Evidence Of Renal Dysfunction Research Articles

A novel acute kidney injury scoring system for renal and clinical outcomes in pediatric heart transplant patients.

The development of acute kidney injury (AKI) has been associated with worse outcomes in children after heart transplantation. Our study compares the application of a cumulative six-point Kidney Diseases Improving Global Outcomes (KDIGO) AKI scoring system, utilizing both creatinine and urine output criteria that we term as the AKI-6 criteria, to traditional AKI staging as a predictor for clinical and renal outcomes in the pediatric heart transplant recipients. We conducted a retrospective single-center chart review on 155 pediatric patients who underwent heart transplantation from May 2014 to December 2021. The primary independent variable was the presence of severe AKI. Severe AKI by KDIGO was defined as Stage ≥2, whereas severe AKI by AKI-6 was defined as cumulative scores ≥4 or Stage 3 AKI based on either KDIGO criterion alone. Primary outcomes included actuarial survival and renal dysfunction by 1-year post-transplant, defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2 . In total, 140 (90%) patients developed AKI; 98 (63%) patients developed severe AKI by KDIGO, and 60 (39%) by AKI-6. Severe AKI by AKI-6 was associated with worse actuarial survival following heart transplantation compared with KDIGO (p = 0.01). Of the 143 patients with 1-year creatinine data, 6 (11%) patients out of 54 with severe AKI by AKI-6 had evidence of renal dysfunction (p = 0.01), compared with 6 (7%) patients out of 88 by KDIGO (p = 0.3). AKI-6 scoring provides greater prognostic utility for actuarial survival and renal dysfunction by 1-year post-heart transplantation in pediatric patients than traditional KDIGO staging.

O15 Tumour-induced osteomalacia: a diagnostic challenge

Case report - IntroductionTumor-induced osteomalacia is a rare acquired metabolic bone disorder characterised by isolated renal phosphate wasting due to abnormal tumour production of fibroblast growth factor 23 (FGF23). Bloods show hypophosphatemia. However, given the lack of awareness of this disease, and the non-specific nature of the presenting symptoms, diagnosis is often delayed for years or even missed.With this case report, we want to shed light on this rare bone disorder and highlight the importance of not ignoring a low phosphate level.Case report - Case descriptionWe report the case of a 63-year-old gentleman who presented to us with a history of progressive bone pain, marked muscle weakness and fatigue. He had a persistently raised parathyroid hormone and very high alkaline phosphatase. Calcium was low normal, but vitamin D was normal. Phosphate was noted to be low and had been so since 6 years prior to being referred. X-ray pelvis showed sclerotic-looking iliac bones, but an isotope bone scan showed no evidence of metastatic disease.We referred him to our endocrinology colleagues to investigate for possible primary hyperparathyroidism. However, ultrasound scan of neck showed no abnormal parathyroid gland. PET and CT scan of the chest, abdomen and pelvis did not show any significant pathology. MIBI scan of parathyroid glands showed diffuse thyroid uptake. The SPECT-CT images showed a well-defined focal area of increased activity, posterior to the mid/lower pole of the right thyroid lobe, possibly indicative of hyperfunctioning parathyroid tissue. The radiologist questioned the possibility of renal osteodystrophy and resultant secondary hyperparathyroidism. However, there was no evidence for renal dysfunction with a creatinine of 80 umol/L.We referred this gentleman to the Oxfordshire Osteoporosis and Metabolic Bone Service. Bloods showed a raised P1NP. This was felt to be consistent with tumour-induced osteomalacia. Oversecretion of FGF23 was confirmed and DOTATATE scan revealed two areas of uptake: one in the right hip and one in the skull.Meanwhile, the patient had been started on Sandoz Phosphate and alfacalcidol, and his bone aches improved on this combination therapy.He had radio-ablation of the hip lesion this year and has now stopped all his medication. His fatigue and muscle strength has improved dramatically. The skull lesion is being monitored for now with yearly imaging and follow-up in the metabolic bone clinic.Case report - DiscussionTumour-induced or oncogenic osteomalacia is extremely rare. Symptoms include chronic muscle and bone pain, weakness, and fatigue and can result in fragility fractures due to osteomalacia. Lack of awareness of these clinical manifestations and relevance of low phosphate levels often leads to a diagnostic delay or misdiagnosis. As seen in our case, it took multiple investigations and almost 2 years before this gentleman had a confirmation of his diagnosis.The pathogenesis of tumour-induced osteomalacia involves tumour expression of fibroblast growth factor 23. This hormone inhibits reabsorption of phosphate in the proximal renal tubule and down-regulates renal conversion of 25-hydroxyvitamin D to its active form, 1,25-dihydroxyvitamin D. Replacing phosphate on its own paradoxically increases PTH levels. The metabolic abnormalities may be partially or completely corrected with phosphate supplementation and calcitriol. In our patient, his PTH levels remained elevated, but alkaline phosphatase improved, as did calcium and phosphate levels.Unlike many other causes of osteomalacia, tumour-induced osteomalacia is curable by resection of the offending tumour. However, finding the responsible FGF23-secreting tumour can be incredibly challenging. There is ongoing research into medical treatment for this condition, especially if the tumour is not found or is unresectable, or the patient is not a surgical candidate.Case report - Key learning pointsLow phosphate levels can be easily overseen, with significant consequences. This case emphasises the need to recognise hypophosphatemia and to look for its cause. Conversely, it also illustrates the need to investigate all patients with persistent musculoskeletal symptoms for hypophosphatemia.Our case underscores the importance of being aware of the rare condition of tumour-induced osteomalacia. This will enable early recognition and treatment of the metabolic abnormality, before the development of any deleterious effects of osteomalacia on the skeleton.

#36: A Review of Maternal and Neonatal Characteristics and Outcomes in Pregnant Women with Serious Infectious Complications from Injection Drug Use

Abstract Background Pregnant people who inject drugs (PWID) and their infants are unique populations that have emerged from the opioid epidemic. Numerous studies have evaluated vertical transmission of HIV, HCV, sequelae of neonatal abstinence syndrome, and maternal and fetal mortality in these mother-infant dyads; however there still remains a large knowledge gap regarding how serious infections in pregnant PWID affect more proximal outcomes such as fetal and maternal distress leading to preterm delivery, risk of neonatal sepsis, need for invasive diagnostic procedures to rule-out neonatal sepsis such as lumbar puncture, neonatal intensive care unit (NICU) admission, and potential consequences of prolonged intrauterine antibiotic exposure. Methods We identified pregnant PWID ≥18 years old with serious infectious complications (defined as (sepsis, endocarditis, osteomyelitis, epidural abscesses, septic arthritis/bursitis, thrombophlebitis, and skin and soft tissue infections requiring IV antibiotics) admitted between 2017–2018 to the University of Kentucky Medical Center and their neonates treated at Kentucky Children’s Hospital. Patients were identified using positive urine or serum pregnancy test results, IVDU-associated ICD9/10 codes, infectious disease, neonatology, and obstetrics notes. Results 261 women with infectious complications from IVDU were identified, 25 were pregnant and 16 dyads were able to be matched with identification of 14 viable neonates born at the University of Kentucky. Mean maternal age was 31 years and median 30 years. Mean gestational age (GA) at time of admission was 25 weeks with median 29 weeks. Sepsis was the most common complication reported 18 (72%) followed by endocarditis 11 (44%). Staphylococcus aureus was the most isolated organism (16) 64% with 12 (48%) of isolates identified as MRSA and MSSA comprising 4 (16%). 96% were screened for HCV, with 72% HCV antibody positive and 32% with detectable viral load. There was 1 reported maternal death, 1 spontaneous abortion and 2 intrauterine fetal demises (IUFD) in the 3rd trimester and no neonatal deaths. Average GA at time of delivery was 33 weeks with median 36 weeks. 6 (42%) were routine deliveries with 3 (22%) deliveries for emergent maternal indications and 5 emergent deliveries for fetal indications (36%). 12 neonates (86%) required NICU admission with average length of stay 17 days and median 10 days. 10 (71%) underwent limited sepsis screen with 9 (64%) receiving at least 48 hours of antibiotics and 3 (22%) receiving an extended course. However none of the blood cultures yielded any organisms. All passed their hearing screening and had no evidence of renal dysfunction or cytopenias. Conclusions Pregnant PWID dyads may be at increased risk for morbidity and mortality secondary to infectious complications of IVDU. The majority of neonates were delivered early for either fetal distress or maternal distress. 2 mothers suffered IUFD in the 3rd trimester and the majority of the neonates required NICU admission (86%) due to prematurity-related factors, concern for neonatal abstinence syndrome or concern for infectious complications. Over half received 48+ hours of antibiotics in the NICU however none of the neonatal blood cultures yielded an organism. Larger cohort studies are needed to better ascertain risk in these expanding populations.

Transplant Associated Thrombotic Microangiopathy (TA-TMA) Commonly Occurs after Steroid-Refractory or Dependent Gastrointestinal (GI) Graft Versus Host Disease (GVHD) and Contributes to Post-Transplant Morbidity

Background: Hematopoietic cell transplantation associated thrombotic microangiopathy (TA-TMA) shares common features with atypical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. TA-TMA affects multiple organ systems resulting in multi-organ failure and non-relapse mortality. Recently, complement activation has been shown to be associated with TA-TMA leading to utilization of complement blockade as a therapeutic intervention in TA-TMA. We sought to evaluate the incidence of TA-TMA in patients with GVHD. We hypothesized that patients with gastrointestinal (GI) GVHD with transfusion dependence and renal dysfunction have a concomitant diagnosis of TA-TMA and that this contributes to worse outcomes.Methods: We performed a retrospective review of 124 patients with grade 3/4 GI GVHD admitted October 2008-October 2016. Patients who did not achieve a response by 7 days of 2mg/kg steroids were defined as steroid-refractory and patients who had flare of GVHD symptoms requiring a second course of 2mg/kg steroids were defined as steroid-dependent GVHD. We collected transplant-related data, number of hospitalizations, infections, length of stay and number of platelet/ pRBC transfusions. We assigned patients to groups by likelihood of TA-TMA based on presence of two out of three criteria: (1) > 2 transfusions after first GI biopsy, (2) evidence of hemolysis (schistocytes or nucleated RBCs) with negative Coombs' test and (3) evidence of renal dysfunction. 29/124 patients had paired samples for measurement of complement activation at time of GVHD diagnosis and 2-6 weeks later. Markers of complement activation included C5a and C5b-9 (terminal complement pathway), C4d (Classical pathway), and BBPlus (Alternative pathway).Results: The median age at transplant was 54 years (19-72) and 40.3% were female. Reduced intensity or non-myeloablative conditioning was used in 66.1% of patients and all but 10 patients received tacrolimus. The median time to GVHD onset was 38 days (range: 12-273).TA-TMA and GVHD. A total of 84 (67.7%) subjects met at least 2 criteria for TA-TMA. TA-TMA typically occurred after GVHD at a median of 142 days post-transplant and 78 days post-GVHD. The median time to GVHD was 38 days (12-273). Patients with steroid-refractory GVHD received more platelet and pRBC transfusions than those with steroid-responsive GVHD (p = 0.0018 and 0.0068, respectively) at 2 and 4 weeks post GVHD diagnosis (Figure 1). Patients with steroid-refractory or dependent GVHD were more likely to develop TA-TMA than those with steroid-responsive GVHD. Regardless of responsiveness of GVHD to steroids and accounting for differences in follow-up, patients with TA-TMA had longer length of hospital stay (median: 53 v. 25.5 days, p < 0.001) than patients without TA-TMA.Post-transplant infections in all patients included CMV reactivation (46.8%), other viral infection (60.5%), fungal infection (12.1%), and bacterial infection (65.3%). Renovascular complications included new or worsening hypertension (18.6%), acute kidney injury (45.2%), need for hemodialysis (16.9%), and proteinuria >30mg/dL (75.8%). In multivariable analysis, the risk factors for developing TA-TMA from time of transplant included acute GVHD, viral infection other than CMV, and fungal infection (Table 1).At 2-4 weeks after GVHD diagnosis, differential upregulation of alternative pathway (BBPlus) was seen in patients who went on to develop TA-TMA. It is notable that no differences in complement activation were seen at initial GVHD diagnosis, suggesting that TA-TMA appears to be a secondary event that follows GVHD.Discussion: We show that GVHD is a risk factor for development of TA-TMA and that patients with steroid-refractory/dependent GVHD are more likely to have TA-TMA than steroid-responsive patients. Patients with both GVHD and TA-TMA receive more transfusions and have longer hospitalizations than those with GVHD alone. Our work suggests that the alternative complement pathway (BBPlus) is upregulated in patients with GVHD and TA-TMA, suggesting that complement blockade may be evaluated as a therapeutic strategy in these patients. Prospective study is warranted to understand the triggers of TA-TMA in patients with GVHD, particularly the role of viral and fungal infections and whether complement biomarkers could differentiate between steroid-responsive and steroid refractory/dependent GVHD. [Display omitted] DisclosuresWilliam:Miragen: Consultancy, Honoraria. Blum:Pfizer: Consultancy; Boerhinger Ingelheim: Research Funding; Astellas: Consultancy. Jaglowski:Pharmacyclics: Consultancy, Research Funding. Mims:Novartis: Honoraria. Brammer:Celgene: Research Funding. Hofmeister:Karyopharm: Research Funding; Roche: Research Funding; Janssen: Research Funding; Thrassos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Celgene: Research Funding. Walker:Gilead: Research Funding. Vasu:Stemline Therapeutics: Research Funding; Boehringer-Ingelheim: Research Funding.

Anterior urethral valves – A rare but challenging congenital pathology

Anterior urethral valves (AUV) and associated anterior urethral diverticula (AUD) are a rare cause of congenital lower urinary tract obstruction. They occur 25-30 times less frequently than posterior urethral valves (PUV) and historically tend to have a less aggressive presentation and outcome. However, due to the low incidence, little is known about management and long-term prognosis. We aim to evaluate the outcomes after AUV valve ablation and compare this group to a previously studied PUV cohort. In this IRB-approved study, we retrospectively identified all patients from 2002 to 2017 undergoing valve ablation using CPT code 52400. Charts were manually reviewed to identify AUV patients, their presenting symptoms, timing of diagnosis, pre and postnatal imaging findings, age at presentation and valve ablation, creatinine, recurrences, additional surgeries and follow-up. The AUV group was then compared to a previously studied PUV cohort of 104 patients from our institution. Nine AUV patients were identified. Only four (44%) patients were diagnosed prenatally. Three (33%) patients were diagnosed neonatally, one for weak stream/dribbling and two for febrile UTIs. The remaining two patients were diagnosed at ages 3 and 4 due to dysuria and penile swelling with micturition. Patients presenting later in life had no evidence of renal dysfunction or VUR. All patients underwent primary TUR-AUV (1 laser, 4 cold knife, 4 cautery), but 55% had residual valves and/or diverticula identified on routine postoperative imaging in two patients and due to development of clinic symptoms in three patients. All five patients with recurrences underwent repeat endoscopic evaluation, and thereafter two patients required urethral reconstruction. In contrast, only 15% (16/104) of PUV patients required re-TUR (p=0.01). At an average follow-up time of 4.24 years (range 0.6-11.4 years), 44% of patients had no evidence of CKD, and two patients (22%) had progressed to CKD of at least stage IIIA, compared to 21.4% in the PUV cohort at a mean follow-up of 2.3 years. The overall incidence of AUV is low, making it difficult to characterize these patients definitively. However, despite a milder phenotype and later presentation in most AUV patients, they do require more aggressive surgical treatment for complete resolution of the AUV. Furthermore, the long-term renal outcomes appear more severe than previously reported. The poorer outcomes of AUV patients both with respect to recurrence and long-term CKD indicate that close urologic follow-up is essential in this group.

Evaluation of the Accuracy of Standard Renal Function Equations in Critically Ill Patients with Subarachnoid Hemorrhage.

Obtaining an accurate estimation of renal function is germane to optimizing care in critically ill patients. However, there is no consensus on the most accurate renal function assessment to utilize in this patient population, particularly in aneurysmal subarachnoid hemorrhage (aSAH) patients. Thus, the objective of this observational study was to determine the comparability of renal function equations to body surface area (BSA)-adjusted 8-h creatinine clearance (CrCl) in aSAH patients. A PubMed search investigated the applicability of various renal function equations in critically ill patient populations. A subset of these equations was compared to BSA-adjusted 8-h CrCl from a previous study with aSAH patients with no evidence of renal dysfunction (admission serum creatinine < 1.5mg/dL) and no history of chronic kidney disease. Area-under-the-curve (AUC) calculations were completed using serial laboratory measurements to validate preliminary findings. A total of 14 renal function equations were identified with seven carried forward for further analysis based upon a priori criteria. Seven equations were excluded for various reasons, including lack of available clinical data, redundancy with other equations, and dissimilar patient populations to this study. When directly compared to the BSA-adjusted 8-h CrCl, only the Cockcroft-Gault and BSA-adjusted Cockcroft-Gault equations were not statistically significantly different (P = 0.0886 and P = 0.4805, respectively); all other equations were statistically significantly different (P < 0.0001). Additionally, only 52% and 44% of patients had average values within 20% of the BSA-adjusted 8-h CrCl using the Cockcroft-Gault and BSA-adjusted Cockcroft-Gault equations, respectively. Finally, the AUC calculations corroborated the preliminary findings with similar results in statistical testing for the Cockcroft-Gault and BSA-adjusted Cockcroft-Gault (P = 0.6300 and P = 0.1513, respectively). The Cockcroft-Gault equation may be the best renal function equation to assess in critically ill patients diagnosed with aSAH. However, accuracy and consistency in assessing renal function when compared to the BSA-adjusted 8-h CrCl were lacking. Thus, this study suggests the BSA-adjusted 8-h CrCl may be the most appropriate assessment of renal function in patients with aSAH.

Enhanced Renal Clearance in Patients With Hemorrhagic Stroke.

To evaluate enhanced renal clearance over time in patients with aneurysmal subarachnoid hemorrhage or intracerebral hemorrhage via measured creatinine clearance and to compare measured creatinine clearance to creatinine clearance calculated by the Cockcroft-Gault equation and estimated glomerular filtration rate calculated by the Modification of Diet in Renal Diseases equation. Prospective, observational study. Neurosciences ICU in a tertiary care academic medical center. Study participants had an admission diagnosis of aneurysmal subarachnoid hemorrhage or intracerebral hemorrhage, an expected neurosciences ICU length of stay greater than 48 hours, no evidence of renal dysfunction (admission serum creatinine < 1.5 mg/dL), and no history of chronic kidney disease. Eight-hour urine collections to measure creatinine clearance were collected daily as the primary method of measuring renal function. Creatinine clearance was also calculated using the Cockcroft-Gault equation and estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease equation. Enhanced renal clearance was defined as a measured creatinine clearance greater than the calculated creatinine clearance via Cockcroft-Gault and estimated glomerular filtration rate via Modification of Diet in Renal Disease. Augmented renal clearance was defined by a measured creatinine clearance greater than or equal to 130 mL/min/1.73 m. Relevant demographic, clinical, and outcome data were recorded. Fifty aneurysmal subarachnoid hemorrhage patients and 30 intracerebral hemorrhage patients were enrolled, contributing 590 individual measurements. Patients with aneurysmal subarachnoid hemorrhage had a higher mean measured creatinine clearance compared with the mean calculated creatinine clearance based on the Cockcroft-Gault equation (147.9 ± 50.2 vs 109.1 ± 32.7 mL/min/1.73 m; p < 0.0001) and higher mean measured creatinine clearance compared with the mean calculated estimated glomerular filtration rate based on the Modification of Diet in Renal Disease equation (147.9 ± 50.2 vs 126.0 ± 41.9 mL/min/1.73 m; p = 0.04). Ninety-four percent of participants with aneurysmal subarachnoid hemorrhage experienced augmented renal clearance on at least 1 day. In patients with intracerebral hemorrhage, there was a higher mean measured creatinine clearance over the study period compared with the mean calculated creatinine clearance (119.5 ± 57.2 vs 77.8 ± 27.6 mL/min/1.73 m; p < 0.0001) and higher mean measured creatinine clearance compared with the mean calculated estimated glomerular filtration rate based on the Modification of Diet in Renal Disease equation (119.5 ± 57.2 vs 93.0.0 ± 32.8 mL/min/1.73 m; p = 0.02). Fifty percent of participants with intracerebral hemorrhage experienced augmented renal clearance on at least 1 day. A substantial group of patients with aneurysmal subarachnoid hemorrhage or intracerebral hemorrhage experienced enhanced renal clearance, which may be otherwise unknown to clinicians. Enhanced renal clearance may lead to increased renal solute elimination over what is expected, resulting in subtherapeutic renally eliminated drug concentrations. This may result in underexposure to critical medications, leading to treatment failure and other medical complications.

Renal function and oral anticoagulant treatment of incident non-valvular atrial fibrillation: a retrospective study.

Aim: To describe the renal function of individuals newly diagnosed with non-valvular atrial fibrillation in England, and describe how oral anticoagulant (OAC) treatment varies according to renal function. Patients & methods: We identified a cohort of individuals with non-valvular atrial fibrillation (n=18,419) and described their renal function at diagnosis and the prevalence of OAC treatment initiation by renal function. Results: 79% of individuals had some evidence of renal dysfunction with 12% having a glomerular filtration rate <30ml/min/1.73m2. OAC treatment initiation in the 6 months following diagnosis was lower in individuals with severe renal dysfunction than in those with normal renal function. Conclusion: The high prevalence of renal dysfunction and low OAC treatment prevalence highlights the need for additional evidence regarding OACs in individuals with severe renal dysfunction.

Prevalence and Risk Factors for Augmented Renal Clearance in a Population of Critically Ill Patients.

Critically ill patients show a high, albeit variable, prevalence of augmented renal clearance (ARC). This condition has relevant consequences on the elimination of hydrophilic drugs. Knowledge of risk factors for ARC helps in the early identification of ARC. The aims of this study were evaluation of (1) risk factors for ARC and (2) the prevalence of ARC in critically ill patients over a period of 1 year. A retrospective cohort study was performed for all consecutive patients admitted to our intensive care unit (ICU). Augmented renal clearance was defined by a creatinine clearance ≥130 mL/min/1.73 m2. "Patient with ARC" was defined as a patient with a median of creatinine clearance ≥130 mL/min/1.73 m2 over the period of admission. Four variables were tested, Simplified Acute Physiology Score II (SAPS II), male gender, age, and trauma as cause for ICU admission. An analysis (patient based and clearance based) was performed with logistic regression. Of 475 patients, 446 were included in this study, contributing to 454 ICU admissions and 5586 8-hour creatinine clearance (8h-CLCR). Overall, the prevalence of patients with ARC was 24.9% (n = 113). In a subset of patients with normal serum creatinine levels, the prevalence was 43.0% (n = 104). Of the set of all 8h-CLCR measurements, 25.4% (1418) showed ARC. In the patient-based analysis, the adjusted odds ratio was: 2.0 (confidence interval [CI]:1.1-3.7; P < .05), 0.93 (CI: 0.91-0.94; P < .01), 2.7 (CI: 1.4-5.3; P < .01), and 0.98 (CI: 0.96 -1.01; P = .15), respectively, for trauma, age, male sex, and SAPS II. In the clearance-based analysis, the adjusted odds ratio were 1.7 (CI: 1.4-1.9; P < .01), 0.94 (CI: 0.932-0.942; P < .01), and 2.9 (CI: 2.4-3.4; P < .01), respectively, for trauma, age, and male sex. Trauma, young age, and male sex were independent risk factors for ARC. This condition occurs in a considerable proportion of critical care patients, which was particularly prevalent in patients without evidence of renal dysfunction.

Assessment of Congenital Vascular and Organ Anomalies in Subjects With Thalidomide Embryopathy Using Non-Contrast Magnetic Resonance Angiography.

To determine the type and frequency of vascular and organ malformations in adults with thalidomide embryopathy (TE) using non-contrast magnetic resonance angiography (MRA) and to assess the effect of the observed malformations on renal function. Methods and Results: The institutional ethics committee approved this prospective study and written informed consent was given by all 78 subjects (50 females) with TE (mean age: 55±1.1 years), who were examined by non-contrast MRA at 3T. ECG-triggered balanced turbo field echo images of the chest, abdomen and pelvis were obtained in coronal and sagittal orientations. Two observers assessed the frequency of vascular and organ malformations. Serum creatinine and estimated glomerular filtration rate (eGFR) were obtained to assess renal function. In 58 subjects, 99 vascular anomalies were observed, including 68 arterial (69%) and 31 venous anomalies (31%); 15 patients had 16 abdominal organ malformations including 12 kidney anomalies and 4 cases of gallbladder agenesis. Most vascular anomalies affected the renal vessels (n=66, 67%) or supraaortic arteries (n=28, 28%). Serum creatinine and eGFR revealed normal renal function in all subjects. Vascular and organ anomalies occurred in a high number of subjects with TE without evidence of renal dysfunction. Information about the presence of malformations may be important for future surgical interventions in subjects with TE.

Calciphylaxis in the Setting of Alcoholic Cirrhosis: Case Report and Literature Review.

Calciphylaxis can be a severe life-threatening dermatologic disease that is a known complication associated with end-stage renal disease. However, multiple non-uremic etiologies that are not yet well studied can cause calciphylaxis. We report a rare care of a 40-year-old female with history of alcoholic cirrhosis without any evidence of renal dysfunction who presents with calciphylaxis.

Prevalence of Asymptomatic Microalbuminuria in HIV Positive Children in India.

To study the prevalence of covert or early renal involvement among human immunodeficiency virus (HIV) positive children. A cross-sectional observational study was carried out on 250 HIV positive children (2-18 y) on follow-up in a tertiary care hospital from January 2014 through June 2015. Those who met the study criteria were evaluated for microalbuminuria and glomerular and tubular dysfunctions. Fifty-one out of two hundred fifty (20%) children were found to have microalbuminuria though none had any other evidence of renal dysfunction. The incidence of microalbuminuria in children on Anti Retroviral Therapy (ART) and those not on ART was 20% and 21% respectively. Neither was there any difference in those with a CD4 count ≤500/cu mm compared with those with counts >500/cu mm. However, the overall CD4 counts were significantly lower in children with microalbuminuria. Microalbuminuria was detected in 20% of asymptomatic HIV positive children suggesting early glomerular dysfunction and need for regular screening and follow-up.

Calciphylaxis in the Setting of Alcoholic Cirrhosis

Calciphylaxis can be a severe life threatening dermatologic disease that is a known complication of end stage renal disease. However, non uremic etiologies can cause calciphylaxis. We report a rare case of a forty year old female with history of alcoholic cirrhosis without any evidence of renal dysfunction who presents with calciphylaxis. A 40 year old female with a history of cirrhosis secondary to progression of alcoholic hepatitis presented to the hospital complaining of painful non- healing but worsening ulcerations on her thighs. For the past several months, the patient has refrained from any type of alcohol abuse, which was represented by marked improvement in liver chemistries. On physical exam, the patient presented with no clinical characteristics of decompensated cirrhosis. The lower extremities were remarkable for a blotchy erythematous pattern in the upper thighs resembling levido reticularis. Extensive areas of eschar and skin necrosis were present and the lesions appeared indurated and were extremely tender to touch. The skin lesion on the thigh was biopsied and it showed ulceration and subcutaneous tissue with fat necrosis. Multiple medium sized vessels in the fat demonstrated prominent concentric calcification of the vascular wall, the characteristic pathological findings consistent with calciphylaxis. Our patient's case is remarkable because she did not have any history of chronic kidney disease and did not present with any transient renal dysfunction. The patient has no history of hyperparathyroidism, calcium or phosphorous related disorders. In alcohol induced liver disease related calciphylaxis, few case reports in the literature have shown that deficiencies in protein C and protein S levels result in vascular injury. Liver disease can lead to low synthesis of coagulation factors and other proteins that can lead to susceptibility to injury. All therapies have been directed towards addressing the elevated calcium and phosphorous levels. In calciphylaxis secondary to non-uremic etiologies, no affective treatment is available. Supportive treatments include wound care, pain control, and empiric antibiotics, a regimen that our patient received. No literature is available at this time to determine if a liver transplant in cirrhotic patients leads to complete resolution of the dermatologic disease. At this time, further investigative studies need to be done to properly understand the relationship between liver disease and calciphyalxis.Figure 1Figure 2Figure 3

Variations in glomerular filtration rate are associated with subclinical atherosclerosis in healthy postmenopausal women.

This study aims to evaluate the potential effects of renal function variations on vascular structure before the development of hypertension. This pilot study included 141 postmenopausal women without evidence of renal dysfunction or hypertension. Markers of renal function and levels of glomerular filtration rate (GFR)--using standard calculations (GFR based on levels of creatinine [GFR(epi)]) and newer creatinine and/or cystatin calculations (GFR based on levels of creatinine and cystatin [GFR(cr cystatin)] and GFR based on levels of cystatin [GFR(cystatin)])--were associated with hemodynamic parameters and markers of vascular structure (intima-media thickness [IMT] and presence of atheromatous plaques in carotid and femoral arteries). Levels of GFR(epi), GFR(cr cystatin), and GFR(cystatin) exhibited a significant negative correlation with femoral artery IMT, whereas levels of GFR(epi) correlated significantly with mean carotid bulb (CB) IMT. Multivariate analysis showed that CB-IMT was predicted by GFR(epi) levels and age (β-coefficient = -0.212, P = 0.020), whereas femoral artery IMT was predicted by GFR(epi) levels (β-coefficient = -0.293, P = 0.001). GFR(epi) levels lower than the 25th percentile were associated with higher CB-IMT (P = 0.009), femoral artery IMT (P = 0.001), and combined IMT (P = 0.035) compared with higher GFR(epi) levels. Moreover, GFR(epi) levels greater than the 25th percentile were associated with lower odds for the presence of atherosclerotic plaques at the CB and carotid arteries combined (CB: odds ratio, 0.146; P = 0.006; combined: odds ratio, 0.249; P = 0.043) compared with lower GFR(epi) levels. A mild decrease in renal function within normal limits of GFR is independently associated with the presence of subclinical atherosclerosis in a sample of apparently healthy young postmenopausal women. Assessment of GFR using creatinine (vs cystatin C) levels is a more sensitive marker of its association with IMT and atherosclerotic plaques in this postmenopausal population.

Outcomes of Second Autologous Peripheral Blood Stem Cell Transplant in Multiple Myeloma Patients with Renal Dysfunction

Second autologous stem cell transplant (ASCT) is a treatment option for multiple myeloma (MM) patients (pts) who have disease progression after first ASCT. About 20% of MM pts have evidence of renal dysfunction and many more develop it subsequently. Outcomes of second ASCT in pts with renal dysfunction have not been described.We identified 18 pts at our institution who underwent a second ASCT for relapsed MM and had evidence of renal dysfunction (creatinine clearance ≤ 60ml/min/1.73m2). Pts who underwent a planned tandem transplant were excluded from this analysis. Patient characteristics are shown in Table 1. The median age of pts was 61 years (range, 49-72). The median time between first and second ASCT was 49.8 months (range, 19.2-81.9). Ten pts received one chemotherapy regimen while nine pts received two or more chemotherapy regimens between first and second ASCT. The chemotherapy regimens used between first and second transplant included IMid based (n=6), proteosome inhibitor based (n=3) and combination of both (n=9). Approximately half of the pts had progressive disease at the time of second ASCT. Median creatinine clearance at the time of second ASCT was 43.5 ml/min//1.73m2. All pts received G-CSF 5µg/Kg from day + 6 till absolute neutrophil count was ≥1500/µL, norfloxacin, acyclovir and fluconazole were used for antimicrobial prophylaxis during the hospitalization. One pt was dialysis dependent. Patients received a median dose of melphalan of 140mg/m2 (range 100-200 mg/m2).Median follow up post second ASCT was 17.1 months (range, 2.4- 100). One pt died 74 days after the transplant due to multi- organ failure. Disease status at day 100 post ASCT is shown in Table 2. Thirteen of 17 pts had a partial response or better after second ASCT. Of 17 evaluable pts at day 100, twelve had an upgrade from the disease response category achieved with the last regimen used prior to second ASCT while five pts had stable disease response. Three pts received maintenance therapy after the second ASCT with bortezomib(n=2) and lenalidomide (n=1). Figures 1 and 2 show the overall survival (OS) and relapse free survival (RFS). Median RFS was 22.2 months and median OS was 27 months.The outcomes of patients with renal dysfunction who underwent ASCT in the era of novel agents at our institution are comparable to those reported for second ASCT. The transplant related mortality was not higher than expected and the median PFS of about 2 years makes the option of second ASCT in this group of patients a valuable treatment modality. The utility of maintenance therapy after the second ASCT is not established, but may have contributed to the durable responses seen in some pts assessed herein and deserves to be investigated further.Table 1:Pt Characteristics (N=18)Patient CharacteristicsN (%)Median Age (range)61 years(49-72)Median Time from First ASCT (range)49.8 months(19.2-81.9)GenderMale9(50%)Females9 (50%)RaceCaucasians13 (72%)Others5 (28%)Disease status at time of ASCTPD9 (50%)SD5 (28%)PR1 (5.5 %)VGPR2 (11%)CR1 (5.5%)Median creatinine clearance (range)43.5 (5-59)SubtypeIgG Kappa10 (56%)IgG Lambda6 (33%)Kappa Light Chain2 (11%)Cytogenetic Risk Standard10 (56%)High Risk4(22%)Unknown4 (22%)Melphalan Dose median mg/m2( range)140 (100-200) {100(2pts), 140(10pts), 180(1pt), 200(4pts)}Median CD 34 Cell dose x106/kg (range)4.66(2.6-27.5)Median Engraftment Day (range)WBC11 (9-16)Platelets21 (12-61)Median Days of Hospitalization (range)19(11-74) PD: Progressive disease, SD: Stable disease; PR: Partial response; VGPR: Very good partial response; CR: complete response; WBC White blood cellsTable 2Disease status at Day 100 post ASCTDisease status at Day 100 post ASCTN(%)CR4 (22%)VGPR4 (22%)PR5 (28%)SD3 (17%)PD1 (5.5%)NOT AVAILABLE *1 (5.5%)PD: Progressive disease, SD: Stable disease; PR: Partial response; VGPR: Very good partial response; CR: complete response; *Pt died at day 74 post second ASCT PD: Progressive disease, SD: Stable disease; PR: Partial response; VGPR: Very good partial response; CR: complete response; * Pt died at day 74 post second ASCT [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Function and Size of the Residual Kidney After Treatment of Wilms Tumor

Long-term damage to the residual kidney is of concern in the survivors of Wilms tumor. Our objective was to evaluate the long-term glomerular function and size of the residual kidney in these patients. Twenty-nine survivors of Wilms tumor diagnosed between July 1999 and June 2004 were enrolled. The glomerular function was assessed by creatinine clearance, 99mTc DTPA radionuclide scintigraphy and 24-hour urinary protein. Renal size was evaluated by ultrasonography. Median age at diagnosis and at enrollment were 2.87 ± 1.8 (range: 0.5–7.5) and 7.9 ± 3.8 years (range: 2.5–18). Median duration of follow-up was 4.78 ± 2.6 years (range: 1–8.8). Evidence of renal dysfunction in the form of either function or size was identified in eight (27.6%) children. Six children had subnormal glomerular filtration rate and one had proteinuria. Subnormal size of the residual kidney was observed in one child. Age at diagnosis, stage, and duration elapsed after nephrectomy had no association with renal dysfunction (P >.05). Long-term follow up is crucial to identify clinical nephrotoxicity among survivors of Wilms tumor.

Aberrant transcriptional regulation could explain phenotypic variability in autosomal recessive polycystic kidney disease.

Autosomal recessive polycystic kidney disease (ARPKD) is an inherited ciliopathy of childhood caused by mutations in the PKHD1 and is less frequent than the better-known ciliopathy, autosomal dominant polycystic kidney disease. Characteristic dilatation of the renal collecting ducts is prominent in ARPKD. The disease can start already in utero and presents at any stage from infancy to adulthood. Early renal insufficiency may develop in utero and can lead to early abortionoroligohydramnios(Potter’s sequence). Half of these children die ofpulmonary hypoplasiaafter delivery. However, children may also be born who have no evidence of renal dysfunction in utero and who have normal renal function at birth. A third of ARPKD patients die in the perinatal period, and those surviving the neonatal period commonly develop end-stage renal disease (ESRD)ininfancy, early childhood,or adolescence. Some patients are first diagnosed as adults. While bilateral renal enlargement with microcystic dilatation is the predominant clinical feature (Fig. 1), arterial hypertension and intrahepatic biliary dysgenesis are also important manifestations. All patients with ARPKD develop congenital hepatic fibrosis. However, the biliary dysgenesis may result in nonobstructive dilation of intrahepatic bile ducts (Caroli’s disease). Cholangitis and variceal bleeding develop in some patients necessitating a two-organ transplantation. Thus, the clinical spectrum of ARPKD is broad and heterogeneous. Buscher et al. [1] recently provided an excellent clinical review. The profound clinical variability can occur within families with the same genotype. Variable phenotypes could also result from differences in genetic background, combinations of mutations, modifying genes, epigenetic factors,

WE‐E‐BRE‐02: BEST IN PHYSICS (THERAPY) – Stereotactic Radiotherapy for Renal Sympathetic Ablation for the Treatment of Refractory Hypertension

Purpose:To determine the safety and efficacy of stereotactic radiotherapy as a novel treatment for patients with refractory hypertension in a swine model. Uncontrolled hypertension is a significant contributor to morbidity and mortality, substantially increasing the risk of ischemic stroke, ischemic heart disease, and kidney failure.Methods:High‐resolution computed tomography (CT) images of anesthetized pigs were acquired and treatment plans for each renal artery and nerve were developed using our clinically implemented treatment planning system. Stereotactic radiotherapy, 40Gy in single fraction was delivered bilaterally to the renal nerves using a state‐of‐the‐art medical linear accelerator under image guidance utilizing dynamic conformal arcs. Dose to nearby critical organs was evaluated by dosevolume histogram analysis and correlated to toxicity data obtained through follow up pathology analysis. The animals were observed for six months with serial measurements of blood pressure, urine analysis, serum laboratories, and overall clinical and behavioral status.Results:All animals survived to the follow‐up point without evidence of renal dysfunction (stable serum creatinine), skin changes, or behavioral changes that might suggest animal discomfort. Plasma norepinephrine levels (ng/ml) were followed monthly for 6 months. The average reduction observed was 63%, with the median reduction at 73.5%. Microscopic evaluation 4–6 weeks after treatment showed evidence of damage to the nerves around treated renal arteries. Considerable attenuation in pan neurofilament expression by immunohistochemistry was observed with some vacuolar changes indicative of injury. There was no histological or immunohistochemical evidence of damage to nearby spinal cord or spinal nerve root structures.Conclusion:Our preclinical studies have shown stereotactic radiotherapy to the renal sympathetic plexus to be safe and effective in reducing blood pressure, thus this approach holds great promise as a novel treatment modality for patients with refractory hypertension.This study was funded by the Stanford University Cardiovascular Institute. B. Loo and P. Maxim have received funding from RaySearch Laboratories.

Exome sequencing and in vitro studies identified podocalyxin as a candidate gene for focal and segmental glomerulosclerosis

Our understanding of focal and segmental glomerulosclerosis (FSGS) has advanced significantly from the studies of rare, monogenic forms of the disease. These studies have demonstrated the critical roles of multiple aspects of podocyte function in maintaining glomerular function. A substantial body of research has suggested that the integral membrane protein podocalyxin (PODXL) is required for proper function of podocytes, possibly by preserving the patency of the slit diaphragm by negative charge-based repulsion. Exome sequencing of affected cousins from an autosomal dominant pedigree with FSGS identified a co-segregating private variant, PODXL p.L442R, affecting the transmembrane region of the protein. Of the remaining 11 shared gene variants, two segregated with disease but their gene products were not detected in the glomerulus. In comparison to wild type, this disease-segregating PODXL variant facilitated dimerization. By contrast, this change does not alter protein stability, extracellular domain glycosylation, cell surface expression, global subcellular localization, or interaction with its intracellular binding partner ezrin. Thus, a variant form of PODXL remains the most likely candidate causing FSGS in one family with autosomal dominant inheritance, but its full effect on protein function remains unknown. Our work highlights the challenge faced in the clinical interpretation of whole exome data for small pedigrees with autosomal dominant diseases.

Clinical manifestations of autosomal recessive polycystic kidney disease (ARPKD): kidney-related and non-kidney-related phenotypes

Autosomal recessive polycystic kidney disease (ARPKD), although less frequent than the dominant form, is a common, inherited ciliopathy of childhood that is caused by mutations in the PKHD1-gene on chromosome 6. The characteristic dilatation of the renal collecting ducts starts in utero and can present at any stage from infancy to adulthood. Renal insufficiency may already begin in utero and may lead to early abortion or oligohydramnios and lung hypoplasia in the newborn. However, there are also affected children who have no evidence of renal dysfunction in utero and who are born with normal renal function. Up to 30 % of patients die in the perinatal period, and those surviving the neonatal period reach end stage renal disease (ESRD) in infancy, early childhood or adolescence. In contrast, some affected patients have been diagnosed as adults with renal function ranging from normal to moderate renal insufficiency to ESRD. The clinical spectrum of ARPKD is broader than previously recognized. While bilateral renal enlargement with microcystic dilatation is the predominant clinical feature, arterial hypertension, intrahepatic biliary dysgenesis remain important manifestations that affect approximately 45 % of infants. All patients with ARPKD develop clinical findings of congenital hepatic fibrosis (CHF); however, non-obstructive dilation of the intrahepatic bile ducts in the liver (Caroli's disease) is seen at the histological level in only a subset of patients. Cholangitis and variceal bleeding, sequelae of portal hypertension, are life-threatening complications that may occur more often in advanced cases of liver disease. In this review we focus on common and uncommon kidney-related and non-kidney-related phenotypes. Clinical management of ARPKD patients should include consideration of potential problems related to these manifestations.