The former group demonstrated more frequent bowel movement disorders (p < 0.01). The scores correlated negatively with eGFR , positively with albuminuria , Hba1c , and diabetes duration . Faecal calprotectin levels did not differ between DKD groups significantly. The most commonly reported histopathological findings of enteric mucosa were infiltration with eosinophils, lymphocytes, plasmacytes, the presence of lymphoid follicles, and lymphoid aggregates. Conclusion: The progression of DKD is positively correlated with gastrointestinal symptoms; however, more research is needed to clarify the causal relationships of the gut-kidney axis in T1D.(1) Background: Little research is conducted on the link between diabetic kidney disease (DKD) progression and diabetic gastroenteropathy in type 1 diabetes (T1D). (2) Methods. We performed a cross-sectional study with 100 T1D patients; 27 of them had progressive DKD, defined as an estimated glomerular filtration rate (eGFR) decline ≥3 mL/min/year or increased albuminuria stage, over a mean follow-up time of 5.89 ± 1.73 years. A newly developed score with 17 questions on gastrointestinal (GI) symptoms was used. Faecal calprotectin was measured by ELISA. Lower GI endoscopies were performed in 21 patients. (3) Results: The gastrointestinal symptom score demonstrated high reliability (Cronbach’s α = 0.78). Patients with progressive DKD had higher GI symptom scores compared to those with stable DKD ( T1D is associated with increased morbidity and mortality, mainly due to its vascular complications, including diabetic kidney disease (DKD), which is the main reason for end-stage renal disease (ESRD) in the developed world ., and coDiabetic gastroenteropathy is a condition characterized by various oesophageal, gastric, intestinal, and anorectal symptoms caused by diabetes ,4. GastrGastrointestinal symptoms are insufficiently recognised and investigated, both in clinical practise and research. Specifically, endoscopic examination of the gastrointestinal tract might be avoided by T1D patients despite indications due to the increased risk of hypoglycemia and other complications . IndirecTo summarize, diabetic gastroenteropathy as assessed by gastrointestinal symptom scores, instrumental examinations, and biomarkers  remains a little studied factor predisposing to or potentiating the progression of DKD. However, such data are of extreme importance for clinical practice, as they could promote the development of novel treatment and prevention options for DKD .To fill this gap, the aim of this work was to analyse the prevalence of gastrointestinal symptoms, history of previous gastrointestinal conditions, data from endoscopic gastrointestinal investigations, levels of faecal calprotectin in patients with T1D, and different velocities of DKD progression in a cross-sectional study. This study is a part of the longitudinal LatDiane study, initiated in 2013 . LatDiane recruits adult patients with T1D diagnosed before the age of 40 with insulin treatment initiated within one year of diagnosis and C-peptide levels below 0.3 nmol/L. Patients with a history of chronic kidney disease apart from DKD are excluded from LatDiane. Follow-up visits and re-assessments of the status of complications of diabetes take place every three years. Currently, more than 400 patients have been recruited, with approximately 150 having attended one or more follow-up visits. Study protocol includes recording diabetes and other disease histories, basic clinical and anthropometric investigation, collection of blood samples for preparation of serum and plasma and DNA extraction, collection of urine, as well as assessment of dietary and physical activity habits, socioeconomic factors, and psychologic condition with the help of questionnaires ,22,23,24Recruitment of this study participants, biobanking, and sample storage were performed in accordance with the procedures of the Genome Database of the Latvian population  and are Recruitment for this study took place between 15 January 2021 and 31 August 2022 in Latvia, Riga, Pilsoņu 13 str., building 10 . Information about this study was disseminated via the webpage and social media of the University of Latvia.Inclusion criteria for this study were: T1D duration of at least 8 years and available data on progression of DKD  .As for exclusion criteria, they were: pregnancy, subjects with a history of inflammatory bowel disease (Crohn disease or Ulcerative colitis), coeliac disease, acute intestinal infection within 2 months of the planned faecal collection, asymptomatic coeliac disease (detected via screening of serum transglutaminase IgA antibodies), clinical signs of acute inflammation, and fever.On the study day, patients were investigated for the collection of anthropometric measures, questionnaires were filled out, blood samples were collected, and subjects received instructions and vials for the collection of the faecal sample.2). We also measured blood pressure. Patients with systolic blood pressure ≥ 140 mmHg (18.7 kPa) or diastolic blood pressure ≥ 90 mmHg (12.0 kPa) or a history of antihypertensive drug usage were defined as having arterial hypertension.Clinical investigation included assessment of weight and height to calculate the body mass index /height (m)Smoking was self-reported in the questionnaire; the “smokers” group referred to patients currently smoking at least one cigarette per day. Assessment of cardiovascular disease (CVD) and complications of diabetes, such as retinopathy, neuropathy, and DKD, was based on medical files. We defined CVD as a history of acute myocardial infarction, coronary bypass/percutaneous transluminal coronary angioplasty stroke, amputation, or peripheral vascular disease. The albumin-to-creatinine ratio in morning spot urine samples was used for the definition of albuminuria at each study visit during the follow-up. The estimated glomerular filtration rate (eGFR) was calculated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).2, dialysis, or kidney transplantation.ESRD was defined as eGFR < 15 mL/min/1.73 m2/year [Progressive DKD was defined as an eGFR decline exceeding 3 mL/min/1.73 mThe blood samples were collected via venous puncture. Blood samples and morning spot urine samples were sent for assessment of clinical markers  to a certified clinical lab.Except for several patients who could collect the stool sample during the recruitment visit, stool samples were collected within two weeks after blood collection and assessment of gastrointestinal symptoms. Participants collected their faecal samples at home using sterile collection tubes without buffer (the collection date and time were marked). Within 24 h samples were delivered to the laboratory for calprotectin measurement in unfrozen samples. ® Calprotectin Elisa kit  in a certified clinical lab. Faecal calprotectin was measured by the AlegriaHaelicobacter pylori infection; lower gastrointestinal disease was defined as hemorrhoids, appendicitis, coeliac disease, irritable bowel syndrome, and lactose intolerance; and liver and pancreas disease were defined as histories of fatty liver, pancreatitis, viral hepatitis, gallstones, diverticulitis, and irritable bowel syndrome. The history of gastrointestinal disease was self-reported via an assisted study questionnaire in the majority of cases, and this information was supported by medical files. For reporting in this paper, we defined upper gastrointestinal disease as gastritis/duodenitis, peptic ulcer, gastroesophageal reflux disease, gastroparesis, diaphragmal hernia, and A newly developed scale questionnaire for assessment of gastrointestinal symptoms was filled out during this study visit. It was elaborated on the basis of the diabetes and bowel symptom questionnaire , which pH. pylori was identified by rapid urease testing (RUT) and histological staining (Giemsa). Patients who had increased calprotectin levels and persistent symptoms of gastrointestinal disorders in the last 2 months were referred to a gastroenterologist for evaluation of indications for endoscopic examination (colonoscopy and/or endoscopy according to indications). As indications for endoscopy, the following criteria were used: unexplained weight loss, clinical suspicion of inflammatory bowel disease, unclear abdominal pain, unclear anaemia , unclear diarrhoea, constipation or changing bowel movements, bowel movements with mucus admixture, family history of inflammatory bowel disease or colorectal cancer, history of polyps, elevated faecal calprotectin >50 µg/g, or as a screening colonoscopy for subjects over the age of 50 ,28,29. OPatients who consented to lower endoscopy received recommendations from endocrinologists for preparation for the procedure based on international recommendations ,30,31,32Descriptive statistics were performed for all study variables. For group variables, we presented numbers and percentages from the whole study sample. We used a one-sample Kolmogorov-Smirnov test and the graphical presentation of data by the histogram to check the normality of this study variables. As all the continuous variables were distributed differently than normal, we presented medians and interquartile ranges (IQR). We performed the univariate analysis to assess the difference in socio-demographic variables between this study groups (we used the Chi-square test for the group variables and the Mann-Whitney test for continuous variables). We calculated the mean value from the 17 questions of the gastrointestinal symptom score to assess the mean frequency and intensity of all investigated gastrointestinal symptoms, as well as the mean value of the frequency of use of medications. The Cronbach Alpha test was applied to check the reliability of this scale. In addition, we evaluated the answers to questions about upper and lower gastrointestinal disease, history of liver and pancreatic diseases, history of gastrointestinal malignancy, and history of abdominal surgery. We investigated the difference between those with stable and progressive DKD in gastrointestinal symptoms (Cramer’s V test), symptom intensity (Mann-Whitney test), use of medications (Mann-Whitney test), and presence and history of diseases (Chi-square test). p values < 0.05 were considered statistically significant. A Spearman correlation was performed to identify the relationship between markers of kidney disease and demographic and blood/urine parameters. The We built multiple logistic regression models to assess the association between the progression of DKD and gastrointestinal symptoms. We adjusted the model for the variables that displayed statistical significance in the univariate analysis or had clinical relevance. The full adjustment set included sex, diabetes duration, HbA1c, and BMI.2. The mean follow-up time in the cohort is 5.89 ± 1.73 years. Most of the participants were non-smokers (63%), and they had hypertension (53%). The mean duration of diabetes was 24.38 ± 11.92 years, and the mean HbA1c was 8.28 ± 1.74%. 52 (52%) of subjects had retinopathy, 27 (27%) had autoimmune thyroid disease, and 16 (16%) had CVD. Study groups (with stable DKD disease and with progressive DKD) differed by smoking (more smokers among those with progressive DKD), hypertension (more patients with hypertension among those with progressive DKD), length of diabetes (longer history of diabetes for patients with progressive DKD), retinopathy, HbA1c, CVD, eGFR, albuminuria, serum bilirubin, blood haemoglobin concentration, and erythrocyte counts. The level of calprotectin in faeces and serum CRP did not differ between the groups of patients with progressive DKD and patients with stable DKD statistically significantly  with a mean age of 42.59 ± 13.18 and a mean BMI of 25.98 ± 4.69 1 kg/mficantly . Moreovep = 0.019). In addition, 14 (52%) of patients with progressive DKD had bowel movement disorders, versus 16 (22%) in patients with stable DKD (p < 0.01) . Patients with progressive DKD had higher gastro-intestinal symptoms scores  compared < 0.01) .p = 0.50 and p = 0.35, respectively). There was no difference between groups in the history of liver and pancreatic diseases (p = 0.74) or in the history of gastrointestinal malignancy (p = 0.10). The history of abdominal surgery was more frequent in patients with progressive DKD at the significance level of p = 0.07. There were no statistically significant differences between DKD patients with progressive DKD and patients with stable DKD in their use of medications for gastrointestinal disorders (p = 0.54). There was no statistically significant difference between the patients with progressive DKD and patients with stable DKD on previous upper and lower gastrointestinal disease (p = 0.001), weight , blood erythrocyte counts , and blood haemoglobin  and positively with albuminuria , Hba1c , and diabetes duration .We investigated correlations between the gastrointestinal symptom score and several clinical markers in this study sample. The scores correlated negatively with eGFR . The association remained significant when the model was adjusted for sex and BMI. However, the association was no longer significant when the model was adjusted for sex, BMI, diabetes duration, and HbA1c, with diabetes duration remaining the only significant predictor of DKD , p = 0.014) in the model and HbA1c demonstrating association at a significance level of 0.075 . The results of the logistic regression analysis are summarised in In univariate regression analysis, higher scores in gastrointestinal symptoms were associated with higher odds of DKD progression , Prevalence of indications for colonoscopy did not differ between the patients with and without DKD progression.From the 47 patients who were selected to undergo colonoscopy, 13 had progressive DKD and 34 did not . Only 21 patients (4 patients with progressive DKD and 17 patients with stable DKD) accepted the invitation and went through the procedure. The reasons for non-acceptance of the invitation included a complicated preparation procedure for the colonoscopy with the necessity of fasting and intensive glucose control, a fear of hypoglycemia, and a fear of complications during anaesthesia. Many patients refused to undergo the investigation because of their poor health status due to complications of diabetes and co-morbidities. Among patients who underwent the endoscopic examination, the most frequent indications for endoscopic examination were abdominal pain , bowel movement disorders , and elevated faecal calprotectin (>50 µg/g) .H. pylori, visible on special staining. Most of the gastric lesions were minor endoscopic findings  had abnormal macroscopic findings and were analysed for H. pylori infection by rapid urease tests (RUT). None of the patients had a positive RUT; however, histopathology identified two patients with findings . Of the In total, 21 colonoscopies were performed. Five (24%) of the colonoscopies performed showed abnormal macroscopic findings . The mosThe main finding of our study is that in patients with T1D and progressive DKD, the frequency and severity of gastrointestinal symptoms are higher compared to patients with stable kidney markers, as assessed by the gastrointestinal symptom score. The link between progressive DKD and diabetic gastroenteropathy was additionally confirmed by statistically significant correlations between gastrointestinal symptom scores, eGFR, and albuminuria, as well as in the logistic regression models. 2 in the group of progressive DKD in our study. Our findings cannot be directly compared to previous data due to the deficiency of studies on the association of diabetic gastroenteropathy with progressive DKD in T1D. We only found one paper by D’Addio and colleagues reporting higher scores of gastrointestinal symptoms in patients with T1D and DKD. However, that paper investigated diabetic gastroenteropathy only in patients with ESRD compared to healthy individuals and did not cover subjects with DKD or the initial stages of chronic kidney disease [We demonstrate in our work that gastrointestinal disorders start to manifest already in the initial stages of DKD progression, as the median eGFR is 72.8140.72–105.27) mL/min/1.73 m disease . More pr disease ,10,33,345.27 mL/mIn contrast to some previous studies in T1D reporting higher calprotectin levels in patients with DKD ,11,35, wOur study’s limitations include a relatively low number of subjects, especially in the group of progressive DKD, which might have influenced the results. Further, the cross-sectional nature of this study does not allow us to evaluate the causal relationship between symptoms of diabetic gastroenteropathy and DKD. Other limitations include the self-evaluation of gastrointestinal symptoms in this study and the self-reporting of previous gastrointestinal diseases in a subset of patients due to unavailable central medical records in Latvia. We also did not perform an evaluation of autonomic neuropathy, which might have influenced the gastrointestinal symptoms; however, to our opinion, these data would not alter our conclusions or the clinical value of our study due to the availability of treatment for autonomic neuropathy nowadays. Lack of endoscopic evaluation in all study participants is another limitation. However, all study participants did not have indications for endoscopy. In addition, not all of the invited patients responded to the invitation due to complicated preparation procedures, fear of hypoglycemia, fear of complications during anaesthesia, or generally poor health status. The major strength of this study is the analysis of gastrointestinal symptoms in patients with different rates of progression of DKD, in contrast to previous studies addressing either patients with T1D generally or patients with T1D and ESRD in comparison to healthy subjects. In addition, we have demonstrated results on histological colon biopsies in 21 patients with T1D, previously described only in one study .To conclude, in patients with T1D and progressive DKD, the frequency and severity of gastrointestinal symptoms are higher compared to patients with stable kidney markers, as assessed by gastrointestinal symptom scores. Moreover, gastrointestinal symptom scores correlate with kidney markers. Further research is needed to clarify the causal relationships of the gut-kidney axis in T1D.


This study aimed to investigate the effect of fluid bolus administration during epidural anesthesia (coload) in female dogs scheduled for elective cesarean section (CS). Hypotension is one of the most common complications of epidural (EA) and spinal (SA) analgesia, and in the case of cesarean section, it may pose a significant risk for placental perfusion and subsequent fetal vitality and puppy survival.2, SpO2, systolic, diastolic and mean arterial blood pressure were measured at three time points  in dams; vitality  and umbilical cord blood parameters  in newborns.Pregnant bitches scheduled for elective CS underwent EA with (treatment group) or without (control group) intravenous fluid bolus administration. The following parameters were measured and compared between both groups: HR, RR, etCOp < 0.05) with significantly fewer episodes of hypotension. Additionally, puppies in the treatment group received higher scores in the 5-min (7.91 ± 1.67 vs. 6.74 ± 2.20) and 20-min (9.38 ± 0.87 vs. 8.39 ± 2.50) assessments without the favorable effect on umbilical blood gas parameters.The results indicated that crystalloid coloading increased maternal systolic, diastolic, and mean blood pressure (treatment vs. control group, 101.46 ± 9.18, 48.01 ± 13.47, and 67.07 ± 13.15 mmHg vs. 80.68 ± 7.29, 36.52 ± 8.75, and 180 52.30 ± 7.77, Based on the obtained results, it can be stated that crystalloid coload offers an effective option in cases of hypotension during cesarean section, with clear benefits for both mothers and newborns. Hypotension is one of the most common complication of epidural (EA) and spinal (SA) analgesia resulting from arterial vasodilation rather than decreased venous return and cardiac output, leading to decreased vascular resistance –4.It has been reported that during cesarean section (CS), hypotension following EA can occur in up to 80% of women –4; similPrevious studies have proposed multiple strategies for preventing hypotension after EA in pregnant women –33. VariInterestingly, despite the similar risk of epidural-induced hypotension in veterinary and human patients, treatment strategies for dogs have received little attention until date. Bosman et al. studied colloid (HES 6%) loading in healthy, non-pregnant dogs . Fluids During CS procedures, the risk of hypotension is high, and can be caused by anesthetic, sedative, and analgesic drugs, as well as the patient's dorsal recumbency during surgery, traction on ovarian pedicles, or sudden removal of the uterus from the abdomen. The combined effects of these factors can lead to severe hypotension. To minimize this risk, one of the recommended strategies is to avoid epidural-induced hypotension , 36.Since there are no references to colloid/crystalloid preload or coload dosing in dogs and there is a wide variation in doses administered to humans, the authors decided to evaluate the effectiveness of crystalloid coload in preventing intraoperative hypotension in dogs undergoing CS and evaluate whether fluid administration would have a beneficial effect on newborn puppy outcomes evaluated based on the Apgar scoring system and umbilical cord blood gas results.The study protocol was approved by the II Local Ethics Committee for Animal Experiments No 047/2020). The twenty four client-owned bitches of different breeds scheduled for elective cesarean section were enrolled in this study. Bitches with a previous history of ongoing health concerns unrelated to pregnancy or developing health problems during pregnancy were excluded from the study. The cardiovascular parameters were checked on admission: heart rate, thorough auscultation of heart sounds and rhythm, capillary refill time, and mucous membrane color. No abnormalities were found. The dogs were healthy, and without any systemic diseases based on routine clinical, hematological, and biochemical examinations. The mean body weight of the females was 14.6 kg (3–46 kg), and the mean age was 4.1 020. The  years. C®, 10 mg/ml B. Braun Melsungen AG, Germany, initial dose 4 mg/kg, to effect) and the dams were intubated. General anesthesia was maintained with isoflurane  in oxygen. Subsequently, the dogs were positioned in sternal recumbency with the pelvic limbs extended cranially. After aseptic preparation of the skin, a spinal needle was introduced into the lumbosacral space and 3 mg/kg lidocaine was administered . Correct placement of the needle was confirmed by the presence of a distinct ‘popping sensation’ as a result of penetrating the ligamentum flavum, the lack of resistance to injection, and the absence of cerebrospinal fluid and blood in the needle hub. Intravenous fluids  were infused at a rate of 5 mL/kg/h during anesthesia in all dogs. An IV bolus of fluid  was administered when hypotension occurred. Furthermore, in the treatment group (group T), the dams received 15 mL/kg of Ringer Lactate Solution , starting at the time of epidural blockage (coload) and administered within 15 min. Throughout the infusion and surgical procedure, females were carefully monitored for signs of fluid overload .The dams were randomly assigned to one of two groups: C, control group (without fluid load) and T, treatment group (with fluid load). All females underwent the same standard anesthetic protocol. The bitches received a single dose of meloxicam  at least 30 min prior to the surgical procedure. The dams were preoxygenated for 3–5 min, and without premedication, general anesthesia was induced with propofol (Propofol-Lipuro2 (etCO2), oxygen saturation (SpO2), systolic, diastolic and mean arterial blood pressure , minimal alveolar concentration of isoflurane (MAC) and esophageal body temperature (T), .After transfer to the surgical theater and complete instrumentation, monitoring was started and the following parameters were continuously monitored and noted at 2 min intervals: heart rate (HR), respiratory rate (RR), end-tidal COTo compare hemodynamic and respiratory changes over time, three time points were considered: T1, immediately before the skin incision, T2, after the last puppy removal, and T3, at the end of surgery. The values were obtained as the mean of 3-4 consecutive measurements observed in each animal during time points T1, T2, and T3.® 3/0, B. Braun Aesculap Chifa Sp. z o.o., Nowy Tomyśl, Poland). The abdominal cavity was flushed with warm saline before closing. The abdominal wall, subcutaneous tissue, and skin were routinely closed using a synthetic absorbable material.The surgical procedure was carried out with a standard midline approach. After the was removed uterus from the abdominal cavity, the incision was made on the ventral or dorsal surface of the uterine body. After removal of the puppies', the uterus was sutured with a single continuous pattern , and thereafter at 5 and 20 min. Finally, each newborn underwent a full clinical evaluation prior to discharge (~90 min after the end of the surgery). The following reference ranges for AS were used for Apgar score: HR >220 bpm (2 points), 180–220 bpm (1 point) and <180 (0 points); RR >15 breaths per minute (2 points), 6–15 (1 point) and <6 (0 points); irritability reflex detected after gentle compression of the tip of a paw was evaluated based on the degree of reaction: crying and quick leg retraction (2 points), weak leg retraction and no or just weak vocalization (1 point), and no leg retraction and vocalization (0 points); spontaneous movement of a newborn: strong movement (2 points), weak movement (1 point), and absent (0 point); mucous membrane color: dark pink (2 points), light pink (1 point) and pale to cyanotic (0 point). The total points received provided the final AS: 7–10, no distress, healthy newborns; 4–6, moderate distress, weak newborn and 0–3, severe distress, critical newborns .t-test. Intra-group differences between considered time points were measured using analysis of variance (ANOVA) for dependent variables. Apgar scores were compared between the groups using the U Mann–Whitney test.Statistical analysis included descriptive statistics and normality testing using the Kolmogorov–Smirnov test with Lilliefors correction. Non-parametric tests were performed when the results did not follow a normal distribution. Pre- and intraoperative parameters of the dams and umbilical blood gas parameters were compared the between groups using p = 0.55) in the total anesthetic time (from the induction to the end of the surgery) between the control (53 ± 15.12 min) and treatment (55.22 ± 12.08 min) groups. Similarly, isoflurane demand was comparable in all investigated females . No signs of fluid overload were observed in any of the mothers who received fluid coload.The mothers in both groups did not differ in terms of mean age, body weight, preoperative respiratory rate (RR), body temperature, dose of propofol required for the induction of general anesthesia, and number of pups per litter . The basp < 0.05) with significantly fewer episodes of hypotension .Intraoperative parameters such as HR, RR, etCO2 and body temperature were also similar in all females. In contrast, blood pressure differed between the groups. In the control group, the mean values of SBP, DBP and MBP were 80.68 ± 7.29, 36.52 ± 8.75, and 52.30 ± 7.77 mmHg, respectively. Up to 91.6% of the investigated females developed hypotension, defined as a mean arterial pressure below 60 mmHg. In dams who received fluid coload, blood pressure was higher , or between the investigated groups at all considered time points. In the treatment group, MBP dropped slightly from T1 (70.00 ± 20.67 mmHg) to T3 (64.47 ± 10.57 mmHg), nevertheless it was still higher than that in the control group at each of the investigated time points.The number of puppies included in the study was 42 in the control group and 33 in the treatment group. Stillborn puppies and those with failed umbilical cord blood collection were excluded from the experiment. No differences were found in any umbilical blood gas parameters in the newborns of either group . HoweverThe present study, for the first time, showed the efficacy of crystalloid fluids coloading in dogs undergoing CS in preventing epidural-induced hypotension. Our results showed, that both SBP and MBP were significantly higher in the treatment group that received coload fluid treatment than those in the control group without additional fluid administration. Furthermore, episodes of hypotension were significantly less frequent in dams that received a fluid bolus (33 vs. 91.6%). Similar improvement in blood pressure have been widely reported in human medicine –20, 29. We found that the investigated parameters of the umbilical cord blood gas analysis were similar in both the treatment and control groups. However, a comprehensive comparison of the obtained results poses some difficulty. Available data on the umbilical cord blood gas evaluation in dogs are limited. To the best of our knowledge, no reports have been published on the effect of maternal fluid infusion during anesthesia on newborn puppies' condition. Only human studies have reported no pH changes in umbilical cord blood after crystalloid or colloid preload administration to the mother before spinal anesthesia , 33, 40.p > 0.05). However, in the following evaluations of newborn vitality at 5 and 20 min, significant differences were found in AS between the treatment and control groups. The newborns of the treatment group had a higher AS both at 5 and 20 min than the puppies born from the dams of the control group . A possible explanation for this could be the results described by Hollmen et al. for humans , increased maternal blood pressure. Crystalloid coload was also beneficial for the vitality of the puppies and increased ASs at 5 and 20 min without a favorable effect on blood gas parameters. However, it was not possible to prevent maternal hypotension completely. Therefore, despite the administration of fluid bolus, maternal blood pressure should be carefully monitored throughout surgery and clinicians must be prepared for rescue hypotension treatment during CS.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The animal study was reviewed and approved by Bioethics Committee of the Hirszfeld Institute of Immunology and Experimental Therapy. Written informed consent for participation was not obtained from the owners because this study included client-owned bitches scheduled for elective cesarean section. The cesarean section was decided independently of this research, solely on clinical indications , the previous dystocia in history, or breed-related factors .AA: conceptualization, data collection, data evaluation, statistical analysis, and writing of the manuscript. MO: conceptualization, data collection, data evaluation, and reviewing and editing the paper. WN and ZK: supervising the study and reviewing and editing the paper. All authors contributed to the article and approved the submitted version.


Despite overwhelming epidemiological evidence, the contribution of hypertension (HTN) to heart failure (HF) development has been undermined in current clinical practice. This is because approximately half of HF patients have been labeled as suffering from HF with preserved left ventricular (LV) ejection fraction (EF) (HFpEF), with HTN, obesity, and diabetes mellitus (DM) being considered virtually equally responsible for its development. However, this suggestion is obviously inaccurate, since HTN is by far the most frequent and devastating morbidity present in HFpEF. Further, HF development in obesity or DM is rare in the absence of HTN or coronary artery disease (CAD), whereas HTN often causes HF per se. Finally, unlike HTN, for most major comorbidities present in HFpEF, including anemia, chronic kidney disease, pulmonary disease, DM, atrial fibrillation, sleep apnea, and depression, it is unknown whether they precede HF or result from it. The purpose of this paper is to provide a contemporary overview on hypertensive HF, with a special emphasis on its inflammatory nature and association with autonomic nervous system (ANS) imbalance, since both are of pathophysiologic and therapeutic interest.  Hypertension (HTN) is the leading cause of cardiovascular disease and premature death worldwide, which largely surpasses other important factors of mortality such as smoking and metabolic diseases ,2,3. HTNDespite overwhelming epidemiological evidence, the contribution of HTN to HF development has been undermined in current clinical practice. This is due to the fact that approximately half of HF patients have been labeled as suffering from HF with preserved left ventricular (LV) ejection fraction (EF) (HFpEF), with HTN, obesity, and diabetes mellitus (DM) being considered virtually equally responsible for its development . HoweverThe purpose of this paper is to provide a contemporary overview on hypertensive HF (HHF), defined as the presence of HF symptoms and signs in a patient with a history of HTN and elevated systolic blood pressure (BP) at presentation (≥130 mmHg)  in the aThe pathophysiological mechanisms responsible for HTN are complex, and act on a genetic background. Further, the probability of developing HTN increases with aging, due to the progressive stiffening of the arterial wall caused by, among other factors, slowly developing changes in vascular collagen and increases in atherosclerosis .The mosaic theory of hypertension, which has prevailed to the present day, proposes that HTN pathophysiology is multifaceted. Accordingly, HTN is caused by multiple factors, including genetics, environment, adaptive, neural, mechanical, and hormonal perturbations, which intertwine to elevate BP ,26. OverOne of the recently proposed pathways for BP elevation involves the gut microbiota. The microbiota and the brain  communicate via various routes including the immune system, the vagus, and the enteric nervous system. Many factors can influence microbiota composition in early life, including infection, type of birth delivery, antibiotics, nutritional provision, environmental stressors, and host genetic factors. On the other hand, microbial diversity decreases with aging .There is compelling evidence that shifts in gut microbiota play a key role in BP regulation. In this regard, intestinal bacteria synthesize metabolites, the most important being short-chain fatty acids (SCFAs), vasoactive hormones, trimethylamine (TMA) and trimethylamine N-oxide (TMAO) and uremic toxins, such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS)  Figure  29]. Mi. Mi29]. In the gut itself, hypertensive stimuli cause gut microbial dysbiosis, gut barrier weakening, and inflammation . WeakeneFinally, there is bidirectional interaction between the microbiota and the renin angiotensin system (RAS), a major determinant of BP levels. Gut bacteria and their metabolites modulate gastrointestinal and systemic RAS, and at the same time, changes in the intestinal habitat caused by alterations in RAS may shape microbiota metabolic activity and composition . Thus, aThe effect of the aforementioned perturbations on BP levels is also affected by genetic factors. Several genes have been identified to play a role in the pathophysiology of HTN, including those involved in the renin–angiotensin–aldosterone system (RAAS), catecholamine/adrenergic system, renal kallikrein–kinin system, epithelial sodium channel, adducin, and those involving lipoprotein metabolism, hormone receptors, and growth factors . Genome-HTN is characterized by chronic LV pressure overload and increased intravascular volume, both affecting the LV structure and function . NeverthHowever, doubt has been raised that the previously mentioned sequence of events is typical in hypertensives, based on the following arguments: (a) concentric LVH may not be the most frequent geometric pattern, and is less commonly seen than eccentric LVH in studies enrolling hypertensive subjects ; (b) theHowever, recent studies have provided compelling evidence that cardiac remodeling is a dynamic process, with phenotypic transitions occurring frequently regardless of the presence or absence of CAD. For example, in the Swedish Heart Failure Registry (SwedeHF), the proportion of patients with HFpEF (approximately 70% were hypertensive) that worsened during follow-up (from HFpEF to HF with mid-range LVEF [HFmrEF] or HF with reduced LVEF [HFrEF]) was 31.2% in the absence of baseline CAD, 33.1% in the presence of baseline CAD, and 57.2% in the case of interim CAD . SimilarWe have developed and promoted the concept of the HF spectrum across phenotypes, according to which each HF phenotype results from a patient-specific trajectory wherein the heart remodels towards concentric LVH, eccentric LVH, or a combination of both ,51,52. WHTN evolves over the lifespan, from predominant sympathetic nervous system (SNS)-driven HTN with elevated mean BP in early and mid-life to a late-life phenotype of increasing systolic and falling diastolic BP, associated with increased arterial stiffness and aortic pulsatility . HoweverThe autonomic dysregulation observed in HTN escalates in HHF. SNS overactivity has long been appreciated as a compensatory mechanism initially supporting the failing heart, which, however, in the long term, triggers a sequence of unfavorable remodeling processes, causing HF progression and the occurrence of major cardiovascular events ,58. The adverse cardiac effects of SNS overactivity in HF have been predominantly studied in dilated LV with eccentric LVH, in which it manifests as an increase in norepinephrine spillover from the cardiac sympathetic endings, leading to chronic β-adrenergic receptor (AR) hyperstimulation and maladaptive GRK2 upregulation (GPCR kinase 2) , therebySNS overactivity is also present in HF with nondilated hearts and lack of eccentric LVH. In this regard, earlier studies suggested that the SNS overdrive which is present in essential HTN is augmented in HF without eccentric LVH ,63. ThesIn contrast to SNS overactivity, there is attenuation of the parasympathetic nervous system (PNS) activity and its physiological effects in HF , includiIn patients with HF, treatment of HTN has been unanimously recommended, but BP targets have been inappropriately defined . HoweverIn the major outcome trials of hypertension, comparison of BP reduction with antihypertensive medications against placebo or no treatment, incident HF was the outcome that showed the largest intergroup risk reductions ,74,75. EIt has been suggested that there is a J-shaped curve describing an inverse relationship between BP and cardiovascular complications, and that this association is more pronounced in patients with preexisting CAD, HTN, or LVH . HoweverThe target BP which should be pursued with medical treatment was evaluated in the pivotal SPRINT , which demonstrated that among patients at high risk for cardiovascular events in the absence of DM, targeting a systolic BP < 120 mmHg , as compared with < 140 mmHg , decreases the incidence of the primary outcome  . NeverthThe results of SPRINT have been confirmed in several subsequent investigations. which demonstrated a significant and direct dose–response between systolic BP levels and ischemic heart disease risk across all systolic BP exposure values (100–200 mmHg), without evidence for a J-shaped curve ,81.According to the 2018 ESC/ESH guidelines, in hypertensive patients with HF, BP-lowering treatment should be considered if an individual’s BP is ≥140/90 mmHg, and systolic BP should be lowered to a range of 120–130 mmHg .Although BP is a continuous and dynamic variable, a single or average BP value has been used for BP monitoring in clinical practice and HTN studies. To overcome this limitation, it has been recommended that doctors should pursue every point of BP monitoring instead of measuring a single value of BP . In thisBased on the above, we believe that a systolic BP target range of 110–130 mmHg with a TTR > 75% should be pursued in all HHF patients regardless of LVEF, provided it is well tolerated. These BP targets may also be applied in elderly HHF patients, as well as in those with coexistent DM  or kidneThe drugs used in the management of HF, except for diuretics, have both cardioprotective and blood pressure-lowering properties . RAASi, that is, ACEi, ARBs, sacubtril/valsartan (ARNI), and MRAs, effectively reduce BP in hypertensive patients . The afoSteroidal MRAs, such as spironolactone and eplerenone, have proved effective in patients with HF, resistant HTN, or CKD . HoweverIn addition to the beneficial effects on the heart, ACEi/ARB, ARNI may slow progression to kidney failure, and thus they are appropriate for initial therapy for managing HHF, especially, and coexistent DM . Fineren2 had a reduced daytime and night-time SBP according to 24 h ambulatory blood pressure monitoring [Finally, as many patients with HHF and DM may manifest a resistant form of HTN, the use of ARNI instead of an ACEi/ARB together with an MRA may be considered. If BP remains elevated, antihypertensive drugs with complementary mechanisms of action and lack or minimal negative inotropy  should be progressively added to lower BP . Subgrounitoring .The SGLT-2i block the sodium–glucose cotransporter 2, which is located on the apical membrane of the proximal convoluted tubules, and therefore target glucose reabsorption  101,102102. The Recent clinical trials have reported that SGLT-2i have a beneficial effect on BP, which is not just an acute effect of treatment initiation, but has a long-term impact on both systolic and diastolic BP . Further+ coupled with glucose and restore renal O2 demand, diminishing neuroendocrine activation [2+ available to mitochondria, thus enabling the synthesis of heme in erythroid precursors and ATP in cardiomyocytes [In addition to HTN, SGLT-2i have proved tremendously effective in reducing morbidity and mortality in HF patients irrespective of LVEF and diabetic status ,112. Regtivation . Alternamyocytes . BBs lower BP as effectively as other major antihypertensive drugs and have solid documentation in preventing cardiovascular complications . BBs canAlthough BBs have proved to be lifesaving in HHF with eccentric LVH , they ha+/K+/2Cl− symporter at the ascending limp loop of Henle, have the most potent diuretic effect, promote excretion of sodium and chloride , and form the backbone of diuretic therapy in congestive HF [Loop diuretics, which inhibit the Nastive HF . Adequat+/Cl− symporter in the distal convoluted tubule, leading to decreased sodium and water reabsorption. They may prescribed for patients with HHF following decongestion instead of loop diuretics due to (a) their efficacy and low side effect profile; (b) their synergistic effect when combined with other antihypertensive agents; and (c) their counteraction of salt and fluid retention caused by other antihypertensive agents [Thiazide diuretics are most commonly used to treat HTN, although they can be adjuncts in HF management on top of loop diuretics in patients with diuretic resistance . They ine agents .The optimal time frame from initiation of antihypertensive therapy to attaining the levels of BP control that influence cardiovascular outcomes is not well defined. Overall, a series of landmark trials in hypertensive patients and additional cardiovascular risk factors collectively support the prompt achievement of BP control, ideally within 1–3 months .The main obstacles to up-titration of medications in HF patients include a low BP, impaired renal function, electrolyte imbalance, and drug intolerance, which are frequently encountered during optimization of HF medications. However, the presence of elevated BP in HHF as well as the renoprotective effects of finerenone, which rarely causes early hyperkalemia , allows p < 0.001) [A majo© iss©e impeding ©he implementation of optimal medical treatment of HTN and HF is poor patient adherence to the prescribed drugs . In this< 0.001) . Many neExercise training is internationally recommended for patients with HF, regardless of LVEF . OptimalAs the gut microbiota and their metabolites may contribute to HTN development, they represent a reasonable treatment target . Since tAs increased SNS and decreased PNS activities are associated with HTN and HF, the neuromodulatory therapies of renal denervation (RDN) and vagus nerve stimulation (VNS) have received recent attention . CatheteThere is no doubt that in most patients with HF, many morbidities coexist (multimorbidity). This is partly because HF patients are elderly, and the prevalence of multimorbidity dramatically increases with age . In this regard, as the prevalence of several of these morbidities is high in the community, their coexistence in elderly HF patients may be due to chance. Alternatively, many cardiac and non-cardiac morbidities  may be present because of cardiac dysfunction. Therefore, it is highly probable that most of the morbidities present in HF did not have the opportunity to contribute to the inflammatory environment that led to HF; instead, they resulted from it. In contrast, HTN always precedes not only the development of HF but CAD as well, which together with HTN are by far the most common and important risk factors for incident HF. Further, as convincingly demonstrated in recent studies, HTN may develop in an inflammatory environment created in the absence of other morbidities, especially in the young. LVEF-based classification of HF phenotypes has served well over the years. However, the time has come to realize that its continuation may lead to erroneous misconceptions, one of them being the mislabeling of HHF patients as suffering from HFpEF; this may undermine the importance of HTN, both in HF’s development and as treatment target. As exercise training is one of the few interventions that may reduce arterial stiffness, it should be an integral part of HHF management.


Nutritional and pharmacological therapies represent the basis for non-dialysis management of CKD patients. Both kinds of treatments have specific and unchangeable features and, in certain cases, they also have a synergic action. For instance, dietary sodium restriction enhances the anti-proteinuric and anti-hypertensive effects of RAAS inhibitors, low protein intake reduces insulin resistance and enhances responsiveness to epoetin therapy, and phosphate restriction cooperates with phosphate binders to reduce the net phosphate intake and its consequences on mineral metabolism. It can also be speculated that a reduction in either protein or salt intake can potentially amplify the anti-proteinuric and reno-protective effects of SGLT2 inhibitors. Therefore, the synergic use of nutritional therapy and medications optimizes CKD treatment. Quality of care management is improved and becomes more effective when compared to either treatment alone, with lower costs and fewer risks of unwanted side effects. This narrative review summarizes the established evidence of the synergistic action carried out by the combination of nutritional and pharmacological treatments, underlying how they are not alternative but complementary in CKD patient care. Chronic kidney disease (CKD) is quite a prevalent disease, affecting up to 10% of the general population, and it is associated with a high rate of morbidity and mortality. By 2040, CKD is predicted to be the fifth leading cause of years of life lost globally [Patients with CKD have an increased risk of cardiovascular diseases and events and progression towards end stage kidney disease (ESKD). Hypertension, proteinuria, anemia and CKD-associated disorders of the mineral and bone metabolism (CKD-MBD) represent major factors influencing cardiovascular and kidney damage progression. All of these modifiable factors are addressed by means of pharmacological therapy. Namely, renin angiotensin aldosterone system (RAAS) inhibitors, sodium glucose transporter 2 (SGLT2) inhibitors, erythropoiesis stimulating agents (ESAs), intestinal phosphate binders and vitamin D derivatives are currently included in the pharmacological treatment of CKD patients.From the 1960s onwards, dietary protein restriction was the sole approach used to correct uremia-related signs and symptoms and, in this way, to delay the need for dialysis. Instead, protein restriction seemed to have a statistically significant but small and clinically negligible effect on slowing the rate of decline in glomerular filtration rate (GFR) . The maiProteinuria is the major risk factor in the progression of kidney damage , as wellAngiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARB) are well-known anti-hypertensive and urine protein-lowering agents. Owing to these features, they are a major reno-protective class of medications. Apart from their anti-hypertensive action and anti-inflammatory, antioxidant and anti-proliferative properties, the effects of RAAS inhibitors include changes in glomerular hemodynamics. Namely, they reduce the vasomotor tone of the efferent arteriole, which reduces intraglomerular pressure and increases renal plasma flow, with a consequent reduction in the filtration fraction. A direct consequence is the reduction in the trans glomerular traffic of proteins and of sheer stress, which, in turn, can activate the local production of growth factors, pro-inflammatory and profibrotic cytokines. This is the reason why RAAS blockers are considered as the first-line therapy for treating hypertension and proteinuria in CKD patients, therefore acting as major renoprotective agents.It is noteworthy that the efficacy of RAAS inhibitors is affected by dietary factors. The anti-hypertensive and anti-proteinuric efficacy of ACE inhibitors in CKD patients is blunted by high dietary sodium intake. A post hoc analysis of the first and second Ramipril Efficacy in Nephropathy (REIN)  studies A multicenter cross-over randomized controlled trial including 52 patients with non-diabetic nephropathy on ACE inhibition therapy compared the effects of the addition of dietary sodium restriction or angiotensin receptor blockade on urine protein excretion and on arterial blood pressure. Sodium urine excretion was assumed as a measure of dietary sodium intake: a regular sodium diet was targeted at 200 mmol sodium daily, whereas a low-sodium diet was targeted at 50 mmol sodium daily. All patients were treated for four 6-week periods, in random order, with ARB  on top of ACE-inhibitor treatment (lisinopril 40 mg/day). Drug interventions were conducted on a double-blind basis; dietary interventions were open label. The addition of a low-sodium diet to ACE inhibition resulted in a 51% reduction in proteinuria, which was significantly greater than the reduction in proteinuria provided by the addition of ARB 21%) to a regular sodium diet. Mean systolic blood pressure was not significantly reduced by the addition of ARB, but it was lowered by the addition of a low-sodium diet and ARB plus a low sodium diet on top of ACE inhibition. The reduction in systolic blood pressure caused by the addition of a low-sodium diet was significantly greater than that occurring due to the addition of ARB and was similar to the reduction in systolic blood pressure caused by the addition of ARB and a low-sodium diet to ACE inhibition % to a re.By interfering with the adaptation mechanisms to changes in body sodium, RAAS blockade makes the arterial blood pressure more sensitive to sodium status. In this way, sodium restriction enhances the response to RAAS blockade on both blood pressure and proteinuria ,24.Lowering sodium serum levels may occur in patients taking ACEI or ARB . In addiSince the 1980s, it has been demonstrated that both the quality and quantity of protein intake can modulate glomerular hemodynamics. A high protein intake induces the release of local and humoral mediators causing hyperfiltration . In partThe hypothesis thus arose that the glomerular changes induced by RAAS inhibitors and protein intakes might be additive. Ruilope et al. reported that nephrotic patients with preserved renal function showed a decrease in proteinuria when shifted from a protein intake of 1.0 g/kg/d to 0.3 g/kg/d . The admIn a retrospective cohort study of 78 proteinuric patients with stage 4–5 CKD, proteinuria decreased significantly after patients were treated with a 0.4 g/kg/d protein diet supplemented with essential amino acids and keto-analogues. The reduction was similar in patients receiving and not receiving ACE inhibition therapy. These data support the hypothesis that the anti-proteinuric effect of low-protein diets and ACE inhibitors have different mechanisms and may be additive . It is rThe recent literature turns the spotlight on new antidiabetic drugs and their effects on CKD patients, i.e., sodium-glucose-transporter 2 (SGLT2) inhibitors. The nephroprotection and antiproteinuric effects, independently from achieving good glucose control, are now well known: in randomized controlled trials, the use of SLGT2 inhibitors reduces progression to kidney disease, reduces hospitalizations and cardiovascular death, particularly in the case of overt proteinuria ,37. The In addition, low salt intake mitigated the drop in eGFR that occurs at the start of therapy and improved the long-term positive effect on the eGFR of SGLT2 inhibitors, suggesting a comprehensive nutritional approach to improve renal outcomes . These sThe potential benefits of using a combination of SGLT2 inhibitors and protein and/or salt restriction are not limited to the glomerular hemodynamic effects. In fact, both treatments act on the metabolism of the kidney and on the autophagy process. It has been reported that protein restriction can restore autophagy in diabetic mice, ameliorates tubulointerstitial damage and kidney function . SimilarAs is indeed known, autophagy has a critical role in CKD: it allows the maintenance of cellular integrity, function and homeostasis via the degradation of cytoplasmatic components and their reuse, namely through normal cell turnover. In cases of dysregulation, acute kidney injury and incomplete repair after damage are favored. The advanced glycation end-products induced injury of mesangial cell in diabetic nephropathy and autophagy counteracts this. Moreover, podocytes have abundant autophagosomes and, in case of impaired autophagy, proteinuria, glomerulopathy and kidney failure can occur. Last but not least, autophagy is also essential for the integrity of proximal tubules and for limiting tubulointerstitial sclerotic evolution .SGLT2 inhibitor therapy can also contribute to body weight loss and possibly to promoting protein catabolism. In this case, the use of SGLT2 inhibitors alongside protein restriction might be of concern, particularly in elderly patients with CKD.The effects of SGLT2 inhibition on muscle mass are not yet definite; decreases and no change in skeletal muscle mass have been reported. Negative energy balance increases circulating amino acid concentrations and stimulates amino acid oxidation. These findings may be an expression of protein catabolism, similarly to the increased fat oxidation. Dapagliflozin treatment causes a reduction in body weight mainly by reducing fat mass, but some changes are reported also in amino acid metabolism . The stuAnemia is a common complication in patients with CKD, especially in stage IV and V. Its prevalence exceeds 50% of patients , and it The term CKD-MBD indicates CKD-associated disorders of the mineral and bone metabolism. It includes biochemical changes regarding serum phosphate, calcium, PTH and vitamin D, bone structure remodeling abnormalities and vascular or soft tissue calcifications.In the pathogenesis of CKD-MBD, a pivotal role is played by fibroblastic growth factor 23 (FGF23). FGF23 is a fosfatonin produced by osteocytes in response to a dietary load of phosphorus, or an increase in phosphorus or calcitriol serum levels. The revised theory of secondary hyperparathyroidism has, as first step, a dietary phosphate load, in the presence of a kidney damage. Under the conditions of GFR loss, the kidney’s capacity to manage a high phosphorus load may be impaired; for this reason, a stimulus to reduce phosphorus tubular reabsorption leading to increased phosphate excretion for a single nephron is needed. This is obtained by means of FGF23 production, together with the co-factor Klotho . FGF23 hThe benefits coming from low-protein or very-low-protein diets in patients that require phosphate binder therapy is easily understandable and well known in terms of synergic effects and reduction in phosphate binder dosage . TherefoIsakova et al. investigated the synergic effect of phosphate binding and phosphate restriction on FGF23 serum levels in a single-blinded, placebo-controlled, 3-month study including CKD patients at stage 3 and 4 and with normal phosphate serum levels. They reported that when an ad libitum diet was compared to a 900 mg phosphate diet, no significant reduction in FGF23 levels occurred; the same was observed when lanthanum carbonate was compared with a placebo. When lanthanum carbonate was associated with a reduction in dietary phosphate, a 35% reduction in FGF23 serum levels was observed by the end of the study period. The authors concluded that only the combination of lanthanum carbonate with a reduction in phosphate intake could decrease FGF23 circulating levels .In another short-term randomized controlled trial, Sigrist et al. compared the effects of a high-phosphate diet (2000 mg/day), low-phosphate diet (750 mg/day) and low-phosphate diet plus an intestinal phosphate binder, namely aluminum hydroxide, at a dosage of 500 mg thrice daily; the two diets supplied comparable macronutrient amounts. Both in CKD and in healthy subjects, serum and urinary phosphate, calcitriol and FGF23 serum levels were measured. Favorable changes in calcitriol and FGF23 serum levels occurred in CKD patients on the low-phosphate diet, as expected. The addition of an intestinal phosphate binder, namely aluminum hydroxide, exerted a synergic action on these two parameters .The care management of CKD patients is complex, and clinical studies have often explored the benefits of a single drug or a specific dietetic approach to avoid possible confounding factors. However, daily clinical practice involves comorbid conditions that undergo different pharmacological and dietary treatment. Therefore, it is interesting to consider the potential synergisms and cooperation between diet and drugs.The transposition “from the bench to bedside” is obviously complex and must be adapted to specific medical and social scenarios. In fact, the results of the trials also depend on the high adherence of the patients and the special attention of the researchers, conditions that are difficult to reproduce in real-world practice. However, nephrologists must know and use all of the arrows in their quiver to optimize and personalize therapy in order to reduce the progression of CKD and dialysis requirement. The use of a dietary approach with RAAS blockers and SGLT2 inhibitors with their synergic effects is the best example of an integrated approach.The synergism between renal diets and medications in CKD patients may be summarized by the following key points. A high sodium intake blunts the efficacy of RAAS inhibitors on proteinuria, blood pressure and progressive kidney damage.Sodium restriction improves the anti-proteinuric and anti-hypertensive effect of RAAS inhibitors and therefore further reduces the risk of progressive kidney damage. Sodium restriction increases the anti-proteinuric and anti-hypertensive action of ACE inhibitors much more than the association with ARB (RAAS double block). A protein-restricted diet has an anti-proteinuric effect additive to ACE inhibitors or ARBs. The reno-protective effects of SGLT2 inhibitors are independent of the level of protein intake, so it is speculated that an additive effect might exist when SGLT2 inhibitors are added on top of a protein-restricted diet, or vice versa. The restriction of phosphorus intake in association with intestinal phosphate binders causes a reduction in FGF23 serum levels in CKD patients. The restriction of protein intake ameliorates the bone marrow’s response to epoetin administration.In conclusion, nutritional and pharmacological therapies represent the basis for the non-dialysis management of CKD patients. Both kinds of treatments have specific and unchangeable features, and, in certain cases, they also have a synergic action . These rAs occurs for all of the effective therapies, the risk of unwanted side effects is present, and special concerns may arise. For instance, sodium restriction coupled with RAAS inhibition increases the risk of hyponatremia, while a protein-restricted diet coupled with SGLT2 inhibitors caused a risk for a loss of muscle mass. Periodic monitoring of sodium serum levels as well as of muscle mass and body composition should be routinely included in the follow-up of CKD patients. The above-mentioned conditions represent one more reason to implement a close follow-up.


People with HIV in sub-Saharan Africa are increasingly developing age-related comorbidities. The purpose of this prospective observational study was to describe 6-month outcomes among Tanzanians with HIV and elevated blood pressure or hyperglycemia under current care pathways.Adults presenting for routine HIV care were enrolled and underwent blood pressure and blood glucose measurements. Participants with abnormal blood pressure or glucose were referred for further care, as per current guidelines. Participants’ blood pressure and point-of-care glucose were re-evaluated during their 6-month follow-up visit. Elevated blood pressure was defined as systolic ≥140 mmHg or diastolic ≥90 mmHg. Hyperglycemia was defined as fasting glucose ≥126 mg/dl or random glucose ≥200 mg/dl. An electrocardiogram was obtained at enrollment and at follow-up. Interim myocardial infarction and interim myocardial ischemia were defined as new pathologic Q waves and new T-wave inversions, respectively.Of 500 participants, 155 had elevated blood pressure and 17 had hyperglycemia at enrolment. At 6-month follow-up, 7 (4.6%) of 155 participants with elevated blood pressure reported current use of an anti-hypertensive medication, 100 (66.2%) had persistent elevated blood pressure, 12 (7.9%) developed interim myocardial infarction, and 13 (8.6%) developed interim myocardial ischemia. Among 17 participants with hyperglycemia, 9 (56%) had persistent hyperglycemia at 6 months and 2 (12.5%) reported current use of an anti-hyperglycemic medication.Interventions are needed to improve non-communicable disease care pathways among Tanzanians with HIV. Globally, hypertension and diabetes mellitus are leading risk factors for cardiovascular diseases (CVDs) such as stroke and myocardial infarction , 2. HumaPreliminary data from across SSA suggests that the prevalence of hypertension and diabetes among PWH is already substantial. Small, cross-sectional studies from Malawi, Tanzania, South Africa, Ethiopia, and Kenya have reported hypertension prevalence of 13–29% and diabetes prevalence of 6–18% among adults engaged in HIV care . Of partMoreover, despite a growing recognition of the substantial burden of poorly controlled noncommunicable comorbidities among PWH in SSA, few prospective studies report longitudinal outcomes of PWH with hypertension or diabetes. Indeed, most of the data describing noncommunicable comorbidities among PWH in the region have come from cross-sectional studies that do not report prospective outcomes, such as medication uptake after diagnosis, subsequent healthcare utilization, CVD incidence, or mortality. To address this knowledge gap, the purpose of this study was to describe six-month prospective outcomes including disease control, medication use, and healthcare utilization among Tanzanian adults with HIV and elevated blood pressure or hyperglycemia under current care models. Our primary aim was to determine the proportion of PWH who, after referral for further care for hyperglycemia or elevated blood pressure within the current siloed system, had persistent hyperglycemia or elevated blood pressure six months later. Since noncommunicable disease screening and care is not currently part of the national HIV treatment protocols in Tanzania, understanding healthcare utilization and outcomes among this population could have important implications for policy-making and clinical care guidelines .This prospective observational cohort study was conducted in the Kilimanjaro Region of Tanzania, where the local prevalence of HIV, hypertension, and diabetes mellitus among the general adult population is 3%, 28%, and 6%, respectively –20. PartAny adult (age ≥ 18 years) presenting to MCTC for HIV care was eligible for enrolment; there were no exclusion criteria. Trained research assistants approached consecutive adult MCTC patients to offer enrolment, which was conducted over a six-month period between September 1st, 2020, and March 1st, 2021. Although all MCTC patients consenting to participation were enrolled in the parent study , 21, onlInitial study procedures have been described in detail elsewhere and are summarized here , 21, 22.Under current care protocols, HIV viral load and CD4 count are typically performed at least annually for MCTC patients in the MCTC lab. In some cases, no CD4 count or HIV viral load from within the past year were available in the medical record, typically because a patient had only recently established care at MCTC or because they had missed their appointment for bloodwork. In these cases where no CD4 count or HIV viral load were available in the medical record, a blood sample was collected by a research clinical officer for these assays during the patient’s six-month follow-up visit (described below). When CD4 count and viral load testing were performed by the study team, these assays were conducted at the Kilimanjaro Christian Research Institute Biotechnology Laboratory, using the BD FACSCount  and Abbott m2000 rt , respectively.At enrolment, a resting twelve-lead electrocardiogram (ECG) was also obtained for all participants using the tablet-based PADECG . At time of initial enrolment, the research assistants measured participant blood pressure, following American Heart Association/American College of Cardiology guidelines: blood pressure was measured with participant seated and arm at heart level, using an appropriately sized cuff, after participants had rested for about five minutes . The Beust 2021 though September 1st 2021. Follow-up surveys and data collection were performed by the same team of research assistants. At follow-up, participants underwent repeat blood pressure measurement, point-of-care glucose assay, and resting 12-lead ECG testing. They also completed a survey about new medication use and any interim unscheduled healthcare visits for chest pain, shortness of breath, hypertension, or diabetes. Participants were also asked if they were interested in more education about noncommunicable diseases. Finally, participants were asked if they would prefer to receive their noncommunicable disease care at their HIV clinic or in another facility. Participants with elevated blood pressure or hyperglycemia at follow-up were again referred to the adjacent medical clinic for further care.Six months after initial enrolment, participants were asked to return to MCTC for a follow-up study visit. Although no compensation was provided to participants at initial enrolment, reimbursement for transportation was provided (5000 Tanzanian shillings or approximately 2 USD) during the follow-up visit. Follow-up study visits were scheduled to coincide with routine clinic return visits to minimize any inconvenience for participants. Follow-up visits were conducted from March 1All ECGs were interpreted by two independent physician adjudicators, trained in either cardiology or emergency medicine. Adjudicators were blinded to all clinical data other than age and sex. Adjudicators were asked to determine presence of prior myocardial infarction and myocardial ischemia according to Fourth Universal Definition of Myocardial Infarction guidelines: prior myocardial infarction was defined as pathologic Q waves in ≥2 contiguous leads and myocardial ischemia was defined as T-wave inversions or ST-segment depressions in ≥2 contiguous leads . In caseElevated blood pressure was defined as measured systolic blood pressure ≥140 mmHg or measured diastolic blood pressure ≥90 mmHg, corresponding to the threshold for Stage II Hypertension as per American Heart Association/American College of Cardiology guidelines . NotablyThis was a purely descriptive study. For the present study, only participants meeting criteria for elevated blood pressure or hyperglycemia at initial enrolment were included in the analysis. All statistical analyses were performed in the R Suite . DescripAll participants provided written informed consent prior to enrolment. This study received approval from ethical review committees at the Tanzania National Institute for Medical Research, Kilimanjaro Christian Medical Centre, and Duke Health.Of 501 MCTC patients approached for study inclusion, 500 (99.8%) consented to participate and were enrolled. Of these, 163 participants were included in the present analysis, including 146 (89.6%) participants with elevated blood pressure alone, 8 (4.9%) participants with hyperglycemia alone, and 9 (5.5%) participants with both elevated blood pressure and hyperglycemia . This reOf note, 18 enrolled patients (3.6%) reported a history of hypertension but had well-controlled blood pressure (<140/90 mmHg) at enrolment and 4 (0.8%) participants reported a history of diabetes but did not have hyperglycemia at enrolment. These participants were excluded from the present analysis and are described elsewhere .The baseline characteristics of participants with elevated blood pressure and hyperglycemia are summarized in Tables Six months after enrolment, 5 (3.1%) participants were lost to follow-up, including 4 participants with elevated blood pressure and one participant with hyperglycemia. This resulted in 151 participants with baseline elevated blood pressure completing six-month follow-up and 16 participants with baseline hyperglycemia completing six-month follow-up. The six-month outcomes of participants with elevated blood pressure are presented in The six-month outcomes of participants with hyperglycemia are presented in To our knowledge this is one of the first studies to report prospective outcomes of PWH with elevated blood pressure or hyperglycemia in SSA. As advancements in HIV care have led to increased life-expectancy for PWH in SSA, there has been an increase in the burden of age-related, NCDs among this population –8, 29. IAt 6-month follow-up, most participants with elevated blood pressure or hyperglycemia did not achieve guideline-recommended blood pressure or glycemic targets. These low rates of NCD control are likely due, at least in part, to the observed low uptake of anti-hypertensive or anti-hyperglycemic medications among participants. Further study is needed to explore reasons for low uptake of these medications, since all participants were referred to an adjacent general practitioner if they were found to have elevated blood pressure or hyperglycemia at initial enrolment. Recent qualitative studies have identified multiple barriers to anti-hypertensive and anti-hyperglycemic therapies among PWH in Tanzania, including fear, lack of understanding, and cost , 31. In Beyond low rates of NCD control, we also observed frequent healthcare utilization in our cohort: roughly one in five participants reported an unscheduled visit to a healthcare facility for chest pain, shortness of breath, or hyperglycemia. This finding suggests that there may be substantial cost benefits, at the individual and system levels, to improving NCD control among this high-risk population. Of further concern, we found that more than one in ten participants with elevated blood pressure developed new ECG changes suggestive of myocardial infarction or myocardial ischemia within 6 months of enrolment. Although ECG findings of Q waves and T-wave inversions are non-specific and may indicate a wide array of pathologies including cardiomyopathies, structural heart disease, and coronary ischemia , 36, theThere was a strong desire for more NCD education among our participants, and most expressed a preference for receiving NCD care at the HIV clinic. In recent years, many public health experts have advocated for an integrated healthcare model in SSA: providing NCD and HIV care at one clinic , 37–39. This study had multiple limitations. Because we only enrolled patients who were already engaged in HIV care, our findings may not be generalizable to PWH who are not engaged in care or are unaware of their HIV status. Patients not engaged in care are likely to have even lower rates of NCD control. Secondly, we relied on random glucose measurements to identify patients with potential diabetes mellitus due to cost restraints. Hemoglobin A1c levels would likely have provided a more accurate measure of the prevalence and control of diabetes mellitus among participants, although hemoglobin A1c may be less accurate in those with HIV . FurtherIn conclusion, among Tanzanians with HIV and comorbid elevated blood pressure and hyperglycemia at a single center, most had not achieved adequate blood pressure or blood glucose control, and most were not taking any anti-hypertensive or anti-hyperglycemic medications six months after initial screening. Importantly, because we do not know whether these participants received a formal diagnosis of hypertension or diabetes or whether they were prescribed any medications, the reasons for their persistently elevated blood pressure or their persistent hyperglycemia are unclear and warrant further exploration. There was a strong desire among patients for more NCD education, and there is an urgent need to develop locally tailored interventions to improve NCD care pathways among PWH in Tanzania.S1 Dataset(XLSX)Click here for additional data file.S1 File(DOCX)Click here for additional data file.


To identify a clinical profile and laboratory findings of a cohort of hypoparathyroidism patients and determine the prevalence and predictors for renal abnormalities. Data from medical records of five different visits were obtained, focusing on therapeutic doses of calcium and vitamin D, on laboratory tests and renal ultrasonography (USG). Fifty-five patients were identified, 42 females and 13 males; mean age of 44.5 and average time of the disease of 11.2 years. The most frequent etiology was post-surgical. Levels of serum calcium and creatinine increased between the first and last visits ; and serum levels of phosphate decreased during the same period (p < 0.001). Out of the 55 patients, 40 had USG, and 10 (25%) presented with kidney calcifications. There was no significant difference in the amount of calcium and vitamin D doses among patients with kidney calcifications and others. No correlation between serum and urinary levels of calcium and the presence of calcification was found. Urinary calcium excretion in 24h was significantly higher in patients with kidney calcification (3.3 mg/kg/d) than in those without calcification (1.8 mg/kg/d) (p < 0.05). The reduction of hypocalcemia and hyperphosphatemia suggest an effectiveness of the treatment, and the increase in serum creatinine demonstrates an impairment of renal function during follow-up. Kidney calcifications were prevalent in this cohort, and higher urinary calcium excretion, even if still within the normal range, was associated with development of calcification. These findings suggest that lower rates of urinary calcium excretion should be aimed for in the management of hypoparathyroidism. Hypoparathyroidism (HP) is a metabolic disorder caused either by deficient or absent production of the parathyroid hormone (PTH) by the parathyroid glands or by resistance to PTH in its target tissues  ,2. HP isHP is clinically characterized by hypocalcemia and hyperphosphatemia ,6. The mHP is one of the few endocrine hyposecretory diseases whose treatment, in most countries, does not consist of administration of the defective hormone. Rather, it consists of supplementation with high doses of calcium and vitamin D analogues, such as calcitriol and cholecalciferol -11. ReceThe aims of this study are to identify a clinical profile and laboratorial findings of patients with hypoparathyroidism and to determine the prevalence as well as the predictors for renal abnormalities.This is a retrospective, analytical, and observational study. Data have come from patients of the Bone Clinic of the Division of Endocrinology at Serviço de Endocrinologia e Metabologia da Universidade Federal do Paraná (SEMPR). This study has the approval of the local Ethics Committee in Research on Human Beings.An active search for patients with HP was performed through the hospital database. The exclusion criterions were disease duration of less than 6 months, which is defined as transient HP . PatientClinical features such as age, gender, HP etiology, age at diagnosis, duration of disease, and doses of treatment  were collected and analyzed. Renal ultrasonography (USG) and cranial tomography (CT), when available, were analyzed to identify the presence of such calcifications as nephrolitiasis and nephrocalcinosis in the kidneys and basal ganglia in the brain. The mean and standard deviation (SD) of serum total calcium, phosphate, creatinine, and PTH as well as 24-hour urinary calcium excretion were collected based on the first and last visit of each patient, as well as on three intermediary visits (5 time points). For the measurement of total serum calcium, phosphorus and creatinine standard kits were used, and analysis was performed using automated spectrophotometric equipment . Levels of iPTH were determined by chemiluminescence . The mean doses along with the range (minimum and maximum) of calcium carbonate, calcitriol, and cholecalciferol used by the patients at the five time points were also calculated.Cockroft-Gault formula  was usedPatients who had renal USG results available were divided into two groups – with and without renal calcification – and were compared with each other regarding their clinical and laboratory features as well as doses of calcium and vitamin D.Data were described as frequency and percentage or by mean and SD for qualitative and quantitative variables, respectively. The results of the first and last visit were analyzed. Student’s t-test for paired samples or nonparametric Wilcoxon test and/or binomial test was performed as appropriate for quantitative and qualitative variables. Spearman’s correlation coefficients were estimated to test the association of disease duration with the laboratory results. For the analysis between the groups with and without renal calcification, Student’s t-test for independent samples or nonparametric Mann-Whitney test was used for the quantitative variables, and Fisher’s exact test for the qualitative variables. Results with values of p < 0.05 have been considered as statistically significant. The data were analyzed using the computational software IBM SPSS Statistics v.20.0.Main clinical characteristics of the patients are presented in Out of the 55 patients, 40 (72.7%) had been submitted to renal USG, whereas 30 (75%) had a normal USG and 10 (25%) had abnormalities such as nephrolithiasis and nephrocalcinosis. No correlation between serum and urinary levels of calcium and the presence of calcification was found. However, weight-adjusted urinary calcium excretion in 24 h was higher in patients with renal calcification than in those without calcification . Mean values of serum calcium, phosphate and creatinine, and 24-h urinary calcium in each of the five moments are shown in Considering all patients, creatinine values increased during this period (0.81 ± 0.17 – 1.1 ± 0.45), also with statistical significance (p = 0.04). The mean of PTH for patients with pseudo-HP was 130 ± 146 pg/mL; and for the others, PTH was 7.8 ± 11 pg/mL.2, and its mean was 92.9 ± 36.2 mL/min/1.73 m2. Consequently, the renal function was in 15 (33.3%) patients in stage II of chronic kidney disease as stated in Kidney Disease Outcomes Quality Initiative (KDIGO)  . The glo (KDIGO) , 4 (8.9% (KDIGO) . Hence, Eleven patients (20%) had a cranial CT evaluation in their records, while 5 (45%) had basal ganglia calcification (BGC). From these patients with BCG, 2 had post-surgical HP, 1 had pseudo-HP, and 2 had HP caused by other etiologies.This is a pioneer study in our country on hypoparathyroidism (HP) patients followed at a reference center describing the etiologies, laboratory findings, doses of calcium and vitamin D, and complications. In this cohort there was a wide range of age at diagnosis and a high proportion of females, with the post-surgical being the most frequent etiology of the disease ,18, agreIn order to avoid these complications, maintenance of serum calcium around the lower limit and serum phosphate around the upper limit of normal ranges is recommended ,5. In adBasal ganglia calcification (BGC) has been established as a possible outcome of HP. Its prevalence demonstrated in the HP cohorts varied significantly from 12% up to 74%. However, it should be noted that the estimated prevalence of BGC in the general population may achieve 12.5% . Some stIn summary, this study obtained data of HP patients followed up in a tertiary care hospital of Curitiba, in the South of Brazil. In this casuistic, it was observed that the treatment led to laboratorial control of calcium and phosphate serum levels. However, the treatment did not avoid an increase in serum creatinine levels and the presence of kidney calcifications. Higher urinary calcium excretion, even if still within the normal range, was associated with development of calcification. Since HP is most commonly a life-long disease, a complete kidney function evaluation, and the search for calcifications is highly recommended. In addition, lower rates of urinary calcium excretion should be aimed for in these patients.


A nomogram model was established based on recipient’s age, anhepatic phase, estimated glomerular filtration rate and triglyceride levels at 30 days after LT. The calibration curves for post-LT CKD prediction in the nomogram were consistent with the actual observation in both the internal and external validation set. In conclusion, severe post-LT CKD resulted in a significantly reduced survival in liver recipient. The newly established nomogram model had good predictive ability for post-LT CKD.Chronic kidney disease (CKD) is a frequent complication after liver transplantation (LT) and associated with poor prognosis. In this study, we retrospectively analyzed 515 adult patients who underwent LT in our center. They were randomly divided into a training set (n = 360) and an internal test set (n = 155). Another 118 recipients in other centers served as external validation set. Univariate and multivariate COX regression analysis were used to determine risk factors. A nomogram model was developed to predict post-LT CKD. The incidence of post-LT CKD in our center was 16.9% (87/515) during a median follow-up time of 22.73 months. The overall survival of recipients with severe CKD (stage IV and V) were significantly lower than those with non or mild CKD (stage III) ( However, the postoperative complications could strongly impair graft function and reduce graft survival. Chronic kidney disease (CKD) is one of the frequent long-term complications in liver recipients. According to the previous reports, the incidence of post-LT CKD ranged from 11.7% to 54%10. Based on data of 1771 liver recipients in Taiwan National Health Insurance Research Database, Wang et al.7 revealed that 323 (18.2%) patients required renal replacement therapy after LT and had a higher mortality.Liver transplantation (LT) is a life-saving treatment for patients with end-stage liver diseases. With the development of LT surgery technology and postoperative management, the 10-year survival rate after LT is nearly 89%4, making it difficult to accurately identify recipients who were at high risk of developing post-LT CKD. Over the past decade, models have been established and tried to serve as tools to predict the development of post-LT CKD. Giusto et al.11 analyzed data from 179 patients and found that arterial hypertension, severe infection and estimated glomerular filtration rate (eGFR) after LT were risk factors for the development of post-LT CKD. A predictive model was established based on these factors and showed a C-index of 0.91, indicating good predictive ability. Levitsky et al.12 proposed another predictive model by integrating one clinical parameter (hepatitis C virus as the major indication for LT) and two renal injury proteins (serum CD 40 antigen and β-2 microglobulin prior to LT), showing an area under the curve (AUC) of 0.814 in the training cohort (n = 60) and 0.801 in the validation cohort (n = 50). Nevertheless, the detection of these individual biomarkers seems to be difficult and increase the time cost as well, limiting their application in clinic. Furthermore, the sample sizes of the two models are relatively small, suggesting that larger cohorts should be considered to validate their efficacy. In a large cohort study with 43,514 adult liver recipients, Sharma et al.13 established a renal risk index, which contained 14 recipient factors, to predict end-stage renal disease (ESRD) after LT. However, the model could not identify patients with CKD stage III or IV who may deteriorate to CKD stage V without being well managed. In addition, it involved too many variables, which might increase the difficulty of clinical application. Therefore, a simple and effective predictive model is needed to identify patients at high risk of post-LT CKD.The etiologies of post-LT CKD are multifactorial  and the risk factors varied from each other in different studiesNomogram is a simple visual graph of statistical prediction model with an easy-to-use graphical interface. Importantly, it could generate personalized predictions, thereby, widely used in risk stratification and personally providing approach to disease management. In our study, we aimed to develop a nomogram predictive model for CKD following donation after circulatory death (DCD) LT.15. An external validation set (n = 118) was obtained from China Liver Transplant Registry (CLTR) database and included adult patients who underwent primary LT from July 1, 2017 to December 31, 2020 in other centers with sufficient data. The study protocol was approved by the clinical ethics review board of hospital and CLTR. All LTs were performed with organs from voluntary donations made by deceased donors, not from executed prisoners. Each organ donation or transplant followed the guidelines of the Organ Transplant Committee of China. The informed consent was obtained from each participant.All adult patients (> 18 years old) undergoing DCD LT between January 1, 2015 and December 31, 2018 at The First Affiliated Hospital, Zhejiang University School of Medicine were enrolled in this retrospective study. At first, 619 LT recipients were included, 10 with age of < 18 years and 94 who died within 3 months after LT were excluded. Then 515 patients were included and randomly divided into a training set (n = 360) and an internal test set (n = 155) according to ratio of 0.7 to 0.316. The following perioperative clinical variables were recorded for the study: patient demographics, medical history, medication history, baseline laboratory findings, medical information about the donor and graft liver, operation time, intraoperative fluid and colloid administration, and intraoperative transfusion amount. The pre-transplant data were collected within 24 h before LT. The post-LT data were recorded during the follow up.Data related to demographic or perioperative variables were collected in accordance with the procedure described in previous studies2 ≥ 3 months, with or without renal injury19. The eGFR calculated using the serum creatinine value and modified diet in renal disease (MDRD) equation20.The primary outcome variable was postoperative CKD defined according to Kidney Disease: Improving Global Outcomes (KDIGO) 2012 CKD Guideline. We used the following criteria: eGFR < 60 mL/min/1.73 mhttp://www.r-project.org/) were used for statistical analysis of data in this study. Quantitative variables were expressed as mean ± SD or median and quartiles. Categorical variables such as sex were presented as values and percentages. Student's t test or the Wilcoxon's rank-sum test was used to compare quantitative variables. The Chi-square test was used to compare categorical variables. The Kaplan–Meier method and log-rank test were used for survival analysis. Multivariate COX regression with LR forward elimination analysis was used to determine independent risk factors for post-LT CKD. We calculated the AUCs of the models and compared the AUCs using De Long’s method21. A nomogram was built and verified in the training set and two test sets respectively.R software version 4.1.0 (http://ame.pub/AME20210218) was used for DCA analysis of the models. P value < 0.05 was considered statistically significant.In this study, the ‘SurvMiner’ and ‘Survival’ packages in R language were used to conduct Cox regression analysis and establish a nomogram prediction model for post-LT CKD. The ‘tidyverse’, ‘SurvivalRoc’, ‘pROC’, ‘ROCR’ packages were used for AUC analysis. The ‘stdca.R’ source code . The median follow-up time was 22.83 months (quartile: 13.62–39.67 months). The average time of CKD diagnosis after LT was 19.61 months (quartile: 11.25–37.34 months). Demographic and clinical characteristics were shown in Table p = 0.53) . The 1-, 2- and 3-year cumulative survival rates in the CKD group were 91.7%, 81.8% and 73.5% and the corresponding survival rates in the non-CKD group were 88.4%, 81.7% and 79.2% respectively. There was no statistically significant difference in survival between the two groups  , anhepatic phase , eGFR at 30 days after LT  and TG levels at 30 days after LT (HR 1.51 95%CI 1.23–1.83) were independent risk factors for post-LT CKD in training set (Table We established a preoperative prediction model (model 1) according to recipient’s age, BMI, history of hepatorenal syndrome and anhepatic phase Fig. A. The AUThen we established another model model 2) using recipient’s age, anhepatic phase, eGFR at 30 days after LT and TG levels at 30 days after LT  was significantly associated with higher mortality after LT23. LaMattina et al.10 retrospectively analyzed 1151 adult deceased LTs and revealed that 3%, 7% and 18% of recipients developed ESRD at 5, 10 and 20 years, which suggested increased incidence of severe CKD with prolonged follow-up time. Thus, there is greatly necessary to identify earlier CKD and cooperate with nephrologists to take early intervention.The relationship between post-LT CKD and adverse prognosis is still a matter of substantial debate. It has been reported that the occurrence of CKD is not associated with a worse survivalIn this study, we established a novel nomogram model to accurately predict post-LT CKD. We found it was difficult to predict the occurrence of post-LT CKD before LT because the AUC of model 1 with preoperative parameters was relatively low. In contrast, when we integrated the postoperative parameters, the predictive ability of model was dramatically improved. The independent risk factors for post-LT CKD were recipient’s old age, prolonged anhepatic phase, low eGFR at 30 days after LT and high TG levels at 30 days after LT.9. Here, we found that for each 1 year increased of age, the risk of CKD increased by 3%, which confirmed the above association. Older liver recipients are commonly at higher risk of preexisting kidney dysfunction, metabolic disorders, hypertension, diabetes, cardiovascular diseases, making it susceptible to CKD after LT25. Given that the declining clearance of immunosuppressive agents in the elderly, they are more likely to be affected by immunosuppressor nephrotoxicity, thereby accelerating the development of post-LT CKD26.Advanced age is a well-recognized risk factor for progressive kidney dysfunction after LT28. In addition, prolonged anhepatic time could increase the risk of graft dysfunction and metabolic disorders, mainly due to the accumulation of cytokines , metabolites and other toxicants, and finally deteriorated renal function and reduced patient survival29.During LT, the inferior vena cava was partially blocked while the portal vein and hepatic artery were completely occluded, strongly impacting the hemodynamics changes in recipients. Additionally, decreased GFR and increased markers of renal injury  were observed during the anhepatic phase, potentially resulting in post-LT CKD30. In our present study, we also found that TG level at 30 days after LT was an independent risk factor for post-LT CKD, suggesting the potential role of hyperlipidemia in CKD development. In patients with CKD, the altered lipid profile includes elevated low-density lipoprotein cholesterol and very low-density lipoprotein cholesterol and reduced high-density lipoprotein cholesterol33. Such alteration could result in increased lipid content , which accumulates in kidney and triggers lipid nephrotoxicity34. Given that the close correlation between hyperlipidemia and CKD, it is necessary to regulate lipid metabolism in recipients at higher risk of post-LT CKD35. A series of clinical trials have indicated the use of statins with or without ezetimibe could prevent and treat CKD41. Moreover, our previous studies also demonstrated that well controlled glucose and lipid levels during the perioperative period of LT could reduce the incidence of post-LT chronic diseases such as metabolic disorders and CKD45.eGFR is commonly served as an indicator of CKD due to its detection is accurate and convenient. In our study, we indicated that low eGFR level at 30 days after LT was an independent risk factor of post-LT CKD, suggesting the renal dysfunction in the early post-LT period may contribute to the development of CKD. In a retrospective cohort study, Sato et al.46 revealed that eGFR < 60 mL/min/1.73 m2 at 1 month following LT was a predictive factor of CKD at 2-year after LT, which proved our hypothesis. During organ procurement and implantation, blood loss could result in intraoperative or post-LT renal injury, thereby influencing the eGFR46. These results highlight the importance of controlling the early post-transplant eGFR. In addition, efforts should be made to avoid massive intraoperative blood loss during LT, usage of nephrotoxic medications and acute kidney injury.Previous study has showed that high levels of TG were significantly associated with low eGFR in liver recipientsThere are several limitations in our study. Firstly, it was an observational study with relatively limited cases and short follow-up time. CKD is a slowly progressive disease with increased incidence as the follow-up time prolonged. Secondly, the nomogram model needs to be validated in prospective studies with well design. Thirdly, given that the fewer ESRD cases in our study, large-scale and adequately powered studies with more samples are necessary to determine independent risk factors of ESRD and construct believable models to identify who deteriorate to ESRD and who doesn’t. At last, although CLTR included more than twenty thousand cases of LTs during 2017–2020, only 118 had sufficient follow-up data to define post-LT CKD. The follow-up data input and management of the national database are needed.As a long-term complication after LT, severe post-LT CKD could result in a significantly reduced survival rate in liver recipients. Prompt management of dyslipidemia and renal dysfunction during the early post-LT period may of help to prevent the development of post-LT CKD. Furthermore, we established a novel nomogram to predict post-LT CKD, showing an excellent diagnostic efficacy.