Risk of malignancy in patients with chronic kidney disease.

BACKGROUND: Fifteen percent of US adults have chronic kidney disease (CKD). The effect of CKD on the development of different malignancies is unknown. Understanding the effect of CKD on the risk of development of cancer could have important implications for screening and early detection of cancer in these patients. METHODS: Adult CKD patients [estimated GFR (eGFR) <60ml/min/1.73m2] between January 2001 and December 2020 were identified in this single institution study. Patients were divided into four stages of CKD by eGFR. The incidence of cancer and time to development of the first cancer were identified. Multivariable models were used to compare the overall cancer incidence while considering death as a competing risk event and adjusting for relevant covariates (sex, race, diabetes, hypertension, CAD, smoking or not, BMI, and CKD stages). Separate multivariable models of the incidence of cancers were conducted in each age group. Multivariable Cox models were used to fit the overall death adjusting for relevant covariates. Patients were censored at the conclusion of the study period (December 31, 2020). Statistical analysis was performed with SAS software (version 9.4). RESULTS: Of the 13,750 patients with a diagnosis of CKD in this cohort, 2,758 (20.1%) developed a malignancy. The median time to development of cancer following a diagnosis of CKD was 8.5 years. Factors associated with the risk of developing cancer in CKD patients included increasing age, male sex and worsening chronic kidney disease, while diabetes was associated with a lower risk of malignancy. On multivariate analysis, the factors associated with increased mortality in patients who developed cancer included increasing age, diabetes and lower eGFR. CONCLUSION: CKD is an increased risk factor for the development of various malignancies. Age appropriate cancer screening should be aggressively pursued in those with progressive CKD.

Hepatitis B Vaccination in Advanced Chronic Kidney Disease: A Quality Improvement Project at a Veteran Affairs Chronic Kidney Disease Clinic.

Hepatitis B vaccination is recommended in all patients with end-stage kidney disease (ESKD). However, only 50-60% of these patients achieve protective antibody levels if immunized after starting dialysis. Strategies to overcome this low seroconversion rate include a 6-month vaccination schedule starting earlier [chronic kidney disease (CKD) stage 4 and 5] to ensure immunity when patients progress to ESKD. We conducted a quality improvement program to immunize pre-dialysis patients. Patients who were found to have a negative baseline serology with a negative hepatitis B surface antibody level (HBsAb) were offered vaccination on a 6-month schedule (0, 1 and 6 months) with one of two available vaccines within the VA system (Recombivax™ or Engerix™). HBsAb titers were checked 3-4 months later, and titers ≥ 12 mIU/mL were indicative of immunity at VA. Patients who did not seroconvert were offered a repeat schedule of three more doses. We screened 198 patients (187 males and 11 females) with CKD 4 and 5 [glomerular filtration rate (GFR) < 29 mL/min/1.73 m2]. The median age of this cohort was 72 years (range 38-92 years). During the study period of 5 years (2015-2020), 10 patients were excluded since their GFR had improved to more than 30 mL/min/1.73 m2, 24 others had baseline immunity and 2 refused vaccination. The hepatitis B vaccination series was not started on 106 patients. Of the remaining 56, 12 patients progressed to ESKD and started dialysis before completion of the vaccination schedule, 6 expired and 1 did not come to clinic in 2020 due to the pandemic. Of the 37 patients who completed the vaccination schedule, 16 achieved seroconversion with adequate HBsAb titers, 10 did not develop immunity despite a second hepatitis B vaccination series, while 11 did not get a second series. Given the low seroconversion rate, albeit in a small cohort, vaccination should be considered in patients with earlier stages of CKD. Other options include studies on FDA approved vaccines of shorter duration. We plan to increase awareness among nephrologists, patients and nursing staff about the importance of achieving immunity against hepatitis B.

Hematopoietic Stem Cell Transplant-Associated Thrombotic Microangiopathy.

Hematopoietic stem cell transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal, multifactorial disorder, which may present with thrombocytopenia, hemolysis, acute renal failure, mental status changes and involvement of other organs. The pathogenesis of TA-TMA is complex and includes multiple risk factors such as certain conditioning regimens, calcineurin inhibitors (CNIs), graft-versus-host disease (GVHD), human leukocyte antigen mismatch, and opportunistic infections. The end result of these insults is endothelial injury in the kidney and other organs. Recent studies also indicate a role of complement activation in tissue damage. The lack of sensitive and specific diagnostic tests for TA-TMA often results in delayed diagnosis. Biopsy is not always possible for diagnosis because of the risk of complications such as bleeding. Recently, an emerging role of renal-centered screening approach has been demonstrated, which utilize the monitoring of blood pressure, urine protein, serum lactate dehydrogenase and hemogram for early detection. Therapeutic options are limited, and plasma exchange plays a minor role. Withdrawal of offending agent such as CNIs and the use of rituximab can be effective in some patients. However, the current treatment strategy is suboptimal and associated with high mortality rate. Recently, eculizumab has been utilized in a few patients with good outcomes. Patients, who develop TA-TMA, are also at an increased risk of GVHD, infection, renal, cardiovascular, and other complications, which can contribute to high mortality. Better understanding of molecular pathogenesis, improvement in posttransplant management, leading to early diagnosis, and management of TA-TMA are required to improve outcomes of this fatal entity.

Ipilimumab-induced hypophysitis and uveitis in a patient with metastatic melanoma and a history of ipilimumab-induced skin rash.

Ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen-4, leading to enhanced T-cell activation and proliferation, is associated with improved overall survival in melanoma. Its use can result in immune-related adverse events, the most common of which are skin rash, diarrhea, and colitis. Ipilimumab-induced hypophysitis is uncommon, mostly involves anterior pituitary, and is associated with abnormalities in pituitary MRI, whereas uveitis has been rarely reported. These immune-related adverse events occur during therapy. This report describes a patient who developed uveitis and hypophysitis involving both anterior and posterior pituitary, without MRI findings more than 3 weeks after the fourth dose of ipilimumab. This case illustrates the unusual presentation of and diagnostic challenges associated with ipilimumab-induced immune-related adverse events.

Hormone replacement therapy is associated with decreased survival in women with lung cancer.

PURPOSE: Lung cancer is the leading cause of cancer-related death in women. Hormone replacement therapy (HRT) is frequently prescribed to postmenopausal women, but there is little data on its effect on lung cancer. Hence, we conducted a retrospective study to examine the impact of HRT on the natural history of lung cancer. METHODS: We conducted a retrospective chart review of women diagnosed with lung cancer between January 1994 and December 1999. Data collected included age, stage, past history of cancer, smoking history, family history of cancer, HRT use, treatment, and overall survival. The effects of various clinical features on survival were examined using Cox proportional hazards regression models. RESULTS: Four hundred ninety-eight women (median age, 67 years; range, 31 to 93 years) with lung cancer were included. A history of smoking was present in 429 women (86%), whereas 86 women (17%) had taken HRT. Women with lung cancer who received HRT were younger than women with lung cancer who never received HRT (63 v 68 years old, respectively; P < .0001). Overall survival was significantly higher in patients with no HRT compared with patients who received HRT (79 v 39 months, respectively; hazard ratio = 1.97; 95% CI, 1.14 to 3.39). This effect seemed to be more pronounced in women with a smoking history. CONCLUSION: HRT may affect outcomes from lung cancer adversely. Further studies examining the role of HRT use on outcomes from lung cancer, especially in women with a history of smoking, are urgently needed to clarify this important problem.

Endothelium and the lipid metabolism: the current understanding.

The endothelium is a dynamic organ and responds to various physical and humoral conditions. The endothelium secretes several biologically active substances, both vasoconstrictors and vasodilators, which control these processes. Endothelial function is most commonly assessed as the vasodilatory response to stimuli. Several endothelium-dependent agonists have been identified, each of which acts through a membrane receptor. Nitric oxide which is continuously synthesized by the endothelium has a wide range of biological properties that maintain vascular homeostasis. It is a potent vasodilator and inhibitor of platelet aggregation and thus has an important protective role. Endothelial dysfunction in hypercholesterolemic patients is in large part due to a reduced bioavailability of NO. Traditional coronary risk factors, especially hypercholesterolemia, produce endothelial dysfunction even in patients with normal blood vessels. The underlying mechanisms involve a local inflammatory response, release of cytokines and growth factors, activation of oxidation-sensitive mechanisms in the arterial wall, modulation of intracellular signaling pathways, increased oxidation of low-density lipoprotein cholesterol, and quenching of nitric oxide. Clinical studies have shown a significant improvement in endothelial dysfunction following lowering of serum cholesterol levels, infusion of nitric oxide donors like L-arginine and exercise training. Clinical trials are underway examining the role of endothelin-1 receptor antagonists like bosentan in the prevention of graft atherosclerosis.