Renal Mass Reduction Research Articles

NaHCO3 loading causes increased arterial pressure and kidney damage in rats with chronic kidney disease.

Sodium bicarbonate (NaHCO3) is commonly utilized as a therapeutic to treat metabolic acidosis in people with chronic kidney disease (CKD). While increased dietary sodium chloride (NaCl) is known to promote volume retention and increase blood pressure, the effects of NaHCO3 loading on blood pressure and volume retention in CKD remain unclear. In the present study, we compared the effects of NaCl and NaHCO3 loading on volume retention, blood pressure, and kidney injury in both 2/3 and 5/6 nephrectomy remnant kidney rats, a well-established rodent model of CKD. We tested the hypothesis that NaCl loading promotes greater volume retention and increases in blood pressure than equimolar NaHCO3. Blood pressure was measured 24 h daily using radio telemetry. NaCl and NaHCO3 were administered in drinking water ad libitum or infused via indwelling catheters. Rats were housed in metabolic cages to determine volume retention. Our data indicate that both NaHCO3 and NaCl promote hypertension and volume retention in remnant kidney rats, with salt-sensitivity increasing with greater renal mass reduction. Importantly, while NaHCO3 intake was less pro-hypertensive than equimolar NaCl intake, NaHCO3 was not benign. NaHCO3 loading significantly elevated blood pressure and promoted volume retention in rats with CKD when compared with control rats receiving tap water. Our findings provide important insight into the effects of sodium loading with NaHCO3 in CKD and indicate that NaHCO3 loading in patients with CKD is unlikely to be benign.

Total Outflow of High-Density Lipoprotein–Cholesteryl Esters from Plasma Is Decreased in a Model of 3/4 Renal Mass Reduction

(1) Background: Previous studies have enriched high-density lipoproteins (HDL) using cholesteryl esters in rabbits with a three-quarter reduction in functional renal mass, suggesting that the kidneys participate in the cholesterol homeostasis of these lipoproteins. However, the possible role of the kidneys in lipoprotein metabolism is still controversial. To understand the role of the kidneys in regulating the HDL lipid content, we determined the turnover of HDL-cholesteryl esters in rabbits with a three-quarter renal mass reduction. (2) Methods: HDL subclass characterization was conducted, and the kinetics of plasma HDL-cholesteryl esters, labeled with tritium, were studied in rabbits with a 75% reduction in functional renal mass (Ntx). (3) Results: The reduced renal mass triggered the enrichment of cholesterol, specifically cholesteryl esters, in HDL subclasses. The exchange of cholesteryl esters between HDL and apo B-containing lipoproteins (VLDL/LDL) was not significantly modified in Ntx rabbits. Moreover, the cholesteryl esters of HDL and VLDL/LDL fluxes from the plasmatic compartment tended to decrease, but they only reached statistical significance when both fluxes were added to the Nxt group. Accordingly, the fractional catabolic rate (FCR) of the HDL-cholesteryl esters was lower in Ntx rabbits, concomitantly with its accumulation in HDL subclasses, probably because of the reduced mass of renal cells requiring this lipid from lipoproteins.

A remnant kidney surgery model in cats induces acute and chronic outcomes that mimic spontaneous chronic kidney disease.

To report acute and chronic outcomes of cats with chronic kidney disease (CKD) induced by a remnant kidney model. 32 purpose-bred cats (n = 15 female, n = 17 male). Cats underwent a 2-stage reduction in renal mass through partial arterial ligation of 1 kidney (day 28) and delayed contralateral nephrectomy (day 0), targeting an 11/12th functional nephrectomy. Acute (days -28 - 29) survival and renal function parameters were compared over time, and the latter were evaluated as predictors for acute mortality. Chronic (days 30 to >1,100) survival, renal function, and morphology were described. Acutely, renal function deteriorated in all cats (mean ± SD baseline and day 28 serum creatinine mean concentration, 1.13 ± 0.23 mg/dL and 3.03 ± 1.20 mg/dL, respectively; P < .001; and GFR, 3.22 mL/min/kg ± 0.12 and 1.21 mL/min/kg ± 0.08, respectively; P < .001). Seven (22%) cats were euthanized after because of clinical signs of uremia after contralateral nephrectomy. Prenephrectomy renal function tests were not significant indicators for survival during this acute phase. Twenty-five cats entered the chronic phase. Ten cats were euthanized at a median of 163 days from nephrectomy because of progressive renal dysfunction. Median survival times were significantly different when stratified by acute kidney injury grade at day 29. Cats in the chronic phase had clinical courses similar to cats with naturally occurring CKD, and most (13/15) were in CKD stage 2. The remnant kidney model is effective at reducing kidney function to an extent that mimics important characteristics of spontaneous CKD in cats.

#3950 EFFECT OF DEHYDRATION, HYPERTENSION, RENAL MASS REDUCTION AND AGE ON TRIPLE WHAMMY-ACUTE KIDNEY INJURY

Abstract Background and Aims Renin-angiotensin system inhibitors, diuretics and non-steroidal anti-inflammatory drugs (NSAIDs) is known as Triple Whammy (TW), a common combination used in hypertensive patients suffering from pain or inflammation; this combination of drugs can cause in some cases acute kidney injury (AKI). The renal outcome of the TW therapy seems to be influenced by additional factors, as the incidence of TW-induced AKI ranges from &amp;lt;1% to up to 22% depending on the study. The incidence of TW-AKI is higher among older adults, therefore age and other clinical conditions such as dehydration could be associated with TW-AKI. Furthermore, loss of functional nephrons in chronic kidney disease is a risk or predisposing factor for new AKI episodes. Consequently, the aim of our study was to analyse in vivo the influence of dehydration, age, renal mass reduction and hypertension (HTA) in TW therapy-induced AKI. Method Five experimental groups were subjected to TW therapy: (1) control group (3 months old Wistar rats); (2) dehydrated rats (3 months old Wistar rats with 60-70% water restriction); (3) aged rats (16 month old Wistar rats); (4) renal mass reduction (RMR) rats (3 months old Wistar rats with a 5/6 reduction of renal mass one month before the experiment); and (5) 3 months old spontaneously hypertensive rats). All rats received antihypertensive double therapy with Trandolapril in water and Furosemide i.p. for 4 days, and then a triple therapy for 2 days with Trandolapril and Ibuprofen in drinking water and Furosemide i.p. Blood and urine samples were collected at baseline (B), after 4 days of double therapy (day 4) and two days after triple therapy (day 6). Renal outcomes of the TW therapy were analysed by plasma creatinine, creatinine clearance, plasma urea and proteinuria. Results Risk factors such as dehydration or the loss of nephrons significantly increase plasma creatinine and urea and reduce creatinine clearance at day 6 compared to 3 months old Wistar rats without risk factors. Creatinine clearance is significantly reduced at day 4 in RMR and dehydration groups. Also, the RMR group shows at baseline and day 4 decreased creatinine clearance and increased plasma creatinine and urea than 3 months old Wistar rats. Proteinuria values are within normal ranges (&amp;lt; 10mg/day) in all experimental groups. Conclusion Renal mass reduction and dehydration are important risk factors in the development of AKI after TW therapy, while hypertension and age do not seem to influence renal outcomes. The knowledge of the specific conditions and the different factors that increase the risk of developing AKI in patients undergoing TW therapy will help us to stratify these patients based on their individual risk and to apply in each case the appropriate individualized treatment. This research was funded by grants from Instituto de Salud Carlos III (ISCIII) PI21/00548 and PI21/01226 co-funded by the European Union and Red de Investigación Renal RICORS2040 (Kidney Disease), RD21/0005/0004 co-funded by the European Union – NextGenerationEU, Mecanismo para la Recuperación y la Resiliencia (MRR). Eva M. Baranda-Alonso is recipient of a predoctoral fellowship from the Junta de Castilla y Leon (Spain) and the European Social Fund from the European Commission.Noelia Diaz-Morales is recipient of a Juan de la Cierva-Formación postdoctoral contract (FJC2020-043205-I) funded by MCIN/AEI/10.13039/501100011033 and European Union “NextGenerationEU/PRTR”.

PS-BPB05-2: ENDOTHELIN A RECEPTOR BLOCKADE INCREASES RENOPROTECTION IN EXPERIMENTAL MODEL OF CONGESTIVE HEART FAILURE COMBINED WITH CHRONIC KIDNEY DISEASE

Objective: Congestive heart failure (CHF) represents an extreme burden to the public healthcare worldwide. The incidence and prevalence of chronic kidney disease (CKD) is also increasing and CKD is known as one of the strongest risk factors for the development of CHF. CHF coexists with CKD in approximately half of CHF patients and results in a poor survival rate. The aim of this study was therefore to examine if the addition of endothelin type A (ETA) receptor antagonist atrasentan (5 mg/kg/day) to the angiotensin-converting enzyme inhibitor (ACEi trandolapril; 2 mg/L) will bring additional beneficial effects. Design and Methods: CKD was induced by 5/6 renal mass reduction (5/6 NX) at the age of 8 weeks and CHF was elicited by volume overload achieved by the creation of aortocaval fistula (ACF) four weeks later in normotensive Hannover Sprague Dawley rats. The follow-up was 24 weeks after the first intervention (5/6 NX). The treatment regimens were initiated 6 weeks after 5/6 NX and 2 weeks after ACF. Results: The final survival in untreated group was 15%. The treatment with ETA receptor antagonist alone or ACEi alone and the combined treatment improved the survival rate to 64%, 71% and 75%, respectively, with no significant difference between the combination and either single treatment regimen. At the end of the study, atrasentan or trandolapril given alone partially reduced albuminuria, but had no effect on albumin/creatinine ratio. In contrast, both parameters were substantially improved by the combined treatment which caused ∼45 % reduction in albuminuria. Moreover, it also reduced markers of renal damage. Conclusions: Our results demonstrated that the treatment with ETA receptor antagonist attenuated the mortality related to CKD or CHF and that the addition of ETA receptor antagonist to the standard blockade of renin angiotensin system by ACEi exhibited additional renoprotective actions.

AW-APSH-1: TARGETING WINDOWS OF PLASTICITY TO PREVENT HYPERTENSION.

Failing lifestyle interventions, there are many classes of anti-hypertensive drugs that are highly effective in most patients if taken appropriately. But multiple agents taken daily may be required to achieve target blood pressure (BP). The problem is that the majority of patients are non-compliant: they do not take their drugs continuously, choose to only take some, or stop taking them completely. It is time to focus on interventions that do not require lifelong daily medications, and this requires understanding and treating the causative factors. For decades, it has been understood that the kidney, under the influence of both the renin-angiotensin-aldosterone system and sympathetic nerves, has a dominant role in the long-term control of extracellular fluid volume and BP. The kidney is an important target for the treatment of hypertension. Early postnatal life is a period of remarkable plasticity and is a neglected window of opportunity to prevent disease onset. Our aim is to preserve and protect function of existing nephrons. If born with reduced renal mass (less nephrons), the compensatory response is to increase the filtration rate of each individual nephron so that GFR is maintained. Clinically, the degree of nephron overload is linked to faster age and disease related reduction in renal functional reserve, glomerular damage, albuminuria and hypertension. By targeting the postnatal period of maturation, our aim is to prevent maladaptive compensatory hypertrophy and hyperfiltration to preserve kidney health-span without the need for lifelong drug therapy. Our studies in a large animal model of congenital renal mass reduction demonstrate the long-term therapeutic potential of a brief period of angiotensin converting enzyme inhibition early in life to alter the trajectory of renal and cardiovascular disease.

Endothelin type A receptor blockade increases renoprotection in congestive heart failure combined with chronic kidney disease: Studies in 5/6 nephrectomized rats with aorto-caval fistula

BackgroundAssociation of congestive heart failure (CHF) and chronic kidney disease (CKD) worsens the patient’s prognosis and results in poor survival rate. The aim of this study was to examine if addition of endothelin type A (ETA) receptor antagonist to the angiotensin-converting enzyme inhibitor (ACEi) will bring additional beneficial effects in experimental rats. MethodsCKD was induced by 5/6 renal mass reduction (5/6 NX) and CHF was elicited by volume overload achieved by creation of aorto-caval fistula (ACF). The follow-up was 24 weeks after the first intervention (5/6 NX). The treatment regimens were initiated 6 weeks after 5/6 NX and 2 weeks after ACF creation. ResultsThe final survival in untreated group was 15%. The treatment with ETA receptor antagonist alone or ACEi alone and the combined treatment improved the survival rate to 64%, 71% and 75%, respectively, however, the difference between the combination and either single treatment regimen was not significant. The combined treatment exerted best renoprotection, causing additional reduction in albuminuria and reducing renal glomerular and tubulointerstitial injury as compared with ACE inhibition alone. ConclusionsOur results show that treatment with ETA receptor antagonist attenuates the CKD- and CHF-related mortality, and addition of ETA receptor antagonist to the standard blockade of RAS by ACEi exhibits additional renoprotective actions.

Muscle plasticity is influenced by renal function and caloric intake through the FGF23-vitamin D axis.

Skeletal muscle, the main metabolic engine in the body of vertebrates, is endowed with great plasticity. The association between skeletal muscle plasticity and two highly prevalent health problems: renal dysfunction and obesity, which share etiologic links as well as many comorbidities, is a subject of great relevance. It is important to know how these alterations impact on the structure and function of skeletal muscle because the changes in muscle phenotype have a major influence on the quality of life of the patients. This literature review aims to discuss the influence of a nontraditional axis involving kidney, bone, and muscle on skeletal muscle plasticity. In this axis, the kidneys play a role as the main site for vitamin D activation. Renal disease leads to a direct decrease in 1,25(OH)2-vitamin D, secondary to reduction in renal functional mass, and has an indirect effect, through phosphate retention, that contributes to stimulate fibroblast growth factor 23 (FGF23) secretion by bone cells. FGF23 downregulates the renal synthesis of 1,25(OH)2-vitamin D and upregulates its metabolism. Skeletal production of FGF23 is also regulated by caloric intake: it is increased in obesity and decreased by caloric restriction, and these changes impact on 1,25(OH)2-vitamin D concentrations, which are decreased in obesity and increased after caloric restriction. Thus, both phosphate retention, that develops secondary to renal failure, and caloric intake influence 1,25(OH)2-vitamin D that in turn plays a key role in muscle anabolism.

A case report: 19-year-old male diagnosed with C1q nephropathy requiring renal replacement therapy

C1q nephropathy is a rare glomerular disease. Clinical presentation is diverse and ranges from asymptomatic hematuria or proteinuria to symptoms and signs of nephrotic/nephritic syndrome. On light microscopy, it can be classified into two subtypes: minimal change disease (MCD)/focal segmental glomerulosclerosis (FSGS) group and immune complex mediated proliferative glomerulonephritis group. A case of a 19-year-old male patient presenting nausea and decreased appetite will be reported. The labs showed severe nephrotic syndrome and a progressive kidney injury over a few months that were never diagnosed. The immune workup came back negative. The patient mentioned that he was taking protein shakes a few months earlier for bettering his physical fitness. A renal biopsy was done and showed a major reduction in renal mass and C1q nephropathy. He received steroids without any improvement. He was started on hemodialysis afterward then got transplanted 8 months later. In front of this rapid deterioration, FSGS might be the underlying etiology rather than MCD. Further studies are warranted to establish a connection between protein supplements, and progression of kidney disease.

Effect of congenital or acquired renal mass reduction on arterial stiffness.

The changes in kidney functions, adversely affect the cardiovascular system. The aim of this study was to investigate whether arterial stiffness (AS), an indicator of subclinical atherosclerosis, was affected in patients with congenital or acquired reduced renal mass. In this prospective study, a total 135 patients (mean age 43.4 ± 8.5 years and 71.9% female) with congenital unilateral small/nonfunctioning kidney or unilateral agenesis or with unilateral nephrectomy were included. As control group, 44 healthy individuals with similar age and gender (mean age, 42.5 ± 7.1 year and 61.4% female) were included. Estimated glomerular filtration rate (eGFR) was calculated by Modification of Diet in Renal Disease formula. Official blood pressures (BP) and 24-h ambulatory noninvasive BP of both groups were measured. AS was assessed with pulse wave velocity (PWV) by using Mobile-O-Graph new genarationarteriograph device using oscillometrical method. There was no difference in terms of BP parameters and body mass index between groups. eGFR values of control group and study group were 93 ± 19 ml/min/1.73 m² and 89 ± 28 ml/min/1.73 m², respectively (p = 0.379). Compared with control group, the study group had higher PWV values (6.72 ± 1.11 m/s vs. 6.29± 0.75 m/s, p = 0.018). In linear regression analysis, PWV was found to be correlated with age (β = 0.752, p < 0.001), and daytime ambulatory systolic BP (β = 0.345, p < 0.001). Our study showed that AS was increased in patients with reduced renal mass and this increase in AS was related to age and systolic BP. No relation was determined between AS and eGFR.

Vitamin D Treatment Prevents Uremia-Induced Reductions in Aortic microRNA-145 Attenuating Osteogenic Differentiation despite Hyperphosphatemia.

In chronic kidney disease, systemic inflammation and high serum phosphate (P) promote the de-differentiation of vascular smooth muscle cells (VSMC) to osteoblast-like cells, increasing the propensity for medial calcification and cardiovascular mortality. Vascular microRNA-145 (miR-145) content is essential to maintain VSMC contractile phenotype. Because vitamin D induces aortic miR-145, uremia and high serum P reduce it and miR-145 directly targets osteogenic osterix in osteoblasts, this study evaluated a potential causal link between vascular miR-145 reductions and osterix-driven osteogenic differentiation and its counter-regulation by vitamin D. Studies in aortic rings from normal rats and in the rat aortic VSMC line A7r5 exposed to calcifying conditions corroborated that miR-145 reductions were associated with decreases in contractile markers and increases in osteogenic differentiation and calcium (Ca) deposition. Furthermore, miR-145 silencing enhanced Ca deposition in A7r5 cells exposed to calcifying conditions, while miR-145 overexpression attenuated it, partly through increasing α-actin levels and reducing osterix-driven osteogenic differentiation. In mice, 14 weeks after the induction of renal mass reduction, both aortic miR-145 and α-actin mRNA decreased by 80% without significant elevations in osterix or Ca deposition. Vitamin D treatment from week 8 to 14 fully prevented the reductions in aortic miR-145 and attenuated by 50% the decreases in α-actin, despite uremia-induced hyperphosphatemia. In conclusion, vitamin D was able to prevent the reductions in aortic miR-145 and α-actin content induced by uremia, reducing the alterations in vascular contractility and osteogenic differentiation despite hyperphosphatemia.

Loss of Renal Mass Exacerbates Renal Damage in a Mouse Model of High‐Renin Hypertension

Chronic renal failure is a growing public health problem. Experimental and clinical data suggest that the loss of functional renal mass itself is a major driver for the progression of renal failure. Surprisingly, mice appear to be largely resistant to this pathogenic mechanism. In patients, chronic renal failure usually develops slowly over years, and increased arterial blood pressure and an activated renin‐angiotensin system are common comorbidities of the clinical phenotype. Hence, we formulated the hypothesis that coexistence of both changes over a prolonged period is required to induce sensitivity to a reduction in renal mass in mouse kidneys. To test this, we examined the effects of a moderate reduction in renal mass (unilateral nephrectomy) in SV‐129 renin transgenic mice, which have chronically elevated blood pressure levels subsequent to a genetically clamped high renin. The reduction in renal mass induced albuminuria and histopathological changes (glomerulosclerosis and protein casts) in renin transgenic animals, which were further enhanced when the mice were fed a high‐salt diet. In contrast, fibrosis of the myocardium and aortic wall was not increased in renin‐transgenic compared with control animals. We conclude that loss of renal mass can be an effective pathogenic factor in the development of chronic renal damage in mice. Renin transgenic mice may be a relevant model for chronic renal failure associated with high‐renin hypertension.

NaCl Intake Promotes Greater Increases in Blood Pressure Than NaHCO3 in Rats with Chronic Kidney Disease

Sodium bicarbonate (NaHCO3) is used in patients with chronic kidney disease (CKD) to treat metabolic acidosis and slow CKD progression. One potential adverse effect of NaHCO3 use in patients with CKD is the increase in dietary sodium (Na+) intake, which may worsen both fluid retention and hypertension in this already vulnerable population. Previous data, however, indicate that anions other than Cl‐ coupled to Na+ may not lead to increases in volume retention and blood pressure. These data raise the possibility that ingestion of NaHCO3 in patients with CKD may be relatively benign. The effects of NaHCO3 loading on fluid retention and blood pressure, however, have not been directly investigated in a model of CKD.We hypothesized that NaHCO3 loading promotes similar levels of Na+ retention and hypertension as NaCl loading in a rat model of CKD. We utilized 21, 12‐week‐old male Sprague Dawley rats that underwent sham (n=6), 2/3 (n=7), or 5/6 nephrectomy (n=8, Nx). In order to limit intra‐animal variability, we utilized a crossover study design. After 4 weeks of recovery from surgery, rats were matched by renal mass reduction and assigned to one of two groups. One group was started on a 0.1M NaHCO3 (n=11) drinking water solution while the other was started on 0.1M NaCl (n=10) in the drinking water for 2 weeks before a wash‐out (tap water for 2 weeks). The first group was then started on 0.1M NaCl while the other received 0.1M NaHCO3 for 2 weeks. Rats were maintained in metabolic cages during the initiation of treatments to allow for daily measurements of urine output, fluid, and food ingestion. Urine Na+ content was measured by atomic absorption spectrometry. Mean arterial pressure was measured in separate group with telemetry over 2 weeks of treatment with NaHCO3 or NaCl.Following the initiation of treatment, there was a significantly greater increase in urinary Na+following NaCl treatment (1.18 ± 0.09 mmol vs 5.74 ± 0.39 mmol) compared to NaHCO3 treatment (1.23 ± 0.06 mmol vs 4.82 ± 0.40 mmol; Two‐Way ANOVA, PRx=0.006). However, there was no significant difference in total retained Na+ following NaCl (2.03 ± 0.73 mmol) and NaHCO3 treatment (2.19 ± 0.62 mmol; unpaired t‐test, P=0.87). There was also no significant difference in Na+ retention between the different levels of Nx after the initiation of NaCl (Two‐Way ANOVA, PLevelofNx=0.50) and NaHCO3 treatments (Two‐Way ANOVA, PLevelofNx=0.53).Despite a similar amount of Na+ retention, we found that 0.1M NaCl resulted in greater increases in mean arterial pressure over 2 weeks in 5/6 Nx rats compared to 0.1M NaHCO3 (RM Two‐Way ANOVA, PInteraction=0.02, PSubjects&lt;0.0001; n=4/5). The change in mean arterial pressure from baseline was greater in 5/6 Nx rats treated with NaCl (40.5 ± 5.6 mmHg) compared to NaHCO3 (20.9 ± 0.82 mmHg; unpaired t‐test, P=0.03).We conclude NaHCO3 supplementation promotes Na+ and fluid retention and increases in blood pressure in rats with CKD, however, blood pressure responses are less than that observed with NaCl. Our data indicate that NaHCO3 loading in patients with CKD is unlikely to be benign. As NaHCO3 loading can promote increases in blood pressure, caution is warranted with chronic NaHCO3 use in patients with CKD.

Oral Acid Load Down-Regulates Fibroblast Growth Factor 23.

Increased dietary acid load has a negative impact on health, particularly when renal function is compromised. Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that is elevated during renal failure. The relationship between metabolic acidosis and FGF23 remains unclear. To investigate the effect of dietary acid load on circulating levels of FGF23, rats with normal renal function and with a graded reduction in renal mass (1/2 Nx and 5/6 Nx) received oral NH4Cl for 1 month. Acid intake resulted in a consistent decrease of plasma FGF23 concentrations in all study groups when compared with their non-acidotic control: 239.3 ± 13.5 vs. 295.0 ± 15.8 pg/mL (intact), 346.4 ± 19.7 vs. 522.6 ± 29.3 pg/mL (1/2 Nx) and 988.0 ± 125.5 vs. 2549.4 ± 469.7 pg/mL (5/6 Nx). Acidosis also decreased plasma PTH in all groups, 96.5 ± 22.3 vs. 107.3 ± 19.1 pg/mL, 113.1 ± 17.3 vs. 185.8 ± 22.2 pg/mL and 504.9 ± 75.7 vs. 1255.4 ± 181.1 pg/mL. FGF23 showed a strong positive correlation with PTH (r = 0.877, p < 0.0001) and further studies demonstrated that acidosis did not influence plasma FGF23 concentrations in parathyroidectomized rats, 190.0 ± 31.6 vs. 215 ± 25.6 pg/mL. In conclusion, plasma concentrations of FGF23 are consistently decreased in rats with metabolic acidosis secondary to increased acid intake, both in animals with intact renal function and with decreased renal function. The in vivo effect of metabolic acidosis on FGF23 appears to be related to the simultaneous decrease in PTH.

Renal Cell Cancer and Chronic Kidney Disease.

The association between chronic kidney disease (CKD) and renal cell carcinoma (RCC) is bidirectional and multifactorial. Risk factors such as hypertension, diabetes mellitus, obesity, and smoking increase the risk of both CKD and RCC. CKD can lead to RCC via an underlying cystic disease or oxidative stress. RCC can cause CKD because of the tumor itself, surgical reduction of renal mass (either partial or radical nephrectomy), and perioperative acute kidney injury. Medical therapies such as immune checkpoint inhibitors and vascular endothelial growth factor inhibitors can lead to acute kidney injury and resultant CKD. Clinicians need to be aware of the complex, bidirectional interplay between both diseases.

Renal mass reduction increases the response to exogenous insulin independent of acid-base status or plasma insulin levels in rats.

Impairments in insulin sensitivity can occur in patients with chronic kidney disease (CKD). Correction of metabolic acidosis has been associated with improved insulin sensitivity in CKD, suggesting that metabolic acidosis may directly promote insulin resistance. Despite this, the effect of acid or alkali loading on insulin sensitivity in a rodent model of CKD (remnant kidney) has not been directly investigated. Such studies could better define the relationship between blood pH and insulin sensitivity. We hypothesized that in remnant kidney rats, acid or alkali loading would promote loss of pH homeostasis and consequently decrease insulin sensitivity. To test this hypothesis, we determined the impact of alkali (2 wk) or acid (5-7 days) loading on plasma electrolytes, acid-base balance, and insulin sensitivity in either sham control rats, 2/3 nephrectomized rats, or 5/6 nephrectomized rats. Rats with 5/6 nephrectomy had the greatest response to insulin followed by rats with 2/3 nephrectomy and sham control rats. We found that treatment with 0.1 M sodium bicarbonate solution in drinking water had no effect on insulin sensitivity. Acid loading with 0.1 M ammonium chloride resulted in significant reductions in pH and plasma bicarbonate. However, acidosis did not significantly impair insulin sensitivity. Similar effects were observed in Zucker obese rats with 5/6 nephrectomy. The effect of renal mass reduction on insulin sensitivity could not be explained by reduced insulin clearance or increased plasma insulin levels. We found that renal mass reduction alone increases sensitivity to exogenous insulin in rats and that this is not acutely reversed by the development of acidosis.NEW & NOTEWORTHY Impairments in insulin sensitivity can occur in patients with chronic kidney disease, and previous work has suggested that metabolic acidosis may be the underlying cause. Our study investigated the effect of acid or alkali loading on insulin sensitivity in a rodent model of chronic kidney disease. We found that renal mass reduction increases the blood glucose response to insulin and that this is not acutely reversed by the development of acidosis.

Chronic Kidney Allograft Disease: New Concepts and Opportunities.

Chronic kidney disease (CKD) is increasing in most countries and kidney transplantation is the best option for those patients requiring renal replacement therapy. Therefore, there is a significant number of patients living with a functioning kidney allograft. However, progressive kidney allograft functional deterioration remains unchanged despite of major advances in the field. After the first post-transplant year, it has been estimated that this chronic allograft damage may cause a 5% graft loss per year. Most studies focused on mechanisms of kidney graft damage, especially on ischemia-reperfusion injury, alloimmunity, nephrotoxicity, infection and disease recurrence. Thus, therapeutic interventions focus on those modifiable factors associated with chronic kidney allograft disease (CKaD). There are strategies to reduce ischemia-reperfusion injury, to improve the immunologic risk stratification and monitoring, to reduce calcineurin-inhibitor exposure and to identify recurrence of primary renal disease early. On the other hand, control of risk factors for chronic disease progression are particularly relevant as kidney transplantation is inherently associated with renal mass reduction. However, despite progress in pathophysiology and interventions, clinical advances in terms of long-term kidney allograft survival have been subtle. New approaches are needed and probably a holistic view can help. Chronic kidney allograft deterioration is probably the consequence of damage from various etiologies but can be attenuated by kidney repair mechanisms. Thus, besides immunological and other mechanisms of damage, the intrinsic repair kidney graft capacity should be considered to generate new hypothesis and potential therapeutic targets. In this review, the critical risk factors that define CKaD will be discussed but also how the renal mechanisms of regeneration could contribute to a change chronic kidney allograft disease paradigm.

Rice Endosperm Protein Improves the Anti-Inflammatory Effects of High-Density Lipoprotein and Produces Lower Atherosclerotic Lesion Accelerated by the Renal Mass Reduction than Casein in a Mouse Model

Background Chronic kidney disease (CKD) impairs the anti-inflammatory effects of high-density lipoprotein (HDL) and increases cardiovascular mortality. Though the potential role of dietary interventions to manage HDL is well studied, the clinical trials aimed to increase HDL levels have failed to reduce cardiovascular risk, rendering HDL function to be explored as a more relevant clinical parameter. This study investigates the effects of rice endosperm protein (REP), a plant-based protein, on the anti-inflammatory properties of HDL and renal injury-driven atherosclerosis in comparison with casein, an animal protein. Materials and methods Ten-week-old apolipoprotein E-deficient hyperlipidemic mice underwent uninephrectomy. The mice (n = 6 each) were pair-fed a normal casein-based diet or a REP-based diet (both with 20.0% protein content) for seven weeks. Atherosclerotic lesions were detected by en face Sudan IV staining of the aorta. Results The number and sizes of the atherosclerotic lesions were significantly lower in the REP-based diet-fed group than the casein-based diet-fed group (p = 0.038). However, the REP-based diet neither elicited an ameliorative effect on kidney function or histology nor impacted the cholesterol profiles. Furthermore, HDL from the REP-based diet-fed mice significantly suppressed the inflammatory cytokine response of human umbilical vein endothelial cells than that from the casein-based diet-fed mice (MCP-1, p = 0.010; IL-6, p = 0.011; IL-1β, p = 0.028). Conclusions The REP-based diet has a higher potential to lessen the atherosclerotic lesions accelerated by renal mass reduction than a casein-based diet, which could be associated with the anti-inflammatory effects of HDL.

Total renal volume and renal function after radical nephrectomy in renal neoplasm

IntroductionThe reduction of renal mass after radical nephrectomy (RN) for renal neoplasm, could be associated with compensatory hypertrophy of the contralateral kidney. The capacity of compensation will determine the renal function (RF) evolution. Measuring of total renal volume (TRV) of the remaining kidney pre and post RN can help assess the RF evolution. ObjectivesTo determine the correlation between TRV pre and post nephrectomy (a year of follow-up) with RF. Materials and methodsA retrospective cohort study was carried out in 47 patients who had undergone RN from 2014 to 2018, due to renal cell carcinoma (confirmed by histopathology).The TRV was calculated, pre and post (a year of follow-up) RN, using ellipsoid formula equation, which were compared with clinical and analytical data. The results were analyzed by multivariate linear logistic models. ResultsThe median age at the time of RN was 70 years old (range, 40–88 years). Most of them were men, 66%. The estimated glomerular filtration rate (eGFR) pre and post nephrectomy was 78 (40–100) and 53.3ml/min/m2 (30–90) respectively (p=0.01). The TRV pre and post-nephrectomy was 168.2ml (100.4–257.2) and 187.8ml (115.5–273.1) respectively (p=0.001).The pre-nephrectomy eGFR (β=0.62; p=0.034) and the TRV (β=1.08; p<0.0001) were positively correlated with the post-nephrectomy TRV, while the eGFR at year of follow-up was correlated negatively (β=−1.18; p=0.047). ConclusionsThe measurement of pre and post nephrectomy TRV can help to predict renal function evolution at a year of follow-up.

MO454A NEW AKI TO CKD PROGRESSION IN VIVO EXPERIMENTAL MODEL

Abstract Background and Aims Chronic kidney disease (CKD) represents an enormous problem for healthcare systems. It is estimated that in USA more than 37 million people suffer from this disease. Risk factors include hypertension, diabetes mellitus, older age, proteinuria and previous episodes of acute kidney injury (AKI). Indeed, several studies have shown that AKI increases the risk of CKD, independently of other risk factors, especially when the episode is severe or recurrent. Under these circumstances, maladaptive responses may occur leading to structural and functional abnormalities. Renal fibrosis is the hallmark for maladaptive repair and is considered the final common outcome of progressive kidney disease. We hypothesized that after multiple renal insults, the mechanisms of adaptive repair could be less effective generating a progressive accumulation of extracellular matrix and a progressive deterioration of kidney function. Method We used 8 weeks old male Wistar rats and we analyse their evolution during 9 months. Animals were subdivided into 4 experimental groups: Control group: SHAM operated rats, saline solution, i.p.; “CDDP5-I/R60-I/R60” group: 5 mg/kg cisplatin i.p., after renal function normalization, 60-minute ischemia-reperfusion (I/R60) on left kidney, and 2 weeks later 60-minute ischemia-reperfusion (I/R60) on right kidney; “5/6 RMR” group: 5/6 renal mass reduction; “UNX” group: nephrectomy. Blood and urine were collected at: day 0 (basal); day 4 (AKI development); day 8 (normalized renal function after AKI and induction of renal ischemia); day 9 (1 day after ischemia); day 13, day 20 and monthly thereafter. Renal function was analyzed by sCr, creatinine clearance, blood urea nitrogen and proteinuria determination using colorimetric methods. Tissue samples were stained with Masson´s trichrome and Sirius Red at days 13, 20, 56, 165 and 270 and renal fibrosis was quantified using Image J program. Results The addition of several AKI episodes induces a progressive accumulation of extracellular matrix. In addition, the “CDDP5-I/R60-I/R60” group presented an initial reduction in renal function that remained stable in the last 6 months of the study. On the contrary, we observed a spontaneous and progressive decline of kidney function in the “5/6 RMR” group, which nevertheless presented a significant lower degree of interstitial fibrosis than the “CDDP5-I/R60-I/R60” group. Conclusion We have generated a new in vivo experimental model of AKI to CKD transition combining nephrotoxic and ischemic AKI. We demonstrate that after recurrent episodes of AKI, kidneys show progressive interstitial fibrosis which however does not correlate with a progressive decline of renal function.