Incremental Hemodialysis: What We Know so Far.

Traditionally, patients that develop progressive chronic kidney disease in need of kidney replacement therapy are prescribed thrice weekly in-center hemodialysis sessions at the beginning of therapy. This empiric prescription is based on historic trials that were comprised of mostly prevalent patients. Incremental hemodialysis is the process of performing <3 sessions of dialysis per week or limiting dialysis dose by duration at the initial onset of treatment to provide a more gradual transition, mimicking the progressive nature of kidney disease. Adding clearance contributions from residual kidney function is the standard of care with peritoneal dialysis but has not routinely been employed with hemodialysis. Accounting for residual kidney function accompanied by improvement in adjuvant pharmacotherapy, such as newer potassium binding agents and dietary modification, can augment dialytic clearances and allow for an incremental approach. Utilizing incremental dialysis has been associated with both preserving residual kidney function as well as improving patient quality of life. Barriers to this approach include concerns regarding patient acceptance of dialysis prescription changes, adherence to therapy, and provider factors that would require a restructuring of the current thrice weekly hemodialysis rubric. Candidacy for incremental therapy has shown the best outcomes when urea clearances exceed 3 mL/min and urine volumes are >500 mL/day, although these measures have been deemed conservative. A significant amount of retrospective and registry data has been supportive of initiating incremental hemodialysis and several pilot studies have shown the feasibility of implementing such an approach. Larger, randomized control trials are needed to fully evaluate safety and efficacy to allow for more widespread acceptance of this patient-centered approach to chronic kidney disease.

Survival outcomes of alternate dosing schedule of pemetrexed as maintenance therapy in NSCLC: Single institution experience.

BACKGROUND: Maintenance therapy with pemetrexed has shown survival benefit in patients with advanced stage non-small cell lung cancer (NSCLC). The recommended dose schedule is 500 mg/m 2 in 21-day cycles. Prolonged treatment with maintenance pemetrexed can result in cumulative toxicities. We sought to compare treatment outcomes in patients receiving an alternate maintenance schedule in realworld practice. METHODS: This single-center, retrospective study investigated patients with advanced stage (IIIB and IV) NSCLC receiving at least two doses of maintenance pemetrexed from May 1, 2011 to June 30, 2016. The objective was to compare time on treatment with maintenance pemetrexed therapy initiated at a standard schedule (q3 weeks) versus an alternate schedule (q4 weeks or longer). Also evaluated were progressionfree survival (PFS) and overall survival (OS) differences between the two groups. RESULTS: 129 patients were included, of whom 40 started the alternate schedule no later than cycle 3 of treatment (29 of 40 patients initiated maintenance treatment on the alternate schedule). Average time on maintenance treatment for patients appeared to be longer in the patients who received the alternate schedule regimen (195 vs 263 days, p =0.008). OS trended towards better survival among patients receiving the alternate schedule regimen (11.9 vs 18.1 months, p =0.3). Limiting the analysis to ALK wildtype, the patients showed a similar trend, with median PFS (7.6 vs 11.5 months, p =0.46) and OS (11.9 vs 17.6 months, p =0.38), still favoring the alternate schedule. CONCLUSIONS: The alternate dosing schedule of maintenance pemetrexed (q4 weeks or longer) is feasible and not detrimental to OS. Future investigations evaluating the optimal administration schedule of maintenance pemetrexed is warranted.

Mutant PPM1D- and TP53-Driven Hematopoiesis Populates the Hematopoietic Compartment in Response to Peptide Receptor Radionuclide Therapy.

PURPOSE: Hematologic toxic effects of peptide receptor radionuclide therapy (PRRT) can be permanent. Patients with underlying clonal hematopoiesis (CH) may be more inclined to develop hematologic toxicity after PRRT. However, this association remains understudied. MATERIALS AND METHODS: We evaluated pre- and post-PRRT blood samples of patients with neuroendocrine tumors. After initial screening, 13 cases of interest were selected. Serial blood samples were obtained on 4 of 13 patients. Genomic DNA was analyzed using a 100-gene panel. A variant allele frequency cutoff of 1% was used to call CH. RESULT: Sixty-two percent of patients had CH at baseline. Persistent cytopenias were noted in 64% (7 of 11) of the patients. Serial sample analysis demonstrated that PRRT exposure resulted in clonal expansion of mutant DNA damage response genes (TP53, CHEK2, and PPM1D) and accompanying cytopenias in 75% (3 of 4) of the patients. One patient who had a normal baseline hemogram and developed persistent cytopenias after PRRT exposure showed expansion of mutant PPM1D (variant allele frequency increased to 20% after exposure from < 1% at baseline). In the other two patients, expansion of mutant TP53, CHEK2, and PPM1D clones was also noted along with cytopenia development. CONCLUSION: The shifts in hematopoietic clonal dynamics in our study were accompanied by emergence and persistence of cytopenias. These cytopenias likely represent premalignant state, as PPM1D-, CHEK2-, and TP53-mutant clones by themselves carry a high risk for transformation to therapy-related myeloid neoplasms. Future studies should consider CH screening and longitudinal monitoring as a key risk mitigation strategy for patients with neuroendocrine tumors receiving PRRT.

Prediction of life-threatening and disabling bleeding in patients with AML receiving intensive induction chemotherapy.

Bleeding in patients with acute myeloid leukemia (AML) receiving intensive induction chemotherapy is multifactorial and contributes to early death. We sought to define the incidence and risk factors of grade 4 bleeding to support strategies for risk mitigation. Bleeding events were retrospectively assessed between day-14 and day +60 of induction treatment according to the World Health Organization (WHO) bleeding assessment scale, which includes grade 4 bleeding as fatal, life-threatening, retinal with visual impairment, or involving the central nervous system. Predictors were considered pretreatment or prior to grade 4 bleeding. Using multivariable competing-risk regression analysis with grade 4 bleeding as the primary outcome, we identified risk factors in the development cohort (n = 341), which were tested in an independent cohort (n = 143). Grade 4 bleeding occurred in 5.9% and 9.8% of patients in the development and validation cohort, respectively. Risk factors that were independently associated with grade 4 bleeding included baseline platelet count ≤40 × 109/L compared with >40 × 109/L, and baseline international normalized ratio of prothrombin time (PT-INR) >1.5 or 1.3 > 1.5 compared with ≤1.3. These variables were allocated points, which allowed for stratification of patients with low- and high-risk for grade 4 bleeding. Cumulative incidence of grade 4 bleeding at day+60 was significantly higher among patients with high- vs low-risk (development: 31 ± 7% vs 2 ± 1%; P < .001; validation: 25 ± 9% vs 7 ± 2%; P = .008). In both cohorts, high bleeding risk was associated with disseminated intravascular coagulation (DIC) and proliferative disease. We developed and validated a simple risk model for grade 4 bleeding, which enables the development of rational risk mitigation strategies to improve early mortality of intensive induction treatment.

Emerging trends of therapy related myeloid neoplasms following modern cancer therapeutics in the United States.

Clonal hematopoiesis (CH) is a risk factor for the development of therapy-related myelodysplastic syndromes (tMDS) and acute myeloid leukemia (tAML). Adoption of targeted-immunotherapeutics since 2011, may alter the risk of CH progression to tMDS/AML. To study this, we evaluated risk of tMDS and tAML in 667 588 ≥ 1-year survivors of non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), melanoma and multiple-myeloma (MM) diagnosed during: 2000-2005, 2006-2010 and 2011-2016. The risk of tMDS increased significantly after NSCLC across all time periods (Ptrend = 0.002) while tAML risk decreased from 2006-2010 to 2011-2016, coinciding with increasing use of non-chemotherapeutic agents. tAML risk after RCC decreased (Ptrend = 0.007) whereas tMDS risk did not significantly change over time. After melanoma, tMDS and tAML risks were similar to the general population. tMDS and tAML risk after MM increased from the first to second time-period, however, only risk of tMDS decreased during last period. We report diverging trends in the risk of tAML and tMDS after adoption of modern cancer therapies for specific cancers. It is imperative to further explore impact of contemporary treatment strategies on clonal evolution. Modern treatments via their discrete mechanism of actions on pre-existing CH may alter the risk of subsequent tMDS and tAML.

Outcomes of Adult Acute Myeloid Leukemia Treated With Gemtuzumab-Ozogamicin: Cue To Optimized Chemotherapy Backbone.

BACKGROUND: The optimal approach to combine gemtuzumab-ozogamicin (GO) with various chemotherapy backbones and other newer agents safely remains to be determined. MATERIALS AND METHODS: We performed a retrospective analysis of the safety and outcomes of adult patients with newly diagnosed acute myeloid leukemia (AML) treated with GO with intensified versus standard anthracycline doses (daunorubicin dose 90 mg/m2 vs 60 mg/m2) ± FLT3 inhibitors. The χ2 test and Mann-Whitney U test were used to compare categorical and continuous data. Survival estimates were calculated by Kaplan-Meier method and survival comparisons made using log-rank test. RESULTS: We report a 97% overall response rate in 34 patients with newly diagnosed AML with a median age of 54 years (19-75 years) treated with GO and standard induction. The 11 patients (100%) receiving GO plus daunorubicin dose 90 mg/m2 as part of 7 + 3 induction achieved complete response versus 91% (20/22) complete response in the standard daunorubicin dose group (P = NS). No increased toxicity was noted with the higher daunorubicin dose or when GO and 7 + 3 were combined with FLT3 inhibitors in 3 younger patients (<60 years). Two older patients treated with GO+7 + 3 and FLT3i experienced grade 3 or higher cardiotoxicity. We observed a longer estimated event-free survival for patients with newly diagnosed AML in our cohort (median, 24 months; 95% confidence interval, 17.2 to not reached) compared with historical data. CONCLUSION: We demonstrate that anthracycline dose intensification with GO may offer higher response rates without increased toxicity in younger patients presenting with de novo AML across European Leukemia Net risk categories.

Predictors of vascular disease in myelodysplastic syndromes.

The escalating link between somatic mutations commonly seen in myelodysplastic syndromes (MDS) and atherosclerotic vascular disease has increased the interest in management and associations of these conditions. We present a retrospective study examining clinical and molecular variables associated with vascular disease in patients with MDS. This study included a comprehensive evaluation of 236 patients with MDS. Our study has multiple findings. Mutations in ASXL1 correlated with increased risk of vascular disease for the entire cohort (P = .013). Though this has been replicated in other studies, there are no guidelines at this time for preventing vascular events in these patients. Our study also showed that lower ferritin levels may be linked to increased vascular events (P = .043), therefore the optimal use of supportive red blood cell transfusions in patients with MDS and the overall impact of inflammatory markers such as erythrocyte sedimentation rate and c-reactive protein should be re-addressed. Furthermore, our study showed that patients with Trisomy 8 in the low-risk MDS cohort (based on IPSS-R scores) were protected from vascular events (P = .036). Our findings of lower ferritin being linked with increased risk of vascular events as well as patients with Trisomy 8 being protected from vascular events may impact patient care. There do not appear to be any prior studies with these findings. In addition, given the connection between MDS and atherosclerotic vascular disease, we believe guideline-based management of cardiac risk factors among MDS patients may improve overall outcomes. Further studies with larger patient cohorts are needed to further investigate these findings.

Risk of further decline in renal function after the use of oral sodium phosphate or polyethylene glycol in patients with a preexisting glomerular filtration rate below 60 ml/min.

OBJECTIVES: The aim of this study was to estimate the risk of further creatinine increase in patients with preexisting renal disease after the use of oral sodium phosphate (OSP) versus polyethylene glycol (PEG), and to study usage patterns of OSP in relation to renal function. METHODS: A cohort study was done using clinical records and electronic patient information from the Henry Ford Health System (HFHS) in patients who had used either OSP or PEG for colonoscopy between February 1999 and April 2006. Among patients with an estimated GFR < 60 ml/min before colonoscopy, we identified cases with an unexplained creatinine increase of > or = 0.5 mg/dl within 14 days after colonoscopy. RESULTS: We identified 7,971 OSP and 1,511 PEG users. Relative use of OSP versus PEG decreased from 88.0% before 2004 to 48.4% in 2006. 70.2% of OSP users had no recorded creatinine determination within 60 days before colonoscopy, and this proportion did not decrease over time. The study population included 317 patients with a baseline GFR < 60 ml/min, and we identified one case with an unexplained creatinine increase > or = 0.5 mg/dl among 191 PEG users (0.5%) versus eight cases among 126 OSP users (6.3%). Unadjusted and adjusted relative risk estimates on comparing OSP with PEG were 12.1 (95% CI, 1.5-95.8) and 12.6 (95% CI, 1.5-106.5), respectively. CONCLUSIONS: In patients with preexisting renal disease, OSP use was associated with an increased risk of aggravated renal dysfunction versus PEG. Creatinine measurement with GFR estimation should be done before OSP administration in order to avoid its use in patients with renal disease.

Safety of Same-Day Vitamin B12 Supplementation in Patients Receiving Pemetrexed for the Treatment of Non-Small-Cell Lung Cancer or Pleural Mesothelioma: A Retrospective Analysis.

BACKGROUND: Pemetrexed is a folate analog inhibitor for the treatment of non-small-cell lung cancer (NSCLC) and malignant pleural mesothelioma. Folic acid and vitamin B12 supplementation before initiating pemetrexed is necessary because of high rates of cytopenias without supplementation. However, the timing of supplementation has not been thoroughly investigated. PATIENTS AND METHODS: This was a single-center, retrospective study investigating patients receiving pemetrexed from January 1, 2012, to June 30, 2015, who received same-day vitamin B12 supplementation versus ≥ 1 day before pemetrexed. The objective was to evaluate safety outcomes in patients who received vitamin B12 on the same day as pemetrexed (group A) versus vitamin B12 ≥ 1 day (group B) before pemetrexed. RESULTS: Two hundred eighty-one patients met the inclusion criteria: 137 patients in group A (same-day administration of vitamin B12) and 144 patients in group B (median time of vitamin B12 administration before pemetrexed, 7 days; range, 1-42 days). Mean changes in hematologic indices from cycle (C) 1 to C2 or C2 to C3 did not differ significantly between groups. There were no significant differences in clinical events between C1 and C2 or C2 and C3 requiring supportive care. There was a significant difference noted in treatment delay in C3 [28/114 (24.6%) group A vs. 14/118 (11.9%) group B, P = .0164]. In group A, significant predictors of delay in C3 were baseline hemoglobin (mean 13.3 g/dL vs. 12.4 g/dL, P = .0137) and ANC (mean 6 × 109/L vs. 5 × 109/L, P = .0003). CONCLUSION: Same-day vitamin B12 and pemetrexed administration is a safe practice in NSCLC and malignant pleural mesothelioma patients.

Diagnosis and management of enteric disease and abdominal catastrophe in peritoneal dialysis patients with peritonitis.

Peritoneal dialysis (PD)-associated peritonitis rates have decreased significantly in recent years, especially Staphylococcus epidermidis and Staphylococcus aureus infections. Rates of gram-negative, polymicrobial, and fungal peritonitis have remained steady. The reported mortality of gram-negative and polymicrobial peritonitis varies widely (4%-50%). Most likely, the reason for this variability is that prognosis depends on the underlying etiology more than the specific microorganisms isolated. Gram-negative, polymicrobial, and fungal infection have variable association with documented visceral disease, and the highest mortality occurs in reports with the highest prevalence of intra-abdominal pathology. The odds ratio of death in PD patients with documented abdominal catastrophe and peritonitis is reported to be 20:1 compared with all other causes. Further reductions in PD-associated peritonitis mortality are likely to depend on earlier diagnosis and better management of intra-abdominal pathology. Presentation with hypotension, sepsis, lactic acidosis, and/or elevation of peritoneal fluid amylase should raise immediate concern for "surgical" peritonitis. Suspicion for visceral disease should also be high in patients with gram-negative, polymicrobial, and fungal infection or those who fail to improve rapidly as judged by clinical signs and symptoms, cell counts, and repeat cultures. Nonlocalizing physical examination and negative or nonspecific results of abdominal computed tomography do not rule out serious intra-abdominal disease. Immediate initiation of broad antibiotic coverage including for anaerobic infection is indicated when bowel pathology is suspected. Urgent surgical consultation, with active discussion and participation by the nephrologist, is advisable when visceral pathology is suspected and the patient is unstable or fails to improve rapidly.

Feasibility of adequate solute clearance in obese patients on peritoneal dialysis: a cross-sectional study.

BACKGROUND: It is widely assumed that obese patients are poorly suited for peritoneal dialysis (PD). Mathematical models predicting weight limits to achieve adequate solute clearance in anuric patients on continuous ambulatory PD therapy do not apply to the majority of obese patients on PD therapy. METHODS: To define the extent to which obesity or large body size interferes with successful PD, the feasibility of achieving adequate solute clearance, defined by the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines, was studied. We reviewed prospectively recorded data for 25 obese patients (body mass index > or = 29) from a group of 58 prevalent PD patients treated in an inner-city ambulatory dialysis center. Adequacy of solute clearances was assessed by comparing weekly Kt/V and weekly creatinine clearance (WCC) with those recommended by the K/DOQI. Adequacy also was examined separately for large patients, defined as those with total-body water (TBW) by the Watson and Watson equation of 48 L or greater. Similar analyses were performed separately for 10 anuric obese patients. RESULTS: Eighty four percent and 88% of the 25 obese patients achieved K/DOQI targets for weekly Kt/V and WCC, respectively. Among the 10 anuric obese patients, 90% and 70% achieved these targets. Only 60% of those with TBW of 48 L or greater met the Kt/V target. CONCLUSION: PD remains a viable option for obese patients with end-stage renal disease. It is possible for the majority of obese patients on PD therapy to achieve solute clearances recommended by the K/DOQI.

Fivefold reduction in peritonitis using a multifaceted continuous quality initiative program.

Despite recent advances in peritoneal dialysis (PD) systems, peritonitis is a significant clinical problem in patients on PD. Risk factors for peritonitis are identifiable and modifiable and require focused intervention. During a baseline period in 1998, we observed consistent differences in peritonitis rates among patients using various PD connection systems. In January 1999, motivated by a need to reduce peritonitis, we initiated a multifaceted continuous quality initiative (CQI) program that included retraining all current patients and all new patients 6 months after initiation and then annually; changing from plastic to titanium adapters between the catheter and the transfer set; and using equipment from a single PD manufacturer for all new patients and for current patients with high peritonitis rates. Furthermore, all patients using HomeChoice cyclers (Baxter Healthcare Corporation, McGaw Park, IL, U.S.A.) were taught to use the Compact Exchange Device II to avoid contamination when spiking solution bags. Peritonitis rates improved from 1 episode per 7.5 patient-months (over 512 patient-months) in 1998 to 1 episode per 36.5 patient-months (over 292 patient-months) as of September 2002. Further analysis also showed a significant difference in peritonitis rates between equipment produced by various manufacturers. There was a statistically significant difference in peritonitis for automated peritoneal dialysis systems. Patients using the Freedom Cycler PD+ (Fresenius Medical Care, Frankfurt, Germany) had an average peritonitis rate of 1 episode per 6.9 patient-months as compared with patients using the HomeChoice cycler (Baxter Healthcare), who experienced 1 episode of peritonitis per 23.9 patient-months on average (p < 0.0001). For continuous ambulatory peritoneal dialysis patients using UltraBag (Baxter Healthcare), the peritonitis rate was 1 episode per 26 patient-months as compared with the Premier Double Bag (Fresenius Medical Care), for which a peritonitis rate of 1 episode per 6.3 patient-months was seen (p < 0.0001). Comparison of the UltraBag (1 episode per 26.0 patient-months) with the Disposable Freedom Set, a single-bag "Y" system (Fresenius Medical Care; 1 episode per 7.5 patient-months) yielded similar results (p < 0.0001). We conclude that ongoing CQI efforts can significantly reduce peritonitis rates. Our efforts included aggressive patient retraining, protocol changes, use of a titanium adapter between the catheter and the transfer set, and careful choice of connectology systems (possible supplier-dependent effect).

A randomized multicenter trial of paricalcitol versus calcitriol for secondary hyperparathyroidism in stages 3-4 CKD.

BACKGROUND AND OBJECTIVES: Calcitriol is used to treat secondary hyperparathyroidism in patients with CKD. Paricalcitol is less calcemic and phosphatemic in preclinical studies and in some trials in dialysis patients, but head-to-head comparisons in nondialysis patients are lacking. A large meta-analysis of trials concluded that these agents did not consistently reduce parathyroid hormone (PTH) and increased the risk of hypercalcemia and hyperphosphatemia. Therefore, the objective of this multicenter trial was to compare the rate of hypercalcemia between calcitriol and paricalcitol, while suppressing PTH 40%-60%. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with stages 3-4 CKD (n=110) with a PTH level >120 pg/ml were recruited and randomized to 0.25 µg/d of calcitriol or 1 µg/d of paricalcitol between April 2009 and July 2011. Subsequent dose adjustments were by protocol to achieve 40%-60% PTH suppression below baseline. The primary endpoint was the rate of confirmed hypercalcemia of >10.5 mg/dl between groups. RESULTS: Forty-five patients in each group completed the 24 weeks of treatment. Both agents suppressed PTH effectively (-52% with paricalcitol and -46% with calcitriol; P=0.17), although the paricalcitol group reached a 40% reduction in PTH sooner at a median 8 weeks (interquartile range [IQR], 4, 12) versus 12 weeks (IQR, 8, 18; P=0.02) and had a lower pill burden of 240 (IQR, 180, 298) versus 292 (IQR, 231, 405; P=0.01). Confirmed hypercalcemia was very low in both groups (three with paricalcitol and one with calcitriol) and was not significantly different (P=0.36). Both groups had small increases in calcium and phosphorus levels (0.3-0.4 mg/dl in each electrolyte) and significant decreases in alkaline phosphatase, a marker of high bone turnover, with no significant differences between groups. CONCLUSIONS: These results show that both calcitriol and paricalcitol achieved sustained PTH and alkaline phosphatase suppression in stages 3-4 CKD, with small effects on serum calcium and phosphorus and a low incidence of hypercalcemia.

Acute renal failure in cardiothoracic surgery patients: what is the best definition of this common and potent predictor of increased morbidity and mortality.

BACKGROUND: Universal agreement on criteria for acute renal failure (ARF) is lacking. The purpose of the current study was to determine which of 6 definitions for ARF best predicted clinical outcomes in postoperative cardiothoracic surgery (CTS) patients. METHODS: Criteria for ARF were retrospectively applied to 1,085 CTS patients. General linear models analyzed length of stay (LOS) and ventilator days with logistic regression for mortality. RESULTS: Thirty-seven percent of patients met at least 1 of 6 definitions of ARF. For each 1-mg/dL increase from the initial creatinine, LOS increased by 6.96 days, ventilator days increased by 3.58 days, and mortality increased by 2.23 times (P < .0001). CONCLUSIONS: One definition that best predicted ARF was not found. ARF was a significant independent predictor of increased mortality, LOS, and ventilator days. Even small increases in creatinine correlate with clinically significant worsening of expected outcomes.