Non-Specific Epileptic Activity, EEG, and Brain Imaging in Loss of Function Variants in SATB1: A New Case Report and Review of the Literature.

SATB1 (MIM #602075) is a relatively new gene reported only in recent years in association with neurodevelopmental disorders characterized by variable facial dysmorphisms, global developmental delay, poor or absent speech, altered electroencephalogram (EEG), and brain abnormalities on imaging. To date about thirty variants in forty-four patients/children have been described, with a heterogeneous spectrum of clinical manifestations. In the present study, we describe a new patient affected by mild intellectual disability, speech disorder, and non-specific abnormalities on EEG and neuroimaging. Family studies identified a new de novo frameshift variant c.1818delG (p.(Gln606Hisfs*101)) in SATB1. To better define genotype-phenotype associations in the different types of reported SATB1 variants, we reviewed clinical data from our patient and from the literature and compared manifestations (epileptic activity, EEG abnormalities and abnormal brain imaging) due to missense variants versus those attributable to loss-of-function/premature termination variants. Our analyses showed that the latter variants are associated with less severe, non-specific clinical features when compared with the more severe phenotypes due to missense variants. These findings provide new insights into SATB1-related disorders.

Clinical Course May Be Independent from Neuroimaging in DEPDC-5-Related Epilepsy.

DEPDC5 is an upstream repressor of the mechanistic target of rapamycin pathway via the GATOR-1 complex. Pathogenic variants causing loss of function typically result in familial focal epilepsy with variable foci. Neuroimaging may either be normal or show brain malformations. Lesional and nonlesional cases may be present within the same family. Here, we describe a parent-child dyad affected by a truncating DEPDC5 pathogenic variant (c.727C > T; p.Arg243*), analyze the epilepsy clinical course, and describe neuroimaging characteristics from a 3T brain magnetic resonance imaging. Despite sharing the same variant, patients diverged both in terms of epilepsy severity and neuroimaging features. Surprisingly, the mother is still suffering from drug-resistant seizures and has normal neuroimaging, while the child has been experiencing prolonged seizure freedom notwithstanding a bottom-of-sulcus focal cortical dysplasia. An increasing gradient of severity has been proposed for families with GATOR1-related epilepsies. We confirm clinical and neuroradiological expressivities are variable and also suggest the prognostication of epilepsy outcome may be particularly difficult. The epilepsy outcome could partially be independent from brain structural abnormalities.

Mapping dependencies of BOLD signal change to end-tidal CO2: Linear and nonlinear modeling, and effect of physiological noise correction.

BACKGROUND: Disentangling physiological noise and signal of interest is a major issue when evaluating BOLD-signal changes in response to breath holding. Currently-adopted approaches for retrospective noise correction are general-purpose, and have non-negligible effects in studies on hypercapnic challenges. NEW METHOD: We provide a novel approach to the analysis of specific and non-specific BOLD-signal changes related to end-tidal CO2 (PETCO2) in breath-hold fMRI studies. Multiple-order nonlinear predictors for PETCO2 model a region-dependent nonlinear input-output relationship hypothesized in literature and possibly playing a crucial role in disentangling noise. We explore Retrospective Image-based Correction (RETROICOR) effects on the estimated BOLD response, applying our analysis both with and without RETROICOR and analyzing the linear and non-linear correlation between PETCO2 and RETROICOR regressors. RESULTS: The RETROICOR model of noise related to respiratory activity correlated with PETCO2 both linearly and non-linearly. The correction affected the shape of the estimated BOLD response to hypercapnia but allowed to discard spurious activity in ventricles and white matter. Activation clusters were best detected using non-linear components in the BOLD response model. COMPARISON WITH EXISTING METHOD: We evaluated the side-effects of standard physiological noise correction procedure, tailoring our analysis on challenging understudied brainstem and subcortical regions. Our novel approach allowed to characterize delays and non-linearities in BOLD response. CONCLUSIONS: RETROICOR successfully avoided false positives, still broadly affecting the estimated non-linear BOLD responses. Non-linearities in the model better explained CO2-related BOLD signal fluctuations. The necessity to modify the standard procedure for physiological-noise correction in breath-hold studies was addressed, stating its crucial importance.

Mycophenolate mofetil versus azathioprine in kidney transplant recipients on steroid-free, low-dose cyclosporine immunosuppression (ATHENA): A pragmatic randomized trial.

BACKGROUND: We compared protection of mycophenolate mofetil (MMF) and azathioprine (AZA) against acute cellular rejection (ACR) and chronic allograft nephropathy (CAN) in kidney transplant recipients on steroid-free, low-dose cyclosporine (CsA) microemulsion maintenance immunosuppression. METHODS AND FINDINGS: ATHENA, a pragmatic, prospective, multicenter trial conducted by 6 Italian transplant centers, compared the outcomes of 233 consenting recipients of a first deceased donor kidney transplant induced with low-dose thymoglobulin and basiliximab and randomized to MMF (750 mg twice/day, n = 119) or AZA (75 to 125 mg/day, n = 114) added-on maintenance low-dose CsA microemulsion and 1-week steroid. In patients without acute clinical or subclinical rejections, CsA dose was progressively halved. Primary endpoint was biopsy-proven CAN. Analysis was by intention to treat. Participants were included between June 2007 and July 2012 and followed up to August 2016. Between-group donor and recipient characteristics, donor/recipient mismatches, and follow-up CsA blood levels were similar. During a median (interquartile range (IQR)) follow-up of 47.7 (44.2 to 48.9) months, 29 of 87 biopsied patients on MMF (33.3%) versus 31 of 88 on AZA (35.2%) developed CAN (hazard ratio (HR) [95% confidence interval (CI)]: 1.147 (0.691 to 1.904, p = 0.595). Twenty and 21 patients on MMF versus 34 and 14 on AZA had clinical [HR (95% CI): 0.58 (0.34 to 1.02); p = 0.057) or biopsy-proven subclinical [HR (95% CI): 1.49 (0.76 to 2.92); p = 0.249] ACR, respectively. Combined events [HR (95% CI): 0.85 (0.56 to 1.29); p = 0.438], patient and graft survival, delayed graft function (DGF), 3-year glomerular filtration rate (GFR) [53.8 (40.6;65.7) versus 49.8 (36.8;62.5) mL/min/1.73 m2, p = 0.50], and adverse events (AEs) were not significantly different between groups. Chronicity scores other than CAN predict long-term graft outcome. Study limitations include small sample size and unblinded design. CONCLUSIONS: In this study, we found that in deceased donor kidney transplant recipients on low-dose CsA and no steroids, MMF had no significant benefits over AZA. This finding suggests that AZA, due to its lower costs, could safely replace MMF in combination with minimized immunosuppression. TRIAL REGISTRATION: ClinicalTrials.gov NCT00494741; EUDRACT 2006-005604-14.

Absence of T1 Hyperintensity in the Brain of High-risk Patients After Multiple Administrations of High-dose Gadobutrol for Cardiac Magnetic Resonance.

PURPOSE: A prospective study was conducted to evaluate signal changes in the dentate nucleus, globus pallidus, pons, and thalamus (normalized to the deep cerebellum white matter) in T1-weighted magnetic resonance (MR) images after serial injections of gadobutrol in patients with thalassemia without neurological lesions. METHODS: In this study three groups were scanned at both 1.5 T and 3 T: 15 thalassemia patients transfused and chelated with ≥4 gadobutrol administrations at a high dose (0.2 mmol/kg per scan) for late gadolinium enhancement (LGE) cardiovascular MR, 8 thalassemia patients and 13 healthy subjects who had never received gadolinium-based contrast agents (GBCA). RESULTS: Signal intensity (SI) ratios at 1.5 T in all regions were comparable among the three groups and were not correlated with the number of gadobutrol administrations. In healthy subjects SI ratios were significantly different among the 4 regions, being higher in the pallidus. The SI ratios at 1.5 T were significantly higher and not correlated with SI ratios at 3 T or with iron overload in the same regions assessed by the T2* technique. CONCLUSION: This article describes the lack of increased SI in T1-weighted MR images after repeated administration of gadobutrol for cardiovascular MR studies in a high-risk population (high dose per scan, iron overload that can facilitate the transmetalation of gadolinium) scanned at 3 T and 1.5 T.

Functional MRI Studies in Friedreich's Ataxia: A Systematic Review.

Friedreich's ataxia (FRDA) is an inherited neurodegenerative movement disorder with early onset, widespread cerebral and cerebellar pathology, and no cure still available. Functional MRI (fMRI) studies, although currently limited in number, have provided a better understanding of brain changes in people with FRDA. This systematic review aimed to provide a critical overview of the findings and methodologies of all fMRI studies conducted in genetically confirmed FRDA so far, and to offer recommendations for future study designs. About 12 cross-sectional and longitudinal fMRI studies, included 198 FRDA children and young adult patients and, 205 healthy controls (HCs), according to the inclusion criteria. Details regarding GAA triplet expansion and demographic and clinical severity measures were widely reported. fMRI designs included motor and cognitive task paradigms, and resting-state studies, with widespread changes in functionally activated areas and extensive variability in study methodologies. These studies highlight a mixed picture of both hypoactivation and hyperactivation in different cerebral and cerebellar brain regions depending on fMRI design and cohort characteristics. Functional changes often correlate with clinical variables. In aggregate, the findings provide support for cerebro-cerebellar loop damage and the compensatory mechanism hypothesis. Current literature indicates that fMRI is a valuable tool for gaining in vivo insights into FRDA pathology, but addressing that its limitations would be a key to improving the design, interpretation, and generalizability of studies in the future.

Three dimensional MRF obtains highly repeatable and reproducible multi-parametric estimations in the healthy human brain at 1.5T and 3T.

Magnetic resonance fingerprinting (MRF) is highly promising as a quantitative MRI technique due to its accuracy, robustness, and efficiency. Previous studies have found high repeatability and reproducibility of 2D MRF acquisitions in the brain. Here, we have extended our investigations to 3D MRF acquisitions covering the whole brain using spiral projection k-space trajectories. Our travelling head study acquired test/retest data from the brains of 12 healthy volunteers and 8 MRI systems (3 systems at 3 T and 5 at 1.5 T, all from a single vendor), using a study design not requiring all subjects to be scanned at all sites. The pulse sequence and reconstruction algorithm were the same for all acquisitions. After registration of the MRF-derived PD T1 and T2 maps to an anatomical atlas, coefficients of variation (CVs) were computed to assess test/retest repeatability and inter-site reproducibility in each voxel, while a General Linear Model (GLM) was used to determine the voxel-wise variability between all confounders, which included test/retest, subject, field strength and site. Our analysis demonstrated a high repeatability (CVs 0.7-1.3% for T1, 2.0-7.8% for T2, 1.4-2.5% for normalized PD) and reproducibility (CVs of 2.0-5.8% for T1, 7.4-10.2% for T2, 5.2-9.2% for normalized PD) in gray and white matter. Both repeatability and reproducibility improved when compared to similar experiments using 2D acquisitions. Three-dimensional MRF obtains highly repeatable and reproducible estimations of T1 and T2, supporting the translation of MRF-based fast quantitative imaging into clinical applications.

Patterns and predictors of language representation and the influence of epilepsy surgery on language reorganization in children and young adults with focal lesional epilepsy.

Mapping brain functions is crucial for neurosurgical planning in patients with drug-resistant seizures. However, presurgical language mapping using either functional or structural networks can be challenging, especially in children. In fact, most of the evidence on this topic derives from cross-sectional or retrospective studies in adults submitted to anterior temporal lobectomy. In this prospective study, we used fMRI and DTI to explore patterns of language representation, their predictors and impact on cognitive performances in 29 children and young adults (mean age at surgery: 14.6 ± 4.5 years) with focal lesional epilepsy. In 20 of them, we also assessed the influence of epilepsy surgery on language lateralization. All patients were consecutively enrolled at a single epilepsy surgery center between 2009 and 2015 and assessed with preoperative structural and functional 3T brain MRI during three language tasks: Word Generation (WG), Rhyme Generation (RG) and a comprehension task. We also acquired DTI data on arcuate fasciculus in 24 patients. We first assessed patterns of language representation (relationship of activations with the epileptogenic lesion and Laterality Index (LI)) and then hypothesized a causal model to test whether selected clinical variables would influence the patterns of language representation and the ensuing impact of the latter on cognitive performances. Twenty out of 29 patients also underwent postoperative language fMRI. We analyzed possible changes of fMRI and DTI LIs and their clinical predictors. Preoperatively, we found atypical language lateralization in four patients during WG task, in one patient during RG task and in seven patients during the comprehension task. Diffuse interictal EEG abnormalities predicted a more atypical language representation on fMRI (p = 0.012), which in turn correlated with lower attention (p = 0.036) and IQ/GDQ scores (p = 0.014). Postoperative language reorganization implied shifting towards atypical language representation. Abnormal postoperative EEG (p = 0.003) and surgical failures (p = 0.015) were associated with more atypical language lateralization, in turn correlating with worsened fluency. Neither preoperative asymmetry nor postoperative DTI LI changes in the arcuate fasciculus were observed. Focal lesional epilepsy associated with diffuse EEG abnormalities may favor atypical language lateralization and worse cognitive performances, which are potentially reversible after successful surgery.

Brain Magnetic Spectroscopy Imaging and Hereditary Spastic Paraplegia: A Focused Systematic Review on Current Landmarks and Future Perspectives.

Magnetic resonance spectroscopy (MRS) is a non-invasive neuroimaging technique used to investigate in vivo brain metabolites. MRS could provide a sensitive tool for the study of hereditary spastic paraplegia (HSP) by helping to unveil the underlying biochemical mechanisms and monitoring response to treatment. This focused systematic review aimed to summarize the brain metabolite findings in studies performed in genetically determined HSP. The second aim was to provide a critical analysis and recommendations for well-designed protocols for future studies. Fourteen MRS studies have been analyzed with overall 61 HSP patients, falling within a wide range of age at onset, disease duration, and age at the MRS scan, including children and adults. The genetic diagnosis included several subtypes (SPG2/3/4/5/10/11/28/31/54). SPG11 and SPG54 have been more frequently investigated. The MRS methodology included different MR field strength, not easily comparable spectra areas varying from whole brain to various cortical areas, brain stem and cerebellum sampling. No consistency in disease severity and other outcome measures was observed. The main MRS findings corresponded to the white matter metabolite abnormalities in the corticospinal tracts. In summary, this focused review provides insights on the current knowledge of brain metabolites in HSP and, in particular, in SPG11 and SPG54. Despite the inhomogeneity of the studies to date reported, brain metabolites as assessed by MRS could represent potentially useful diagnostic markers and prognostic indicators of disease progression in HSP. Specific recommendations regarding the MRS technical protocol, CNS area sampling, study design, and applicability of findings are given.

Multimodal MRI Longitudinal Assessment of White and Gray Matter in Different SPG Types of Hereditary Spastic Paraparesis.

Hereditary spastic paraplegias (HSP) are a group of genetically and clinically heterogeneous neurologic disorders. Hereby we describe a relatively large group of patients (pts) affected by HSP studied at baseline (31 pts) and at follow-up (mean period 28.9 ± 8.4 months; 23 pts) with multimodal advanced MRI: high-resolution T1 images for voxel-based morphometry (VBM) analysis, magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI). An age-matched healthy control (HC) group underwent the same neuroimaging protocol in a time schedule matched with the HSP patients. At baseline, VBM showed gray matter (GM) reduction in HSP in the right pre-frontal cortex and bilaterally in the thalami. MRS at baseline depicted in HSP patients compared to the HC group reduction of NAA/Cr ratio in the right pre-frontal region, increase of Cho/Cr ratio in the right pre-central regions, and increase of mI/Cr ratio on the left pre-central area. At cross-sectional follow-up analysis and longitudinal evaluation, no VBM and MRS statistically significant results were obtained. Tract-based spatial statistics (TBSS) analysis showed widespread DTI brain white matter (WM) alterations in patients compared to HC at baseline, which are characterized by reduction of fractional anisotropy (FA) and increase of mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity, as confirmed on cross-analysis of the follow-up dataset. A longitudinal analysis with TBSS in HSP patients did not show significant variations, while upon applying region-based analysis we found increased FA and decreased MD and AD in specific brain WM fiber complex during follow-up. The changes were not correlated with the clinical presentation (pure vs complicated HSP), motor function, and motility indexes or history of specific treatments (botulinum toxin). In conclusion, the cross-sectional analysis of the multiparametric MRI data in our HSP patients confirmed the non-prominent involvement of the cortex in the primary motor regions but rather of other more associative areas. On the contrary, DTI demonstrated a widespread involvement of the brain WM, including the primary motor regions, which was confirmed at follow-up. The longitudinal analysis revealed an apparent inversion of tendency when considering the expected evolution of a neurodegenerative process: we detected an increase of FA and a decrease of MD and AD. These time-related modifications may suggest a repair attempt by the residual central WM fibers, which requires confirmation with a larger group of patients and with a longer time interval.

Acute rejection in kidney transplantation and the evaluation of associated polymorphisms (SNPs): the importance of sample size.

Background Acute rejection (AR) is one of the most frequent complications after kidney transplantation (KT). Scientific evidence reports that some single-nucleotide polymorphisms (SNPs) located in genes involved in the immune response and in the pharmacokinetics and pharmacodynamics of immunosuppressive drugs are associated with rejection in renal transplant patients. The aim of this study was to evaluate some SNPs located in six genes: interleukin-10 (IL-10), tumor necrosis factor (TNF), adenosine triphosphate-binding cassette sub-family B member 1 (ABCB1), uridine diphosphate glucuronosyltransferase family 1 member A9 (UGT1A9), inosine monophosphate dehydrogenase 1 (IMPDH1) and IMPDH2. Methods We enrolled cases with at least one AR after KT and two groups of controls: patients without any AR after KT and healthy blood donors. Genetic analysis on DNA was performed. The heterozygosity (HET) was determined and the Hardy-Weinberg equilibrium (HWE) test was performed for each SNP. The sample size was calculated using the QUANTO program and the genetic associations were calculated using the SAS program (SAS Institute Inc., Cary, NC, USA). Results In our previous preliminary study (sample size was not reached for cases), the results showed that patients with the C allele in the SNP rs1045642 and the A allele in the SNP rs2032582 of the ABCB1 gene had more frequent AR. In contrast, with the achievement of sample size, the trend of the previous data was not confirmed. Conclusions Our study highlights a fundamental aspect of scientific research that is generally presumed, i.e. the sample size of groups enrolled for a scientific study. We believe that our study will make a significant contribution to the scientific community in the discussion of the importance of the analysis and the achievement of sample size to evaluate the associations between SNPs and the studied event.

On the Use of Linear-Modelling-based Algorithms for Physiological Noise Correction in fMRI Studies of the Central Breathing Control.

A full characterization of the physiological behavior of human central chemoreceptors through fMRI is crucial to understand the pathophysiology of central abnormal breathing patterns. In this scenario, physiological noise and activity of interest may be naturally correlated. Here, we examined the adequacy of linear-modelling-based retrospective physiological noise correction for studies of the central breathing control. We focused on the relationship between a nonlinear model of BOLD response, hypothesized to describe neuronal specific activity, and noise modelled by correction algorithms. Analyses were performed on fMRI acquisitions from healthy subjects during a breath hold task. A general linear model including static nonlinearities in the response to end-tidal CO2 was applied to data preprocessed both with and without physiological noise correction. Relations between physiological noise and PETCO2 were explored both with linear and nonlinear measures. Lastly, parametric maps of noise spatial distribution were extracted. Our results evidenced that correction algorithms based on linear modelling remove components that are both linearly and nonlinearly related to end-tidal CO2, whereas uncorrected data showed spurious activations in regions outside gray matter. Thus, despite a correction step is fundamental, these algorithms are shown to be over-conservative approaches to noise correction and need to be adapted to the specific purpose.

Exploring the supra linear relationship between PetCO2 and fMRI signal change with ICA.

The relationships between brain functions and the respiratory system are complex. Disentangling brain activity related to CO2 changes from nonspecific vasoreactivity is a challenge when studying brain activity involved in the control of breathing with fMRI. In this work, we analyzed a dose dependent relationship between arterial CO2 levels and brain response. To accomplish this goal, we developed a gas administration protocol, together with multi-subject ICA and specific nonlinear post-processing analysis. Our results highlighted a supra-linear response to CO2 challenges in brainstem, thalamus and putamen. Results were discussed in the light of current knowledge about the central respiratory network.

Cortical BOLD responses to moderate- and high-speed motion in the human visual cortex.

We investigated the BOLD response of visual cortical and sub-cortical regions to fast drifting motion presented over wide fields, including the far periphery. Stimuli were sinusoidal gratings of 50% contrast moving at moderate and very high speeds (38 and 570 °/s), projected to a large field of view (~60°). Both stimuli generated strong and balanced responses in the lateral geniculate nucleus and the superior colliculus. In visual cortical areas, responses were evaluated at three different eccentricities: central 0-15°; peripheral 20-30°; and extreme peripheral 30-60°. "Ventral stream" areas (V2, V3, V4) preferred moderate-speeds in the central visual field, while motion area MT+ responded equally well to both speeds at all eccentricities. In all other areas and eccentricities BOLD responses were significant and equally strong for both types of moving stimuli. Support vector machine showed that the direction of the fast-speed motion could be successfully decoded from the BOLD response in all visual areas, suggesting that responses are mediated by motion mechanisms rather than being an unspecific preference for fast rate of flicker. The results show that the visual cortex responds to very fast motion, at speeds generated when we move our eyes rapidly, or when moving objects pass by closely.

Relationships Between Morphologic and Functional Patterns in the Polymicrogyric Cortex.

Polymicrogyria is a malformation of cortical folding and layering underlying different cognitive and neurological manifestations. The polymicrogyric cortex has heterogeneous morphofunctional patterns, qualitatively described at magnetic resonance imaging (MRI) by variable severity gradients and functional activations. We investigated the link between abnormal cortical folding and cortical function in order to improve surgical planning for patients with polymicrogyria and intractable epilepsy. We performed structural and functional MRI on 14 patients with perisylvian polymicrogyria and adopted surface-based methods to detect alterations of cortical thickness (CT) and local gyrification index (LGI) compared with normal cortex (30 age-matched subjects). We quantitatively assessed the grade of anatomic disruption of the polymicrogyric cortex and defined its relationship with decreased cortical function. We observed a good matching between visual analysis and morphometric measurements. CT maps revealed sparse clusters of thickening, while LGI maps disclosed circumscribed regions of maximal alteration with a uniformly decreasing centrifugal gradient. In polymicrogyric areas in which gyral and sulcal patterns were preserved, functional activation maintained the expected location, but was reduced in extent. Morphofunctional correlations, evaluated along cortico-cortical paths between maximum morphologic alterations and significant activations, identified an interindividual threshold for LGI (z-value = -1.09) beyond which functional activations were no longer identifiable.

Area Prostriata in the Human Brain.

Area prostriata is a cortical area at the fundus of the calcarine sulcus, described anatomically in humans [1-5] and other primates [6-9]. It is lightly myelinated and lacks the clearly defined six-layer structure evident throughout the cerebral cortex, with a thinner layer 4 and thicker layer 2 [10], characteristic of limbic cortex [11]. In the marmoset and rhesus monkey, area prostriata has cortical connections with MT+ [12], the cingulate motor cortex [8], the auditory cortex [13], the orbitofrontal cortex, and the frontal polar cortices [14]. Here we use functional magnetic resonance together with a wide-field projection system to study its functional properties in humans. With population receptive field mapping [15], we show that area prostriata has a complete representation of the visual field, clearly distinct from the adjacent area V1. As in the marmoset, the caudal-dorsal border of human prostriata-abutting V1-represents the far peripheral visual field, with eccentricities decreasing toward its rostral boundary. Area prostriata responds strongly to very fast motion, greater than 500°/s. The functional properties of area prostriata suggest that it may serve to alert the brain quickly to fast visual events, particularly in the peripheral visual field.

Mathematical rationalization for the renal tubular transport: revised concepts.

The current emphasis on kinetics and in situ control of molecular exchanges, across the tubular membrane, has not been paralleled by corresponding improvements in our understanding of tubular behaviour at the macroscopic level of classical physiology. In this paper, we propose a mathematical rationalization of macroscopic tubular transport by means of a principal transport equation, originating from the law of mass action between substrate and carrier. The other equations, derived from the main one, demonstrate the possibility of distinguishing between transporters with low affinity and high capacity and transporters with high affinity and low capacity. Moreover, our model formalizes both tubular reabsorption and tubular secretion. Regarding the renal calcium handling, our model confirms the two-compartment system proposed by Mioni in 1971, with some important variants, which are in agreement with the fractional reabsorptions of this cation along the tubule, as verified by micro-puncture technique. To obtain the frequency distribution of saturated tubules, we have utilized the infinitesimal analysis method, starting from the equations proposed by Smith in 1943, concluding that all titration curves result from the combined effect of enzymatic approach and anatomical heterogeneity of the nephrons. The theoretical equations included in our manuscript reflect substantial and palpable physiological mechanisms able to suggest diagnosis and therapy of some electrolyte and hormonal disorders. At the end of this paper, we highlight advantages and disadvantages detectable by comparing our mathematical approach with Marshall's and Bijvoet's methods, proposed, respectively, in 1976 and 1984.

Outcomes of Pregnancies After Kidney Transplantation: Lessons Learned From CKD. A Comparison of Transplanted, Nontransplanted Chronic Kidney Disease Patients and Low-Risk Pregnancies: A Multicenter Nationwide Analysis.

BACKGROUND: Kidney transplantation (KT) may restore fertility in chronic kidney disease (CKD). The reasons why maternofetal outcomes are still inferior to the overall population are only partially known. Comparison with the CKD population may offer some useful insights for management and counselling.Aim of this study was to analyse the outcomes of pregnancy after KT, compared with a large population of nontransplanted CKD patients and with low-risk control pregnancies, observed in Italy the new millennium. METHODS: We selected 121 live-born singletons after KT (Italian study group of kidney in pregnancy, national coverage about 75%), 610 live-born singletons in CKD, and 1418 low-risk controls recruited in 2 large Italian Units in the same period (2000-2014). The following outcomes were considered: maternal and fetal death; malformations; preterm delivery; small for gestational age (SGA) baby; need for the neonatal intensive care unit; doubling of serum creatinine or increase in CKD stage. Data were analyzed according to kidney diseases, renal function (staging according to CKD-epidemiology collaboration), hypertension, maternal age, parity, ethnicity. RESULTS: Maternofetal outcomes are less favourable in CKD and KT as compared with the low-risk population. CKD stage and hypertension are important determinants of results. Kidney transplantation patients with estimated glomerular filtration rate greater than 90 have worse outcomes compared with CKD stage 1 patients; the differences level off when only CKD patients affected by glomerulonephritis or systemic diseases ("progressive CKD") are compared with KT. In the multivariate analysis, risk for preterm and early-preterm delivery was linked to CKD stage (2-5 vs 1: relative risk 3.42 and 3.78) and hypertension (RR 3.68 and 3.16) while no difference was associated with being a KT or a CKD patient. CONCLUSIONS: The maternofetal outcomes in patients with kidney transplantation are comparable with those of nontransplanted CKD patients with similar levels of kidney function impairment and progressive and/or immunologic kidney disease.