Comparative physiological anthropogeny: exploring molecular underpinnings of distinctly human phenotypes.

Anthropogeny is a classic term encompassing transdisciplinary investigations of the origins of the human species. Comparative anthropogeny is a systematic comparison of humans and other living nonhuman hominids (so-called "great apes"), aiming to identify distinctly human features in health and disease, with the overall goal of explaining human origins. We begin with a historical perspective, briefly describing how the field progressed from the earliest evolutionary insights to the current emphasis on in-depth molecular and genomic investigations of "human-specific" biology and an increased appreciation for cultural impacts on human biology. While many such genetic differences between humans and other hominids have been revealed over the last two decades, this information remains insufficient to explain the most distinctive phenotypic traits distinguishing humans from other living hominids. Here we undertake a complementary approach of "comparative physiological anthropogeny," along the lines of the preclinical medical curriculum, i.e., beginning with anatomy and considering each physiological system and in each case considering genetic and molecular components that are relevant. What is ultimately needed is a systematic comparative approach at all levels from molecular to physiological to sociocultural, building networks of related information, drawing inferences, and generating testable hypotheses. The concluding section will touch on distinctive considerations in the study of human evolution, including the importance of gene-culture interactions.

Glycoprotein NMB promotes tumor formation and malignant progression of laryngeal squamous cell carcinoma.

Laryngeal squamous cell carcinoma (LSCC), although one of the most common head and neck cancers, has a static or slightly decreased survival rate because of difficulties in early diagnosis, lack of effective molecular targeting therapy, and severe dysfunction after radical surgical treatments. Therefore, a novel therapeutic target is crucial to increase treatment efficacy and survival rates in these patients. Glycoprotein NMB (GPNMB), whose role in LSCC remains elusive, is a type 1 transmembrane protein involved in malignant progression of various cancers, and its high expression is thought to be a poor prognostic factor. In this study, we showed that GPNMB expression levels in LSCC samples are significantly higher than those in normal tissues, and GPNMB expression is observed mostly in growth-arrested cancer cells. Furthermore, knockdown of GPNMB reduces monolayer cellular proliferation, cellular migration, and tumorigenic growth, while GPNMB protein displays an inverse relationship with Ki-67 levels. Therefore, we conclude that GPNMB may be an attractive target for future LSCC therapy.

Polyvinyl alcohol scaffolds and supplementation support 3D and sphere culturing of human cancer cell lines by reducing apoptosis and promoting cellular proliferation.

Three-dimensional (3D) culturing mimics the heterogeneous cellular conditions of the in vivo tumor microenvironment compared to 2D monolayer-cultured cells and 3D cultures of established cancer cell lines (sphere culture) or patient-derived cancer cells (organoid culture) are frequently used for cancer research or drug screening and evaluation. To establish more cost and time-efficient 3D culture methods for cancer cell lines, we supplemented sphere culture medium with polyvinyl alcohol (PVA) and found that 3D sphere cultures of breast and pancreatic cancer cell lines were significantly increased. Mechanistically, we found that PVA prevented cell death and promoted cellular proliferation while maintaining levels of stemness-related gene expression. Furthermore, we showed that polyvinyl formal resin (PVF) 3D scaffolds made by cross-linked PVA can function in serum-free, long-term 3D cultures to support maintenance of sphere- or tumor-like cell masses for diverse cancer cell types. Taken together, we demonstrate the effectiveness of PVA and PVF in human cancer cell line culture protocols.

Serum Antibodies to N-Glycolylneuraminic Acid Are Elevated in Duchenne Muscular Dystrophy and Correlate with Increased Disease Pathology in Cmah-/-mdx Mice.

Humans cannot synthesize the common mammalian sialic acid N-glycolylneuraminic acid (Neu5Gc) because of an inactivating deletion in the cytidine-5'-monophospho-(CMP)-N-acetylneuraminic acid hydroxylase (CMAH) gene responsible for its synthesis. Human Neu5Gc deficiency can lead to development of anti-Neu5Gc serum antibodies, the levels of which can be affected by Neu5Gc-containing diets and by disease. Metabolic incorporation of dietary Neu5Gc into human tissues in the face of circulating antibodies against Neu5Gc-bearing glycans is thought to exacerbate inflammation-driven diseases like cancer and atherosclerosis. Probing of sera with sialoglycan arrays indicated that patients with Duchenne muscular dystrophy (DMD) had a threefold increase in overall anti-Neu5Gc antibody titer compared with age-matched controls. These antibodies recognized a broad spectrum of Neu5Gc-containing glycans. Human-like inactivation of the Cmah gene in mice is known to modulate severity in a variety of mouse models of human disease, including the X chromosome-linked muscular dystrophy (mdx) model for DMD. Cmah-/-mdx mice can be induced to develop anti-Neu5Gc-glycan antibodies as humans do. The presence of anti-Neu5Gc antibodies, in concert with induced Neu5Gc expression, correlated with increased severity of disease pathology in Cmah-/-mdx mice, including increased muscle fibrosis, expression of inflammatory markers in the heart, and decreased survival. These studies suggest that patients with DMD who harbor anti-Neu5Gc serum antibodies might exacerbate disease severity when they ingest Neu5Gc-rich foods, like red meats.

Dietary Neu5Ac Intervention Protects Against Atherosclerosis Associated With Human-Like Neu5Gc Loss-Brief Report.

Objective: Species-specific pseudogenization of the CMAH gene during human evolution eliminated common mammalian sialic acid N-glycolylneuraminic acid (Neu5Gc) biosynthesis from its precursor N-acetylneuraminic acid (Neu5Ac). With metabolic nonhuman Neu5Gc incorporation into endothelia from red meat, the major dietary source, anti-Neu5Gc antibodies appeared. Human-like Ldlr-/-Cmah-/- mice on a high-fat diet supplemented with a Neu5Gc-enriched mucin, to mimic human red meat consumption, suffered increased atherosclerosis if human-like anti-Neu5Gc antibodies were elicited. Approach and Results: We now ask whether interventional Neu5Ac feeding attenuates metabolically incorporated Neu5Gc-mediated inflammatory acceleration of atherogenesis in this Cmah-/-Ldlr-/- model system. Switching to a Neu5Gc-free high-fat diet or adding a 5-fold excess of Collocalia mucoid-derived Neu5Ac in high-fat diet protects against accelerated atherosclerosis. Switching completely from a Neu5Gc-rich to a Neu5Ac-rich diet further reduces severity. Remarkably, feeding Neu5Ac-enriched high-fat diet alone has a substantial intrinsic protective effect against atherosclerosis in Ldlr-/- mice even in the absence of dietary Neu5Gc but only in the human-like Cmah-null background. Conclusions: Interventional Neu5Ac feeding can mitigate or prevent the red meat/Neu5Gc-mediated increased risk for atherosclerosis, and has an intrinsic protective effect, even in the absence of Neu5Gc feeding. These findings suggest that similar interventions should be tried in humans and that Neu5Ac-enriched diets alone should also be investigated further.

Sodium Glucose Co-Transporter 2 Inhibitors Improve Renal Congestion and Left Ventricular Fibrosis in Rats With Hypertensive Heart Failure.

BACKGROUND: Elevated central venous pressure (CVP) in heart failure causes renal congestion, which deteriorates prognosis. Sodium glucose co-transporter 2 inhibitor (SGLT2-i) improves kidney function and heart failure prognosis; however, it is unknown whether they affect renal congestion. This study investigated the effect of SGLT2-i on the kidney and left ventricle using model rats with hypertensive heart failure.Methods and Results: Eight rats were fed a 0.3% low-salt diet (n=7), and 24 rats were fed an 8% high-salt diet, and they were divided into 3 groups of untreated (n=6), SGLT2-i (canagliflozin; n=6), and loop diuretic (furosemide; n=5) groups after 11 weeks of age. At 18 weeks of age, CVP and renal intramedullary pressure (RMP) were monitored directly by catheterization. We performed contrast-enhanced ultrasonography to evaluate intrarenal perfusion. In all high-salt fed groups, systolic blood pressure was elevated (P=0.287). The left ventricular ejection fraction did not differ among high-salt groups. Although CVP decreased in both the furosemide (P=0.032) and the canagliflozin groups (P=0.030), RMP reduction (P=0.003) and preserved renal medulla perfusion were only observed in the canagliflozin group (P=0.001). Histological analysis showed less cast formation in the intrarenal tubule (P=0.032), left ventricle fibrosis (P<0.001), and myocyte thickness (P<0.001) in the canagliflozin group than in the control group. CONCLUSIONS: These results suggest that SGLT2-i causes renal decongestion and prevents left ventricular hypertrophy, fibrosis, and dysfunction.

Human species-specific loss of CMP-N-acetylneuraminic acid hydroxylase enhances atherosclerosis via intrinsic and extrinsic mechanisms.

Cardiovascular disease (CVD) events due to atherosclerosis cause one-third of worldwide deaths and risk factors include physical inactivity, age, dyslipidemia, hypertension, diabetes, obesity, smoking, and red meat consumption. However, ∼15% of first-time events occur without such factors. In contrast, coronary events are extremely rare even in closely related chimpanzees in captivity, despite human-like CVD-risk-prone blood lipid profiles, hypertension, and mild atherosclerosis. Similarly, red meat-associated enhancement of CVD event risk does not seem to occur in other carnivorous mammals. Thus, heightened CVD risk may be intrinsic to humans, and genetic changes during our evolution need consideration. Humans exhibit a species-specific deficiency of the sialic acid N-glycolylneuraminic acid (Neu5Gc), due to pseudogenization of cytidine monophosphate-N-acetylneuraminic acid (Neu5Ac) hydroxylase (CMAH), which occurred in hominin ancestors ∼2 to 3 Mya. Ldlr-/- mice with human-like Cmah deficiency fed a sialic acids (Sias)-free high-fat diet (HFD) showed ∼1.9-fold increased atherogenesis over Cmah wild-type Ldlr-/- mice, associated with elevated macrophage cytokine expression and enhanced hyperglycemia. Human consumption of Neu5Gc (from red meat) acts as a "xeno-autoantigen" via metabolic incorporation into endogenous glycoconjugates, as interactions with circulating anti-Neu5Gc "xeno-autoantibodies" potentiate chronic inflammation ("xenosialitis"). Cmah-/-Ldlr-/- mice immunized with Neu5Gc-bearing antigens to generate human-like anti-Neu5Gc antibodies suffered a ∼2.4-fold increased atherosclerosis on a Neu5Gc-rich HFD, compared with Neu5Ac-rich or Sias-free HFD. Lesions in Neu5Gc-immunized and Neu5Gc-rich HFD-fed Cmah-/-Ldlr-/- mice were more advanced but unexplained by lipoprotein or glucose changes. Human evolutionary loss of CMAH likely contributes to atherosclerosis predisposition via multiple intrinsic and extrinsic mechanisms, and future studies could consider this more human-like model.

Literature review of allograft adenovirus nephritis and a case presenting as mass lesions in a transplanted kidney without symptoms of urinary tract infection or acute kidney injury.

Adenovirus (AdV) infection is a common complication in bone marrow/hematopoietic stem cell transplant and solid organ transplant recipients. AdV infection usually presents as hemorrhagic cystitis, but sometimes it can progress to acute kidney injury showing AdV nephritis (AdVN). We present the case of a 52-year-old Japanese female who had received a living kidney transplantation (KT) from her husband. At 21 months post-KT, the patient presented with a fever, but no renal dysfunction and no abnormal urine findings. A contrast-enhanced computed tomography (CT) scan revealed a few mass lesions with hypoperfusion in the transplanted kidney. An enhanced CT-guided biopsy targeting one of these lesions revealed a necrotizing tubulointerstitial nephritis suggesting AdVN. The polymerase chain reaction tests for ADV were negative in a urine sample but positive in the sera and the frozen kidney biopsy samples. AdVN can manifest as an unusual pattern of acute lobar nephritis/acute focal bacterial nephritis-like localization without symptoms of acute kidney injury or urinary tract infection. Enhanced CT can provide clues for clinical diagnosis.

Unusual ischemic kidney injury presenting as slowly declining graft function and successful use of oral desmopressin in a kidney transplant recipient with subclinical central diabetes insipidus.

Polyuria in post-kidney transplant (KT) patients is a common condition generally attributed to delayed tubular function, fluid administration, and solute diuresis. Since excessive water intake post-KT physiologically suppresses arginine vasopressin (AVP) secretion, central diabetes insipidus (CDI) caused by deficient primary AVP release can be overlooked. Although DDAVP (desmopressin) - a selective AVP V2 receptor agonist - has been used to treat massive polyuria, CDI rarely progresses to kidney injury due to the preservation of fluid balance by thirst-dependent osmoregulation. Administration of DDAVP in post-KT recipients with mild polyuria and subclinical CDI is difficult to assess, and whether long-term use of DDAVP is beneficial for the transplanted kidney has not been established. We present the case of a 36-year-old Japanese female who was diagnosed with subclinical/partial CDI post KT. CDI was caused by a sequela of suprasellar germinoma. Graft function gradually declined without evidence of hypovolemia or hypernatremia, and a kidney biopsy revealed advanced ischemic kidney injury. Although daily oral DDAVP administration did not increase extracellular fluid volume, treatment resulted in a gradual improvement of graft function, and a follow-up transplanted kidney biopsy indicated substantial recovery.

Monoclonal immunoglobulin G deposits on tubular basement membrane in renal allograft: is this significant for chronic allograft injury?

BACKGROUND: Tubular basement membrane immune deposits (TBMID) has rarely been observed in renal allografts. It is usually found in BK virus nephropathy and immune complex glomerulonephritis; however, its significance is not well understood. We conducted a retrospective clinicopathological study on monoclonal immunoglobulin G (IgG) TBMID. METHODS: We studied 7177 renal allograft biopsy specimens obtained from Tokyo Women's Medical University from 2007 to 2015 and performed light microscopic, electron microscopic and immunofluorescence studies. RESULTS: Tubular basement membrane (TBM) deposits of IgG were found in 73 biopsies from 61 patients and the IgG subclass was obtained in 31 biopsies. There were no cases of monoclonal IgA or IgM TBMID. In total, 13 biopsies from 10 patients showed monoclonal IgG TBMID. Of these, seven showed monoclonal IgG1κ TBMID and one each showed monoclonal IgG2κ, IgG2λ and IgG3κ TBMID. Conversely, eight patients showed polyclonal IgG TBMID. In electron microscopy, large granular electron-dense deposits (EDDs) in the TBM were detected in all patients with monoclonal IgG1κ TBMID. EDDs were absent in TBM in patients with monoclonal IgG2κ, IgG2λ or IgG3κ TBMID. Progression of interstitial fibrosis and tubular atrophy (IFTA) was significantly higher in patients with monoclonal IgG1κ TBMID than in those with polyclonal IgG TBMID (P < 0.05). There were no significant differences in the other clinical parameters between monoclonal IgG1κ and polyclonal IgG TBMID. CONCLUSIONS: This is the first study of patients with monoclonal IgG TBMID in renal allografts. We found that monoclonal IgG1κ TBMID was associated with EDD formation in TBM and IFTA progression.

Fate of full-house immunofluorescence staining in renal allograft: A case report.

Here, we report the case of a patient with renal allograft with full-house immunofluorescence staining in the zero-hour biopsy. Full-house immunofluorescence staining is a well-known characteristic of lupus nephritis. Previous studies have reported patients with full-house immunofluorescence staining, but without other symptoms or serological findings; this condition is referred to as full-house nephropathy. We identified only one case out of 2203 zero-hour biopsies over 13 years. Zero-hour biopsy presented no glomerular changes but showed full-house immunofluorescence staining. Electron microscopy revealed a nonorganized electron-dense deposit mainly in the mesangial lesion. Systemic lupus erythematosus (SLE)-associated antibodies were negative, and complement deficiency was not observed in the donor patients. Deposition of immunoglobulin and complement levels markedly decreased within 1-3 years post transplantation. Neither donor nor recipient developed clinical or biological features of SLE; they showed good renal prognosis.

Biopsy-proven vancomycin-induced acute kidney injury: a case report and literature review.

BACKGROUND: Vancomycin is the first-line antibiotic for methicillin-resistant Staphylococcus aureus and coagulase-negative strains. The risk of vancomycin-induced acute kidney injury increases with plasma vancomycin levels. Vancomycin-induced acute kidney injury is histologically characterized by acute interstitial nephritis and/or acute tubular necrosis. However, only 12 biopsy-proven cases of vancomycin-induced acute kidney injury have been reported so far, as renal biopsy is rarely performed for such cases. Current recommendations for the prevention or treatment of vancomycin-induced acute kidney injury are drug monitoring of plasma vancomycin levels using trough level and drug withdrawal. Oral prednisone and high-flux haemodialysis have led to the successful recovery of renal function in some biopsy-proven cases. CASE PRESENTATION: We present the case of a 41-year-old man with type 1 diabetes mellitus, who developed vancomycin-induced acute kidney injury during treatment for Fournier gangrene. His serum creatinine level increased to 1020.1 µmol/L from a baseline of 79.6 µmol/L, and his plasma trough level of vancomycin peaked at 80.48 µg/mL. Vancomycin discontinuation and frequent haemodialysis with high-flux membrane were immediately performed following diagnosis. Renal biopsy showed acute tubular necrosis and focal acute interstitial nephritis, mainly in the medullary rays (medullary ray injury). There was no sign of glomerulonephritis, but mild diabetic changes were detected. He was discharged without continuing haemodialysis (serum creatinine level, 145.0 µmol/L) 49 days after initial vancomycin administration. CONCLUSIONS: This case suggests that frequent haemodialysis and renal biopsy could be useful for the treatment and assessment of vancomycin-induced acute kidney injury, particularly in high-risk cases or patients with other renal disorders.

Two cases of kidney transplantation-associated thrombotic microangiopathy successfully treated with eculizumab.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is relatively rare and requires immediate intervention to avoid irreversible organ damage or death; however, consensus regarding the treatment approach is lacking. Atypical haemolytic uraemic syndrome (aHUS) is a rare disease caused by dysregulation of the alternative complement pathway resulting in TMA. aHUS is histologically similar to TA-TMA; approximately 60% of TA-TMA patients have complement dysregulation. Eculizumab, a humanized anti-C5 monoclonal antibody, inhibits terminal membrane-attack complex formation and TMA progression. Eculizumab has been successfully used to treat aHUS post-transplant. We present two cases of kidney TA-TMA due to unknown causes, suspected antibody-mediated rejection, or calcineurin inhibitor (CNI)-related toxicity that developed on day 1 or 2 post-kidney transplantation. Low platelet count and haemoglobin level with red cell fragments were detected. Despite steroid pulse, plasma exchange (PE), and intravenous immunoglobulin therapy, TA-TMA did not improve; therefore, eculizumab was administered despite no genetic testing. Laboratory data, including renal function, improved immediately. TA-TMA treatment primarily involves PE initiation or CNI discontinuation; eculizumab can be used to safely treat TA-TMA and then be ceased in the short term. Therefore, eculizumab administration might be beneficial for kidney TA-TMA as early as the diagnosis of refractory to PE.

Proliferative glomerulonephritis with monoclonal immunoglobulin G deposits complicated by immunoglobulin A nephropathy in the renal allograft.

Immunoglobulin (Ig) A nephropathy (IgAN) is a known autoimmune disease due to abnormal glycosylation of IgA1, and occasionally, IgG co-deposition occurs. The prognosis of IgG co-deposition with IgAN is adverse, as shown in the previous studies. However, in the clinical setting, monoclonality of IgG co-deposition with IgAN has not been observed. We describe a case of proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) combined with IgAN in a renal allograft. A-21-year-old man developed end-stage renal failure with unknown aetiology and underwent living-donor kidney transplantation from his mother 2 years after being diagnosed. One year after kidney transplantation, proteinuria 2+ and haematuria 2+ were detected; allograft biopsy revealed mesangial IgA and C3 deposits, indicating a diagnosis of IgAN. After tonsillectomy and steroid pulse therapy, proteinuria and haematuria resolved. However, 4 years after transplantation, pedal oedema, proteinuria (6.89 g/day) and allograft dysfunction (serum creatinine (sCr) 203.3 µmol/L) appeared. A second allograft biopsy showed mesangial expansion and focal segmental proliferative endocapillary lesions with IgA1λ and monoclonal IgG1κ depositions. Electron microscopic analysis revealed a massive amount of deposits, located in the mesangial and subendothelial lesions. A diagnosis of PGNMID complicated with IgAN was made, and rituximab and plasmapheresis were added to steroid pulse therapy. With this treatment, proteinuria was alleviated to 0.5 g/day, and the allograft dysfunction recovered to sCr 132.6 µmol/L. This case suggests a necessity for investigation of PGNMID and IgA nephropathy in renal allografts to detect monoclonal Ig deposition disease.

Atypical hemolytic uremic syndrome diagnosed four years after ABO-incompatible kidney transplantation.

Atypical hemolytic uremic syndrome (aHUS) in allograft kidney transplantation is caused by various factors including rejection, infection, and immunosuppressive drugs. We present a case of a 32 year old woman with aHUS four years after an ABO-incompatible kidney transplantation from a living relative. The primary cause of end-stage renal disease was unknown; however, IgA nephropathy (IgAN) was suspected from her clinical course. She underwent pre-emptive kidney transplantation from her 60 year old mother. The allograft preserved good renal function [serum creatinine (sCr) level 110-130 µmol/L] until a sudden attack of abdominal pain four years after transplant, with acute renal failure (sCr level, 385.3 µmol/L), decreasing platelet count, and hemolytic anemia with schizocytes. On allograft biopsy, there was thrombotic microangiopathy in the glomeruli, with a cellular crescent formation and mesangial IgA and C3 deposition. Microvascular inflammation, such as glomerulitis, peritubular capillaritis, and arteriole endarteritis were also detected. A disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) did not decrease and Shiga toxin was not detected. Donor-specific antibodies or autoantibodies, including anti-neutrophil cytoplasmic antibody and anti-glomerular basement membrane (anti-GBM) antibody, were negative. The patient was diagnosed with aHUS and received three sessions of plasmapheresis and methylprednisolone pulse therapy, followed by oral methylprednisolone (0.25-0.5 mg/kg) instead of tacrolimus. She temporarily required hemodialysis (sCr level, 658.3 µmol/L). Thereafter, her sCr level improved to 284.5 µmol/L without dialysis therapy. This case is clinically considered as aHUS after kidney transplantation, associated with various factors, including rejection, glomerulonephritis, and toxicity from drugs such as tacrolimus.

A case of recurrent focal segmental glomerulosclerosis after kidney transplantation associated with variant conversion in the Columbia classification.

Focal segmental glomerulosclerosis commonly recurs following kidney transplantation. A 33-year-old man underwent living donor kidney transplantation. Proteinuria appeared two months after transplantation, and an episode biopsy on postoperative day 66 revealed recurrent focal segmental glomerulosclerosis lesions of the cellular variant by Columbia classification. We reviewed the native kidney biopsy and confirmed collapsing variant focal segmental glomerulosclerosis. Plasma exchange therapy was performed, and his proteinuria temporarily resolved. A second allograft biopsy performed on postoperative day 200 showed no evidence of focal segmental glomerurosclerosis. He experienced incomplete remission with a proteinuria of 0.5 g/day during the subsequent three years until his urinary protein level rose to 1.3 g/day. A third biopsy performed on postoperative day 1248 showed focal segmental glomerulosclerosis cellular variant lesions. Plasma exchange was resumed in combination with additional rituximab, but his proteinuria persisted. Intermittent plasma exchange was performed 42 times in total. However, his proteinuria continued, and his renal function gradually worsened. A fourth biopsy performed on postoperative day 2540 showed focal segmental glomerulosclerosis collapsing variant lesions with severe interstitial fibrosis and tubular atrophy. He ultimately required hemodialysis seven years after transplantation. Intensive therapy with long-term intermittent plasma exchange and rituximab suppressed proteinuria and preserved graft function for seven years, at which time graft failure occurred. We here present the clinical course and histological findings from consecutive allograft biopsies.

Morphological characteristics in peritoneum in patients with neutral peritoneal dialysis solution.

Peritoneal dialysis solution (PDS) plays a role in functional and morphological damage to the peritoneum. This study aimed to clarify the effect of neutral PDS in preventing morphological changes by assessing peritoneal damage and comparing morphological alterations between PD patients treated with neutral PDS and acidic PDS. Sixty-one patients participated from seven hospitals. All patients were treated with neutral PDS excluding icodextrin, during their entire PD treatment, and experienced no episode of peritonitis. The thickness of submesothelial compact (SMC) zone and the presence of vasculopathy in the anterior parietal abdominal peritoneum were assessed. The impact of icodextrin, hybrid therapy, and peritoneal rest and lavage in morphological alterations were determined. There was no significant difference in the average SMC thickness between neutral and acidic PDS. The vessel patency in patients using neutral PDS was significantly higher compared to that in acidic PDS at any time during PD. There were no significant suppressive effects from interventions or use of icodextrin with respect to peritoneal morphological injury. A monolayer of mesothelial cell was observed in approximately half the patients, especially in their receiving lavage patients. Neutral PDS, accompanied by other preventive approaches against peritoneal injury, might suppress the development of peritoneal morphological alterations.

Assessment of renal congestion in a rat model with congestive heart failure using superb microvascular imaging.

PURPOSE: Renal congestion is a therapeutic target in congestive heart failure. However, its detailed evaluation in a clinical setting is challenging. This study sought to assess renal congestion impairment using superb microvascular imaging (SMI), a simple and accessible method. METHODS: Dahl salt-sensitive rats, used as a model for congestive heart failure, underwent central venous pressure (CVP) measurements. Renal congestion was evaluated through measurements of renal medullary pressure (RMP) and assessment of renal perfusion using contrast-enhanced ultrasonography at both the early (control group) and heart failure phases (HF group). All rats were assessed with SMI. The region of interest (ROI) was set in interlobular vessels, interlobar vessels, and a combination of these areas. The area ratio was calculated from the color pixel count in the ROI divided by the total pixel count in the ROI. Intrarenal perfusion index (IRPI) was defined as (maximum area ratio-minimum area ratio) / maximum area ratio. RESULTS: There were no significant differences in renal function and left ventricular ejection fraction between the two groups. CVP, time-to-peak (TTP) in the medulla, and RMP were higher in the HF group than in the control group. In the HF group, IRPI, evaluated in the interlobular vessels, was significantly higher than in the control group. IRPI was positively correlated with TTP in the medulla (p = 0.028, R = 0.60) and RMP (p < 0.001, R = 0.84), indicating that IRPI reflected renal congestion. CONCLUSIONS: IRPI is a useful tool for assessing renal congestion in rats with congestive heart failure.