Mild Renal Disease Research Articles

Migraine Management in Medically Complex Patients: a Narrative Review.

The current review aims to provide an overview of migraine treatment strategies in medically complex patients, including those with renal, liver, and cardiovascular disease. In cardiovascular disease, gepants are likely safe for acute therapy; NSAIDs, ergotamines, and triptans are not recommended. Beta-blockers, ACEi/ARBs, and verapamil have potential cardiovascular benefits in addition to migraine preventive benefit. Frovatriptan requires no dose adjustments in kidney disease or in mild to moderate liver disease. Gepants are safe acute and preventive treatment options in mild and moderate renal and hepatic disease. TCAs and valproic acid require no dose adjustments in renal disease. OnabotulinumtoxinA is likely safe in cardiac, renal, and hepatic impairment. Although CGRP monoclonal antibodies are likely safe in renal and hepatic disease, further study is needed in these conditions as well as in cardiac disease, and no dosing recommendations are available. Effective options are available for those with complex medical comorbidities. Further research is required on the safety of newer migraine-specific therapies in these complex populations.

Monoallelic pathogenic IFT140 variants are a common cause of autosomal dominant polycystic kidney disease-spectrum phenotype.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder, characterized by development and enlargement of kidney cysts, eventually leading to end-stage kidney disease (ESKD). Pathogenic variants in the PKD1 and PKD2 genes are the major cause of ADPKD; additional rare variants in the GANAB, DNAJB11, ALG5 and ALG9 genes have been found in a minority of ADPKD patients. More recently, a significant number of ADPKD families have been linked to monoallelic variants in the IFT140 gene. In this retrospective study, we tested the prevalence of the known causative genes of ADPKD-spectrum phenotype, including the PKD1, PKD2, GANAB, DNAJB11, ALG5, ALG and IFT140 genes, in a cohort of 129 ADPKD patients who consecutively underwent genetic testing in a single centre in Italy. Genetic testing utilized a combination of targeted next-generation sequencing, long-range polymerase chain reaction, Sanger sequencing and multiplex ligation-dependent probe amplification. Clinical evaluation was conducted through renal function testing and imaging features, including ultrasonography, computer tomography and magnetic resonance imaging. Of the 129 enrolled patients, 86 (66.7%) had pathogenic variants in PKD1 and 28 (21.7%) in PKD2, loss of function pathogenic variants in the IFT140 gene were found in 3 unrelated patients (2.3%), no pathogenic variants were found in other ADPKD genes and 12 patients (9.3%) remained genetically unresolved (ADPKD-GUR). Familial clinical and genetic screening of the index patients with ADPKD due to an IFT140 pathogenic variant (ADPKD-IFT140) allowed identification of eight additional affected relatives. In the 11 ADPKD-IFT140 patients, the renal phenotype was characterized by mild and late-onset PKD, with large renal cysts and limited kidney insufficiency. Extrarenal manifestations, including liver cysts, were rarely seen. Our data suggest the monoallelic pathogenic IFT140 variants are the third most common cause of the ADPKD-spectrum phenotype in Italy, usually associated with a mild and atypical renal cystic disease.

Reduction of urinary felinine in domestic cats with renal diseases leads to decreased catty odor.

Cats with progressive renal diseases often exhibit a weakened urinary odor, in contrast to normal cat urine which emits odorants with catty odor, such as 3-mercapto-3-methyl-1-butanol, 3-mercapto-3-methylbutyl formate, 3-methyl-3-methylthio-1-butanol, and 3-methyl-3-(2-methyldisulfanyl)-1-butanol. Felinine, an amino acid, is a precursor of these odorants and metabolized from its precursor, 3-methylbutanol glutathione (MBG), via 3-methylbutanol-cysteinylglycine (MBCG). While previous studies have reported felinine excretion in normal cats, its levels in cats with renal diseases remain unclear. This study investigates the urinary excretion of felinine and its precursors in cats with renal diseases and explores whether changes in these metabolites are linked to reduced volatile felinine derivatives with catty odor. Liquid chromatography/mass spectrometry quantified urinary felinine, MBCG, and MBG in 40 normal cats and 66 cats with renal diseases (classified into mild, moderate, and severe renal diseases), revealing a significant decrease in urinary felinine levels in cats with advanced renal disease, while urinary MBG levels increased. The felinine-to-MBG ratio was significantly lower in cats with severe renal disease compared to normal cats and those with mild renal disease. Gas chromatography/mass spectrometry analysis further showed that the emission of felinine derivatives decreased markedly with renal disease progression. A significant correlation was found between urinary felinine excretion and its major derivative, 3-methyl-3-methylthio-1-butanol. These findings suggest that impaired felinine metabolism, likely due to reduced kidney enzyme activity, contributes to both diminished urinary felinine levels and reduced sulfurous odor in cats with renal diseases.

#5907 RENAL INJURY IN RELATION TO OBESITY AND THE ADDITIVE EFFECT OF HYPERTENSION IN FEMALE AND MALE OBESE AND LEAN ZSF1 RATS

Abstract Background and Aims Chronic kidney disease co-exists with heart failure with preserved ejection fraction (HFpEF), which is characterized by the presence of obesity, hypertension, and diabetes mellitus type 2. Obese ZSF1 rats, a model of HFpEF, exhibit multiple of these comorbidities that can disturb cardiac function. Little attention has been paid to how these comorbidities affect renal disease in the ZSF1 rats. HFpEF is found predominantly in women in whom obesity and hypertension are particularly prevalent. Therefore, we aimed to characterize the renal phenotype in female and male, lean and obese, ZSF1 rats and investigated additional effects of worsened hypertension on disease severity. Method Systolic blood pressure and renal function were assessed biweekly in female and male, lean and obese, ZSF1 rats from 12 to 26 weeks of age by tail-cuff plethysmography, urine collection via metabolic cages and plasma collection, respectively. From 19 weeks of age, rats were implanted with either a deoxycorticosterone acetate pellet (DOCA) and fed high salt diet (6% NaCl) or with a placebo pellet and fed a normal salt diet. At 26 weeks of age, terminal GFR was assessed via inulin clearance under isoflurane. Renal sections were processed for histological analysis. Results Lean and obese placebo ZSF1 rats, both female and male, were mildly hypertensive (systolic blood pressure 140-150 mmHg). All obese rats showed HFpEF, evidenced by elevated E/e’ ratio. In female normoglycemic ZSF1 rats, obesity associates with mild proteinuria, decreased GFR and glomerular hypertrophy. The addition of DOCA-salt worsened hypertension in female obese ZSF1 rats, but not in their lean counterparts. DOCA-salt-worsened hypertension enhanced proteinuria and triggered glomerulosclerosis in female obese rats. Male obese placebo ZSF1 rats were hyperglycemic and showed proteinuria, glomerular hypertrophy and sclerosis, and tubulo-interstitial damage. DOCA-salt worsened hypertension in both male lean and obese rats and further aggravated proteinuria, tubulo-interstitial damage, glomerular hypertrophy and sclerosis in obese male rats. No effect of DOCA-salt was observed on GFR in both male and female ZSF1 rats. Conclusion Female obese ZSF1 rats developed mild renal disease and DOCA-salt-worsened hypertension deteriorated renal function and structure in normoglycemic female obese ZSF1 rats similar to hyperglycemic male obese ZSF1 rats.

MO099: Elastography in the Assessment of Chronic Kidney Disease: A Meta-Analysis

Abstract BACKGROUND AND AIMS We require an imagistic quantitative technique for the diagnosis and assessment of chronic kidney disease (CKD). Renal elastography has been widely used in the last years in different studies; however, the results across them are not consistent and, as a result, we conducted a meta-analysis of the published literature on this topic. METHOD The databases of PubMed, Medscape and Medline were searched for all studies published in English from 2010 until November 2021 that evaluated kidney shear wave speed (KSWS) by elastography in patients with CKD. Trial design, methodological information, patient characteristics, interventions, results and outcome data were all collected from each study according to a set protocol. RESULTS We found 33 publications, yet only 18 studies that utilized point shear wave elastography (Virtual Touch Quantification—VTQ system) were compared because the values achieved using different types of elastography are not evaluable. Finally, 1995 attendees (1241 patients with CKD versus 781 healthy subjects as the control group) were included. When comparing mean values of KSWS between studies, we found increased heterogeneity Q = 513.133; DF = 10; P < .001, I2 (inconsistency) = 98.12% (95% CI for I2 97.52–98.57%). With a standardized mean difference of –0.216, patients with CKD have a lower KSWS than healthy controls. A positive association between KSWS and eGFR was also discovered across the presented studies, with a pooled correlation coefficient of 0.38 (Z = 10.3, P < .001), Q = 73.3, DF = 5, P < .001, I2 = 93.18% (95% CI for I2 87.86–96.18). The pooled area under the ROC curve for KSWS to predict mild renal disease was 0.831 (95% CI, P < .001), Q = 28.32, DF = 6, P = .0001, I2 = 78.8% (95% CI for I2 56.37–89.72). In the four articles that used the Elast-PQ method, the data presented were insufficient for statistical analysis: area under the curve values are used to compare distinct characteristics (differentiating KSWS between mildly and moderately impaired kidneys, between non-diabetic, prediabetic and diabetic patients, or KSWS between CKD and control group), therefore not being suitable for further evaluation. CONCLUSION The results show that patients with CKD have a lower KSWS than healthy controls. It remains a viable method for monitoring the progression of CKD but because the number of studies involving renal elastography that have been published is limited and show an increased heterogeneity more research is needed to determine which factors actually influence KSWS in CKD patients and, as a result, to specify the role and indication of renal elastography in clinical practice.

Effect of Renal and/or Hepatic Impairment on the Pharmacokinetics and Safety of Inotuzumab Ozogamicin in Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

▪Introduction: Inotuzumab ozogamicin (InO) is an antibody drug conjugate targeting CD22 antigen linked to N-acetyl-g-calicheamicin dimethyl hydrazide, a potent cytotoxic antibiotic that induces double strand DNA breaks. The pharmacokinetics of InO has been characterized in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). The primary objective of this analysis was to assess the pharmacokinetics and safety of InO in patients with renal and/or hepatic impairment.Methods: The effects of renal and hepatic impairment on the pharmacokinetics of InO clearance (CL) were evaluated in adult patients with relapsed or refractory ALL (n=234) following administration of 1.2-1.8 mg/m2 fractionated over 2 or 3 doses given weekly. For assessment of renal function, patients were stratified into 5 subgroups using baseline creatinine clearance (BCrCL): normal (≥90 mL/min), mild (60-89 mL/min), moderate (30-59 mL/min), severe (15-29 mL/min), and end-stage renal disease (<15 mL/min).For assessment of hepatic impairment, patients were stratified into 5 subgoups per criteria from the National Cancer Institute (NCI) Organ Dysfunction Working Group (ODWG), which categorizes impairment based on baseline total bilirubin (TB) and aspartate aminotransferase (AST): normal (TB and AST ≤ upper limit of normal [ULN]), mild B1 (TB ≤ ULN and AST > ULN), mild B2 (TB >1-1.5 x ULN, any AST), moderate (TB >1.5-3 x ULN, any AST), and severe (TB >3 x ULN, any AST).Data from adult patients with relapsed or refractory ALL (n=161) who received InO at a starting fractionated dose of 1.8 mg/m2 were used to evaluate the safety of InO in patients with some degree of renal and/or hepatic dysfunction. For each of the renal function and NCI ODWG hepatic impairment subgroups, the percentage of patients exhibiting Grade ≥3 for any adverse events and Grade ≥3 hepatoxicity adverse event, respectively, was reported. Severity of hepatoxicity was determined through standardized search criteria with Standard Medical Dictionary for Regulatory Activities queries (cholestasis and jaundice of hepatic origin; hepatic failure, fibrosis and cirrhosis, and other liver damage-related conditions; hepatitis, noninfectious; and liver-related investigations, signs, and symptoms) and preferred terms (veno-occlusive liver disease or veno-occlusive disease; hepatic vein occlusion or thrombosis; portal vein thrombosis; Budd-Chiari syndrome; chronic graft versus host disease in liver; and acute graft versus host disease in liver).Results: For renal impairment, the median InO CL was 0.0394, 0.0403, 0.0308, and 0.0273 L/h, respectively, in individuals with normal (n=184), mild (n=32), moderate (n=17), and severe renal impairment (n=1). There were no patients with end-stage renal disease. Grade ≥3 adverse events were reported in 91.7% of patients with normal, 81.8% with mild, 100% with moderate, and 0% with severe or end-stage renal disease renal impairment.For hepatic impairment, the median InO clearance was 0.0363, 0.0520, 0.0382, and 0.0238 L/h, respectively, in individuals with normal (n=167), mild B1 (n=58), mild B2 (n=8), and moderate hepatic impairment (n=1). There were no patients with severe hepatic impairment. Hepatotoxicity Grade ≥3 adverse events were reported in 23.6% of patients with normal, 6.8% with mild B1, and 3.1% with mild B2 hepatic function; no such events occurred in patients with moderate or severe hepatic impairment.Conclusions: InO pharmacokinetics were not affected by renal or hepatic impairment status, and safety was similar regardless of renal and/or hepatic function. Therefore, no starting-dose adjustment is required for patients with relapsed or refractory ALL with pre-existing mild to severe renal dysfunction or mild hepatic impairment. DisclosuresGarrett:Pfizer: Employment. Kantarjian:Delta-Fly Pharma: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. DeAngelo:Amgen: Consultancy, Research Funding; Celgene: Research Funding; BMS: Consultancy; Glycomimetics: Research Funding; Incyte: Consultancy, Honoraria; Blueprint Medicines: Honoraria, Research Funding; Takeda Pharmaceuticals U.S.A., Inc.: Honoraria; Shire: Honoraria; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding; Immunogen: Honoraria, Research Funding; ARIAD: Consultancy, Research Funding. Boni:ADC Therapeutics: Employment, Other: Potential equity interest.

Impaired perfusion in the myocardial microcirculation in asymptomatic patients with Stages 1-4 chronic kidney disease with intrarenal arterial lesions.

Even mild renal disease is a powerful cardiovascular risk factor. However, the association between these pathophysiologic processes (especially in the early asymptomatic stage) is not known. We recruited 243 asymptomatic patients with Stages 1-4 chronic kidney disease (CKD) without obstructive coronary artery disease (CAD). We distinguished different degrees of severity of intrarenal arterial lesions (IALs) according to the Oxford classification. Myocardial microcirculation perfusion was measured using single-photon emission computed tomography (SPECT). Summed scores of 17 stress and rest image segments produced the summed stress score (SSS) and summed rest score (SRS), respectively. The summed difference score (SDS) was calculated as the difference between the SSS and SRS. Coronary microvascular disease (CMD) was defined as abnormal SPECT (SSS ≥4 or SDS ≥2) in the absence of obstructive CAD. Participants showed a stepwise increase in CMD severity with IAL aggravation. SSS of no/mild/moderate/severe IALs was 1.64 ± 1.08, 2.56 ± 1.35, 4.42 ± 2.17 and 6.48 ± 3.52, respectively (P < 0.05 for all). SDS of no/mild/moderate/severe IALs was 1.29 ± 0.49, 1.75 ± 0.56, 3.06 ± 1.12 and 4.16 ± 1.85, respectively (P < 0.05 for all). The percentage of subclinical CMD in CKD patients with IALs was significantly higher than in those without IALs (69.57% versus 14.71%; P = 0.01). Multiple regression analysis showed that renal arteriolar hyalinization (odds ratio = 1.578, P = 0.009) was associated independently with subclinical CMD. We demonstrated, for the first time, that impaired perfusion in the myocardial microcirculation in asymptomatic patients with Stages 1-4 CKD with IALs. Renal arteriolar hyalinization may be a useful marker of CMD in CKD.

Expanded Comorbidity Definitions Improve Application of the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) for Children and Young Adults with Non-Malignant Diseases Receiving Allogeneic Hematopoietic Cell Transplantation

Expanded Comorbidity Definitions Improve Application of the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) for Children and Young Adults with Non-Malignant Diseases Receiving Allogeneic Hematopoietic Cell Transplantation

Expanded Comorbidity Definitions Improve Applicability of the Hematopoietic Stem Cell Transplantation-Comorbidity Index for Children, Adolescents, and Young Adults with Hematologic Malignancies Undergoing Allogeneic Stem Cell Transplantation

Expanded Comorbidity Definitions Improve Applicability of the Hematopoietic Stem Cell Transplantation-Comorbidity Index for Children, Adolescents, and Young Adults with Hematologic Malignancies Undergoing Allogeneic Stem Cell Transplantation

Risk factors for subsequent hip fractures and fatality after an initial hip fracture in Korea: using nationwide claims data.

The purpose of this study was to analyze the risk factors for subsequent hip fractures and fatality after an initial hip fracture among Koreans older than 50 years of age using information in the national claims database. Our study was conducted using data from the Korean National Health Insurance Service database from 2007 to 2016. A total of 16,915 Korean patients aged ≥ 50 years with a first hip fracture in 2012 were followed for 4 years. Data on fracture, comorbidity, and prescription variables were retrieved from the national registry. The Cox proportional hazards model was used to identify the risk factors affecting subsequent hip fractures and fatality after the initial hip fracture. A total of 952 patients had subsequent hip fractures, and 6793 patients died. The cumulative incidence rates were 1.3% after 1 year and 5.6% after 4 years. Old age, renal disease, dementia, and Parkinson's disease were associated with a higher risk of subsequent hip fractures. The fatality rate after the initial hip fracture was 1.6 times higher among men than among women. Certain risk factors for fatality, such as pneumonia after fracture, cerebrovascular disease, mild liver disease, renal disease, and malignancy, were more prevalent among men. During the study period, the risk of fatality after hip fracture but not the risk of subsequent hip fractures was higher among men. The gender difference in fatality might be explained by the larger burden of comorbid diseases among men.

P0702IMPAIRED MYOCARDIAL MICROCIRCULATION PERFUSION IN ASYMPTOMATIC STAGE 1-4 CHRONIC KIDNEY DISEASE PATIENTS WITH INTRARENAL ARTERIAL LESIONS

Abstract Background and Aims Even mild renal disease is a powerful cardiovascular (CV) risk factor. However, the association between these pathophysiological processes, especially in the early asymptomatic stage, remains unclear. This study aimed to explore the relationship of cardio-renal microvascular disease in asymptomatic stage 1-4 chronic kidney disease (CKD) patients without obstructive coronary artery disease (CAD). Method This study consisted of 243 asymptomatic patients with stage 1-4 CKD who had no obstructive CAD. We distinguished different degrees of severity of intrarenal arterial lesions according to Oxford classification. Myocardial microcirculation perfusion was measured using single-photon emission computed tomography (SPECT). The summed stress score (SSS), summed rest score (SRS), and summed difference score (SDS) were estimated with the standard 17-segment, 5-point scoring model. Coronary microvascular disease (CMD) was defined as abnormal SPECT MPI (SSS ≥4 or SDS≥2 on SPECT images) in the absence of obstructive CAD. Results The study subjects showed a stepwise increase in CMD severity with the aggravation of intrarenal arterial lesions; The SSS of no/mild/moderate/severe arterial lesions were 1.64±1.08, 2.56±1.35, 4.42±2.17, 6.48±3.52, respectively (all P&amp;lt;0.05); The SDS of no/mild/moderate/severe arterial lesions were 1.29±0.49, 1.75±0.56, 3.06±1.12, 4.16±1.85, respectively (all P&amp;lt;0.05). The percentage of subclinical CMD in CKD patients with intrarenal arterial lesions was significantly higher than those without arterial lesions (69.57% vs. 14.71%; P=0.01). Vice versa, the scores of intrarenal arterial lesions were significantly higher in patients who had myocardial perfusion defect (4.79±2.01 vs. 2.22±2.07, P=0.000), myocardial ischemia (3.69±2.16 vs. 2.35±1.69, P=0.001) compared to those without arterial lesions. Multiple regression analysis further supported renal arterioles hyalinization (OR=1.109, P=0.027) were independently associated with subclinical CMD in stage 1-4 CKD patients with no obstructive CAD. Conclusion This study demonstrated for the first time impaired myocardial microcirculation perfusion in asymptomatic stage 1-4 CKD patients with intrarenal arterial lesions. Renal arteriolar hyalinization may be a useful marker of the presence of CMD in CKD.

Relationship between mild renal dysfunction and coronary artery disease in young patients with stable angina pectoris.

Aim: We investigated the relationship between mild renal dysfunction (MRD) and the presence of coronary artery disease (CAD) in people under 60 years of age. Materials & methods:A total of634 (317 patients with vessel stenosis ≥50% and 317 with normal angiography) individuals diagnosed with stable angina pectoris and estimated glomerular filtration rate (eGFR) ≥60ml/min/1.73m2 were included in the present study. Results: The mean eGFR was lower (95.3±23.7 vs 109.7±22.3, respectively, p=0.002) and the number of patients with MRD was higher in patients with CAD (137, 43.2%) than in the control group (52, 16.4%, p<0.001). The multivariate analysis showed that lower eGFR is an independent risk factor for presence of CAD in people under 60 years of age with stable angina pectoris. Conclusion: According to our retrospective study, the risk of developing CAD appears to be slightly increased in individuals under 60 years of age with MRD.

Cardiovascular Disease Outcomes Related to Early Stage Renal Impairment After Liver Transplantation.

In the general population, even mild renal disease is associated with increased cardiovascular (CV) complications. Whether this is true in liver transplant recipients (LTR) is unknown. This was a retrospective cohort study of 671 LTR (2002-2012) from a large urban tertiary care center and 37 322 LTR using Vizient hospitalization data linked to the United Network for Organ Sharing. The 4-variable Modification of Diet in Renal Disease equation estimated glomerular filtration rate (eGFR). Outcomes were 1-year CV complications (death/hospitalization from myocardial infarction, heart failure, atrial fibrillation, cardiac arrest, pulmonary embolism, or stroke) and mortality. Latent mixture modeling identified trajectories in eGFR in the first liver transplantation (LT) year in the 671 patients. Mean (SD) eGFR was 72.1 (45.7) mL/min per 1.73 m. Six distinct eGFR trajectories were identified in the local cohort (n = 671): qualitatively normal-slow decrease (4% of cohort), normal-rapid decrease (4%), mild-stable (18%), mild-slow decrease (35%), moderate-stable (30%), and severe-stable (9%). In multivariable analyses adjusted for confounders and baseline eGFR, the greatest odds of 1-year CV complications were in the normal-rapid decrease group (odds ratio, 10.6; 95% confidence interval, 3.0-36.9). Among the national cohort, each 5-unit lower eGFR at LT was associated with a 2% and 5% higher hazard of all-cause and CV-mortality, respectively (P < 0.0001), independent of multiple confounders. Even mild renal disease at the time of LT is a risk factor for posttransplant all-cause and CV mortality. More rapid declines in eGFR soon after LT correlate with risk of adverse CV outcomes, highlighting the need to study whether early renal preservation interventions also reduce CV complications.

Type 2 diabetes and in-hospital complications after revision of total hip and knee arthroplasty.

PurposeTo assess the effect of type 2 diabetes (T2DM) on hospital outcomes such as in hospital postoperative complications (IHPC), length of hospital stay (LOHS) and in-hospital mortality (IHM) after the revision of total hip arthroplasty (RHA) and total knee arthroplasty (RKA) and to identify factors associated with IHPC among T2DM patients undergoing these procedures.MethodsWe performed a retrospective study using the Spanish National Hospital Discharge Database, 2005–2014. We included patients who were ≥40 years old that had undergone RHA and RKA. For each T2DM patient, we selected a year-, gender-, age- and Charlson Comorbidity Index-matched non-diabetic patient.ResultsWe identified 44,055 and 39,938 patients who underwent RHA (12.72% with T2DM) and RKA (15.01% with T2DM). We matched 4,700 and 5,394 couples with RHA and RKA, respectively. Any IHPC was more frequent among patients with T2DM than among non-T2DM patients (19% vs. 15.64% in the RHA cohort and 12.94% vs. 11.09% in the RKA cohort, respectively). For patients who underwent RHA, postoperative infection (4.51% vs. 2.94%, p<0.001), acute post-hemorrhagic anemia (9.53% vs. 7.70%, p<0.001), mean LOHS and IHM were significantly higher in patients with T2DM. Among RKA patients, the incidence of acute posthemorrhagic anemia (7.21% vs. 5.62%; p = 0.001) and urinary tract infection (1.13% vs. 0.72%; p = 0.029) was significantly higher in patients with diabetes. Older age, obesity, infection due to internal joint prosthesis, myocardial infarction, congestive heart failure, mild liver disease and renal disease and emergency room admission were significantly associated with a higher risk of IHPC in T2DM patients. IHPC decreased over time only in T2DM patients who underwent RHA (OR 0.94, 95%CI 0.89–0.98).ConclusionsPatients with T2DM who underwent RHA and RKA procedures had more IHPC after controlling for the effects of possible confounders. LOHS and IHM were also higher among RHA patients with diabetes. Older age, comorbidity, obesity and emergency room admission were strong predictors of IHPC in diabetic patients.

Generation and phenotypic characterization of Pde1a mutant mice.

It has been proposed that a reduction in intracellular calcium causes an increase in intracellular cAMP and PKA activity through stimulation of calcium inhibitable adenylyl cyclase 6 and inhibition of phosphodiesterase 1 (PDE1), the main enzymes generating and degrading cAMP in the distal nephron and collecting duct, thus contributing to the development and progression of autosomal dominant polycystic kidney disease (ADPKD). In zebrafish pde1a depletion aggravates and overexpression ameliorates the cystic phenotype. To study the role of PDE1A in a mammalian system, we used a TALEN pair to Pde1a exon 7, targeting the histidine-aspartic acid dipeptide involved in ligating the active site Zn++ ion to generate two Pde1a null mouse lines. Pde1a mutants had a mild renal cystic disease and a urine concentrating defect (associated with upregulation of PDE4 activity and decreased protein kinase A dependent phosphorylation of aquaporin-2) on a wild-type genetic background and aggravated renal cystic disease on a Pkd2WS25/- background. Pde1a mutants additionally had lower aortic blood pressure and increased left ventricular (LV) ejection fraction, without a change in LV mass index, consistent with the high aortic and low cardiac expression of Pde1a in wild-type mice. These results support an important role of PDE1A in the renal pathogenesis of ADPKD and in the regulation of blood pressure.

Pharmacokinetics and safety of carfilzomib in patients with relapsed multiple myeloma and end-stage renal disease (ESRD): an open-label, single-arm, phase I study

PurposeThe pharmacokinetics (PK) of carfilzomib have been previously studied in multiple myeloma patients with varying degrees of renal impairment (normal, mild, moderate, severe, and end-stage renal disease [ESRD]) at doses of 15 and 20 mg/m2. This study evaluated carfilzomib PK at higher doses of 27 and 56 mg/m2 in normal renal function and ESRD patients.MethodsPatients received carfilzomib on two consecutive days/week for 3 weeks every 28-day cycle: 20 mg/m2 (cycle 1 day 1–2), escalated to 27 mg/m2 on cycle 1 day 8; if tolerated, 56 mg/m2 starting cycle 2 day 1. The primary objective was PK assessment with safety/tolerability and response rate as secondary and exploratory objectives, respectively.Results26 patients were enrolled (15 normal, 11 ESRD). There was a trend toward higher area under the concentration time curve (AUC) and maximum concentration in ESRD versus normal renal function patients; however, high interpatient PK variability was discerned. Relative to patients with normal renal function, ESRD patients showed 33% higher AUC. Overall response rate was 43% for the normal renal function and 60% for the ESRD groups. Safety findings were generally similar between the two groups and consistent with the known safety profile of carfilzomib in multiple myeloma patients.ConclusionThere were no meaningful differences in PK between patients with normal renal function and ESRD in light of carfilzomib exposure–response relationships. These results continue to support dosing recommendation that no starting dose adjustment of carfilzomib appears warranted in patients with baseline renal impairment.

Comparison of Chronic Kidney Disease Epidemiology Collaboration Equations with Other Accepted Equations for Estimation of Glomerular Filtration Rate in Indian Chronic Kidney Disease Patients

Background and Aim: In routine clinical practice, the estimation of glomerular filtration rate (GFR) based on serum creatinine has been followed. However, the reliability of creatinine in estimation of GFR is biased and imprecise, leading to the misdiagnosis of chronic kidney disease (CKD). The serum cystatin C is an alternative marker for estimating GFR. Hence, we aimed to compare the newly proposed Chronic Kidney Disease Epidemiology Collaboration Equations (CKD-EPI) with four approved equations based on both creatinine and cystatin C with reference to Tc-99m-diethylenetriamine pentaacetate (Tc-99m-DTPA) considered as a standard.Materials and Methods:Two hundred and one patients were enrolled in the study from a private nephrology outpatient clinic(OPD), Tiruchirappalli, India. The serum creatinine and cystatin C were measured along with routine biochemistry tests. The measurement of GFR was done by Tc-99m-DTPA gates method. The estimated GFR (eGFR) were calculated using serum cystatin C and creatinine based formulae along with the new CKD-EPI formulae. All eGFR estimations were compared with the measured GFR by gates method.Results: The average measured GFR of end stage, severe, moderate, mild renal disease and normal patient groups were 10.17±2.47, 22.58±4.40, 39.05±7.06, 69.62±24.64 and 118.06±29.23 respectively. When comparing the diagnostic accuracy for predicting GFR using well established formulae, the cystatin C based formulae have shown to be highly accurate in all stages of CKD than creatinine based formulae. Among cystatin C based formulae, CKD-EPI Cystatin C had relatively better diagnostic accuracy for predicting GFR in all stages of CKD.Conclusion: CKD-EPI Cystatin C formula has unbiased and more accurate to predict GFR in all stages of CKD.Bangladesh Journal of Medical Science Vol.16(2) 2017 p.238-244

CTL-Promoting Effects of IL-21 Counteract Murine Lupus in the Parent→F1 Graft-versus-Host Disease Model.

IL-21 promotes B cell and CTL responses in vivo, conferring IL-21 with a role in both humoral and cellular responses. Because CTL can target and eliminate autoreactive B cells, we investigated whether IL-21R signaling in CD8 T cells would alter the expansion of autoreactive B cells in an autoimmune setting. We addressed this question using the parent→F1 murine model of acute and chronic (lupus-like) graft-versus-host disease (GVHD) as models of a CTL-mediated or T-dependent B cell-mediated response, respectively. Induction of acute GVHD using IL-21R-deficient donor T cells resulted in decreased peak donor CD8 T cell numbers and decreased CTL effector function due to impaired granzyme B/perforin and Fas/Fas ligand pathways and a phenotype of low-intensity chronic GVHD with persistent host B cells, autoantibody production, and mild lupus-like renal disease. CTL effector maturation was critically dependent on IL-21R signaling in Ag-specific donor CD8, but not CD4, T cells. Conversely, treatment of DBA/2J→F1 chronic GVHD mice with IL-21 strongly promoted donor CD8 T cell expansion and rescued defective donor anti-host CTLs, resulting in host B cell elimination, decreased autoantibody levels, and attenuated renal disease, despite evidence of concurrently enhanced CD4 help for B cells and heightened B cell activation. These results demonstrate that, in the setting of lupus-like CD4 T cell-driven B cell hyperactivity, IL-21 signaling on Ag-specific donor CD8 T cells is critical for CTL effector maturation, whereas a lack of IL-21R downregulates CTL responses that would otherwise limit B cell hyperactivity and autoantibody production.

Severe antenatally diagnosed renal disorders: background, prognosis and practical approach.

Nowadays most renal disorders, especially urinary tract malformations and renal cystic disease, are diagnosed antenatally. In cases of severe bilateral disease, intrauterine renal dysfunction may lead to renal oligohydramnios (ROH), resulting in pulmonary hypoplasia which affects perinatal mortality and morbidity as well as the long-term outcome. However, some infants may only have mild pulmonary and renal disease, and advances in postnatal and dialysis treatment have resulted in improved short- and long-term outcome even in those infants with severe ROH. Here, we review the current state of knowledge and clinical experience of patients presenting antenatally with severe bilateral renal disorders and ROH. By addressing underlying mechanisms, intrauterine tools of diagnosis and treatment as well as published outcome data, we hope to improve antenatal counselling and postnatal care. KEY SUMMARY POINTS: 1. Nowadays most renal disorders are diagnosed antenatally, especially urinary tract malformations and renal cystic disease. 2. Severe kidney dysfunction may lead to renal oligohydramnios, which can cause pulmonary hypoplasia and is a risk factor of perinatal mortality and postnatal renal outcome. However, as considerable clinical heterogeneity is present, outcome predictions need to be treated with caution. 3. Advances in postnatal and dialysis treatment have resulted in improved short- and long-term outcomes even in infants with severe renal oligohydramnios. 4. A multidisciplinary approach with specialist input is required when counselling a family with an ROH-affected fetus as the decision-making process is very challenging.

Acute renal failure is prevalent in patients with thrombotic thrombocytopenic purpura associated with low plasma ADAMTS13 activity

Among patients with thrombotic microangiopathies, acute kidney injury (AKI) is the hallmark of hemolytic uremic syndrome (HUS) and is largely underestimated in patients with thrombotic thrombocytopenic purpura (TTP). We sought to report AKI features and outcomes in patients with TTP. We conducted a retrospective study of 92 patients with TTP assessed by low ADAMTS13 activity (< 10%) between 2001 and 2013. A logistic regression identified variables independently associated with AKI. Among the 92 patients, 54 (58.7%) presented with AKI, including 25 (46.3%) with stage 3 AKI. Fourteen (27.4%) patients had a nephrotic-range proteinuria and 21 (45.6%) had hemoglobinuria. Hematuria and leucocyturia were detected in 19 (41.3%) and 16 patients (36.4%), respectively. Renal replacement therapy (RRT) was required in 14 patients (25.9%). Six months after TTP remission, RRT-free patients had median (IQR) MDRD (Modification of Diet in Renal Disease formula estimating the glomerular filtration rate) of 93 mL min(-1) per 1.73 m(2) (68.8-110) and three patients required long-term dialysis. Mild or moderate chronic renal disease occurred in 23/54 (42.6%) AKI patients. By multivariate analysis, serum level of complement component 3 at admission was the only factor independently associated with AKI (OR per 0.25 unit decrease of C3, 0.85; CI, 1.82-8.33; P = 0.001). In patients with TTP, AKI is present in more than half the patients, and half of those will have lasting renal effects. Further studies to better understand the pathophysiology of renal involvement in patients with TTP and to identify a subset of patients with TTP syndrome overlapping HUS are warranted.