Optimal use of SGLT2 inhibitors in diabetic kidney transplant recipients.

Sodium-glucose cotransporter 2 inhibitor (SGLT2i), a glucosuric agent initially approved for use as an antidiabetic agent, was unexpectedly found to confer cardio-and reno-protective effects in individuals with or without type 2 diabetes mellitus. Despite mounting evidence suggesting that SGLT2i provides cardio- and reno-protective benefits in both diabetic and non-diabetic and in chronic kidney disease (CKD) patients in the general population, reservations for its use in the transplant setting persist due to concerns for increased risk of genital mycotic and urinary tract infections. A comprehensive review of the literature on the efficacy and safety of SGLT2i use in diabetic kidney transplant recipients is herein presented followed by authors' opinion on its optimal use in this patient population.

Acute Kidney Failure in a Young African American Male.

Retroperitoneal fibrosis (RPF) is a condition characterized by chronic inflammatory and fibrotic changes in the retroperitoneum that can lead to serious complications including kidney failure, mesenteric and limb ischemia, and deep venous thrombosis among others. Affected individuals may present with nonspecific symptomology that would require a high clinical index of suspicion for prompt diagnosis. We herein discuss a case of a young African-American man with recurrent deep venous thrombosis who presents with a 4-week history of constant aching pain of abdomen and back and kidney failure. Initial noncontrast computed tomogram (CT) only revealed mild bilateral hydroureteronephrosis with inflammatory changes but without obvious mass or lymphadenopathy. At the insistence of the renal consulting team to rule out RPF, a CT-urogram was performed which revealed an infiltrative mass encasing the aorta, inferior vena cava, and common iliac vessels. Laparoscopic biopsy revealed dense fibroadipose tissue, lymphocytic aggregates, focal scattered IgG4-positive plasma cells, and fibrin deposition. Patient underwent bilateral nephrostomy placement and empirical corticosteroid therapy with resolution of kidney failure. Our case illustrates a classic presentation of RPF with relatively benign findings on noncontrast CT that could have been missed if clinicians did not keep a high index of suspicion for the condition.

Correction of hyponatremia and osmotic demyelinating syndrome: have we neglected to think intracellularly?

BACKGROUND: Osmotic demyelination syndrome (ODS) is a complication generally associated with overly rapid correction of hyponatremia. Traditionally, nephrologists have been trained to focus solely on limiting the correction rate. However, there is accumulating evidence to suggest that the prevention of ODS is beyond achieving slow correction rates. METHODS: We (1) reviewed the literature for glial intracellular protective alterations during hyperosmolar stress, a state presumed equivalent to the rapid correction of hyponatremia, and (2) analyzed all available hyponatremia-associated ODS cases from PubMed for possible contributing factors including correction rates and concurrent metabolic disturbances involving hypokalemia, hypophosphatemia, hypomagnesemia, and/or hypoglycemia. RESULTS: In response to acute hyperosmolar stress, glial cells undergo immediate extracellular free water shift, followed by active intracellular Na(+), K(+) and amino acid uptake, and eventual idiogenic osmoles synthesis. At minimum, protective mechanisms require K(+), Mg(2+), phosphate, amino acids, and glucose. There were 158 cases of hyponatremia-associated ODS where both correction rates and other metabolic factors were documented. Compared with the rapid correction group (>0.5 mmol/L/h), the slow correction group (≤0.5 mmol/L/h) had a greater number of cases with concurrent hypokalemia (49.4 vs. 33.3 %, p = 0.04), and a greater number of cases with any concurrent metabolic derangements (55.8 vs. 38.3 %, p = 0.03). CONCLUSION: Glial cell minimizes volume changes and injury in response to hyperosmolar stress via mobilization and/or utilization of various electrolytes and metabolic factors. The prevention of ODS likely requires both minimization of correction rate and optimization of intracellular response during the correction phase when a sufficient supply of various factors is necessary.

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.

Membranoproliferative glomerulonephritis in patients with chronic venous catheters: a case report and literature review.

Chronic indwelling catheters have been reported to be associated with membranoproliferative glomerulonephritis (MPGN) via the activation of the classical complement pathway in association with bacterial infections such as coagulase negative staphylococcus. We herein provide supporting evidence for the direct causal relationship between chronic catheter infections and MPGN via a case of recurrent MPGN associated with recurrent catheter infections used for total parenteral nutrition (TPN) in a man with short gut syndrome. We also present a literature review of similar cases and identify common clinical manifestations that may serve to aid clinicians in the early identification of MPGN associated with infected central venous catheterization or vice versa. The importance of routine monitoring of kidney function and urinalysis among patients with chronic central venous catheterization is highlighted as kidney injury may herald or coincide with overtly infected chronic indwelling central venous catheters.

Kidney transplantation in the obese transplant candidates: to transplant or not to transplant?

The prevalence of obesity (body mass index ≥30 kg/m(2)) at the time of transplantation among kidney transplant recipients in the United States has doubled between 1987 and 2001 and continues to increase inexorably. Single-center and large registry studies in kidney transplant recipients demonstrated that high body mass index (BMI) at transplant is associated with increased risk of wound and surgical site infections, delayed graft function (DGF), acute rejection episodes, and graft loss, among others. Hence, in many centers, obese transplant candidates are denied a transplant based on their body mass index (BMI) alone. The impact of obesity on short- and long-term graft and patient outcomes after kidney transplantation are herein revisited, followed by the authors' proposed approach to evaluate and select obese transplant candidates for a kidney transplant. Suggested interventions to optimize the health of such candidates are also discussed.

Screening strategies and predictive diagnostic tools for the development of new-onset diabetes mellitus after transplantation: an overview.

New-onset diabetes mellitus after transplantation (NODAT) is a serious and common complication following solid organ transplantation. NODAT has been reported 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. Limited clinical studies in liver, heart, and lung transplants similarly suggested that NODAT has an adverse impact on patient and graft outcomes. Early detection and management of NODAT must, therefore, be integrated into the treatment of transplant recipients. Studies investigating the best screening or predictive tool for identifying patients at risk for developing NODAT early after transplantation, however, are lacking. We review the clinical predictive values of fasting plasma glucose, oral glucose tolerance test, and A1C in assessing the risk for NODAT development and as a screening tool. Simple diabetes prediction models that incorporate clinical and/or metabolic risk factors (such as age, body mass index, hypertriglyceridemia, or metabolic syndrome) are also presented.

Patients with diabetes mellitus type 2 and hypomagnesemia may have enhanced glomerular filtration via hypocalcemia.

INTRODUCTION: Hypomagnesemia and glomerular hyperfiltration are commonly observed in patients with diabetes mellitus Type 2 (DM2). In the current study, we examined the relationship between hypomagnesemia and glomerular filtration rates in DM2 patients. MATERIALS AND METHODS: Data were obtained for DM2 patients without documented kidney disease seen at UCLAOlive View Medical Center during January through March 2001. Data for hemoglobin, hemoglobin A1C (HbA1C), routine electrolytes, lipid profiles, urinalyses, history of hypertension, and pharmacy profiles were retrieved. Estimation of glomerular filtration rate (eGFR) was based on the CKD-epi formula. Multivariate analyses were performed to determine the correlations between eGFR and clinical factors including age, gender, history of hypertension, the use of diuretics, renin angiotensin system (RAS) inhibitors, acetylsalicylic acid, and statins, serum calcium, magnesium, hemoglobin, HbA1C lipid profile, and degree of proteinuria. RESULTS: 550 patients (54% females) with mean age 57.5 ± 11.0 years and eGFR 95.7 ± 14.8 ml/min/1.73 m2 were included. Multivariate analysis revealed negative correlations with eGFR for age (Pearson-correlationcoefficient: -0.7, p < 0.0001), hypertension (-0.32, p < 0.0001), magnesium (-0.21, p < 0.0001), calcium (-0.13, p = 0.009), proteinuria (-0.17, p < 0.0001), and the use of RAS inhibitors (-0.21, p < 0.0001), and diuretics (-0.24, p < 0.0001) and a positive correlation for HbA1C (0.28, p < 0.0001). Further analysis of the interaction between serum magnesium and calcium, defined as magnesium × calcium (Mg × Ca), revealed a more significant correlation with eGFR than either cation alone (-0.24, p < 0.0001). CONCLUSIONS: Serum magnesium, calcium, and (Mg × Ca) all had significant negative correlations with eGFR. In particular, (Mg × Ca) had the strongest correlation with eGFR.

The impact of mycophenolate mofetil versus azathioprine as adjunctive therapy to cyclosporine on the rates of renal allograft loss due to glomerular disease recurrence.

BACKGROUND: Given the reported efficacy of mycophenolate mofetil (MMF) in the treatment of glomerular diseases, we question whether MMF can reduce the rate of renal allograft loss due to glomerular disease recurrence compared to azathioprine (AZA) as adjunctive therapy to cyclosporine (CSA)-based immunosuppression. METHODS: This is a retrospective study based on the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) database designed to compare the Kaplan-Meier rates of graft loss due to disease recurrence stratified by primary renal diagnoses between recipients receiving CSA+AZA versus CSA+MMF. Recipients of primary kidney transplants (both deceased donor and living, related and unrelated) renal transplants performed between 1 January 1988 and 31 December 2007 with the primary renal diagnosis of IgA nephropathy (IgAN), membranous glomerulonephropathy (MGN), membranoproliferative glomerulonephropathy (MPGN), lupus nephritis (LN) or focal segmental glomerulosclerosis (FSGS) with a functioning allograft at discharge were included. RESULTS: Seven thousand eight hundred and twenty-six recipients of primary deceased donor kidney transplants (DDKT) [CSA + AZA: IgAN (890), MGN (380), MPGN (193), LN (1324), FSGS (1314) and CSA+MMF: IgAN (855), MGN (614), MPGN (116), LN (715), FSGS (1425)] and 5498 recipients of living donor kidney transplants (LDKT) [CSA+AZA: IgAN (694), MGN (229), MPGN (100), LN (592), FSGS (654) and CSA+MMF: IgAN (1066), MGN (435), MPGN (89), LN (530), FSGS (1109)] were included in the analysis. At 10-year follow-up (mean duration was 5.6 to 6.7±1.8 years in DDKT and 6.2 to 7.4±1.7 years in LDKT), mean times of transplantation (era of transplantation) were: 1992±1.6 years and 2002±1.9 years for the CSA+AZA and CSA+MMF groups, respectively. There was no statistically significant difference in the Kaplan-Meier rates of graft loss due to disease recurrence of any glomerular disease studied between the CSA+AZA and CSA+MMF groups in either DDKT or LDKT recipients. Chi-square analysis revealed no statistically significant difference between the two immunosuppressive regimen groups in terms of age, gender and ethnic background. CONCLUSION: The OPTN/UNOS database revealed no difference in the rates of renal allograft loss due to disease recurrence of IgAN, MGN, MPGN, LN and FSGS among recipients receiving either CSA+AZA or CSA+MMF maintenance immunosuppressive therapy at 10-year follow-up.

Graft loss due to recurrent lupus nephritis in living-related kidney donation.

BACKGROUND AND OBJECTIVES: Major predisposing risks for the development of SLE in the nontransplant setting have been reported to include female gender, ethnicity, and genetic factors among others. In the current study, we aimed to determine whether increasing haplotype match in living donor renal transplantation would have a negative impact on the long-term rates of graft loss due to lupus nephritis recurrence. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Data were provided by the Organ Procurement and Transplantation Network--United Network for Organ Sharing. Living-related primary kidney transplants performed between January 1, 1988, and December 31, 2007 with the native renal diagnosis of lupus nephritis for all patients alive and with functioning graft at discharge were included. The cumulative probability rates of allograft loss due to recurrence of lupus nephritis (RLN) stratified by haplotype match and immunosuppression were obtained. RESULTS: The cumulative probability rates of graft loss due to RLN in primary kidney transplant recipients receiving cyclosporine-based immunosuppression were 4.8% (n = 187), 2.9% (n = 602), and 0.7% (n = 192) for recipients with 0-, 1-, and 2-haplotype matches, respectively. Similarly, recipients receiving "all maintenance" immunosuppressive therapy with 0-, 1-, and 2-haplotype matches had graft loss rates of 4.3% (n = 433), 2.3% (n = 1049), and 0.5% (n = 303), respectively. Chi-squared analyses revealed no significant gender or ethnic background differences among haplotype groups. Compared with 0-haplotype, 1- and 2-haplotype matched recipients were generally younger. CONCLUSIONS: Living-related kidney donation with increasing haplotype match is unexpectedly associated with lower rates of allograft loss due to RLN. Potential contributory factors to this positive effect are not known.

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.

Antithrombotic strategies in patients undergoing percutaneous coronary intervention for acute coronary syndrome.

In patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS), both periprocedural acute myocardial infarction and bleeding complications have been shown to be associated with early and late mortality. Current standard antithrombotic therapy after coronary stent implantation consists of lifelong aspirin and clopidogrel for a variable period depending in part on the stent type. Despite its well-established efficacy in reducing cardiac-related death, myocardial infarction, and stroke, dual antiplatelet therapy with aspirin and clopidogrel is not without shortcomings. While clopidogrel may be of little beneficial effect if administered immediately prior to PCI and may even increase major bleeding risk if coronary artery bypass grafting is anticipated, early discontinuation of the drug may result in insufficient antiplatelet coverage with thrombotic complications. Optimal and rapid inhibition of platelet activity to suppress ischemic and thrombotic events while minimizing bleeding complications is an important therapeutic goal in the management of patients undergoing percutaneous coronary intervention. In this article we present an overview of the literature on clinical trials evaluating the different aspects of antithrombotic therapy in patients undergoing PCI and discuss the emerging role of these agents in the contemporary era of early invasive coronary intervention. Clinical trial acronyms and their full names are provided in Table 1.

The evolving role of alemtuzumab (Campath-1H) in renal transplantation.

The introduction of new immunosuppressive agents into clinical transplantation in the 1990s has resulted in excellent short-term graft survival. Nonetheless, extended long-term graft outcomes have not been achieved due in part to the nephrotoxic effects of calcineurin inhibitors (CNIs) and the adverse effects of steroid on cardiovascular disease risk factors. Induction therapy with lymphocyte depleting antibodies has originally been introduced into renal transplantation to provide intense immunosuppression in the early post-transplant period to prevent allograft rejection. Over the past half decade, induction therapy with both non-lymphocyte depleting (basiliximab and daclizumab) and lymphocyte-depleting antibodies (antithymocyte antibodies, OKT3, alemtuzumab) has increasingly been utilized in steroid or CNI sparing protocols in the early postoperative period. Alemtuzumab is a humanized monoclonal antibody targeted against CD52 on the surface of circulatory mononuclear cells. The ability of alemtuzumab (Campath-1H) to provide rapid and profound depletion of lymphocytes from the peripheral blood has sparked interest in the use of this agent as induction therapy in steroid and/or CNI minimization or avoidance protocols. This article provides an overview of the literature on the evolving role of alemtuzumab in renal transplantation.

Acute kidney injury after liver, heart, and lung transplants: dialysis modality, predictors of renal function recovery, and impact on survival.

Recipients of nonrenal organ transplants including the liver, heart, and lung are at risk for developing acute kidney injury (AKI) and chronic kidney disease (CKD). Underlying hepatic or cardiopulmonary failure, prolonged intraoperative hemodynamic instability, and the use of calcineurin inhibitors and nephrotoxic medications have all been suggested to be contributory. The incidence of perioperative AKI has been reported to occur in 17% to 95% in liver transplant recipients, 5% to 30% in heart transplant recipients, and 5% to 60% in recipients of lung transplants. Among those who develop AKI, renal replacement therapy is required in 5% to 35%, 5% to 15%, and 8% to 10% in liver, heart, and lung transplant recipients, respectively. The current article presents an overview of the literature on the choice of dialysis modality and its associated advantages and disadvantages in the management of AKI after liver, heart, and lung transplants. Predictive factors for renal function recovery and the impact of AKI and CKD on survival will also be discussed.

Management of renal dysfunction in the liver transplant recipient.

PURPOSE OF REVIEW: Acute 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 FINDINGS: In 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. SUMMARY: The 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.

Pain management in patients with chronic kidney disease.

Pain has been reported to be a common problem in the general population and end-stage renal disease (ESRD) patients. Although similar data for pre-ESRD patients are lacking, we recently reported that the prevalence of pain is also very high (>70%) among pre-ESRD patients at a Los Angeles County tertiary referral centre. The high prevalence of pain in the CKD population is particularly concerning because pain has been shown to be associated with poor quality of life. Of greater concern, poor quality of life, at least in dialysis patients, has been shown to be associated with poor survival. We herein discuss the pathophysiology of common pain conditions, review a commonly accepted approach to the management of pain in the general population, and discuss analgesic-induced renal complications and therapeutic issues specific for patients with reduced renal function.

Conivaptan: a step forward in the treatment of hyponatremia?

Hyponatremia is one of the most common electrolyte abnormalities linked to adverse outcomes and increased mortality in hospitalized patients. While the differential diagnosis for hyponatremia is diverse, most cases stem from arginine vasopressin (AVP) dysregulation, where hypoosmolality fails to suppress AVP synthesis and release. The physiological effects of AVP are currently known to depend on its interaction with any of 3 receptor subtypes V1A, V2, and V1B. Activation of V2 by AVP is the key in renal water regulation and maintenance of total body volume and plasma tonicity. Despite the long-recognized problem with excess AVP in euvolemic and hypervolemic hyponatremia, traditional therapeutic options have relied on nonspecific and potentially problematic strategies. More recently, a new class of drugs, introduced as "aquaretics," has gained great attention among clinicians because of its ability to correct hyponatremia via direct competitive inhibition of AVP at V2 receptors to induce renal electrolyte-free water excretion. In this paper, we aim to review available clinical data on the only FDA-approved aquaretic, dual V1A/V2 receptor antagonist conivaptan, discuss its clinical indications, efficacy, safety profile, and comment on its clinical limitations.