Optimal Respiratory Syncytial Virus intervention programmes using Nirsevimab in England and Wales.

INTRODUCTION: Respiratory Syncytial Virus (RSV) is a major cause of acute lower respiratory tract infections (ALRI) in infants. There are no licensed vaccines and only one monoclonal antibody available to protect infants from disease. A new and potentially longer-lasting monoclonal antibody, Nirsevimab, showed promising results in phase IIb/III trials. We evaluate the cost-effectiveness of Nirsevimab intervention programmes in England and Wales. METHODS: We used a dynamic model for RSV transmission, calibrated to data from England and Wales. We considered a suite of potential Nirsevimab programmes, including administration to all neonates (year-round); only neonates born during the RSV season (seasonal); or neonates born during the RSV season plus infants less than six months old before the start of the RSV season (seasonal + catch-up). RESULTS: If administered seasonally to all infants at birth, we found that Nirsevimab would have to be priced at £63 or less per dose for at least 50% certainty that it could cost-effectively replace the current Palivizumab programme, using an ICER threshold of £20,000/QALY. An extended seasonal programme which includes a pre-season catch-up becomes the optimal strategy at a purchasing price of £32/dose or less for at least 50% certainty. At a purchasing price per dose of £5-32, the annual implementation costs of a seasonal programme could be as high as £2 million before a switch to a year-round strategy would be optimal. DISCUSSION: Nirsevimab has the potential to be cost-effective in England and Wales not only for use in high-risk infants.

Mapping the plague through natural language processing.

Pandemic diseases such as plague have produced a vast amount of literature providing information about the spatiotemporal extent, transmission, or countermeasures. However, the manual extraction of such information from running text is a tedious process, and much of this information remains locked into a narrative format. Natural Language processing (NLP) is a promising tool for the automated extraction of epidemiological data, and can facilitate the establishment of datasets. In this paper, we explore the utility of NLP to assist in the creation of a plague outbreak dataset. We produced a gold standard list of toponyms by manual annotation of a German plague treatise published by Sticker in 1908. We investigated the performance of five pre-trained NLP libraries (Google, Stanford CoreNLP, spaCy, germaNER and Geoparser) for the automated extraction of location data compared to the gold standard. Of all tested algorithms, spaCy performed best (sensitivity 0.92, F1 score 0.83), followed closely by Stanford CoreNLP (sensitivity 0.81, F1 score 0.87). Google NLP had a slightly lower performance (F1 score 0.72, sensitivity 0.78). Geoparser and germaNER had a poor sensitivity (0.41 and 0.61). We then evaluated how well automated geocoding services such as Google geocoding, Geonames and Geoparser located these outbreaks correctly. All geocoding services performed poorly - particularly for historical regions - and returned the correct GIS information only in 60.4%, 52.7% and 33.8% of all cases. Finally, we compared our newly digitized plague dataset to a re-digitized version of the plague treatise by Biraben and provide an update of the spatio-temporal extent of the second pandemic plague outbreaks. We conclude that NLP tools have their limitations, but they are potentially useful to accelerate the collection of data and the generation of a global plague outbreak database.

Determinants of RSV epidemiology following suppression through pandemic contact restrictions.

INTRODUCTION: COVID-19 related non-pharmaceutical interventions (NPIs) led to a suppression of RSV circulation in winter 2020/21 in the UK and an off-season resurgence in Summer 2021. We explore how the parameters of RSV epidemiology shape the size and dynamics of post-suppression resurgence and what we can learn about them from the resurgence patterns observed so far. METHODS: We developed an age-structured dynamic transmission model of RSV and sampled the parameters governing RSV seasonality, infection susceptibility and post-infection immunity, retaining simulations fitting the UK's pre-pandemic epidemiology by a set of global criteria consistent with likelihood calculations. From Spring 2020 to Summer 2021 we assumed a reduced contact frequency, returning to pre-pandemic levels from Spring 2021. We simulated transmission forwards until 2023 and evaluated the impact of the sampled parameters on the projected trajectories of RSV hospitalisations and compared these to the observed resurgence. RESULTS: Simulations replicated an out-of-season resurgence of RSV in 2021. If unmitigated, paediatric RSV hospitalisation incidence in the 2021/22 season was projected to increase by 30-60% compared to pre-pandemic levels. The increase was larger if infection risk was primarily determined by immunity acquired from previous exposure rather than age-dependent factors, exceeding 90 % and 130 % in 1-2 and 2-5 year old children, respectively. Analysing the simulations replicating the observed early outbreak in 2021 in addition to pre-pandemic RSV data, we found they were characterised by weaker seasonal forcing, stronger age-dependence of infection susceptibility and higher baseline transmissibility. CONCLUSION: COVID-19 mitigation measures in the UK stopped RSV circulation in the 2020/21 season and generated immunity debt leading to an early off-season RSV epidemic in 2021. A stronger dependence of infection susceptibility on immunity from previous exposure increases the size of the resurgent season. The early onset of the RSV resurgence in 2021, its marginally increased size relative to previous seasons and its decline by January 2022 suggest a stronger dependence of infection susceptibility on age-related factors, as well as a weaker effect of seasonality and a higher baseline transmissibility. The pattern of resurgence has been complicated by contact levels still not back to pre-pandemic levels. Further fitting of RSV resurgence in multiple countries incorporating data on contact patterns will be needed to further narrow down these parameters and to better predict the pathogen's future trajectory, planning for a potential expansion of new immunisation products against RSV in the coming years.

The influence of temperature on the seasonality of historical plague outbreaks.

Modern plague outbreaks exhibit a distinct seasonal pattern. By contrast, the seasonality of historical outbreaks and its drivers has not been studied systematically. Here, we investigate the seasonal pattern, the epidemic peak timing and growth rates, and the association with latitude, temperature, and precipitation using a large, novel dataset of plague- and all-cause mortality during the Second Pandemic in Europe and the Mediterranean. We show that epidemic peak timing followed a latitudinal gradient, with mean annual temperature negatively associated with peak timing. Based on modern temperature data, the predicted epidemic growth of all outbreaks was positive between 11.7°C and 21.5°C with a maximum around 17.3°C. Hence, our study provides evidence that the growth of plague epidemics across the whole study region depended on similar absolute temperature thresholds. Here, we present a systematic analysis of the seasonality of historical plague in the Northern Hemisphere, and we show consistent evidence for a temperature-related process influencing the epidemic peak timing and growth rates of plague epidemics.

Outbreaks of publications about emerging infectious diseases: the case of SARS-CoV-2 and Zika virus.

BACKGROUND: Outbreaks of infectious diseases generate outbreaks of scientific evidence. In 2016 epidemics of Zika virus emerged, and in 2020, a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a pandemic of coronavirus disease 2019 (COVID-19). We compared patterns of scientific publications for the two infections to analyse the evolution of the evidence. METHODS: We annotated publications on Zika virus and SARS-CoV-2 that we collected using living evidence databases according to study design. We used descriptive statistics to categorise and compare study designs over time. RESULTS: We found 2286 publications about Zika virus in 2016 and 21,990 about SARS-CoV-2 up to 24 May 2020, of which we analysed a random sample of 5294 (24%). For both infections, there were more epidemiological than laboratory science studies. Amongst epidemiological studies for both infections, case reports, case series and cross-sectional studies emerged first, cohort and case-control studies were published later. Trials were the last to emerge. The number of preprints was much higher for SARS-CoV-2 than for Zika virus. CONCLUSIONS: Similarities in the overall pattern of publications might be generalizable, whereas differences are compatible with differences in the characteristics of a disease. Understanding how evidence accumulates during disease outbreaks helps us understand which types of public health questions we can answer and when.

Epidemiology of a bubonic plague outbreak in Glasgow, Scotland in 1900.

On 3 August 1900, bubonic plague (Yersinia pestis) broke out in Glasgow for the first time during the Third Pandemic. The local sanitary authorities rigorously tracked the spread of the disease and they found that nearly all of the 35 cases could be linked by contact with a previous case. Despite trapping hundreds of rats in the area, there was no evidence of a rat epizootic and the investigators speculated that the outbreak could be due to human-to-human transmission of bubonic plague. Here we use a likelihood-based method to reconstruct transmission trees for the outbreak. From the description of the outbreak and the reconstructed trees, we infer several epidemiological parameters. We found that the estimated mean serial interval was 7.4-9.2 days and the mean effective reproduction number dropped below 1 after implementation of control measures. We also found a high rate of secondary transmissions within households and observations of transmissions from individuals who were not terminally septicaemic. Our results provide important insights into the epidemiology of a bubonic plague outbreak during the Third Pandemic in Europe.

Human ectoparasites and the spread of plague in Europe during the Second Pandemic.

Plague, caused by the bacterium Yersinia pestis, can spread through human populations by multiple transmission pathways. Today, most human plague cases are bubonic, caused by spillover of infected fleas from rodent epizootics, or pneumonic, caused by inhalation of infectious droplets. However, little is known about the historical spread of plague in Europe during the Second Pandemic (14-19th centuries), including the Black Death, which led to high mortality and recurrent epidemics for hundreds of years. Several studies have suggested that human ectoparasite vectors, such as human fleas (Pulex irritans) or body lice (Pediculus humanus humanus), caused the rapidly spreading epidemics. Here, we describe a compartmental model for plague transmission by a human ectoparasite vector. Using Bayesian inference, we found that this model fits mortality curves from nine outbreaks in Europe better than models for pneumonic or rodent transmission. Our results support that human ectoparasites were primary vectors for plague during the Second Pandemic, including the Black Death (1346-1353), ultimately challenging the assumption that plague in Europe was predominantly spread by rats.

Zika Virus Infection as a Cause of Congenital Brain Abnormalities and Guillain-Barré Syndrome: Systematic Review.

BACKGROUND: The World Health Organization (WHO) stated in March 2016 that there was scientific consensus that the mosquito-borne Zika virus was a cause of the neurological disorder Guillain-Barré syndrome (GBS) and of microcephaly and other congenital brain abnormalities based on rapid evidence assessments. Decisions about causality require systematic assessment to guide public health actions. The objectives of this study were to update and reassess the evidence for causality through a rapid and systematic review about links between Zika virus infection and (a) congenital brain abnormalities, including microcephaly, in the foetuses and offspring of pregnant women and (b) GBS in any population, and to describe the process and outcomes of an expert assessment of the evidence about causality. METHODS AND FINDINGS: The study had three linked components. First, in February 2016, we developed a causality framework that defined questions about the relationship between Zika virus infection and each of the two clinical outcomes in ten dimensions: temporality, biological plausibility, strength of association, alternative explanations, cessation, dose-response relationship, animal experiments, analogy, specificity, and consistency. Second, we did a systematic review (protocol number CRD42016036693). We searched multiple online sources up to May 30, 2016 to find studies that directly addressed either outcome and any causality dimension, used methods to expedite study selection, data extraction, and quality assessment, and summarised evidence descriptively. Third, WHO convened a multidisciplinary panel of experts who assessed the review findings and reached consensus statements to update the WHO position on causality. We found 1,091 unique items up to May 30, 2016. For congenital brain abnormalities, including microcephaly, we included 72 items; for eight of ten causality dimensions (all except dose-response relationship and specificity), we found that more than half the relevant studies supported a causal association with Zika virus infection. For GBS, we included 36 items, of which more than half the relevant studies supported a causal association in seven of ten dimensions (all except dose-response relationship, specificity, and animal experimental evidence). Articles identified nonsystematically from May 30 to July 29, 2016 strengthened the review findings. The expert panel concluded that (a) the most likely explanation of available evidence from outbreaks of Zika virus infection and clusters of microcephaly is that Zika virus infection during pregnancy is a cause of congenital brain abnormalities including microcephaly, and (b) the most likely explanation of available evidence from outbreaks of Zika virus infection and GBS is that Zika virus infection is a trigger of GBS. The expert panel recognised that Zika virus alone may not be sufficient to cause either congenital brain abnormalities or GBS but agreed that the evidence was sufficient to recommend increased public health measures. Weaknesses are the limited assessment of the role of dengue virus and other possible cofactors, the small number of comparative epidemiological studies, and the difficulty in keeping the review up to date with the pace of publication of new research. CONCLUSIONS: Rapid and systematic reviews with frequent updating and open dissemination are now needed both for appraisal of the evidence about Zika virus infection and for the next public health threats that will emerge. This systematic review found sufficient evidence to say that Zika virus is a cause of congenital abnormalities and is a trigger of GBS.

Heterogeneity in District-Level Transmission of Ebola Virus Disease during the 2013-2015 Epidemic in West Africa.

The Ebola virus disease (EVD) epidemic in West Africa in 2013-2015 spread heterogeneously across the three hardest-hit countries Guinea, Liberia and Sierra Leone and the estimation of national transmission of EVD provides little information about local dynamics. To investigate district-level transmissibility of EVD, we applied a statistical modelling approach to estimate the basic reproduction number (R0) for each affected district and each country using weekly incident case numbers. We estimated growth rates during the early exponential phase of the outbreak using exponential regression of the case counts on the first eight weeks since onset. To take into account the heterogeneity between and within countries, we fitted a mixed effects model and calculated R0 based on the predicted individual growth rates and the reported serial interval distribution. At district level, R0 ranged from 0.36 (Dubréka) to 1.72 (Beyla) in Guinea, from 0.53 (Maryland) to 3.37 (Margibi) in Liberia and from 1.14 (Koinadugu) to 2.73 (Western Rural) in Sierra Leone. At national level, we estimated an R0 of 0.97 (95% CI 0.77-1.18) for Guinea, 1.26 (95% CI 0.98-1.55) for Liberia and 1.66 (95% CI 1.32-2.00) for Sierra Leone. Socio-demographic variables related to urbanisation such as high population density and high wealth index were found positively associated with R0 suggesting that the consequences of fast urban growth in West Africa may have contributed to the increased spread of EVD.

Renal Blood Oxygenation Level-dependent Imaging in Longitudinal Follow-up of Donated and Remaining Kidneys.

Purpose To determine renal oxygenation changes associated with uninephrectomy and transplantation in both native donor kidneys and transplanted kidneys by using blood oxygenation level-dependent (BOLD) MR imaging. Materials and Methods The study protocol was approved by the local ethics committee. Thirteen healthy kidney donors and their corresponding recipients underwent kidney BOLD MR imaging with a 3-T imager. Written informed consent was obtained from each subject. BOLD MR imaging was performed in donors before uninephrectomy and in donors and recipients 8 days, 3 months, and 12 months after transplantation. R2* values, which are inversely related to tissue partial pressure of oxygen, were determined in the cortex and medulla. Longitudinal R2* changes were statistically analyzed by using repeated measures one-way analysis of variance with post hoc pair-wise comparisons. Results R2* values in the remaining kidneys significantly decreased early after uninephrectomy in both the medulla and cortex (P < .003), from 28.9 sec(-1) ± 2.3 to 26.4 sec(-1) ± 2.5 in the medulla and from 18.3 sec(-1) ± 1.5 to 16.3 sec(-1) ± 1.0 in the cortex, indicating increased oxygen content. In donors, R2* remained significantly decreased in both the medulla and cortex at 3 (P < .01) and 12 (P < .01) months. In transplanted kidneys, R2* remained stable during the first year after transplantation, with no significant change. Among donors, cortical R2* was found to be negatively correlated with estimated glomerular filtration rate (R = -0.47, P < .001). Conclusion The results suggest that BOLD MR imaging may potentially be used to monitor renal functional changes in both remaining and corresponding transplanted kidneys. (©) RSNA, 2016.

Urinary biomarkers at early ADPKD disease stage.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by a decline in renal function at late disease stage when the majority of functional renal parenchyma is replaced by cystic tissue. Thus, kidney function, assessed by estimated glomerular filtration rate (eGFR) does not well represent disease burden in early disease. Here, we investigated various urinary markers for tubular injury and their association with disease burden in ADPKD patients at early disease course. METHODS: ADPKD patients between 18 and 40 years with an eGFR greater or equal to 70 ml per min per 1.73m2 were eligible for this cross-sectional study. Urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL), Kidney Injury Molecule-1 (KIM-1), and Uromodulin (UMOD) were investigated by Enzyme-Linked Immunosorbent Assay. Clara Cell Protein 16 (CC16) was investigated by Latex Immuno Assay. Cryoscopy was performed to assess urine osmolality and Urinary Albumin-to-Creatinine Ratio (UACR) was calculated. The association and the predictive properties of the markers on eGFR and height adjusted total kidney volume (htTKV) was evaluated using multiple regression analysis, incorporating different control variables for adjustment. Internal bootstrapping validated the obtained results. RESULTS: In 139 ADPKD patients (age 31 ±7 years, mean eGFR of 93 ± 19 ml per min per 1.73 m2) the total kidney volume was negatively correlated with eGFR and UMOD and positive associated with age, UACR, KIM-1 and urine osmolality after adjustment for possible confounders. Urine osmolality and htTKV were also associated with eGFR, whereas no association of CC16, NGAL and UMOD with eGFR or htTKV was found. CONCLUSION: UACR and urinary KIM-1 are independently associated with kidney size but not with renal function in our study population. Urine osmolality was associated with eGFR and kidney volume following adjustment for multiple confounders. Despite statistical significance, the clinical value of our results is not yet conceivable. Further studies are needed to evaluate the property of the aforementioned biomarkers to assess disease state at early ADPKD stage.

Urinary proteomic biomarkers for diagnosis and risk stratification of autosomal dominant polycystic kidney disease: a multicentric study.

Treatment options for autosomal dominant polycystic kidney disease (ADPKD) will likely become available in the near future, hence reliable diagnostic and prognostic biomarkers for the disease are strongly needed. Here, we aimed to define urinary proteomic patterns in ADPKD patients, which aid diagnosis and risk stratification. By capillary electrophoresis online coupled to mass spectrometry (CE-MS), we compared the urinary peptidome of 41 ADPKD patients to 189 healthy controls and identified 657 peptides with significantly altered excretion, of which 209 could be sequenced using tandem mass spectrometry. A support-vector-machine based diagnostic biomarker model based on the 142 most consistent peptide markers achieved a diagnostic sensitivity of 84.5% and specificity of 94.2% in an independent validation cohort, consisting of 251 ADPKD patients from five different centers and 86 healthy controls. The proteomic alterations in ADPKD included, but were not limited to markers previously associated with acute kidney injury (AKI). The diagnostic biomarker model was highly specific for ADPKD when tested in a cohort consisting of 481 patients with a variety of renal and extrarenal diseases, including AKI. Similar to ultrasound, sensitivity and specificity of the diagnostic score depended on patient age and genotype. We were furthermore able to identify biomarkers for disease severity and progression. A proteomic severity score was developed to predict height adjusted total kidney volume (htTKV) based on proteomic analysis of 134 ADPKD patients and showed a correlation of r = 0.415 (p<0.0001) with htTKV in an independent validation cohort consisting of 158 ADPKD patients. In conclusion, the performance of peptidomic biomarker scores is superior to any other biochemical markers of ADPKD and the proteomic biomarker patterns are a promising tool for prognostic evaluation of ADPKD.

Low-dose oral sirolimus and the risk of menstrual-cycle disturbances and ovarian cysts: analysis of the randomized controlled SUISSE ADPKD trial.

UNLABELLED: Sirolimus has been approved for clinical use in non proliferative and proliferative disorders. It inhibits the mammalian target of rapamycin (mTOR) signaling pathway which is also known to regulate ovarian morphology and function. Preliminary observational data suggest the potential for ovarian toxicity but this issue has not been studied in randomized controlled trials. We reviewed the self-reported occurrence of menstrual cycle disturbances and the appearance of ovarian cysts post hoc in an open label randomized controlled phase II trial conducted at the University Hospital Zürich between March 2006 and March 2010. Adult females with autosomal dominant polycystic kidney disease, an inherited kidney disease not known to affect ovarian morphology and function, were treated with 1.3 to 1.5 mg sirolimus per day for a median of 19 months (N = 21) or standard care (N = 18). Sirolimus increased the risk of both oligoamenorrhea (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.1 to 29) and ovarian cysts (HR 4.4, CI 1.1 to 26); one patient was cystectomized five months after starting treatment with sirolimus. We also studied mechanisms of sirolimus-associated ovarian toxicity in rats. Sirolimus amplified signaling in rat ovarian follicles through the pro-proliferative phosphatidylinositol 3-kinase pathway. Low dose oral sirolimus increases the risk of menstrual cycle disturbances and ovarian cysts and monitoring of sirolimus-associated ovarian toxicity is warranted and might guide clinical practice with mammalian target of rapamycin inhibitors. TRIAL REGISTRATION: ClinicalTrials.gov NCT00346918.

Soluble klotho and autosomal dominant polycystic kidney disease.

BACKGROUND AND OBJECTIVES: Fibroblast growth factor 23 (FGF23) levels are elevated in patients with autosomal dominant polycystic kidney disease (ADPKD) and X-linked hypophosphatemia (XLH), but only the latter is characterized by a renal phosphate wasting phenotype. This study explored potential mechanisms underlying resistance to FGF23 in ADPKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: FGF23 and klotho levels were measured, and renal phosphate transport was evaluated by calculating the ratio of the maximum rate of tubular phosphate reabsorption to GFR (TmP/GFR) in 99 ADPKD patients, 32 CKD patients, 12 XLH patients, and 20 healthy volunteers. ADPKD and CKD patients were classified by estimated GFR (CKD stage 1, ≥90 ml/min per 1.73 m(2); CKD stage 2, 60-89 ml/min per 1.73 m(2)). RESULTS: ADPKD patients had 50% higher FGF23 levels than did XLH patients; TmP/GFR was near normal in most ADPKD patients and very low in XLH patients. Serum klotho levels were lowest in the ADPKD group, whereas the CKD and XLH groups and volunteers had similar levels. ADPKD patients with an apparent renal phosphate leak had two-fold higher klotho levels than those without. Serum klotho values correlated inversely with cyst volume and kidney growth. CONCLUSIONS: Loss of klotho might be a consequence of cyst growth and constrain the phosphaturic effect of FGF23 in most patients with ADPKD. Normal serum klotho levels were associated with normal FGF23 biologic activity in all XLH patients and a minority of ADPKD patients. Loss of klotho and FGF23 increase appear to exceed and precede the changes that can be explained by loss of GFR in patients with ADPKD.

Growth of arachnoid cysts in patients with autosomal dominant polycystic kidney disease: serial imaging and clinical relevance.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder that results in the growth of cysts in the kidneys and other organs. Multisystemic involvement is common including affection of the central nervous system with cerebral aneurysms and arachnoid cysts. METHODS: This is a prospective cohort study to investigate the prevalence and growth rate of arachnoid cysts in ADPKD patients. Participants enrolled in the SUISSE ADPKD cohort were offered cranial imaging for the detection of intracranial alterations. In the case of identified arachnoid cysts, patients were suggested to undergo follow-up imaging to assess the growth rate of the cysts. Volume of arachnoid cysts at the baseline and at follow-up visits was assessed by manual segmentation on a dedicated workstation. RESULTS: A total of 109 ADPKD patients agreed to undergo cranial imaging. In 14 (12.8%) patients (9 males and 5 females), 18 singular arachnoid cysts were identified. The baseline volumes of individual cysts ranged from 1.8 to 337.6 cm(3). During a mean follow-up period of 24 months, the volume changes of 12 individual arachnoid cysts of nine patients ranged from -3.1 to 3.7 cm(3). Cystic lesions were mostly localized in the middle fossa. All affected patients were clinically asymptomatic. CONCLUSIONS: We found a higher prevalence of arachnoid cysts in ADPKD patients with more advanced disease. There was a large variability in size and growth. These arachnoid cysts were clinically silent and their growth pattern was subtle and unpredictable, in contrast to the much more foreseeable growth of the renal cysts.

Patients with autosomal dominant polycystic kidney disease have elevated fibroblast growth factor 23 levels and a renal leak of phosphate.

Fibroblast growth factor 23 (FGF23) and parathyroid hormone blood levels rise following progressive loss of renal function. Here we measured parameters of phosphate metabolism in 100 patients with autosomal dominant polycystic kidney disease (ADPKD) in stage 1 or 2 of chronic kidney disease, 20 patients with non-diabetic chronic kidney disease, and 26 with type 2 diabetes. Twenty healthy volunteers served as controls. The mean levels of FGF23 were significantly (4-fold) higher in ADPKD compared to non-diabetic and diabetic patients, and healthy volunteers. Mean serum phosphate levels were significantly lower in ADPKD patients compared to non-diabetic and diabetic patients, and the healthy volunteers. The prevalence of hypophosphatemia was 38, 25, 27, and 5% in ADPKD, non-diabetic and diabetic patients, and healthy volunteers, respectively. The tubular maximum of phosphate reabsorption per glomerular filtration rate was lowest in ADPKD patients with a significantly high positive correlation with serum phosphate levels. Estimated glomerular filtration rates were approximately 100 ml/min per 1.73 m² in all groups and parathyroid hormone and vitamin D metabolite levels were in the normal range. Thus, FGF23 was substantially elevated in ADPKD patients compared to other CKD patients matched for glomerular filtration rate, and was associated with increased renal phosphate excretion. The mechanism for this anomaly will require further study.

Sirolimus and kidney growth in autosomal dominant polycystic kidney disease.

BACKGROUND: In autosomal dominant polycystic kidney disease (ADPKD), aberrant activation of the mammalian target of rapamycin (mTOR) pathway is associated with progressive kidney enlargement. The drug sirolimus suppresses mTOR signaling. METHODS: In this 18-month, open-label, randomized, controlled trial, we sought to determine whether sirolimus halts the growth in kidney volume among patients with ADPKD. We randomly assigned 100 patients between the ages of 18 and 40 years to receive either sirolimus (target dose, 2 mg daily) or standard care. All patients had an estimated creatinine clearance of at least 70 ml per minute. Serial magnetic resonance imaging was performed to measure the volume of polycystic kidneys. The primary outcome was total kidney volume at 18 months on blinded assessment. Secondary outcomes were the glomerular filtration rate and urinary albumin excretion rate at 18 months. RESULTS: At randomization, the median total kidney volume was 907 cm3 (interquartile range, 577 to 1330) in the sirolimus group and 1003 cm3 (interquartile range, 574 to 1422) in the control group. The median increase over the 18-month period was 99 cm3 (interquartile range, 43 to 173) in the sirolimus group and 97 cm3 (interquartile range, 37 to 181) in the control group. At 18 months, the median total kidney volume in the sirolimus group was 102% of that in the control group (95% confidence interval, 99 to 105; P=0.26). The glomerular filtration rate did not differ significantly between the two groups; however, the urinary albumin excretion rate was higher in the sirolimus group. CONCLUSIONS: In adults with ADPKD and early chronic kidney disease, 18 months of treatment with sirolimus did not halt polycystic kidney growth. (Funded by Wyeth and others; ClinicalTrials.gov number, NCT00346918.)

Kidney function and volume progression in unilateral autosomal dominant polycystic kidney disease with contralateral renal agenesis or hypoplasia: a case series.

BACKGROUND: The occurrence of unilateral autosomal dominant polycystic kidney disease (ADPKD) with absence of the contralateral kidney has been described only rarely in the literature. Whether unilateral ADPKD is associated with faster disease progression is not known. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: In a prospective cohort of 182 patients with ADPKD, we identified 3 patients with ADPKD and unilateral renal agenesis (2 patients) or severe hypoplasia (1 patient). MEASUREMENTS & OUTCOMES: Genetic analysis of the PKD1 and PKD2 genes was performed for all 3 patients. Serum creatinine levels and kidney volumes based on magnetic resonance imaging were determined twice, with a 6-month interval between measurements. Characteristics of the 3 patients were compared with age- and sex-matched controls from the full cohort. RESULTS: Genotyping of the 3 patients indicated that each had a different [corrected] mutation in the PKD1 gene that is predicted to cause frameshift and/or truncation of the protein product. [corrected] All 3 patients with unilateral ADPKD had renal volumes and progression rates greater than the mean values of their matched control groups. However, their glomerular filtration rates were well preserved, with estimated single-kidney creatinine clearances much greater than their controls. LIMITATIONS: The number of cases in this study is small and time of follow-up was limited. CONCLUSIONS: Unilateral renal agenesis or hypoplasia in patients with ADPKD might not be as rare as previously thought. Glomerular filtration rate was preserved despite unilateral renal absence, suggesting that renal compensatory mechanisms are well conserved in patients with ADPKD.