HLA mismatch is important for 20-year graft survival in kidney transplant patients.

BACKGROUND: Human leukocyte antigens (HLA) matching is gradually being omitted from clinical practice in evaluation for renal allograft transplant. While such practices may yield shorter wait times and adequate short-term outcomes, graft longevity in HLA mismatched patients remains unclear. This study aims to demonstrate that HLA matching may still play an important role in long-term graft survival. METHODS: We identified patients undergoing an index kidney transplant in the United Network for Organ Sharing (UNOS) data from 1990 to 1999, with one-year graft survival. The primary outcome of the analysis was graft survival beyond 10 years. We explored the long-lasting impact of HLA mismatches by landmarking the analysis at established time points. RESULTS: We identified 76,530 patients receiving renal transplants in the time frame, 23,914 from living donors and 52,616 from deceased donors. On multivariate analysis, more HLA mismatches were associated with worse graft survival beyond 10 years for both living and deceased donor allografts. HLA mismatch continued to remain an essential factor in the long term. CONCLUSIONS: A greater number of HLA mismatches was associated with progressively worse long-term graft survival for patients. Our analysis reinforces the importance of HLA matching in the preoperative evaluation of renal allografts.

Executive Summary of the KDIGO 2022 Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease.

Infection with the hepatitis C virus (HCV) has adverse liver, kidney, and cardiovascular consequences in patients with chronic kidney disease (CKD), including those on dialysis therapy or with a kidney transplant. Since the publication of the Kidney Disease: Improving Global Outcomes (KDIGO) HCV Guideline in 2018, advances in HCV management, particularly in the field of antiviral therapy and treatment of HCV-associated glomerular diseases, coupled with increased usage of HCV-positive kidney grafts, have prompted a reexamination of the 2018 guideline. As a result, the Work Group performed a comprehensive review and revised the 2018 guidance. This Executive Summary highlights key aspects of the updated guideline recommendations for 3 chapters: Chapter 2: Treatment of HCV infection in patients with CKD; Chapter 4: Management of HCV-infected patients before and after kidney transplantation; and Chapter 5: Diagnosis and management of kidney diseases associated with HCV infection.

Potential Mechanisms Involved in Chronic Kidney Disease of Unclear Etiology.

BACKGROUND AND OBJECTIVES: The etiology of chronic kidney disease of unclear etiology, also known as Mesoamerican nephropathy, remains unclear. We investigated potential etiologies for Mesoamerican nephropathy in an immigrant dialysis population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Migrants with Mesoamerican nephropathy kidney failure (n=52) were identified by exclusion of known causes of kidney disease and compared using a cross-sectional survey with demographically similar patients with kidney failure from other causes (n=63) and age/sex/place of origin-matched healthy participants (n=16). Survey results were extended to the bench; C57BL/6 mice (n=73) received 10-15 weekly intraperitoneal injections of paraquat (a reactive oxygen species-generating herbicide) or vehicle. Kidney function, histology, and expression of organic cation transporter-2 (proximal tubule entry for paraquat) and multidrug and toxin extrusion 1 (extrusion pathway) were examined. Kidney biopsies from Nicaraguan patients with acute Mesoamerican nephropathy were stained for the above transporters and compared with patients with tubulointerstitial nephritis and without Mesoamerican nephropathy. RESULTS: Patients with Mesoamerican nephropathy and kidney failure were young agricultural workers, almost exclusively men; the majority were from Mexico and El Salvador; and they had prior exposures to agrochemicals, including paraquat (27%). After adjustment for age/sex, exposure to any agrochemical or paraquat was associated with Mesoamerican nephropathy kidney failure (odds ratio, 4.86; 95% confidence interval, 1.82 to 12.96; P=0.002 and odds ratio, 12.25; 95% confidence interval, 1.51 to 99.36; P=0.02, respectively). Adjusted for age/sex and other covariates, 1 year of agrochemical exposure was associated with Mesoamerican nephropathy kidney failure (odds ratio, 1.23; 95% confidence interval, 1.04 to 1.44; P=0.02). Compared with 16 matched healthy controls, Mesoamerican nephropathy kidney failure was significantly associated with exposure to paraquat and agrochemicals. Paraquat-treated male mice developed kidney failure and tubulointerstitial nephritis consistent with Mesoamerican nephropathy. Organic cation transporter-2 expression was higher in male kidneys versus female kidneys. Paraquat treatment increased organic cation transporter-2 expression and decreased multidrug and toxin extrusion 1 expression in male kidneys; similar results were observed in the kidneys of Nicaraguan patients with Mesoamerican nephropathy. CONCLUSIONS: Exposure to agrochemicals is associated with Mesoamerican nephropathy, and chronic exposure of mice to paraquat, a prototypical oxidant, induced kidney failure similar to Mesoamerican nephropathy.

Determinants of hypokalemia following hypertonic sodium bicarbonate infusion.

The hypokalemic response to alkali infusion has been attributed to the resulting extracellular fluid (ECF) expansion, urinary potassium excretion, and internal potassium shifts, but the dominant mechanism remains uncertain. Hypertonic NaHCO3 infusion (1 N, 5 mmol/kg) to unanesthetized dogs with normal acid-base status or one of the four chronic acid-base disorders decreased plasma potassium concentration ([K+]p) at 30 min in all study groups (Δ[K+]p, - 0.16 to - 0.73 mmol/L), which remained essentially unaltered up to 90-min postinfusion. ECF expansion accounted for only a small fraction of the decrease in ECF potassium content, (K+)e. Urinary potassium losses were large in normals and chronic respiratory acid-base disorders, limited in chronic metabolic alkalosis, and minimal in chronic metabolic acidosis, yet, ongoing kaliuresis did not impact the stability of [K+]p. All five groups experienced a reduction in (K+)e at 30-min postinfusion, Δ(K+)e remaining unchanged thereafter. Intracellular fluid (ICF) potassium content, (K+)i, decreased progressively postinfusion in all groups excluding chronic metabolic acidosis, in which a reduction in (K+)e was accompanied by an increase in (K+)i. We demonstrate that hypokalemia following hypertonic NaHCO3 infusion in intact animals with acidemia, alkalemia, or normal acid-base status and intact or depleted potassium stores is critically dependent on mechanisms of internal potassium balance and not ECF volume expansion or kaliuresis. We envision that the acute NaHCO3 infusion elicits immediate ionic shifts between ECF and ICF leading to hypokalemia. Thereafter, maintenance of a relatively stable, although depressed, [K+]e requires that cells release potassium to counterbalance ongoing urinary potassium losses.

The impact of diabetes on young transplant recipients: An American perspective.

Despite advancements in diabetic care, diabetic kidney transplant recipients have significantly worse outcomes than non-diabetics. AIM: Our study aims to demonstrate the impact of diabetes, types I and II, on American young adults (18-40 years old) requiring kidney transplantation. METHODS: Using the United Network for Organ Sharing database, we conducted a population cohort study that included all first-time, kidney-only transplant recipients during 2002-2019, ages 18-40 years old. Patients were grouped according to indication for transplant. Primary outcomes were cumulative all-cause mortality and death-censored graft failure. Death-censored graft failure and patient survival at 1, 5, and 10 years were calculated via the Kaplan-Meier method. Multivariate Cox regression was used to assess for potential confounders. RESULTS: Of 42 466 transplant recipients, 3418 (8.1%) had end-stage kidney disease associated with diabetes. At each time-point, cumulative mortality was higher in diabetics compared to patients with non-diabetic causes of renal failure. Conversely, cumulative graft failure was similar between the groups. Adjusted hazard ratios for all-cause mortality and graft failure in diabetics were 2.99 (95% CI 2.67-3.35; p < .01) and 0.98 (95% CI 0.92-1.05, p < .01), respectively. CONCLUSION: Diabetes mellitus in young adult kidney transplant recipients is associated with a nearly three-fold increase in mortality, reflecting a relatively vulnerable patient population. Identifying the underlying causes of poor outcomes in this population should be a priority for future study.

The impact of COVID-19 on kidney transplantation and the kidney transplant recipient - One year into the pandemic.

The COVID-19 pandemic has significantly changed the landscape of kidney transplantation in the United States and worldwide. In addition to adversely impacting allograft and patient survival in postkidney transplant recipients, the current pandemic has affected all aspects of transplant care, including transplant referrals and listing, organ donation rates, organ procurement and shipping, and waitlist mortality. Critical decisions were made during this period by transplant centers and individual transplant physicians taking into consideration patient safety and resource utilization. As countries have begun administering the COVID vaccines, new and important considerations pertinent to our transplant population have arisen. This comprehensive review focuses on the impact of COVID-19 on kidney transplantation rates, mortality, policy decisions, and the clinical management of transplanted patients infected with COVID-19.

Prevalence, correlates and outcomes of absolute and functional iron deficiency anemia in nondialysis-dependent chronic kidney disease.

BACKGROUND: Anemia is associated with adverse outcomes in those with chronic kidney disease (CKD). We examined the association of absolute and functional iron deficiency anemia (IDA) with adverse outcomes (cardiovascular hospitalization, dialysis and mortality) in those with nondialysis-dependent CKD. METHODS: Nondialysis-dependent CKD patients followed in the US Veterans Administration with hemoglobin level measured within 90 days of the date of the second estimated glomerular filtration rate <60 mL/min/1.73 m2 were included. Logistic regression, multivariate Cox proportional hazards and Poisson regression models adjusted for demographics and comorbidities were used to assess the prevalence and correlates of absolute [transferrin saturation (TSAT) ≤20%, ferritin <100 ng/mL] and functional (TSA T≤20%, ferritin >100-500 ng/mL) IDA and the associations of absolute and functional IDA with mortality, dialysis and cardiovascular hospitalization. RESULTS: Of 933 463 patients with CKD, 20.6% had anemia. Among those with anemia, 23.6% of patients had both TSAT and ferritin level measured, of whom 30% had absolute IDA and 19% had functional IDA. Absolute IDA in CKD was not associated with an increased risk of mortality or dialysis but was associated with a higher risk of 1-year {risk ratio [RR] 1.20 [95% confidence interval (CI) 1.12-1.28]} and 2-year cardiovascular hospitalization [RR 1.11 (95% CI 1.05-1.17)]. CKD patients with functional IDA had a higher risk of mortality [hazard ratio (HR) 1.11 (95% CI 1.07-1.14)] along with a higher risk of 1-year [RR 1.21 (95% CI 1.1-1.30)] and 2-year cardiovascular hospitalization [RR 1.13 (95% CI 1.07-1.21)]. Ferritin >500 ng/mL (treated as a separate category) was only associated with an increased risk of mortality [HR 1.38 (95% CI 1.26-1.51)]. CONCLUSIONS: In a large population of CKD patients with anemia, absolute and functional IDA were associated with various clinical covariates. Functional IDA was associated with an increased risk of mortality and cardiovascular hospitalization, but absolute IDA was associated only with a higher risk of hospitalization.

Pre-ESKD Nephrology Care and Employment at the Start of Dialysis.

INTRODUCTION: Employment is associated with an improved sense of well-being and quality of life in patients with kidney disease. Earlier nephrology referral and longer duration of pre-end-stage kidney disease (ESKD) nephrology care are associated with improved health outcomes in patients with advanced kidney disease who initiate dialysis. It is unknown if pre-ESKD nephrology care helps patients stay employed leading up to dialysis initiation. METHODS: We used the US ESKD registry to identify adults aged 18-54 years who initiated dialysis between 2007 and 2014. Analyses were restricted to patients who reported being employed 6 months prior to ESKD. We used multivariable regression models with estimated average marginal effects to examine the independent association between ≥6 months of pre-ESKD nephrology care and employment at dialysis initiation. To reduce bias, we conducted an instrumental variable (IV) analysis based on geographic variation in pre-ESKD care. RESULTS: Of 75,700 patients included in study cohort, 49% reported receiving pre-ESKD nephrology care for ≥6 months, and 62% were employed at dialysis initiation. Although geographic variation in pre-ESKD nephrology care was strongly associated with the likelihood that working-aged patients in our analytic cohort received pre-ESKD care, the receipt of pre-ESKD nephrology care was not significantly associated with employment at dialysis initiation; estimated probability: 5%; 95% confidence interval (CI) -6% to 14%. CONCLUSIONS: Pre-ESKD nephrology care 6 months prior to initiation of dialysis is not associated with the likelihood of remaining employed at the initiation of dialysis. Although nephrology care has potential to help patients remain employed, this benefit is not manifested in current practice.

Sodium Fate after Sodium Bicarbonate Infusion: Influence of Altered Acid-Base Status.

BACKGROUND: We have previously investigated the fate of administered bicarbonate infused as a hypertonic solution in animals with each of the 4 chronic acid-base disorders. Those studies did not address the fate of sodium, the coadministered cation. METHODS: We examined baseline total body water (TBW), Na+ space, HCO3- space, and urinary sodium and bicarbonate excretion after acute hypertonic NaHCO3 infusion (1-N solution, 5 mmol/kg body weight) in dogs with each of the 4 chronic acid-base disorders. Observations were made at 30, 60, and 90 min postinfusion. Retained sodium that remains osmotically active distributes in an apparent space that approximates TBW. Na+ space that exceeds TBW uncovers nonosmotic sodium storage. RESULTS: Na+ space approximated TBW at all times in normal and hyperbicarbonatemic animals (metabolic alkalosis and respiratory acidosis), but exceeded TBW by ~30% in hypobicarbonatemic animals (metabolic acidosis and respiratory alkalosis). Such osmotic inactivation was detected at 30 min and remained stable. The pooled data revealed that Na+ space corrected for TBW was independent of the initial blood pH but correlated with initial extracellular bicarbonate concentration (y = -0.01x + 1.4, p= 0.002). The fate of administered sodium and bicarbonate (internal distribution and urinary excretion) was closely linked. CONCLUSIONS: This study demonstrates that hypobicarbonatemic animals have a Na+ space that exceeds TBW after an acute infusion of hypertonic NaHCO3 indicating osmotic inactivation of a fraction of retained sodium. In addition to an expanded Na+ space, these animals have a larger HCO3- space compared with hyperbicarbonatemic animals. Both phenomena appear to reflect the wider range of titration of nonbicarbonate buffers (Δ pH) occurring during NaHCO3- loading whenever initial [HCO3-]e is low. The data indicate that the fate of administered bicarbonate drives the internal distribution and the external disposal of sodium, the co-administered cation, and is responsible for the early, but non-progressive, osmotic inactivation of a fraction of the retained sodium.

Hepatitis C in Chronic Kidney Disease: An Overview of the KDIGO Guideline.

Hepatitis C virus (HCV) infection is a global health problem with significant health and economic burden, which can lead to chronic kidney disease (CKD) and affect multiple organ systems. In addition, prevalence of hepatitis C remains higher in patients with CKD, including those on chronic hemodialysis and in individuals with a kidney transplant than in the general population. There has been a dramatic shift in the management of hepatitis C since Kidney Disease: Improving Global Outcome (KDIGO) published its 2008 guideline for the prevention, diagnosis and management of hepatitis C in CKD. As a result, KDIGO published in 2018 an update to this guideline. In this narrative review, we present a synopsis of the guideline, including recommendations for screening and detection of HCV in CKD, treatment of HCV in patients with CKD, treatment of HCV before and after kidney transplantation, prevention of HCV transmission in hemodialysis units, and treatment of kidney disease related to HCV infection. We focus on the clinical aspects of using direct acting antivirals (DAAs) in patients with advanced CKD (G4 and G5), those on dialysis and kidney transplant recipients. We emphasize the importance of carefully managing drug-drug interactions between DAAs and immunosuppressive agents. We discuss timing of HCV treatment before vs. after kidney transplantation. Finally, we highlight areas of uncertainty where further research is needed before any definitive recommendations can be made.

Trends in the Causes of Death among Kidney Transplant Recipients in the United States (1996-2014).

BACKGROUND: Death with graft function remains an important cause of graft loss among kidney transplant recipients (KTRs). Little is known about the trend of specific causes of death in KTRs in recent years. METHODS: We analyzed United States Renal Data System data (1996-2014) to determine 1- and 10-year all-cause and cause-specific mortality in adult KTRs who died with a functioning allograft. We also studied 1- and 10-year trends in the various causes of mortality. RESULTS: Of 210,327 KTRs who received their first kidney transplant from 1996 to 2014, 3.2% died within 1 year after transplant. Cardiovascular deaths constituted the majority (24.7%), followed by infectious (15.2%) and malignant (2.9%) causes; 40.1% of deaths had no reported cause. Using 1996 as the referent year, all-cause as well as cardiovascular mortality declined, whereas mortality due to malignancy did not. For analyses of 10-year mortality, we studied 94,384 patients who received a first kidney transplant from 1996 to 2005. Of those, 22.1% died over 10 years and the causative patterns of their causes of death were similar to those associated with 1-year mortality. CONCLUSIONS: Despite the downtrend in mortality over the last 2 decades, a significant percentage of KTRs die in 10-years with a functioning graft, and cardiovascular mortality remains the leading cause of death. These data also highlight the need for diligent collection of mortality data in KTRs.

Supraventricular Tachycardia and Tricuspid Regurgitation in the Setting of Misplaced Implantable Port Catheter Tip.

We present the case of a 31-year-old female with a past medical history of B-cell leukemia, on maintenance chemotherapy administered via centrally placed implantable catheter port, who presented to the emergency room with fever, chills, and generalized body pain of one day's duration. After initial workup, the patient was admitted to the intensive care unit and managed for severe sepsis. The patient was found to have a new-onset 3/6 holosystolic murmur at the left lower sternal border. Furthermore, she developed an episode of supraventricular tachycardia that responded to adenosine. Transthoracic echocardiogram revealed severe tricuspid regurgitation but without valvular vegetation. Transesophageal echocardiogram further confirmed the absence of vegetation, in addition to visualizing the tip of the catheter tip in the right atrium and interfering with coaptation of the tricuspid valve. It was postulated that the severe tricuspid regurgitation and supraventricular tachycardia were caused by the catheter tip malposition. The catheter was subsequently removed. The patient's acute condition resolved and she was referred to cardiothoracic surgery for valvular surgery.