A case of primary aldosteronism with excessive secretion of renin that was unmasked by kidney transplantation.

A 42-year-old man showed marked hypokalemia after kidney transplantation. He was diagnosed with hypertension and suffered from acute myocardial infarction at 33 and 38 years of age. At 40 years of age, hemodialysis was introduced. A left adrenal tumor was noted and suspected as a non-functional adrenal adenoma at that time. Therefore, he received a living-donor kidney transplant at 42 years of age. After kidney transplantation, the serum creatinine level dropped. His blood pressure remained high, and the serum potassium level decreased. The PRA and PAC were elevated, and ARR was not elevated. Based on the results of various confirmatory tests and vein sampling, he was diagnosed with excessive secretion of renin from the native kidneys that was complicated by primary aldosteronism (PA), and left nephrectomy and adrenalectomy were performed. The overproduction of aldosterone in the resected adrenal adenoma and over secretion of renin in the kidney with arteriolosclerosis were immunohistologically confirmed. After surgery, the PAC decreased, but the PRA did not decrease. The postoperative serum potassium level improved, and the blood pressure was well controlled with a small dose of medication. This is the first reported case of PA with hyperreninemia after kidney transplantation. It should be noted that PA in dialysis patients and kidney transplant recipients may not fulfill the usual diagnostic criteria of an elevated ARR. In such patients, PA should be suspected based on the absolute value of the PAC and responsiveness to ACTH stimulation, and adrenal and renal vein sampling is required for a definitive diagnosis.

A Patient with Mitochondrial Disease on Dialysis with Long-term Follow-up of Cardiomyopathy: An Autopsy Case Report.

A 59-year-old man developed diabetes at 24 years old and underwent hemodialysis at 42 years old. At 54 years old, cardiac dysfunction with left ventricular hypertrophy was detected, followed by complete atrioventricular block at 57 years old. The patient was diagnosed with mitochondrial disease based on a myocardial biopsy and the presence of a mitochondrial DNA mutation (3243A>G). He died of septic shock at 59 years old, and an autopsy confirmed mitochondrial cardiomyopathy. If progressive cardiac hypertrophy and conduction disturbances are observed in patients with diabetes mellitus on long-term hemodialysis, mitochondrial disease needs to be considered.

Concordance between practice and published evidence in the management of ANCA-associated vasculitis in Japan: A cross-sectional web-questionnaire survey.

OBJECTIVES: We conducted a descriptive study of the physicians' evidence-practice gap for adults covered by the 2017 clinical practice guidelines for the management of antineutrophil cytoplasmic antibody-associated vasculitis in Japan. METHODS: This web-based survey, conducted between January and February 2021, involved physicians who had treated at least five patients in the preceding year at a regional core hospital. The outcome was the physicians' experience in treating patients with microscopic polyangiitis or granulomatosis with polyangiitis [prevalence with 95% confidence intervals (CIs)], defined as treating at least 60% of their patients with the recommended therapy during the year. A modified Poisson regression analysis was performed to explore the factors associated with concordance. RESULTS: The 202 participants included 49 pulmonologists, 65 nephrologists, 61 rheumatologists, and other physicians. The concordance was 31.5% (95% CI, 25.1-38.5) of physicians who used cyclophosphamide or rituximab for the induction of remission. Rheumatology showed the highest concordance with published evidence (risk ratio = 2.4; 95% CI, 1.10-5.22, p = .03). CONCLUSIONS: These results suggest an evidence-practice gap, which varies substantially among subspecialties. Further studies and a new promotional initiative are necessary to close this gap in clinical practice.

Economies of scale in constructing plant factories with artificial lighting and the economic viability of crop production.

Since the introduction of LED lamps a decade ago, the plant factory with artificial lighting (PFAL) has been expected to be a savior that overcomes the food crisis, brings food safety, and enhances environmental friendliness. Despite such high expectations, the diffusion of commercial crop production in PFALs has been slow. It has been said that the main reason for this is the huge initial investment required to construct PFALs. This situation has attracted studies to access the economic feasibility of the crop production in PFALs. One thing strange in these studies is that they pay little attention to the scale of their PFALs. PFALs are factories so that they would be subject to economies of scale. If so, the scale of PFALs is an important factor that determines the economic feasibility of plant production in PFALs. However, no study has thus far attempted to examine whether economies of scale exist in the construction of PFALs. To fill this gap, this paper tries to examine, based on the data on the investment cost of PFAL construction collected from various countries and regions in the world, whether economies of scale exist in PFAL construction and, if yes, how it affects the economic viability of the plant production in PFALs by searching for the minimum scale that ensures PFAL crop production economically viable. The results show that economies of scale exist in PFAL construction, and that the production of lettuce, PFALs' most popular crop, is now well on a commercial basis with the technology level of the most advanced PFAL operators, but strawberries has not reached that stage yet. It is also shown that crop production in PFALs is highly sensitive to changes in the yield and the price of the crops: A 30% decline either in the yield or the price of lettuce would easily bring PFALs bankruptcy. It is discussed that the optimum scale of PFALs would depend not only on the economies of scale but also on the transaction costs, such as the costs of searching and keeping a sufficient number of buyers who offer good and stable crop prices.

Dural arteriovenous fistula following cerebral venous sinus thrombosis in a patient with minimal change disease: A case report.

A 78-year-old man presented with nephrotic syndrome and new-onset disorientation. Plasma D-dimer level was increased, and a lower leg deep vein thrombosis was identified on ultrasound. Histopathologic analysis of percutaneous renal biopsy samples confirmed the diagnosis of minimal change disease. Treatment with prednisone (20 mg/day), cyclosporine (50 mg/day), and anticoagulant therapy with edoxaban tosylate hydrate led to the complete resolution of nephrotic syndrome after 4 weeks. Despite this, his disorientation persisted. Head CT and MRI have revealed cerebral venous sinus thrombosis and dural arteriovenous fistula, which was considered a possible complication of nephrotic syndrome. Embolization dramatically improved his disorientation. This paper highlights that cerebral venous sinus thrombosis and dural arteriovenous fistula should always be considered in patients with nephrotic syndrome and new-onset disorientation.

Detection of Treponema pallidum by immunocytochemistry of cervical smear: A case report.

Syphilis is an infectious disease caused by Treponema pallidum (T. pallidum). A cervical smear is useful when screening for sexually transmitted diseases; however, T. pallidum is not detected in the usual Papanicolaou smear. We report the detection of T. pallidum by immunocytological examination of a cervical smear. A 22-year-old woman presented with nephrotic syndrome. On admission, we performed screening tests for infections, and her serology was positive for syphilis. A Papanicolaou cervical smear (Thin-Prep) showed slight nuclear enlargement, nuclear irregularity, and mild hyperchromasia in the superficial cells, but no organism was detected. T. pallidum was detected in the remaining specimen using immunocytochemistry. We also detected the T. pallidum DNA in a cervical biopsy specimen by polymerase chain reaction (PCR). Our findings suggest that immunocytological examination and PCR assay examination are useful tests for syphilis diagnosis.

Continuous Lighting and High Daily Light Integral Enhance Yield and Quality of Mass-Produced Nasturtium (Tropaeolum majus L.) in Plant Factories.

Nasturtium (Tropaeolum majus L.), as a medicinal plant, has a high phenolic content in its leaves and flowers. It is often used in salads as a dietary vegetable. Attracting strong demand, it could be a good candidate crop for a plant factory with artificial lighting (PFAL) that can achieve the mass production of high-quality crops with high productivity by regulating environmental conditions such as light. In this study, two experiments were conducted to investigate the effects of continuous lighting (CL) and different daily light integrals (DLIs) under CL on the growth, secondary metabolites, and light use efficiency (LUE) of nasturtium, all of which are essential in the successful cultivation in PFALs. In Experiment 1, two lighting models, the same DLI of 17.3 mol m-2 d-1 but different light periods (24 and 16 h) with different light intensities (200 and 300 µmol m-2 s-1, respectively), were applied to nasturtium. The results showed that leaf production, secondary metabolites, and LUE were higher under the 24-h CL treatment than under the 16-h non-CL treatment. In Experiment 2, three DLI levels (17.3, 25.9, and 34.6 mol m-2 d-1) under the CL condition were applied. The results showed that the growth parameters were positively correlated with the DLI levels under CL. The lowest DLI had the highest LUE. We conclude that the mass production of nasturtium under CL in PFALs is feasible, and the yield increases as DLI increases from 17.3 to 34.6 mol m-2 d-1 under CL without causing physiological stress on plants.

Development of a novel AlphaLISA ImmunoAssay for Big angiotensin-25.

We previously described the discovery of Big angiotensin-25 (Bang-25), an angiotensin-related peptide isolated from human urine. Bang-25 consists of the first 25 amino acids of the N-terminus of angiotensinogen (Aogen), with N-linked glycosylation on the 14th amino acid and a cysteine conjugated to the 18th amino acid. Bang-25 is rapidly converted into angiotensin II (Ang II) by chymase. Because Bang-25 is widely distributed in human tissues, including islet cells in the pancreas and podocytes in the kidney, we hypothesized that it may participate in the Ang II production system in these tissues. To test this hypothesis, we developed a specific assay for Bang-25 and used it to examine the urinary concentrations of Bang-25 in patients with diabetes mellitus (DM). The assay used the Amplified Luminescent Proximity Homogeneous Assay (Alpha)-based ELISA method (AlphaLISA) of PerkinElmer Japan and included antibodies specific to the N-terminus of Ang II and the C-terminus of Bang-25. The AlphaLISA ImmunoAssay specifically recognized Bang-25 and had no cross-reactivity with Aogen or Ang I. Bang-25 was detected in healthy volunteers' urine samples but not in their plasma samples. In patients with DM, the urinary Bang-25 concentration was significantly higher than in healthy volunteers. Moreover, the results indicated that the Bang-25 concentration in the urine may offer a different perspective on disease status from that provided by urinary albumin. This assay could provide a useful tool for determining urinary Bang-25, which may prove an important biomarker for diabetic kidney disease.

Urinary podocyte mRNAs precede microalbuminuria as a progression risk marker in human type 2 diabetic nephropathy.

Earlier detection of progression risk in diabetic nephropathy will allow earlier intervention to reduce progression. The hypothesis that urinary pellet podocyte mRNA is a more sensitive progression risk marker than microalbuminuria was tested. A cross sectional cohort of 165 type 2 diabetics and 41 age and sex-matched controls were enrolled. Podocyte stress (Urinary pellet podocin:nephrin mRNA ratio), podocyte detachment (Urinary pellet podocin mRNA:creatinine ratio: UPPod:CR) and a tubular marker (Urinary pellet aquaporin 2:creatinine ratio) were measured in macro-albuminuric, micro-albuminuric and norm-albuminuric groups. eGFR was reassessed after 4 years in 124 available diabetic subjects. Urinary pellet podocyte and tubular mRNA markers were increased in all diabetic groups in cross-sectional analysis. After 4 years of follow-up univariable and multivariate model analysis showed that the only urinary markers significantly related to eGFR slope were UPPod:CR (P < 0.01) and albuminuria (P < 0.01). AUC analysis using K-fold cross validation to predict eGFR loss of ≥ 3 ml/min/1.73m2/year showed that UPPod:CR and albuminuria each improved the AUC similarly such that combined with clinical variables they gave an AUC = 0.70. Podocyte markers and albuminuria had overlapping AUC contributions, as expected if podocyte depletion causes albuminuria. In the norm-albuminuria cohort (n = 75) baseline UPPod:CR was associated with development of albuminuria (P = 0.007) and, in the tertile with both normal kidney function (eGFR 84 ± 11.7 ml/min/1.73m2) and norm-albuminuria at baseline, UPPod:CR was associated with eGFR loss rate (P = 0.003). In type 2 diabetics with micro- or macro-albuminuria UPPod:CR and albuminuria were equally good at predicting eGFR loss. For norm-albuminuric type 2 diabetics UPPod:CR predicted both albuminuria and eGFR loss.

Concurrent minimal change nephrotic syndrome and type 1 diabetes mellitus in an adult Japanese woman: a case report.

BACKGROUND: Concurrent type 1 diabetes mellitus (T1DM) and idiopathic nephrotic syndrome is rare, and most previously reported cases were in children. We report the case of an adult woman who developed T1DM and minimal change nephrotic syndrome (MCNS) nearly simultaneously. CASE PRESENTATION: A 24-year-old woman had first presented to another hospital with nausea, vomiting, and fatigue. She was diagnosed with diabetic ketoacidosis and T1DM on the basis of her hyperglycemia, ketoacidosis, and positive anti-glutamic acid decarboxylase antibody test result. Rapid infusion of normal saline and insulin administration alleviated hyperglycemia and ketoacidosis. Two weeks after admission, however, she developed nephrotic syndrome (NS) with rapidly decreasing urine volume. She was referred to our hospital with a diagnosis of acute kidney injury. Although she temporarily required dialysis and high doses of insulin, within 1 month NS and acute kidney injury had been alleviated by oral prednisolone and low-density lipoprotein apheresis. Renal biopsy showed minor glomerular abnormalities without diabetic nephropathy, so we diagnosed her with MCNS. Seven weeks after the discharge, NS relapsed, and cyclosporine was added to prednisolone. However, NS relapsed twice within the next 4 months, so we started her on rituximab. At 6 months after initiating rituximab therapy, she remained in complete remission. Her mother also had T1DM but not MCNS. The patient had HLA-DRB1*09:01/09:01, DQB1*03:03/03:03, and her mother had HLA-DRB1*04:05/09:01, DQB1*03:03/04:01. CONCLUSIONS: Concurrent T1DM and MCNS is rare and their coexistence might be coincidental. Alternatively, they might have been caused by an underlying, unidentified genetic predisposition. Previous reports and our patient's findings suggest that specific HLA alleles and haplotypes or a Th1/Th2 imbalance might be associated with T1DM and MCNS that occurred nearly simultaneously.

Case Report: A Case of Encephalopathy Presenting the Lentiform Fork Sign on MRI in a Diabetic Dialysis Patient.

Basal ganglia lesions showing an expansile high signal intensity on T2-weighted MRI are termed the lentiform fork sign. This specific finding is mainly observed in diabetic patients with uremic encephalopathy with metabolic acidosis, although there are also reports in patients with ketoacidosis, dialysis disequilibrium syndrome, intoxication, and following drug treatment (e.g., metformin). A 57-year-old Japanese man on chronic hemodialysis for 4 years because of diabetic nephropathy was admitted to our hospital for relatively rapid-onset gait disturbance, severe dysarthria, and consciousness disturbance. Brain T2-weighted MRI showed the lentiform fork sign. Hemodialysis was performed the day before admission, and laboratory tests showed mild metabolic (lactic) acidosis, but no uremia. Surprisingly, metformin, which is contraindicated for patients with end-stage kidney disease, had been prescribed for 6 months in his medication record, and his sluggish speaking and dysarthria appeared gradually after metformin treatment was started. Thus, the encephalopathy was considered to be related to metformin treatment. He received hemodialysis treatment for 6 consecutive days, and his consciousness disturbance and dysarthria improved in 1 week. At the 8-month follow-up, the size of the hyperintensity area on MRI had decreased, while the mild gait disturbance remained. Considering the rapid onset of gait and consciousness disturbance immediately before admission, diabetic uremic syndrome may also have occurred with metformin-related encephalopathy, and resulted in the lentiform fork sign, despite the patient showing no evidence of severe uremia on laboratory data.

Urinary podocyte mRNA is a potent biomarker of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

BACKGROUND: Anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN) is a critical kidney disease that sometimes results in an unfavorable renal outcome. Cellular crescent formation is a hallmark of ANCA-GN and is associated with renal prognosis, response to treatment, and it was reportedly associated with podocyte detachment. Because there is a need to explore non-invasive biomarkers for the evaluation of ANCA-GN activity, we tested whether urinary podocyte mRNA might be a potent non-invasive biomarker. METHODS: We measured two different types of urinary podocyte mRNA, including podocin mRNA in relation to urine creatinine concentration (U-PodCR) and urinary podocin mRNA in relation to nephrin mRNA (U-PNR), which were reportedly associated with the activity of various glomerular diseases. RESULTS: In ANCA-GN patients (n = 19), we discovered that U-PodCR was positively correlated with the percent of crescent formation until 50% crescent was reached because of podocyte depletion; U-PNR was correlated with the percent of crescent formation in all patients. Furthermore, patients with high levels of urinary podocyte mRNA exhibited a favorable renal outcome compared with the outcomes of patients with low levels of urinary podocyte mRNA. The levels of urinary podocyte mRNA were correlated with the rate of improvement in estimated glomerular filtration rate. CONCLUSIONS: U-PodCR, U-PNR or a combination of these parameters might serve as a non-invasive potential biomarker in patients with ANCA-GN to predict the percent of crescent formation and renal prognosis.

Podocyte hypertrophic stress and detachment precedes hyperglycemia or albuminuria in a rat model of obesity and type2 diabetes-associated nephropathy.

Type2 diabetes-associated nephropathy is the commonest cause of renal failure. Mechanisms responsible are controversial. Leptin-deficient hyperphagic Zucker (fa/fa) rats were modeled to test the hypothesis that glomerular enlargement drives podocyte hypertrophic stress leading to accelerated podocyte detachment, podocyte depletion, albuminuria and progression. By 6weeks, prior to development of either hyperglycemia or albuminuria, fa/fa rats were hyperinsulinemic with high urinary IGF1/2 excretion, gaining weight rapidly, and had 1.6-fold greater glomerular volume than controls (P < 0.01). At this time the podocyte number per glomerulus was not yet reduced although podocytes were already hypertrophically stressed as shown by high podocyte phosphor-ribosomal S6 (a marker of mTORC1 activation), high urinary pellet podocin:nephrin mRNA ratio and accelerated podocyte detachment (high urinary pellet podocin:aquaporin2 mRNA ratio). Subsequently, fa/fa rats became both hyperglycemic and albuminuric. 24 hr urine albumin excretion correlated highly with decreasing podocyte density (R2 = 0.86), as a consequence of both increasing glomerular volume (R2 = 0.70) and decreasing podocyte number (R2 = 0.63). Glomerular podocyte loss rate was quantitatively related to podocyte detachment rate measured by urine pellet mRNAs. Glomerulosclerosis occurred when podocyte density reached <50/106um3. Reducing food intake by 40% to slow growth reduced podocyte hypertrophic stress and "froze" all elements of the progression process in place, but had small effect on hyperglycemia. Glomerular enlargement caused by high growth factor milieu starting in pre-diabetic kidneys appears to be a primary driver of albuminuria in fa/fa rats and thereby an under-recognized target for progression prevention. Progression risk could be identified prior to onset of hyperglycemia or albuminuria, and monitored non-invasively by urinary pellet podocyte mRNA markers.

Non-canonical Expression of Cardiac Troponin-T in Neuroendocrine Ethmoid Sinus Carcinoma Following Immune Checkpoint Blockade.

We describe the case of a patient with neuroendocrine ethmoid sinus carcinoma, who exhibited markedly elevated levels of serum cardiac troponin-T and creatine kinase (CK)-MB isoenzyme without any symptom after the administration of nivolumab, immune checkpoint inhibitor. The repeated 12-leads-electrocardiogram did not show any changes in the ST-T segments or arrhythmias. The echocardiogram showed normal ranges of left ventricular contraction in the clinical course. Cardiac magnetic resonance imaging showed minimal myocardial edema and inflammation. Blood clots in the metastatic lesion of bone marrow aspirates exhibited positive staining for cardiac troponin-T and CK-MB in the cytoplasm and nucleoplasm of neoplastic cells. Although we did not perform a second cardiac magnetic resonance imaging and autopsy, we postulate that the attack of the neoplastic cells by the immune checkpoint inhibitor or the secretion from neoplastic cell-derived extracellular vesicles may have exacerbated the increase in concentrations of these molecules in the blood. Our case should warrant consideration a false-positive value of cardiac troponin-T and CK-MB can be obtained in cases with malignancy.

Characterisation of N-terminal pro-brain natriuretic peptide in dialysis patients and its reduced prognostic significance in the elderly.

Characterisation of N-terminal pro-brain natriuretic peptide (NT-proBNP) in chronic haemodialysis patients and its prognostic significance in age stratification have not been addressed. A prospective cohort study with cross-sectional analyses at baseline was performed. Outcomes were all-cause mortality, non-malignancy-related mortality, and cardiovascular disease (CVD)-related mortality. NT-proBNP was significantly higher in elderly, female, and low dry weight patients. Study patients were divided into two groups: Group-O (≥75 years) and Group-Y (<75 years). The 7-year follow-up receiver operating curve analysis showed that NT-proBNP significantly predicted all outcomes. All-cause mortality cut-off points were significantly different among the groups (total cohort, 5375 pg/mL; Group-Y, 3682 pg/mL; Group-O, 11750 pg/mL). Cox regression analysis showed risks for all outcomes by tertile NT-proBNP significantly higher in the total cohort and Group-Y as adjusted by potential confounders. For all-cause mortality, hazard ratios and 95% confidence intervals (CI) were T2 1.70 (0.89 to 3.25), p = 0.11, T3 2.95 (1.54 to 5.67), p < 0.01 in Group-Y; and T2 1.00 (0.64 to 1.58), p = 1.00; T3 1.50 (0.94 to 2.40), p = 0.09 in Group-O. In conclusion, NT-proBNP was significantly higher in elderly, female, and low dry weight chronic dialysis patients. NT-proBNP was significantly associated with all outcomes. However, this association was reduced in elderly patients.

Geriatric screening tools predict survival outcomes in older patients with diffuse large B cell lymphoma.

The proportion of elderly patients with diffuse large B cell lymphoma (DLBCL) appears to be increasing, with outcomes varying widely because of the patients' heterogeneity. Geriatric assessment is used to predict prognosis in elderly patients with DLBCL, but the utility of two simple screening tools for patients with DLBCL, the Flemish version of the Triage Risk Screening Tool (fTRST) and G8, has remained to be elucidated. We retrospectively assessed patients using fTRST and G8, and evaluated the impacts of the scores on survival outcomes in older patients with newly diagnosed DLBCL. A total of 59 patients aged 65 years or older and who were diagnosed with DLBCL were included. The median age was 77 years (range, 65-91 years), and the initial treatments were R-CHOP (63%) and R-THPCOP (31%). The estimated 2-year overall survival (OS) rate was significantly lower in patients with abnormal fTRST scores (≥ 2; N = 17) than in those with normal fTRST scores (< 2; N = 42): (50.5% (95% CI, 22.7-73.0%) vs. 82.2% (95% CI, 63.8-91.8%), P = 0.007). The estimated 2-year OS rate was significantly lower also in patients with abnormal G8 scores (≤ 14; N = 38) than in those with normal G8 scores (> 14; N = 21): (66.1% (95% CI, 46.7-79.5%) vs. 86.8% (95% CI, 55.7-96.7%), P = 0.03, respectively). These associations were independently significant after adjusting for other significant factors by multivariate analysis. These results suggest that the easy-to-use geriatric screening tools, fTRST and G8, have strong prognostic value for OS in older patients with DLBCL.

Diminishing dry weight is strongly associated with all-cause mortality among long-term maintenance prevalent dialysis patients.

OBJECTIVES: To investigate the relationship between dry weight (DW) change and survival in long-term maintenance prevalent dialysis patients. METHODS: We conducted a prospective data collection study with retrospective analysis of the registered data. Patients were followed up for 5 years (1-year observation of DW changes and subsequent 4-year follow-up). The outcome was all-cause mortality. The predictors were 1-year DW change rates. The hazard ratios (HRs) for all-cause mortality were calculated using multivariable Cox regression analysis, fully adjusted for age, sex, basal kidney disease, dialysis vintage, current smoking, past cardiovascular events, serum albumin, DW at enrollment, serum creatinine, mean predialysis systolic blood pressure, and cardiothoracic ratio or 1-year cardiothoracic ratio change rate. Propensity score (PS) analysis was also conducted using the same covariates of Cox regression analysis. RESULTS: In total, 899 dialysis patients (mean dialysis vintage: 101.2 months) were followed up, and 180 deaths were recorded, of which 90 were of cardiovascular origin. Each 2% decrement of DW showed adjusted HR, and the 95% confidence interval was 1.24 [1.16-1.33]. According to the 1-year DW change rate, participants were divided into five groups (group A, ≥+3%; group B, +1 to +2.9%; group C, -0.9 to +0.9%; group D, -2.9 to -1.0%; and group E, ≤-3%). For survival curves based on grouping, group B had the best and group E had the worst survival rate (p<0.01, log-rank test). Therefore, we set group B as a reference; adjusted risks for death of groups D and E were 2.16 [1.23-3.79] and 2.66 [1.54-4.58], respectively. However, this relation was blunted in patients of heavier DW. The PS-matched cohort showed a poorer prognosis in patients with diminishing DW divided by DW change rate at -0.635% (mean value of DW change rate). CONCLUSION: In the long-term maintenance hemodialysis cohort, 1-year DW decrement, especially ≤-3.0%, was significantly associated with all-cause mortality, and cardiovascular disease-related death was prominent in these patients.

FSGS as an Adaptive Response to Growth-Induced Podocyte Stress.

Glomerular sclerotic lesions develop when the glomerular filtration surface area exceeds the availability of podocyte foot process coverage, but the mechanisms involved are incompletely characterized. We evaluated potential mechanisms using a transgenic (podocin promoter-AA-4E-BP1) rat in which podocyte capacity for hypertrophy in response to growth factor/nutrient signaling is impaired. FSGS lesions resembling human FSGS developed spontaneously by 7 months of age, and could be induced earlier by accelerating kidney hypertrophy by nephrectomy. Early segmental glomerular lesions occurred in the absence of a detectable reduction in average podocyte number per glomerulus and resulted from the loss of podocytes in individual glomerular capillary loops. Parietal epithelial cell division, accumulation on Bowman's capsule, and tuft invasion occurred at these sites. Three different interventions that prevented kidney growth and glomerular enlargement (calorie intake reduction, inhibition of mammalian target of rapamycin complex, and inhibition of angiotensin-converting enzyme) protected against FSGS lesion development, even when initiated late in the process. Ki67 nuclear staining and unbiased transcriptomic analysis identified increased glomerular (but not podocyte) cell cycling as necessary for FSGS lesion development. The rat FSGS-associated transcriptomic signature correlated with human glomerular transcriptomes associated with disease progression, compatible with similar processes occurring in man. We conclude that FSGS lesion development resulted from glomerular growth that exceeded the capacity of podocytes to adapt and adequately cover some parts of the filtration surface. Modest modulation of the growth side of this equation significantly ameliorated FSGS progression, suggesting that glomerular growth is an underappreciated therapeutic target for preservation of renal function.