Phuong-Thu T. Pham

Sirolimus-associated pulmonary toxicity

Background. Pulmonary toxicity has recently been recognized as a potentially serious complication associated with sirolimus therapy. We further detail this condition on the basis of our own cases and those reported in the literature. Methods. We report three cases of suspected sirolimus-induced pulmonary toxicity that occurred in three renal transplant recipients and searched PubMed for all previously reported cases. Results. Including our current cases, 43 patients with sirolimus-induced pulmonary toxicity have now been reported. Clinical data were incomplete in 28 cases. Analysis of available data for 15 patients revealed that the most commonly presenting symptoms were dyspnea on exertion and dry cough followed by fatigue and fever. Chest radiographs and high-resolution computed tomography scans commonly revealed bilateral patchy or diffuse alveolo-interstitial infiltrates. Bronchoalveolar fluid analysis and lung biopsy in selected case reports revealed several distinct histologic features, including lymphocytic alveolitis, lymphocytic interstitial pneumonitis, bronchoalveolar obliterans organizing pneumonia, focal fibrosis, pulmonary alveolar hemorrhage, or a combination thereof. The diagnosis of sirolimus-associated pulmonary toxicity was made after an exhaustive work-up to exclude infectious causes and other pulmonary disease. Sirolimus discontinuation or dose reduction resulted in clinical and radiologic improvement in all 15 patients within 3 weeks. Conclusion. The temporal relationship between sirolimus exposure and onset of pulmonary symptoms in the absence of infectious causes and other alternative pulmonary disease and the associated clinical and radiologic improvement after its cessation suggests a causal relationship. Because the use of sirolimus in organ transplantation has become more widespread, clinicians must remain vigilant to its potential pulmonary complication.

New onset diabetes after transplantation (NODAT): an overview

Although renal transplantation ameliorates cardiovascular risk factors by restoring renal function, it introduces new cardiovascular risks including impaired glucose tolerance or diabetes mellitus, hypertension, and dyslipidemia that are derived, in part, from immunosuppressive medications such as calcineurin inhibitors, corticosteroids, or mammalian target of rapamycin inhibitors. New onset diabetes mellitus after transplantation (NODAT) is a serious and common complication following solid organ transplantation. NODAT has been reported to occur in 2% to 53% of all solid organ transplants. Kidney transplant recipients who develop NODAT have variably been reported to be at increased risk of fatal and nonfatal cardiovascular events and other adverse outcomes including infection, reduced patient survival, graft rejection, and accelerated graft loss compared with those who do not develop diabetes. Identification of high-risk patients and implementation of measures to reduce the development of NODAT may improve long-term patient and graft outcome. The following article presents an overview of the literature on the current diagnostic criteria for NODAT, its incidence after solid organ transplantation, suggested risk factors and potential pathogenic mechanisms. The impact of NODAT on patient and allograft outcomes and suggested guidelines for early identification and management of NODAT will also be discussed.

Lower serum magnesium levels are associated with more rapid decline of renal function in patients with diabetes mellitus type 2.

AIMS Hypomagnesemia has been implicated in adversely affecting diabetic complications. This is a retrospective study designed to determine whether there is any association between serum magnesium concentration [Mg2+] and the rate of renal function deterioration, as determined by the slope of serum creatinine reciprocals versus time (1/SCr-vs-t), in patients with diabetes mellitus type 2 (DM2). MATERIALS AND METHODS DM2 patients without known kidney disease seen at Olive View-UCLA Medical Center for any reason during January-March 2001 were included. For each patient, all available data from our electronic database for [Mg2+], hemoglobin A(1C) (HbA(1C), serum creatinine (SCr), lipid profiles, routine urinary analysis, as well as history of hypertension and pharmacy profiles were retrieved. The average of all parameters obtained and linear regression analyses for the slope of 1/SCr-vs-t plot were performed for each patient. Patients were stratified by gender and divided into four groups based on increasing [Mg2+]. Correlations between each parameter including the slope of 1/SCr-vs-t and the four magnesium groups were analyzed. RESULTS 252 males and 298 females with a mean follow-up of 62.6 +/- 22.5 months were included. Patients belonging to lower [Mg2+] groups for both genders had significantly worse slopes of 1/SCr-vs-t plot independent of the presence of hypertension and use of ACEI/ARB, diuretics, HMG-CoA enzyme inhibitors or aspirin. In a multivariate regression analysis controlling for age, HbA(1C) and various components of the lipid profile, [Mg2+] remained an independent predictor for the slope of 1/SCr-vs-t. A trend for worse proteinuria based on routine urinary analysis was observed among patients belonging to the lowest [Mg2+] group. CONCLUSIONS Lower [Mg2+] is associated with a faster renal function deterioration rate in DM2 patients.

Predictors and Risk Factors for Recurrent Scleroderma Renal Crisis in the Kidney Allograft: Case Report and Review of the Literature

Scleroderma renal crisis (SRC) can lead to end‐stage renal disease (ESRD) and subsequent need for dialysis and/or renal transplantation. We review all reported cases of renal transplantations in scleroderma patients from PubMed search, present UNOS data on transplant outcomes, and identify predictors for allograft SRC. Of the five cases with recurrent SRC, all developed ESRD within a year of onset of native kidney SRC, whereas none of those who developed ESRD more than 1–2 years after the onset of SRC developed recurrence. Anemia preceded allograft SRC in two cases, pericardial effusion in one, and skin tightening in two others. UNOS data (October 1987–July 2004) documented 260 transplants performed for the renal diagnosis of scleroderma, with a 5‐year graft survival rate of 56.7%. The risk for allograft SRC recurrence appears to correlate with early native renal function loss following the onset of SRC. Recurrent SRC in the allograft may be heralded by multiple clinical markers known to be predictive of severe scleroderma, including progression of diffuse skin thickening, new‐onset anemia and cardiac complications.

Outcomes of Dual Adult Kidney Transplants in the United States: An Analysis of the OPTN/UNOS Database

Background. The organ shortage has resulted in increased use of kidneys from expanded criteria donors (ECD). For ECD kidneys unsuitable for single use, dual kidney transplants (DKT) may be possible. There are limited data comparing outcomes of DKT to single kidney ECD transplants, making it unclear where DKT fits in the current allocation scheme. Our purpose was to compare outcomes of DKT and ECD transplants in the United States. Methods. From 2000 to 2005, a total of 625 DKT, 7686 single kidney ECD, and 6,044 SCD transplants from donors aged ≥50 years were identified from the Organ Procurement and Transplantation Network/United Network for Organ Sharing data. Allograft survival was the primary outcome. Results. DKT comprised 4% of kidney transplants from donors aged ≥50 years. Compared to the ECD donor group, the DKT donor group was older (mean age 64.6±7.7 years vs. 59.9±6.2 years) and consisted of more African Americans (13.1% vs. 9.9%), and more diabetic donors (16.3% vs. 10.4%; P<0.001). Mean cold ischemic time was longer in DKT (22.2±9.7 hr), but rates of delayed graft function were lower (29.3%) compared to ECD transplants (33.6%, P=0.03). Three-year overall graft survival was 79.8% for DKT and 78.3% for ECD transplants. Conclusion. DKT were infrequent and had outcomes comparable to ECD transplants, despite the use of organs from higher risk donors. With a more upfront approach to DKT by offering this option to patients at the time of wait-listing as part of an ECD algorithm, we may be able to further optimize outcomes of DKT and minimize discard of potential organs.

Kidney dysfunction in the recipients of liver transplants

1 Pretransplant kidney function is an important predictor of posttransplant kidney function. 2 Chronic kidney disease is present in 20% of liver transplant recipients by 5 years. 3 Kidney function is impacted by pretransplant management of the consequences of the hepatorenal syndrome. 4 The use of calcineurin inhibitor (CNI)–based immunosuppression is an important factor in the development of chronic kidney disease, and the use of mycophenolic acid– or sirolimus‐based immunosuppression with reduced‐dose CNI may be of benefit. (Liver Transpl 2005;11:S47–S51.)

Concurrent FSGS and Hodgkin's lymphoma: case report and literature review on the link between nephrotic glomerulopathies and hematological malignancies

BackgroundThe link between the nephrotic syndrome (NS) and malignancy was first described in 1922. In solid tumors, the NS is most often due to membranous glomerulonephropathy, whereas in common hematological malignancies, minimal-change disease predominates. Focal segmental glomerulosclerosis (FSGS) is among the least frequently reported renal lesion associated with malignancy.MethodsWe report a case of the simultaneous diagnoses of FSGS and Hodgkins lymphoma, and review the literature on various nephrotic glomerulonephropathies associated with common leukemia and lymphoma.ResultsAlthough nephrotic glomerulonephropathies rarely occur in association with acute leukemia, they have often been described in chronic lymphocytic leukemia (CLL). Membranoproliferative glomerulonephropathy and membranous glomerulonephropathy are the most common lesions observed in CLL. Nephrotic glomerulonephropathies have also been well documented among patients with lymphomas, in particular, Hodgkins lymphoma. While minimal-change disease is most commonly found in association with Hodgkins lymphoma, more diverse and complex renal lesions are associated with non-Hodgkins lymphoma. FSGS remains a rare association with hematological malignancies.ConclusionsNephrotic glomerulonephropathies are not only linked to solid-organ tumors, but also to hematolo-gical malignancies. A thorough evaluation, including a physical examination for lymphadenopathy and organomegaly, as well as a hematological evaluation, must be performed in all patients presenting with nephrotic glomerulonephropathies.

Intermediate-term outcomes associated with kidney transplantation in recipients 80 years and older: an analysis of the OPTN/UNOS database.

Background. An increasing number of patients 80 years and older have received a kidney transplant in the United States, but their outcomes are not well described. Using Organ Procurement and Transplantation Network/United Network of Organ Sharing data, outcomes of recipients 80 years and older were evaluated. Methods. Thirty-one thousand one hundred seventy-nine elderly recipients defined by age 60 years and older receiving kidney transplants from 2000 to 2008 were stratified: ages 60 to 69 years (n=24,877), 70 to 79 years (n=6,103), and 80 years and older (n=199). Cox regression models were used to compare patient, graft, and death-censored graft survival. Results. The majority of recipients 80 years and older was male (82.9%), white (87.9%), and less likely to have diabetes or coronary artery disease. More expanded criteria donor (ECD) but fewer living donor transplants were performed among 80 years and older compared with those younger than 80 years. Perioperative mortality, defined as death within 30 days posttransplant, was rare (60–69 years: 1.4%; 70–79 years: 1.5%; and ≥80 years: 2.5%) but tended to be higher among those 80 years and older compared with recipients 60 to 69 years (hazard ratio [HR] 1.67; 95% confidence interval [CI] 0.69–4.05). At 2 years, survival was lower for 80 years and older (73%; HR 2.42; 95% CI 1.91–3.06) and 70 to 79 years (86%; HR: 1.42; 95% CI: 1.34–1.51) compared with recipients 60 to 69 years (89%). There was a greater risk of graft loss among recipients 80 years and older compared with those 60 to 69 years (HR 1.78; 95% CI 1.42–2.23); however, no difference in death-censored graft survival was observed (0.89; 0.57–1.39). Among recipients 80 years and older, no difference in survival was observed between standard criteria donor and ECD recipients. Conclusion. Although perioperative mortality was uncommon among elderly recipients (1.5%), a trend toward higher perioperative mortality was observed in recipients 80 years and older. There was no difference in survival among standard criteria donor and ECD recipients.

Donor biopsy and kidney transplant outcomes: an analysis using the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) database.

Background. Although the degree of glomerulosclerosis on pretransplant donor biopsy is one criterion used in the decision to accept a deceased donor kidney, its relationship with graft survival remains controversial. This study compared graft survival with the degree of glomerulosclerosis found on donor biopsy. We also examined the agreement in degree of glomerulosclerosis between paired kidneys. Methods. Biopsy results from 12,129 adult deceased donor transplants between January 1, 2000 and December 31, 2005 were identified in the Organ Procurement and Transplantation Network/United Network for Organ Sharing data, as of September 11, 2006. Of these, 2696 donors had both kidneys biopsied and subsequently transplanted. Results. Among the groups with greater than 5% glomerulosclerosis, there was no statistically significant difference in graft survival rates (log-rank, P=0.44). The overall graft survival rates of the 0–5% group were significantly superior to those of the >5% groups (1-, 3-, and 5-year rates: 85.9%, 72.4%, and 59.0% for 0–5% group vs. 81.6%, 68.1%, and 53.6% for >5% group, log-rank P<0.001). Agreement between paired kidneys from the same donor was highest for the 0–5% glomerulosclerosis groups (90.6% for pairs with 0–5% glomerulosclerosis in the left kidney vs. 42.5% for pairs with >5% glomerulosclerosis in the left kidney). Conclusion. Donor kidneys with less than 6% glomerulosclerosis were associated with better graft outcomes and intrapair agreement in the degree of glomerulosclerosis. Among kidneys with greater than 5% glomerulosclerosis, the degree of glomerulosclerosis did not help predict graft outcomes. Sampling error may contribute to the lack of outcome differences seen among these kidneys, given the low intrapair agreement.

Renal function outcomes following liver transplantation and combined liver–kidney transplantation

Acute renal failure (ARF) is common immediately after orthotopic liver transplantation (OLT), whereas the incidences of chronic kidney disease (CKD) and end-stage renal disease increase with time. Introduction of the Model for End-stage Liver Disease (MELD) score—intended to prioritize patients with more-severe pretransplantation liver disease in general, and worse pretransplantation renal function in particular—for the allocation of liver grafts led to concerns about compromised patient and allograft survival and increased incidence of postoperative ARF and CKD. Nonetheless, it has been suggested that early OLT of candidates with baseline renal dysfunction improves post-transplantation renal outcomes. For OLT candidates with mild to moderate chronic renal impairment or recent-onset ARF, the decision of whether to perform OLT alone or combined liver–kidney transplantation (CLKT) can be challenging because no single factor has been shown to be predictive of the degree of renal function recovery or CKD progression following successful OLT. In this article, we provide an overview of the literature on renal function outcomes following OLT and CLKT, share our perspectives on the potential predictors of renal dysfunction or nonrecovery of renal function after OLT, and present United Network for Organ Sharing data on patient and allograft outcomes in CLKT recipients in the pre-MELD and post-MELD eras. Mechanisms that might underlie immunological protection of kidney grafts by liver allografts are also discussed.