Clinicopathologic Characteristics, Treatment, and Outcomes of Post-transplant Lymphoproliferative Disorders: A Single-institution Experience Using 2017 WHO Diagnostic Criteria.

The World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues (WHO 2017) included updated criteria for diagnosis and classification of post-transplant lymphoproliferative disorders (PTLDs). This study evaluated the clinicopathologic spectrum using WHO 2017 criteria and adult PTLD patients' outcomes over 30 years between 1987 and 2017 at Mayo Clinic (Rochester, MN). Patients were retrospectively reviewed for clinical features, outcomes, and diagnostic pathology material and classified based on WHO 2017 criteria. A total of 227 patients were diagnosed with PTLD, with a median time from transplant to PTLD of 45 months. PTLD occurred >1 year after transplant in 149 (66%) patients. Monomorphic PTLD was the most common subtype (173, 76%), with diffuse large B cell lymphoma as the commonest morphology (n = 137). Epstein-Barr virus was positive in 61% of total cases and 90% of PTLD that developed within 1 year from transplant. The median event-free survival (EFS) and overall survival for the entire cohort were 21 months (95% confidence interval [CI]: 9-35) and 82 months (95% CI: 39-115), respectively. The EFS or overall survival was not impacted by Epstein-Barr virus status but differed based on WHO subtypes and year of diagnosis. Management changed over time with increased use of rituximab or chemotherapy + immunosuppression reduction as initial therapy. When compared to the matched general population and de novo diffuse large B cell lymphoma, patients not achieving EFS 24 status (no progression/treatment or death within 24 mo of diagnosis) had a worse standardized mortality ratio 16.75 (95% CI: 13.91-20) versus SMR 1.72 (95% CI: 1.26-2.28) in those who achieved EFS24. Cause of death was mostly attributed to non-lymphoma-related causes in those achieving EFS 24.

Familial antiglomerular basement membrane disease in zero human leukocyte antigen mismatch siblings
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Reported cases of familial Antiglomerular basement membrane (anti-GBM) disease are extremely rare. The single gene mutations that may play a role in the development of familial anti-GBM disease are currently unidentified. While human leukocyte antigen (HLA)-DR15 is known to be associated with an increased risk of anti-GBM disease, HLA types in patients with familial anti-GBM disease have never been reported. We present a case of a 65-year-old woman with rapidly-progressive glomerulonephritis and pulmonary involvement, consistent with Goodpasture's syndrome. Two of her 15 siblings also had a history of anti-GBM disease during adolescence and both received a kidney transplant. Our patient and her siblings were smokers and had also had exposure to kerosene, a low-viscosity hydrocarbon. HLA testing was performed and showed identical HLA typing (0 of 6 HLA mismatch) as one of her brothers with anti-GBM disease. Interestingly, they both had HLA-DR15. Despite severe acute kidney injury requiring hemodialysis, the patient responded well to the standard therapy with cyclophosphamide, plasmapheresis, and systemic corticosteroids. At her 3-month follow-up visit, the patient's kidney functions had recovered, and hemodialysis was discontinued. Concluding, we illustrate an extremely rare familial anti-GBM disease involving 3 siblings with potential links of HLA-DR15 and environmental triggers with the development of familial anti-GBM disease.
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Diurnal blood pressure changes one year after kidney transplantation: relationship to allograft function, histology, and resistive index.

Loss of circadian BP change has been linked to target organ damage and accelerated kidney function loss in hypertensive patients with and without chronic kidney disease. Ambulatory BP-derived data from 119 consecutive kidney transplant recipients who presented for the first annual evaluation were examined in relation to allograft function, histology, and ultrasound findings. A total of 101 (85%) patients were receiving antihypertensive medications (median 2), and 85 (71%) achieved target awake average systolic BP (SBP) of <135 mmHg. A day-night change in SBP by 10% or more (dippers) was detected in 29 (24%). Dipping status was associated with younger recipient age, lack of diabetes, low chronic vascular score, and low resistive index. Nondippers and reverse dippers had lower GFR compared with dippers (P = 0.04). For every 10% nocturnal drop in SBP, GFR increased by 4.6 ml/min per 1.73 m(2) (R = 0.3, P = 0.003). Nondippers and reverse dippers were equally common in recipients with normal histology and in those with pathologic findings on surveillance biopsy. On multivariate analysis, percentage of nocturnal fall in SBP and elevated resistive index independently correlated with GFR. This study indicates that lack of nocturnal fall in SBP is related to poor allograft function, high chronic vascular score, and high resistive index irrespective of allograft fibrosis. Further studies are needed to determine whether restoration of normal BP pattern will confer better allograft outcome.

Living donor kidney and autologous stem cell transplantation for primary systemic amyloidosis (AL) with predominant renal involvement.

Primary systemic amyloidosis (AL) is characterized by multiorgan deposition of monoclonal immunoglobulin light chain. Renal involvement is common and impaired kidney function is associated with reduced median survival. Autologous stem cell transplantation (SCT) for AL achieves superior response rates compared to chemotherapy alone but patients with end-stage renal disease (ESRD) may be excluded from consideration. A treatment approach consisting of living donor kidney transplantation (LDKTx) followed by autologous SCT was developed for AL with ESRD. Eight patients underwent LDKTx with immediate graft function. Two suffered unanticipated complications post-KTx and died 10 and 3 months later. Two cases of subclinical acute cellular rejection (ACR) and one case of clinical ACR occurred--all reversible with corticosteroid. Six patients had successful stem cell harvests performed and five of these underwent SCT with satisfactory trilineage engraftment. Renal function remained stable following SCT in four and was reduced in one due to infectious and bleeding complications. One patient, who has thus far elected not to undergo SCT, has proteinuria and histologic evidence of recurrent renal amyloidosis. This experience supports the feasibility of sequential living donor KTx and autologous SCT for carefully selected patients with ESRD due to AL.

Patient and graft outcomes from older living kidney donors are similar to those from younger donors despite lower GFR.

BACKGROUND: Donor age adversely affects deceased-donor kidney transplant outcomes, but its influence on living-donor transplantation is less well characterized. METHODS: Living-donor kidney transplants at a single center between 1998 and 2000 were reviewed. Data were abstracted for 52 transplants from donors aged > or =50 years and for a matched group of 104 transplants from donors aged <50 years. Survival indices were compared during the first three years' post-transplantation. Functional indices, including serial iothalamate clearances, were compared at 1, 12, and 24 months. RESULTS: Predonation glomerular filtration rate (GFR) was lower among older donors (94 +/- 12 vs. 108 +/- 17 mL/min/SA) but post-transplant compensatory hypertrophy was similar (11.7 +/- 26.3% vs. 7.7 +/- 31.4%). Recipients of older-donor grafts were older (52.8 +/- 16.5 vs. 46.1 +/- 15.1 years) and more frequently unrelated to the donor (54% vs. 39%). Trends toward higher frequency of slow graft function, cytomegalovirus (CMV) infection, and polyomavirus nephropathy were observed for older-donor grafts. Three-year recipient, graft, and death-censored graft survivals were > or =90% for both groups. At 1, 12, and 24 months, serum creatinine was higher and GFR was lower among recipients of older- compared with younger-donor grafts. Other functional indices (urine total protein, serum potassium and uric acid, hemoglobin, and number of antihypertensives) were not different. Donor age correlated with graft GFR at 1, 12, and 24 months for the entire study cohort by linear regression. CONCLUSION: Older donor age does not preclude excellent results from living-donor kidney transplantation but should be appreciated as being associated with relatively lower GFR.

Pancreas-after-kidney transplantation: an increasingly attractive alternative to simultaneous pancreas-kidney transplantation.

BACKGROUND: Historically, the clinical acceptability of pancreas-after-kidney (PAK) transplantation has been hampered by relatively high acute rejection rates and lower pancreas graft survival rates when compared with the more commonly performed simultaneous pancreas-kidney (SPK) transplantation. The purpose of this study was to compare PAK transplantation to SPK transplantation in the Thymoglobulin induction era. METHODS: The authors reviewed all bladder-drained PAK (n=47) transplants receiving rabbit antithymocyte globulin induction from June 1998 to June 2002 and compared them with SPK (n=25) transplants during the same time period at their institution. The authors retrospectively studied data on demographics, patient survival, graft (pancreas and kidney) survival, complications, and biopsy-proven rejection episodes. RESULTS: The actuarial 1-year patient survival was 93% for the PAK group versus 100% for the SPK group (P =not significant [NS]). The actuarial 1-year pancreas graft survival was 87% for the PAK group versus 92% for the SPK group (P =NS). Waiting time for PAK was significantly shorter than for SPK (6.3 +/- 5.2 vs. 16.2 + -13.7 months, P <0.05). Clinical acute rejection rates were similar in the two groups (4.3% for PAK vs. 4.0% for SPK). PAK recipients demonstrated a greater decline in renal function after transplantation compared with SPK. A multivariate analysis failed to elucidate the cause. CONCLUSIONS: Newer immunosuppressive regimens allow PAK transplant patients to achieve immunologic outcomes similar to SPK transplant patients. Although the shorter waiting time and the ability to use living-donor kidneys make PAK an increasingly attractive alternative to SPK transplantation, its effect on renal allograft function deserves further attention.

Decline in native renal function early after bladder-drained pancreas transplantation alone.

BACKGROUND: Pancreas transplant alone (PTA) has become accepted therapy for select nonuremic patients with type 1 diabetes mellitus. However, PTA may lead to significant complications including a decline in native renal function. This study examines trends in native renal function during the first posttransplant year in PTA recipients with a spectrum of pretransplant glomerular filtration rates (GFR). METHODS: Renal function was studied in 23 recipients of bladder-drained PTA who underwent transplantation from April 1998 through September 2001. GFR was measured by corrected iothalamate clearance at the time of transplant evaluation and 1 year posttransplant and also calculated using the Cockcroft-Gault method at the transplant evaluation; at the day of transplantation; and at 1, 6, and 12 months posttransplant. RESULTS: Iothalamate clearance decreased in the first year in 96% of patients (22 of 23). The mean measured GFR decreased from 84 +/- 33 mL/min/1.73 m2 pretransplant to 52 +/- 26 mL/min/1.73 m2 at 1 year (P <0.001). Calculated creatinine clearance declined in the majority of patients at both 1 and 12 months after PTA, but some patients, including a few with low GFR, maintained stable renal function. Calculated GFR generally correlated well with measured GFR in most patients, with a few notable exceptions. One patient (baseline GFR, 42 mL/min/1.73 m2) developed renal failure in the first year after transplant and required kidney transplantation. CONCLUSIONS: Bladder-drained PTA results in a decline in native renal function in the majority of patients regardless of the pretransplant GFR. These data suggest the need for strategies to prevent or minimize the decline in renal function after PTA.

Histologic findings of antibody-mediated rejection in ABO blood-group-incompatible living-donor kidney transplantation.

The purpose of this study was to characterize the histology of antibody-mediated rejection (AMR) in ABO blood-group-incompatible (ABOI) kidney transplants as well as on protocol biopsies performed at the time of stable allograft function. Between 5/99 and 1/02, we performed 32 ABOI kidney transplants (13 A2, 19 non-A2 blood-group living donors). Nineteen biopsies were performed for allograft dysfunction, and 127 protocol biopsies were performed 0, 3, 7, 14, 28 days and 3 and 12 months post transplant. Twenty-five of 32 patients have functioning allografts (mean 585 days post transplant). Nine of 32 (28%) developed clinical AMR. Biopsy revealed glomerular thrombi (78%), mesangiolysis (78%), peritubular capillary C4d staining (56%) and neutrophil infiltration (67%), interstitial hemorrhage and necrosis (56%) and arteriolar thrombi (33%). Subclinical AMR was diagnosed by protocol biopsies in four patients. Findings consisted of glomerular thrombi (100%), mesangiolysis (25%), and C4d staining (100%). In late protocol biopsies performed 214-420 days post transplant, mild mesangiolysis was seen in 2/17 (11.7%), and C4d immunostaining was detected in 3/12 (25%). AMR is characterized by glomerular thrombi, mesangiolysis, peritubular capillary neutrophil infiltration interstitial hemorrhage, necrosis, and C4d deposition. Glomerular thrombi appear early in AMR and may appear prior to graft dysfunction.

Influence of surveillance renal allograft biopsy on diagnosis and prognosis of polyomavirus-associated nephropathy.

BACKGROUND: Polyomavirus-associated nephropathy (PVAN) is an increasingly prevalent cause of allograft dysfunction. METHODS: In 18 histologically proven cases of PVAN managed by reduced immunosuppression, monitoring of serum creatinine, and repeated biopsy, graft outcomes were correlated with clinical and histologic indices. Six months postdiagnosis the status of each graft was classified as poor (N = 7) or satisfactory (N = 11). Poor transplant status was defined as graft loss, increased severity of PVAN on repeat biopsy, or serum creatinine>3.0 mg/dL. Diagnosis resulted from either surveillance allograft biopsies (N = 8) or biopsies performed for increased serum creatinine (nonsurveillance, N = 10). RESULTS: The surveillance biopsy group was more likely than the nonsurveillance group to have satisfactory graft status at 6 months (eight of eight vs. three of ten, P = 0.004) and had significantly lower serum creatinine at diagnosis, 3, and 6 months. Histologic scoring for chronic interstitial and tubular injury was lower in diagnostic surveillance biopsies compared to nonsurveillance biopsies (P = 0.01). Satisfactory transplant status was also associated with reduced or absent virus on repeat biopsy (P = 0.01). Poor transplant status was associated with a higher frequency of recipientneg/donorpos cytomegalovirus (CMV) serology (71% vs. 9%, P = 0.01). CONCLUSION: Surveillance allograft biopsy provides an important means for earlier detection of PVAN and permits timely alterations to immunosuppression. Early diagnosis is associated with a lesser degree of interstitial fibrosis at diagnosis and lower baseline and subsequent serum creatinine.

Overcoming a positive crossmatch in living-donor kidney transplantation.

Many patients who have an otherwise acceptable living-kidney donor do not undergo transplantation because of the presence of antibodies against the donor cells resulting in a positive crossmatch. In the current study, 14 patients with a positive cytotoxic crossmatch (titer

ABO-incompatible kidney transplantation using both A2 and non-A2 living donors.

BACKGROUND: Given the scarcity of cadaveric organs, efforts are intensifying to increase the availability of living donors. The current study assessed the feasibility of using ABO-incompatible living-donor kidneys to expand the donor pool. METHODS: The authors performed 18 ABO-incompatible living-donor kidney transplants between May 1999 and April 2001. Ten patients received living-donor kidneys from A2 and eight patients received kidneys from non-A2 blood group donors. Immunosuppression consisted of Thymoglobulin antibody induction, tacrolimus, mycophenolate mofetil, and prednisone. Eight non-A2 and two A2 kidney recipients also received a pretransplant conditioning regimen of four plasmapheresis treatments followed by intravenous immunoglobulin and splenectomy at the time of transplantation. Antidonor blood group antibody titer was measured at baseline, pretransplant, at 1- to 3-month and 1-year follow-up, and at the time of diagnosis of antibody-mediated rejection. RESULTS: No hyperacute rejection episodes occurred. One-year graft and patient survival rates in the 18 ABO-incompatible recipients were only slightly lower than those of 81 patients who received ABO-compatible kidney transplants during the same period (89% vs. 96% and 94% vs. 99%, respectively). Glomerular filtration rate and serum creatinine levels did not differ between the groups. Antibody-mediated rejection occurred in 28% of ABO-incompatible recipients, and was reversible with plasmapheresis, intravenous immunoglobulin, and increasing immunosuppression in all patients except one. CONCLUSIONS: ABO-incompatible living donor kidney transplants can achieve an acceptable 1-year graft survival rate using an immunosuppressive regimen consisting of Thymoglobulin induction, tacrolimus, mycophenolate mofetil, and prednisone combined with pretransplant plasmapheresis, intravenous immunoglobulin, and splenectomy.

Can a transplanted living donor kidney function equivalently to its native partner?

Early renal functional adaptation was examined in 81 haploidentical donor and recipient pairs, as well as long-term stability of glomerular filtration rate (GFR) in 78 recipients. GFR was determined pre- and 1 month postnephrectomy in donors and 1 month post-transplant and yearly thereafter in recipients. Compensatory increase in filtration (CIF) of transplanted and native kidneys was calculated using donor pretransplant GFR: [CIF= (GFR at 1 month/donor prenephrectomy GFR) x 100]. Annual rates of change in GFR were estimated using within-patient linear regression analysis (slopes). Recipients without rejection (n = 62) and their donors had similar early GFR and CIF. Those with acute rejection (n = 19) had significantly lower GFR and CIF than their donors (61 +/- 16 mL/min/1.73 m2 and 57 +/- 14% vs. 75 +/- 11 and 69 +/- 9; p = 0.01 and p < 0.001). Recipients without cyclosporine (n = 52) had 1 month GFR and CIF of 70 +/- 14 and 67 +/- 14 vs. 72 +/- 11 and 69 +/- 11 for their donors. Those with cyclosporine (n = 29) had 1 month GFR and CIF of 64 +/- 14 and 62 +/- 16 vs. 69 +/- 12 and 67 +/- 11 for their donors (p = 0.15 and 0.16). Comparison of median (25th, 75th) rates of change of GFR with and without acute rejection or cyclosporine did not demonstrate significant effects of either on stability of allograft function, although there was a trend towards greater loss of GFR in cyclosporine-treated patients [-1.1 (-2.5, 0.8) vs. 0.0 (-1.8, 1.2) mL/min/1.73 m2/year, p = 0.47]. We conclude that, in the absence of rejection, the transplanted kidney maintains the same capacity for functional adaptation as its native partner. Therapy with cyclosporine does not significantly inhibit early physiological adaptation of renal transplants.

Subclinical rejection in tacrolimus-treated renal transplant recipients.

BACKGROUND: Subclinical rejection, defined as histologic acute rejection in the absence of graft dysfunction, has been suggested as a cause of chronic allograft rejection. In cyclosporine-treated patients, the incidence of subclinical rejection 3 months after transplant is reported to be approximately 30%. The intent of our study was to determine the incidence of subclinical rejection in tacrolimus-treated renal allograft recipients. METHODS: We prospectively studied the incidence of subclinical rejection on surveillance biopsies performed 3 months after transplantation in 114 patients transplanted between September 1, 1998 and November 30, 2000. All patients received tacrolimus, mycophenolate mofetil, and prednisone, and 56% received antibody induction. RESULTS: Subclinical rejection was detected in 2.6% of patients (3/114, 95% confidence interval 0.5-7.5%). Borderline changes were detected in 11% (12/114). Subclinical rejections were treated with bolus methylprednisolone. CONCLUSIONS: The incidence of subclinical rejection early after kidney transplantation is extremely low in tacrolimus-treated patients in whom early rejections are aggressively treated, suggesting that surveillance biopsies may not be necessary with this regimen.