/1 0/12
(29%)
Transplant Loss
Non-GsA
111
112 0/1 0/1
111
1/1
2/2
(+ 1') Oxalosis De novo disease GN Mesangiocapillary GN Nonpurulent focal GN in sepsis (Membranous GN HUS Nodular sclerosis in diabetes
2/2 6/583
4 3 1 14
(100%) (1%)
2
(2.4%)
1 7
112 2 2 0 7 0 0
0/1 0/2 0/2 0/7)
NOTE. Nonfunctioning transplants are excluded. Abbreviations: GN, glomerulonephritis; RPGN, rapidly progressive GN; GBM, glomerular basement membrane; FSGS, focal segmental glomerulosclerosis; HUS, hemolytic-uremic syndrome. 'Suspected, but not histologically confirmed HUS of orthotopic kidneys.
526 the three patients with recurrence of FSOS, one treated without CsA and one with CsA, developed proteinuria within 14 days after transplantation; transplant loss occurred within 4 months; both patients were treated by steroid pulses and one also by plasmapheresis. However, these measures proved ineffective. One patient treated with CsA still has tolerable graft function 2lh years after transplantation and 2 years after the onset of nephrotic syndrome (serum creatinine, 350 /Lmol/L [4.0 mgl dL]; proteinuria, 12 gIL). Comparing clinical parameters of the three patients with recurrence of FSOS and the 12 patients with a functioning graft without recurrence showed that the parameters differed significantly only with respect to the maximal quantitative protein excretion during the course of the original disease (FSOS with recurrence v FSOS without recurrence: proteinuria, 17.7 ± 8.7 v 4.5 ± 5.0 g124 h, P ~ 0.04). The following parameters did not differ significantly between FSOS patients with or without recurrence: age (27.7 ± 11.7 v 28.3 ± 13.7 years, NS); percentage of males (100% v75%, NS); duration of original renal disease (39.0 ± 22.1 v 41.2 ± 18.9 months, NS); duration of hemodialysis (18.3 ± 5.9 v 23.2 ± 15.2 months, NS); HLA identity (2.7 ± 0.6 v 3.3 ± 1.0 loci, NS); HLA mismatch (2.5 ± 0.9 v 2.7 ± 0.6 loci, NS); mesangial proliferation (67% v 25%, NS); and treatment with CsA (67% v 25%, NS).
Recurrence of Membranous GN One man, who was 46 years old at the time of his transplantation in December 1976 and who was treated with azathioprine and steroids, had a recurrence of membranous ON. He developed proteinuria (6 gIL) within 2 months after transplantation and suffered transplant loss due to recurrent disease after 4lh months. Treatment with steroid pulses was ineffective. The patient died of stomach cancer 8 years after transplant loss.
Recurrence of Mesangiocapillary GN Type / A 26-year-old man had recurrence of mesangiocapillary ON type I. He had been treated first with azathioprine and steroids and 2 years later with CsA. Proteinuria (4 gIL) was determined 3 weeks after transplantation (April 1982) and remained stable for 5lh years. Transient gross hematuria and concomitant development of hypertension were observed 1 year after transplantation. Recurrence of the disease was diagnosed by needle biopsy 3 years after transplantation. The patient lost his transplant due to chronic rejection 6 years after transplanation; this was confirmed by two additional biopsies.
Recurrence of /gA Nephropathy Without Recurrence of Rapidly Progressive GN (RPGN) A 22-year-old man received a living-related kidney transplantation from his brother in May 1985; long-term immunosuppression was achieved by CsA. In 1984, 1 year earlier, a rapidly progressive form of IgA nephropathy was diagnosed (75 % crescent). The onset of this disease was heralded by gross hematuria subsequent to acute tonsillitis, which was treated by penicillin. Final-stage renal failure developed despite high immunosuppression, which included prednisolone pulse therapy, cyclophosphamide, azathioprine, and plasmapheresis. After transplantation, the patient had two episodes of gonococcal infection without complications. However, the development of a
SCHWARZ ET AL tonsillar abscess 3 years after transplantation led to severe deterioration of renal function within 3 days after an episode of gross hematuria (serum creatinine increase 110 to 274 /LmollL [1.2 to 3.1 mg/dL]). Immunohistological evaluation of a needle biopsy specimen from the transplant showed diffuse mesangial deposition of IgA; no crescents were seen. Abscess tonsillectomy resulted in immediate restitution of renal function without additional treatment.
Recurrence of HUS Two of 12 cases with histologically confirmed HUS had recurrent disease (29 %; Table I). HUS was also seen in the transplant of one other patient with suspected, but not bioptically confirmed, HUS of the orthotopic kidneys. A 42-year-old man, who underwent transplantation in April 1977 and was treated with azathioprine and steroids, experienced an early recurrence. He had a rapid increase of creatinine, hemolysis with erythrocyte fragmentation, and thrombocytopenia (60,OOO/nL) 2 months after transplantation; transplant loss occurred shortly thereafter. A 32-year-old woman, who underwent transplantation in December 1984 and was treated with CsA and azathioprine, developed hemolytic crisis 3 V2 years after transplantation with thrombocytopenia (40 ,OOO/nL) and erythrocyte fragmentation, as well as a concomitant Escherichia coli urinary tract infection. A 34-year-old woman, who underwent transplantation in March 1988 and was treated with CsA and steroids, developed mild hemolysis and thrombocytopenia (80,OOO/nL); renal function deteriorated over a period of 1 month, 9 months after transplantation. She suffered from relapsing urinary tract infection. Recurrent disease resulted in transplant loss within 5 weeks after the onset of symptoms in all three patients, in two cases, despite fresh frozen plasma treatment. The three HUS patients who had recurrent disease did not differ significantly from the five other HUS patients with successful transplantations and no recurrence with respect to the following parameters: age (36.0 ± 6.2 v 33.0 ± 20.9 years, NS); percentage of males (33% v 80%, NS); duration of original renal disease (6.3 ± 1.5 v 61.8 ± 49.1 months, NS); duration of hemodialysis (20.3 ± 9.3 v 18.8 ± 13.4 months, NS); HLA identity (n ~ 3.3 ± 1.5 v 2.6 ± 0.6 loci, NS); HLA mismatch (n = 3.0 ± 1.5 v 2.2 ± 0.8 loci, NS); urinary tract infection (67% v40%, NS); treatment with CsA (67% v 100%, NS). Clinical signs of HUS with hemolysis, thrombocytopenia, and erythrocyte fragmentation were essential in diagnosis of recurrence, since in biopsy at the onset of symptoms, the early stage of HUS with necrotizing arteriolopathy and intravascular thrombi in light microscopy and positive arteriolar staining for immunoglobulins and fibrin in immunofluorescence studies was similar to vascular rejection. However, in all cases, further biopsies confirmed the diagnosis of HUS with onion-like proliferation of the arterioles and afferent vessels.
Recurrence of Oxalosis Oxalosis recurred twice in a young woman, who was 25 years old at the time of her first transplantation. She received two successive transplants in June 1974 and April 1980, both under treatment with azathioprine and steroids. The disease was not diagnosed before the first transplantation; the kidney
RECURRENT RENAL DISEASE AFTER TRANSPLANT
527
was donated by the patient's HLA -identical sister. The transplant functioned for several days and then failed despite rejection treatment. Histology showed oxalate crystals in the epithelial cells and tubular lumen, as well as interstitial edema and lymphocyte cell infIltration. The patient had several rejection episodes with the second transplant from a nonliving donor; several successive transplant biopsies showed calcium oxalate deposition like in the first transplant, as well as signs of interstitial and vascular rejection. However, the second transplant functioned for I Ih years with a moderate renal function until the patient died of inflammatory gangrene of the arm and leg (serum creatinine, 200 to 300 I'mollL [2.3 to 3.4 mg/dL]) . Oxalosis is a rare disease, with a 100% recurrence rate. l4 · " Recurrent calcium oxalate deposition does not always cause transplant loss. It has been suggested that heterozygous kidneys may be more susceptible to oxalate deposition. I'
was treated with azathioprine and steroids. During a bout of staphylococcal septicemia, he had a sudden increase in serum creatinine and proteinuria (maximum , 6 gIL). Needle biopsy showed focal ON with microthrombi in the capillary loops and crescents in one third of the glomeruli. The patient was placed on dialysis from that time on; steroid pulse treatment was ineffective. Nonpurulent focal ON in septicemia is rare, even in orthotopic kidneys.I6-18
De Novo Mesangiocapillary GN Type I Three patients had de novo mesangiocapillary ON type I in the transplant (Table 1). These were a 41-year-old woman with histologically verified analgesic nephropathy (papillary necrosis and interstitial nephritis in one nephrectomized kidney); a 41-year-old man with presumed malignant nephrosclerosis; and a 50-year-old man with polycystic kidney disease. High proteinuria (10 gIL and 6 gIL, respectively, in two cases) with initially only gradually increasing serum creatinine was observed 12, 27, and 36 months after transplantation. The first patient, transplanted in 1976 and treated with azathioprine and steroids, experienced a sharp creatinine increase 14 months after the onset of proteinuria with rapid transplant loss. The second patient, transplanted in 1985 and treated with esA and steroids , had severe problems with his nephrotic syndrome and heart insufficiency (relapsing pulmonary edema) and had to be dialyzed occasionally because of fluid problems from 19 months after the onset of proteinuria until his death of myocardial infarction 2 months later. The third patient, transplanted in 1984 and treated with esA and steroids, has only slowly progressive renal insufficiency beside a moderate nephrotic syndrome 39 months after the onset of proteinuria (serum creatinine, 300 I'mollL [3.4 mg/dL] ; proteinuria, 4 gIL). In all three patients, an early biopsy was performed because of the diagnosis of rejection within the first 6 months after transplantation showing normal glomeruli. Further biopsies at the onset of proteinuria and creatinine increase showed in light microscopy typical signs of mesangiocapillary ON with thickening of peripheral capillary loops and hyaline deposits, mesangial cell proliferation, lobulation of capillary loops, and doubling of the glomerular basement membrane. In the two slowly progressive cases, signs of interstitial and vascular rejection were also seen. All cases had classical immunohistopathological changes with garland-like coarse granular peripheral deposits of complement and immunoglobulins. The constant and progressive findings in the follow-up biopsies with the same immunohistological picture confirmed the diagnosis in each of the cases and allowed differentiation of them from transplant glomerulopathy.
De Novo Nonpurulent Focal GN in Septicemia A 39-year-old man with biopticaIly confirmed secondary malignant nephrosclerosis had a severe pancreatitis with fistula formation 32 months after transplantation (February 1981); he
De Novo BUS A 38-year-old man with a history of probable chronic ON (high proteinuria, microhematuria, high blood pressure) underwent transplantation in January 1976 under treatment with azathioprine and steroids. Initially, transplant function was good. Three weeks after transplantation, renal function deteriorated sharply despite rejection treatment. At the time of transplantectomy, the patient had septic listeriosis with mild leukocytopenia (2,OOO/nL) and thrombocytopenia (60,OOO/nL), but no signs of hemolysis. The histologic examination of the explanted kidney confirmed the diagnosis of HUS.
Nodular Glomerulosclerosis (Kimmelstiel-Wilson) In January 1979, a 43-year-old woman with analgesic nephropathy underwent transplantation under treatment with azathioprine and steroids; the transplant functioned excellently for years. She developed insulin-dependent diabetes 8 months after transplantation. Signs of diabetic retinopathy (microaneurysms and hard exudates) were seen in March 1985, followed by diabetic gangrene of the foot and polyneuropathy. Proteinuria was mild and did not increase « 1 gIL). A serum creatinine increase within months from normal values to 500 I'moi/L (5 .7 mg/dL) was neither diagnosed nor treated, since the patient refused observation at that time. The transplant biopsy at restart of hemodialysis showed advanced chronic vascular and interstitial rejection. Moreover, considerable mesangial expansion with nodular transformation and slight mesangial cell proliferation was present. Forty-five transplantations were performed in 34 patients with diabetes type I. We performed 17 biopsies in 10 of these patients who had received their transplant more than 1 year earlier. We observed full-blown recurrent diabetic nephropathy in none of these biopsies. Only nine of 17 biopsies demonstrated early signs such as mesangial expansion (n = 7), thickening of the glomerular basement membrane (n = 2), and hyalinization of the afferent and efferent vessels (n = 3). The lack of recurrence of full-blown diabetes certainly is influenced by the well-known bad graft survival rate in diabetic patients compared with others (after 3 years , 50.9% ± 11.9% v 66 .6% ± 2.9% under esA treatment, P
R
ECURRENT renal disease in the transplant was a major problem in the early days of kidney transplantations in identical twins (65 %). 1 The lesion is rare now that mainly unrelated kidneys are transplanted. The immunosuppressive effect of renal replacement therapy before transplantation and subsequent routine prophylactic immunosupression may also playa role. However, in some renal diseases like focal glomerulosclerosis (FSGS) and hemolytic uremic syndrome (HUS), recurrent disease is still a frequent and serious complication, which is often associated with transplant loss.2-6 Our aim was to investigate whether the superior immunosuppressive effect of cyclosporine A (CsA) alters the incidence and clinical course of recurrent or de novo kidney disease in renal transplants.
From the Department ofNephrology, Free University, and the Department of Pathology, NeukOlln Hospital, Berlin, Germany. Address reprint requests to Anke Schwarz, MD, Department of Nephrology, Klinikum Steglitz, Hindenburgdamm 30, 1000 Berlin 45, Germany. © 1991 by the National Kidney Foundntion, Inc. 0272-6386/9111705-0004$3.0010
524
METHODS The clinical course of 700 transplantations in a total of 611 patients was evaluated by reviewing the medical records. Long-term immunosuppressive treatment was performed either with azathioprine and methylprednisolone (1970 to 1982) or with CsA alone or in combination with methylprednisolone or azathioprine (1982 to 1988). CsA was routinely introduced into the treatment in December 1982. These two treatment groups , ie, with or without CsA, were compared with respect to the incidence of recurrent or de novo kidney disease. Details of the immunsuppression protocol have been published elsewhere. 7 •s The graft was considered "functioning" if urine excretion was more than 750 mUd and serum creatinine less than 450 p.mollL (5.0 mg/dL) for at least 14 days. We reviewed the histology of 1,305 transplant specimens from 522 of 700 transplants in 488 of 611 patients. Tissue specimens were obtained by percutaneous biopsy or from explanted organs. Indication for biopsy was the lack of function of a transplant shortly after transplantation or a creatinine increase of at least 10 %; or high proteinuria of more than 1. 5 gIL. Additionally, routine biopsies were performed from 1983 to 1986 in 100 CsA-treated patients 7 to 9 months after transplantation befnre discontinuation of steroid medication. 7 Tissue was fixed in formalin, embedded in paraffin, cut in 3- to 4-p.m thick sections, and stained by hematoxylin and eosin, periodic acidSchiff (PAS), acid fuchsin orange-G (AFOG), silver stain (MOVAT), chromotrope-aniline blue (CAB), and Kossa for light microscopic evaluation. Immunofluorescent studies were performed on formalin-fixed and paraffin-embedded tissue after pretreatment by pronase digestion using fluorescein isothiocynate (FITC)-Iabeled antibody to IgG, IgM, IgA, com-
American Journal of Kidney Diseases, Vol XVII, No 5 (May), 1991: pp 524-531
525
RECURRENT RENAL DISEASE AFTER TRANSPLANT
plement (e3), and fibrinogen according to the method of Huang.' The transplant histologies were evaluated nearly exclusively by one investigator (P.-H.K.). Rejection was diagnosed as described elsewhere lO ; the diagnosis of glomerulonepritis (GN) was made according to the classification of ehurg and Sobin l l and Zollinger and Mihatsch.'2 Values are given as arithmetic mean (± SD). Statistical significance was determined by the Student's t test (absolute quantities), Fisher's exact test (relative quantities), or log-rank analysis (graft survival). A P value of less than 0.05 was regarded as statistically significant. \3
Patients Seven hundred kidney transplantations were performed in 611 patients at the Klinikum Steglitz in Berlin between June 1960 and November 1988; 73 patients received two transplants, and II patients received three transplants. Living-related transplantation was performed in 34 cases (5%) and was done significantly less often in the group treated without esA than in the group treated with it (1 % v 8%, P = 10- 5). Graft survival in living-related transplantations was significantly better than in others (under esA treatment, 81.1 % ± 13.3 % v 48.1 % ± 5.6% after 5 years, P = 0.005). The mean age of the recipients at the time of transplantation was 41 ± 11 years; 27 recipients were under 18 (4%). Five patients were lost to observation after 3 to 5 years. Long-term immunosuppression Table 1.
was obtained by azathioprine and steroids in 288 cases and by esA, alone or combined with steroids or azathioprine, in 412 cases. No transplant function was seen in 117 cases (17%), ie, 22 % of nonfunctioning grafts in patients treated without esA and 13% in those treated with esA (P = 0.002). The observation time was significantly longer in patients treated without esA than in those treated with esA (4.2 ± 4 v 2.8 ± 2 years, P = 0.0001). The cumulative number of patient years with a functioning graft was comparable in both groups (1,182.2 v 1,113.8 years). The incidence of biopsies was higher in the group treated without esA than in that treated with it (2.1 ± 2.0 v 1.7 ± 1.5 biopsies per transplant, P = 0.01). High proteinuria (> 1.5 gIL) was the main reason for biopsy in 38 transplants (20 without and 18 with esA) with 55 biopsies (27 without and 28 with esA) without significant difference between the two treatment groups (27/603 v 281702 biopsies, NS). Graft survival was 61 % after 1 year and 42 % after 5 years in patients treated without esA and 80% after 1 year and 57% after 5 years in those treated with esA (P = 0.001).
Recurrence of FSGS Nephrotic syndrome and FSGS recurred in three of 15 functioning transplants in patients with FSGS (20%). The three transplantations with recurrence were performed in September 1979, January 1986, and November 1986. One patient had been treated without esA and two with esA (Table 1). 1\\'0 of
Incidence of Recurrent and De Novo Renal Disease With or Without CsA Incidence All
Recurrent disease GN (histologically confirmed) Idiopathic RPGN Goodpasture's syndrome Anti-GBM nephritis Schonlein-Henoch RPGN Wegener's disease FSGS Mesangiocapillary GN Mesangioproliferative GN IgA nephropathy Membranous GN Postinfectious GN GN with lupus erythematosus GN unclarified HUS
11/583 6/108 0/7 0/7 0/1 0/2 0/3 3/15 1117 0/9 1/8 1/10 0/3 0/3 0/23 2/7
(2%) (6%)
(20%) (6%) (13%) (10%)
GsA
Non..csA
GsA
5/225 2/44 0/2 0/1
3/5 2/2
3/6 1/4
111
6/358 4/64 0/5 0/6 0/1 0/1 0/2 2/8 1/12 0/3 1/6 0/5 0/2 0/2 0/11 2/7
2/2 2/225
4/358
3/4 2/2 1/1 1/1 1/7 1/1 0/1
0/1 0/1 117 0/5 0/6 0/2
115 0/1 0/1 0/12
(29%)
Transplant Loss
Non-GsA
111
112 0/1 0/1
111
1/1
2/2
(+ 1') Oxalosis De novo disease GN Mesangiocapillary GN Nonpurulent focal GN in sepsis (Membranous GN HUS Nodular sclerosis in diabetes
2/2 6/583
4 3 1 14
(100%) (1%)
2
(2.4%)
1 7
112 2 2 0 7 0 0
0/1 0/2 0/2 0/7)
NOTE. Nonfunctioning transplants are excluded. Abbreviations: GN, glomerulonephritis; RPGN, rapidly progressive GN; GBM, glomerular basement membrane; FSGS, focal segmental glomerulosclerosis; HUS, hemolytic-uremic syndrome. 'Suspected, but not histologically confirmed HUS of orthotopic kidneys.
526 the three patients with recurrence of FSOS, one treated without CsA and one with CsA, developed proteinuria within 14 days after transplantation; transplant loss occurred within 4 months; both patients were treated by steroid pulses and one also by plasmapheresis. However, these measures proved ineffective. One patient treated with CsA still has tolerable graft function 2lh years after transplantation and 2 years after the onset of nephrotic syndrome (serum creatinine, 350 /Lmol/L [4.0 mgl dL]; proteinuria, 12 gIL). Comparing clinical parameters of the three patients with recurrence of FSOS and the 12 patients with a functioning graft without recurrence showed that the parameters differed significantly only with respect to the maximal quantitative protein excretion during the course of the original disease (FSOS with recurrence v FSOS without recurrence: proteinuria, 17.7 ± 8.7 v 4.5 ± 5.0 g124 h, P ~ 0.04). The following parameters did not differ significantly between FSOS patients with or without recurrence: age (27.7 ± 11.7 v 28.3 ± 13.7 years, NS); percentage of males (100% v75%, NS); duration of original renal disease (39.0 ± 22.1 v 41.2 ± 18.9 months, NS); duration of hemodialysis (18.3 ± 5.9 v 23.2 ± 15.2 months, NS); HLA identity (2.7 ± 0.6 v 3.3 ± 1.0 loci, NS); HLA mismatch (2.5 ± 0.9 v 2.7 ± 0.6 loci, NS); mesangial proliferation (67% v 25%, NS); and treatment with CsA (67% v 25%, NS).
Recurrence of Membranous GN One man, who was 46 years old at the time of his transplantation in December 1976 and who was treated with azathioprine and steroids, had a recurrence of membranous ON. He developed proteinuria (6 gIL) within 2 months after transplantation and suffered transplant loss due to recurrent disease after 4lh months. Treatment with steroid pulses was ineffective. The patient died of stomach cancer 8 years after transplant loss.
Recurrence of Mesangiocapillary GN Type / A 26-year-old man had recurrence of mesangiocapillary ON type I. He had been treated first with azathioprine and steroids and 2 years later with CsA. Proteinuria (4 gIL) was determined 3 weeks after transplantation (April 1982) and remained stable for 5lh years. Transient gross hematuria and concomitant development of hypertension were observed 1 year after transplantation. Recurrence of the disease was diagnosed by needle biopsy 3 years after transplantation. The patient lost his transplant due to chronic rejection 6 years after transplanation; this was confirmed by two additional biopsies.
Recurrence of /gA Nephropathy Without Recurrence of Rapidly Progressive GN (RPGN) A 22-year-old man received a living-related kidney transplantation from his brother in May 1985; long-term immunosuppression was achieved by CsA. In 1984, 1 year earlier, a rapidly progressive form of IgA nephropathy was diagnosed (75 % crescent). The onset of this disease was heralded by gross hematuria subsequent to acute tonsillitis, which was treated by penicillin. Final-stage renal failure developed despite high immunosuppression, which included prednisolone pulse therapy, cyclophosphamide, azathioprine, and plasmapheresis. After transplantation, the patient had two episodes of gonococcal infection without complications. However, the development of a
SCHWARZ ET AL tonsillar abscess 3 years after transplantation led to severe deterioration of renal function within 3 days after an episode of gross hematuria (serum creatinine increase 110 to 274 /LmollL [1.2 to 3.1 mg/dL]). Immunohistological evaluation of a needle biopsy specimen from the transplant showed diffuse mesangial deposition of IgA; no crescents were seen. Abscess tonsillectomy resulted in immediate restitution of renal function without additional treatment.
Recurrence of HUS Two of 12 cases with histologically confirmed HUS had recurrent disease (29 %; Table I). HUS was also seen in the transplant of one other patient with suspected, but not bioptically confirmed, HUS of the orthotopic kidneys. A 42-year-old man, who underwent transplantation in April 1977 and was treated with azathioprine and steroids, experienced an early recurrence. He had a rapid increase of creatinine, hemolysis with erythrocyte fragmentation, and thrombocytopenia (60,OOO/nL) 2 months after transplantation; transplant loss occurred shortly thereafter. A 32-year-old woman, who underwent transplantation in December 1984 and was treated with CsA and azathioprine, developed hemolytic crisis 3 V2 years after transplantation with thrombocytopenia (40 ,OOO/nL) and erythrocyte fragmentation, as well as a concomitant Escherichia coli urinary tract infection. A 34-year-old woman, who underwent transplantation in March 1988 and was treated with CsA and steroids, developed mild hemolysis and thrombocytopenia (80,OOO/nL); renal function deteriorated over a period of 1 month, 9 months after transplantation. She suffered from relapsing urinary tract infection. Recurrent disease resulted in transplant loss within 5 weeks after the onset of symptoms in all three patients, in two cases, despite fresh frozen plasma treatment. The three HUS patients who had recurrent disease did not differ significantly from the five other HUS patients with successful transplantations and no recurrence with respect to the following parameters: age (36.0 ± 6.2 v 33.0 ± 20.9 years, NS); percentage of males (33% v 80%, NS); duration of original renal disease (6.3 ± 1.5 v 61.8 ± 49.1 months, NS); duration of hemodialysis (20.3 ± 9.3 v 18.8 ± 13.4 months, NS); HLA identity (n ~ 3.3 ± 1.5 v 2.6 ± 0.6 loci, NS); HLA mismatch (n = 3.0 ± 1.5 v 2.2 ± 0.8 loci, NS); urinary tract infection (67% v40%, NS); treatment with CsA (67% v 100%, NS). Clinical signs of HUS with hemolysis, thrombocytopenia, and erythrocyte fragmentation were essential in diagnosis of recurrence, since in biopsy at the onset of symptoms, the early stage of HUS with necrotizing arteriolopathy and intravascular thrombi in light microscopy and positive arteriolar staining for immunoglobulins and fibrin in immunofluorescence studies was similar to vascular rejection. However, in all cases, further biopsies confirmed the diagnosis of HUS with onion-like proliferation of the arterioles and afferent vessels.
Recurrence of Oxalosis Oxalosis recurred twice in a young woman, who was 25 years old at the time of her first transplantation. She received two successive transplants in June 1974 and April 1980, both under treatment with azathioprine and steroids. The disease was not diagnosed before the first transplantation; the kidney
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was donated by the patient's HLA -identical sister. The transplant functioned for several days and then failed despite rejection treatment. Histology showed oxalate crystals in the epithelial cells and tubular lumen, as well as interstitial edema and lymphocyte cell infIltration. The patient had several rejection episodes with the second transplant from a nonliving donor; several successive transplant biopsies showed calcium oxalate deposition like in the first transplant, as well as signs of interstitial and vascular rejection. However, the second transplant functioned for I Ih years with a moderate renal function until the patient died of inflammatory gangrene of the arm and leg (serum creatinine, 200 to 300 I'mollL [2.3 to 3.4 mg/dL]) . Oxalosis is a rare disease, with a 100% recurrence rate. l4 · " Recurrent calcium oxalate deposition does not always cause transplant loss. It has been suggested that heterozygous kidneys may be more susceptible to oxalate deposition. I'
was treated with azathioprine and steroids. During a bout of staphylococcal septicemia, he had a sudden increase in serum creatinine and proteinuria (maximum , 6 gIL). Needle biopsy showed focal ON with microthrombi in the capillary loops and crescents in one third of the glomeruli. The patient was placed on dialysis from that time on; steroid pulse treatment was ineffective. Nonpurulent focal ON in septicemia is rare, even in orthotopic kidneys.I6-18
De Novo Mesangiocapillary GN Type I Three patients had de novo mesangiocapillary ON type I in the transplant (Table 1). These were a 41-year-old woman with histologically verified analgesic nephropathy (papillary necrosis and interstitial nephritis in one nephrectomized kidney); a 41-year-old man with presumed malignant nephrosclerosis; and a 50-year-old man with polycystic kidney disease. High proteinuria (10 gIL and 6 gIL, respectively, in two cases) with initially only gradually increasing serum creatinine was observed 12, 27, and 36 months after transplantation. The first patient, transplanted in 1976 and treated with azathioprine and steroids, experienced a sharp creatinine increase 14 months after the onset of proteinuria with rapid transplant loss. The second patient, transplanted in 1985 and treated with esA and steroids , had severe problems with his nephrotic syndrome and heart insufficiency (relapsing pulmonary edema) and had to be dialyzed occasionally because of fluid problems from 19 months after the onset of proteinuria until his death of myocardial infarction 2 months later. The third patient, transplanted in 1984 and treated with esA and steroids, has only slowly progressive renal insufficiency beside a moderate nephrotic syndrome 39 months after the onset of proteinuria (serum creatinine, 300 I'mollL [3.4 mg/dL] ; proteinuria, 4 gIL). In all three patients, an early biopsy was performed because of the diagnosis of rejection within the first 6 months after transplantation showing normal glomeruli. Further biopsies at the onset of proteinuria and creatinine increase showed in light microscopy typical signs of mesangiocapillary ON with thickening of peripheral capillary loops and hyaline deposits, mesangial cell proliferation, lobulation of capillary loops, and doubling of the glomerular basement membrane. In the two slowly progressive cases, signs of interstitial and vascular rejection were also seen. All cases had classical immunohistopathological changes with garland-like coarse granular peripheral deposits of complement and immunoglobulins. The constant and progressive findings in the follow-up biopsies with the same immunohistological picture confirmed the diagnosis in each of the cases and allowed differentiation of them from transplant glomerulopathy.
De Novo Nonpurulent Focal GN in Septicemia A 39-year-old man with biopticaIly confirmed secondary malignant nephrosclerosis had a severe pancreatitis with fistula formation 32 months after transplantation (February 1981); he
De Novo BUS A 38-year-old man with a history of probable chronic ON (high proteinuria, microhematuria, high blood pressure) underwent transplantation in January 1976 under treatment with azathioprine and steroids. Initially, transplant function was good. Three weeks after transplantation, renal function deteriorated sharply despite rejection treatment. At the time of transplantectomy, the patient had septic listeriosis with mild leukocytopenia (2,OOO/nL) and thrombocytopenia (60,OOO/nL), but no signs of hemolysis. The histologic examination of the explanted kidney confirmed the diagnosis of HUS.
Nodular Glomerulosclerosis (Kimmelstiel-Wilson) In January 1979, a 43-year-old woman with analgesic nephropathy underwent transplantation under treatment with azathioprine and steroids; the transplant functioned excellently for years. She developed insulin-dependent diabetes 8 months after transplantation. Signs of diabetic retinopathy (microaneurysms and hard exudates) were seen in March 1985, followed by diabetic gangrene of the foot and polyneuropathy. Proteinuria was mild and did not increase « 1 gIL). A serum creatinine increase within months from normal values to 500 I'moi/L (5 .7 mg/dL) was neither diagnosed nor treated, since the patient refused observation at that time. The transplant biopsy at restart of hemodialysis showed advanced chronic vascular and interstitial rejection. Moreover, considerable mesangial expansion with nodular transformation and slight mesangial cell proliferation was present. Forty-five transplantations were performed in 34 patients with diabetes type I. We performed 17 biopsies in 10 of these patients who had received their transplant more than 1 year earlier. We observed full-blown recurrent diabetic nephropathy in none of these biopsies. Only nine of 17 biopsies demonstrated early signs such as mesangial expansion (n = 7), thickening of the glomerular basement membrane (n = 2), and hyalinization of the afferent and efferent vessels (n = 3). The lack of recurrence of full-blown diabetes certainly is influenced by the well-known bad graft survival rate in diabetic patients compared with others (after 3 years , 50.9% ± 11.9% v 66 .6% ± 2.9% under esA treatment, P
