Phuong-Chi 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.

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.

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.

Management of renal dysfunction in the liver transplant recipient.

Purpose of reviewAcute and chronic kidney injury following orthotopic liver transplantation (OLT) is associated with increased morbidity and mortality. With the increasing longevity of liver transplant recipients, chronic kidney disease (CKD) has become an increasingly prevalent complication among long-term survivors. This article provides an overview of the literature on suggested risk factors for acute and CKD following OLT and a discussion of an approach to their medical management. Recent findingsIn OLT candidates with pretransplant renal dysfunction, the use of interleukin-2 receptor blockers or antithymocyte globulin induction therapy in conjunction with delayed introduction of calcineurin inhibitors may preserve early renal function. In long-term stable OLT recipients with established calcineurin inhibitor nephrotoxicity, calcineurin inhibitor minimization or withdrawal protocols may halt or ameliorate renal dysfunction without compromising patient and graft survival. However, large-scale, multicenter, randomized controlled trials are still needed. SummaryThe occurrence of acute kidney injury is common immediately after OLT, whereas the incidence of CKD and end-stage renal disease increases with time. Identifying patients at risk for acute kidney injury and CKD following OLT and early implementation of measures to preserve, halt, or ameliorate the progression of renal dysfunction should be an integral part in the management of OLT recipients.

Hypomagnesemia: a clinical perspective.

Although magnesium is involved in a wide spectrum of vital functions in normal human physiology, the significance of hypomagnesemia and necessity for its treatment are under-recognized and underappreciated in clinical practice. In the current review, we first present an overview of the clinical significance of hypomagnesemia and normal magnesium metabolism, with a focus on renal magnesium handling. Subsequently, we review the literature for both congenital and acquired hypomagnesemic conditions that affect the various steps in normal magnesium metabolism. Finally, we present an approach to the routine evaluation and suggested management of hypomagnesemia.

BK virus infection following kidney transplantation: an overview of risk factors, screening strategies, and therapeutic interventions.

Purpose of reviewIn recipients of kidney transplants, the emergence of BK virus (BKV)-associated clinical syndromes, such as viruria, viremia, and BK nephropathy, coincided with the advent of potent immunosuppressive therapy. There is currently no standardized protocol for the management of BK viruria or viremia, or established BK nephropathy. Suggested risk factors for BKV replication and a literature overview on various treatment strategies for BKV-associated clinical syndromes are presented, followed by the authors’ proposed approach for screening, monitoring, and treatment of post-transplant BKV infection. Recent findingsBKV infection can occur under all combinations of immunosuppressive therapy. Although both humoral and cellular immunity may be essential, BKV-specific T-cell immunity appears to play a pivotal role in controlling BKV replication. Monitoring BKV-specific immune response might prove useful in guiding therapeutic intervention. The beneficial effects of antiviral agents remain unclear. Development of T-cell or antibody-based vaccines against BKV is a subject of future research. SummaryIn the absence of conclusive evidence that any particular immunosuppressive agent has a specific influence over another on BKV infection risk and the unclear benefit of antiviral agents, intensive monitoring of serum BKV using PCR and immunological containment of BKV replication should remain the mainstay of therapy. The routine recommendations of antiviral agents in the treatment of BKV-associated clinical syndromes await results of large prospective randomized trials.

Evaluation of Adult Kidney Transplant Candidates

Important advances in immunosuppressive therapy and refinement in surgical techniques have allowed renal transplantation to become the treatment of choice for virtually all suitable candidates with end‐stage renal disease. Compared to dialysis, kidney transplantation improves both patient survival and quality of life and, over time, can reduce the total cost of medical care. It must be noted, however, that although the risk of death in the first year after transplantation is <5%, not all patients qualify for the surgery because of their unacceptable risks for complications. The transplant evaluation process requires a comprehensive assessment of each patient’s medical, surgical, and psychosocial histories. Selection of the suitable transplant candidate remains a challenge for transplant physicians owing, predominantly, to the presence of complex medical issues in the potential candidates and nonstandardized criteria for acceptance or rejection among transplant centers. Furthermore, with the ever‐increasing disparity between donor organ supply and demand and resultant increased wait‐list times, the transplant physicians must further consider the optimal management and re‐evaluation of wait‐list patients during the waiting period. This article describes a systematic approach for the evaluation of a potential renal transplant candidate. Various medical issues that arise during the evaluation process are discussed.