Progression Of Renal Pathology Research Articles

High-Resolution Spatial Lipidomic Profiling of the Kidney During Periods of Cyst Expansion in a Mouse Model of ADPKD

Introduction: The progression of renal pathology in autosomal dominant polycystic kidney disease (ADPKD) involves a complex series of changes including renal cyst formation, interstitial cyst expansion, tubular atrophy, and fibrosis. Changes to in tissue metabolism and cyst fluid metabolite composition have been shown in ADPKD models, however it has been diffcult to discretely localize these compounds to specific regions of the kidney. Further, very little is known about lipid profiles within the kidney during ADPKD. We hypothesized that spatial lipidomic analysis during periods of cyst expansion would reveal new understanding of changes in lipid metabolism during this critical window of pathology. In this study we focused on changes in the mcwPkd1nl/nl mouse, a hypomorphic ADPKD model that rapidly develops a cystic phenotype. Methods: Kidneys were collected from female cystic mcwPkd1nl/nl mice at postnatal days 7, 14 and 28, representing periods preceding, during and at maximal cyst expansion, respectively. Control kidneys were collected from female wild-type littermates at postnatal day 7 and 28. Tissues were rapidly cryoembedded for 10 mm sectioning onto Intellislides (BrukerDaltonik). Slides were scanned on a Reflecta MF-5000 scanner and sprayed with 7 mg/mL CHCA in 70% Acetonitrile, 30% water and 0.1% TFA using a TM Sprayer Model M3 (HTX Technologies, LLC). Mass spec imaging data was acquired with a Bruker timsTOF Flex system (BrukerDaltonik) with a Smartbeam 3D laser at 10kHz and 10 μm resolution. Imaging data analysis was performed in SCiLS Lab software (version 2023b, Bruker). Calculations were performed on data normalized to total ion count (TIC). Spatial segmentation analysis of data was performed using an unsupervised bisecting k-means algorithm and resulting clusters were investigated by ROC. Lipid annotation was performed the Lipid Species annotation tool with MSDial VS68 spectral library in Metaboscape (version 2022b, Bruker). Results: There were vast global differences between lipid composition of wild-type and cystic kidneys at postnatal day 28. When comparing cystic to wild-type kidneys phosphoinositol and ceremide lipid species were decreased and other metabolites, such as thiophene-3-carboxylate and benzothiazine-2-carbonitrile, were increased at both PN7 and PN28. Further numerous lipid compounds were identified only within cystic fluid that have not been previously annotated. Conclusions: The results of this study, for the first time, reveals alterations in lipid molecule profiles throughout the cystic kidney in tandem with morphological changes. This is a major step forward in understanding how lipid metabolism changes in response to cyst expansion during the progression of ADPKD, as well as revealing molecular changes that precede cellular pathology. This work has been supported by Children’s Wisconsin Foundation and Children’s Research Institute. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Beneficial Effects of Mild Hyperuricemia in Salt-Sensitive Hypertension

Hyperuricemia (HrU) or increased plasma uric acid (UA) is associated with worsening hypertension (HTN) and kidney damage. Paradoxically, UA is also known to be an endogenous antioxidant. Some studies suggest that only HrU with crystals, but not asymptomatic HrU promotes the progression of these diseases. We hypothesized that mild asymptomatic HrU is beneficial in controlling the progression of salt-sensitive (SS) HTN. Due to sex differences in urate handling and SS HTN, we used both male and female Dahl SS rats in this study. Radiotelemetry was used to measure blood pressure and various approaches, including RNA-Seq, were employed to assess kidney injury and identify potential molecular mechanisms. Mild HrU was induced using 2% oxonic acid in the diet, a uricase inhibitor that prevents the breakdown of UA further into more soluble allantoin. Groups: 1-2) male and female 4% NaCl high salt (HS) diet; 3-4) male and female HS + 2% oxonic acid (HS/oxo) diet. After 3 weeks, in response to oxonic acid supplementation, both sexes showed a significant increase of UA in plasma compared to their respective HS-only controls (Males: 0.63 ±0.07 vs. 2.17 ±0.34; Females 0.78 ±0.15 vs. 2.04 ±0.35 mg/dl, HS vs. HS/oxo). Interestingly, only male HS/oxo rats showed a significant increase in uricosuria (Males: 0.23 ±0.03 vs. 0.45 ±0.06; Femaels: 0.26 ±0.06 vs. 0.26 ±0.001 UA/Cre, HS vs. HS/oxo). Moreover, the mild HrU was associated with a significant attenuation of the progression and magnitude of the mean arterial pressure in male but not female rats (Males: 157 ±3 vs. 136 ±3; Females: 155 ±6 vs. 154 ±5 mmHg, HS vs. HS/oxo). Xanthine oxidase (XO) is one of the enzymes that produce UA, and its activity has been shown to affect HTN as well. Therefore, we examined the level of XO activity in the plasma after the treatment. While there was no difference in the activity based on the diet within each sex, females had significantly lower levels of XO activity compared to males in each of the diets. To further investigate the beneficial phenotype seen in male rats, we evaluate changes in the progression of renal pathology. The HS/oxo group compared to the HS group had a lower kidney weight/body weight ratio and lower protein cast accumulation, indicating lower kidney damage. RNA-Seq analysis showed that the attenuated HTN phenotype was associated with an increased expression in Mas1 (MAS receptor), Klk-1 (Kallikrein-1), and Pcsk6 (PCSK6 enzyme) which can all lead to the activation of different vasodilatory pathways. Our study showed that in male but not female Dahl SS rats, asymptomatic mild HrU accompanied by hyperuricosuria ameliorates the progression of SS HTN and protects kidneys from further damage. This work is supported by the American Society of Nephrology Ben J. Lipps Research Fellowship Program (Dimitrios G. Oreopoulos Research Fellowship Award to L.V.D.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Oxidized Albumin: Evaluation of Oxidative Stress as a Marker for the Progression of Kidney Disease.

Oxidative stress has been reported to be associated with the progression of renal pathology as well as with the onset of complications associated with this condition. Bardoxolone methyl, a nuclear factor-erythroid 2-related factor 2 (Nrf2) activator with anti-oxidative and inflammatory modulation effects, has been reported to improve renal function in clinical trials. As of this writing, there have been no systems for the quantitative evaluation of oxidative stress that could be applied as a clinical test. We recently reported on post-translational modifications of albumin using electrospray-ionization time-of-flight mass spectrometry (ESI-TOF MS) and the results indicated that oxidized albumin (cysteinylated albumin: a molecule that was oxidatively cysteinylated at Cys34) was found to increase with the progression of renal pathology. A clinical study demonstrated that monitoring the levels of oxidized albumin could be useful for the early diagnosis of diabetic kidney disease and for predicting renal prognosis. Higher levels of serum oxidized albumin were also associated with cardiovascular complications or sarcopenia in patients who were undergoing hemodialysis. The overall findings indicate that oxidized albumin could also be an index of therapeutic efficacy against kidney disease. Oxidized albumin is not only a marker for kidney disease but also a nephrotoxic substance. This suggests that measuring the levels of oxidized albumin could be a biomarker for diagnosing the progression of and complications associated with renal disease in addition to evaluating the efficacy of therapeutic drugs.

Malabsorption syndrome aggravates calcium homeostasis impairment in chronic kidney disease patients

Abstract. Recent data on the role of digestive pathology in the progression of chronic kidney disease (CKD) remain scarce. Calcium homeostasis plays an important role in the progression of renal pathology, especially in patients with malabsorption syndrome (MAS).
 The research aimed to evaluate calcium homeostasis in CKD patients with MAS.
 Methods. In this cross-sectional observational study, 99 CKD patients with MAS were enrolled. The patients were divided into 4 groups according to the CKD stage and the presence of MAS. Group I included 25 patients with CKD stages 1 and 2 without MAS; Group II consisted of 26 patients with CKD stages 1 and 2, and MAS; Group ІІІ (n = 23) and Group ІV (n = 25) included patients with CKD stage 3 without and with MAS, respectively. According to the morphological study of in vivo biopsies of the small intestinal mucosa, mild and moderate morphological changes were observed among all patients. The levels of calcium, phosphorus, parathyroid hormone, osteocalcin, and calcitonin in the blood, as well as urinary calcium levels, were detected.
 Results. Pathological changes in calcium metabolism were observed among CKD patients with MAS. The severity of calcium homeostasis disorders was more evident among patients with CKD stage 3 compared with stages 1 and 2. Urinary calcium levels were reduced in the patients of Groups III and IV. No changes were detected in phosphorus levels. Changes in parathyroid hormone and osteocalcin are caused primarily by combined renal pathology with impaired renal calcium absorption.
 Conclusion. MAS in CKD patients leads to deep violations of calcium homeostasis resulting in rapid CKD progression and bone tissue violation.

Ураження нирок при геморагічному васкуліті Шенлейна — Геноха, що почався в дитячому і дорослому віці

Метою роботи стала порівняльна оцінка клініко-лабораторних і морфологічних проявів ниркової патології при геморагічному васкуліті Шенлейна — Геноха, що почався в дитячому та дорослому віці. Ураження нирок відзначено у 71 % від числа хворих (незалежно від віку пацієнтів у дебюті хвороби нефропатія зустрічалася з однаковою частотою), серед яких нефротичний синдром сформувався у 4 % випадків, хронічна хвороба нирок II, III, IV i V стадій — у 28 % спостережень (співвідношення 10 : 5 : 1 : 1), причому, за даними нефробіоптатів, у пацієнтів із трансформацією хвороби з ювенільної виявилися меншими ступені ураження ниркових артеріол, клубочків, канальців й строми, нижчими темпи прогресування ниркової недостатності, рівні артеріального тиску та периферійного судинного опору, а в цілому дебютний вік хворих впливає на подальшу частоту IV, V і VI класів генохівського гломерулонефриту, визначає рівень лімфогістіоцитарної інфільтрації судинних стінок й депозицій імуноглобулінів в клубочках та судинах.

Scanning ion conductance microscopy of live human glomerulus.

Podocyte damage is a hallmark of glomerular diseases, such as focal segmental glomerulosclerosis, typically associated with marked albuminuria and progression of renal pathology. Podocyte structural abnormalities and loss are also linked to minimal change disease and more common diabetic kidney disease. Here we applied the first‐time scanning ion conductance microscopy (SICM) technique to assess the freshly isolated human glomerulus's topology. SICM provides a unique opportunity to evaluate glomerulus podocytes as well as other nephron structural segments with electron microscopy resolution but in live samples. Shown here is the application of the SICM method in the live human glomerulus, which provides proof of principle for future dynamic analysis of membrane morphology and various functional parameters in living cells.

Diagnostic And Prognostic Importance Of Proteinuria In Development Of Chronic Kidney Disease In Persons With High Risk Factor

Proteinuria, which is a predictor of early diagnosis of chronic kidney disease, is also a risk factor for the development and progression of renal pathology. The relationship is multifaceted and is built according to the type of feedback. On the one hand, the kidney can act as a target organ for most risk factors such as arterial hypertension, ischemic heart disease, diabetes mellitus, age, obesity associated with albuminuria. On the other hand, decreased renal function and severe albuminuria are an important reason for the accelerated development of end-stage chronic kidney disease.

EFFECT OF RENAL DYSFUNCTION ON THE CARDIACVASCULAR SYSTEM. THE POSSIBILI TIES OF EARLY DIAGNOSIS OF THE RENAL DYSFUNCTION

The review is devoted to the discussion of modern concepts of the role of renal dysfunction in the development of chronic myocardial dysfunction in the context of cardio-renal syndrome (RVC) type 4. At the beginning of the review, the definition of cattle is given, general questions of pathogenesis and diagnosis of the disease are addressed. It is indicated that in patients with the initial stage of CKD, cardiovascular disorders are already registered which in the late stages of development of renal dysfunction are the leading causes of death and the true severity of the disease in patients with renal dysfunction is associated with an increased risk of cardiovascular events, rather than an achievement terminal renal failure and requiring renal replacement therapy. The progression of renal pathology leads to damage to the heart through various mechanisms and factors, both traditional and non-traditional, some of which, at the culmination of the renal continuum, are the result of the dialysis procedure itself in patients with terminal renal dysfunction. Mechanisms for the development of congestive heart failure in type 4 cattle include pressure overload (arterial hypertension) and volume (anemia, edematous syndrome), which increase in proportion to the decrease in renal function. Increase in blood pressure, changes in intracardial hemodynamics, deterioration of arterial compliance contribute to the acceleration of cardiovascular events. The role of laboratory predictors of renal dysfunction in the progression of cardiovascular disorders is discussed. The general approaches of echocardiographic visualization of the heart cavities and its importance in the diagnosis of cardiovascular diseases are discussed. Special attention is paid to the development of pulmonary arterial hypertension, changes in the left and right ventricle of the myocardium with renal dysfunction.

Aminoguanidine pyridoxal adduct is superior to aminoguanidine for preventing diabetic nephropathy in mice.

Aminoguanidine inhibits the formation of advanced glycation end-products, and has been extensively examined in animals. However, administration of aminoguanidine decreases the hepatic content of pyridoxal phosphate. In order to avoid this problem, we developed an aminoguanidine pyridoxal Schiff base adduct and examined its efficacy in vitro as well as in a model of diabetic nephropathy. Mice with streptozotocin-induced diabetes were treated with aminoguanidine or aminoguanidine pyridoxal adduct for 9 weeks. An in vitro study was also performed to assess the antioxidant activity of aminoguanidine and its pyridoxal adduct. Neither drug altered glycemic control. Aminoguanidine pyridoxal adduct significantly improved urinary albumin excretion by 78.1 % compared with the diabetic control, and also had a better preventive effect on the progression of renal pathology than aminoguanidine did. Inhibition of glycation by both drugs was similar, but the antioxidant activity of the pyridoxal adduct was far superior. These findings suggest that aminoguanidine pyridoxal adduct may be superior to aminoguanidine, as it not only prevents vitamin B6 deficiency but is also better at controlling diabetic nephropathy, as this adduct inhibits oxidation as well as glycation.