50 replies to this topic

[Ark]

If you had to build the ultimate kidney stack what would you take and supplelents drugs to avoid at all cost?


Cheers, Ark

[Ark]

So far, for me my real only hope is FOXO4. As studies in mice showed renal cell regeneration.


I've managed to stay off dialysis therapy, by taking Nilotinib so far. But things are progressing for the worse and my time seems to be ticking away and without help my time on earth might be even shorter. So this is a call for help for myself. Anyone can recommend supplements / drugs that will help I'm beyound grateful for any help.

Not that it probably matters to anyone, but I work with a non profit helping homeless, at risk youth and refugees with Ugm.org and my death would mean I could no longer do what my soul tells me to do which is to help as many people as I can.

If you have any knowledge that might help me please share here...



My Symptoms so far,

Sometimes my energy feels sapped badly.
I get chills randomly.
My urine is bubbly more often then not.
I've had 2 ourbreaks of spots once on my arm and once on my leg.
Last but not least, from time to time I feel my libido disappear and suffer from ED but this comes and goes.

I currently am trying to stick to a kidney friendly diet, 1-2 gallons of water a day and sleep plus exercise. I have a doctors appointment this weekend, I'm hoping I won't have to go on dialysis and that I can have a few more years before that happens if the FOXO4 doesn't do the trick. My next goal is to survive until stem cell technology can help me.

Thanks for reading and Blessings to all.

Cheers, Ark

Edited by Ark, 09 August 2017 - 02:25 AM.

[Evan Yang]

You would say your best bet is Niagen (Nicotinamide Riboside). NAD+ deficit is a major factor

of renal diseases. Supplementing NAD+ will increase Sirt1 expression and repair kidney damage.

 

https://www.ncbi.nlm...pubmed/28163307

 

https://www.ncbi.nlm...pubmed/20595677

 

https://www.ncbi.nlm...pubmed/28246130

Edited by Evan Yang, 11 August 2017 - 11:47 AM.

[tunt01]

ACE inhibitors and ARBs tend to be a choice for kidney diesease.  I think Telmisartan would be ideal, given its longer half-life and dual role as an AMPK/sirt1 activator and ppar-y agonist.  Supposedly hepatocyte growth factor is downstream from ppar-y, making telmisartan possibly regenerative of kidney function (in what capacity/scope - podocytes, tubules, etc. I don't know exactly).

 

If you are still in the immediate post-injury period, maybe some kind of Wnt regulator.  I don't know if melatonin is the answer, but address klotho in some capacity.

 

There was an interesting paper I read about prospects for stem cell repair in kidney and kidney regeneration by Wingert et al, but there may be better reviews and more comprehensive papers published since then.

 

I know there are essential amino acid (EAA) replacement supplements for kidney patients.  I'm not sure how they work, other than to simulate a low protein, low metabolic stress.  I think most kidney disease individuals are histidine deficient, therefore any amino acid supplement that replacements protein should have sufficient histidine.  Ketosteril (Fresenius), Aflalog (RPG life sciences), and others are around.  Going low protein, low phosphorous and using EAA supplements would probably be a good idea.  See also ketoanalogs on the progression of kidney disease in a low protein diet.

[zen]

Dr. Greger has some kidney related videos which I found to be interesting.

https://nutritionfac...sease-with-food
https://nutritionfac...tent_type=video

HTH

 

[FrankEd]

Hi zen,

 

I´m a CKD patient too and my doctor said that I must avoid high potassium/phosporus fruits and veggies (bananas, avocados, potatoes, spinach for example)..

 

So I´m very confused how to create a diet for my condition.

 

Frankly speaking, actually I think that I can eat very few fruits and veggies and some of them must be cooked and the water must be thrown down. 

 

That way I wil become weak because I can´t eat proteins and a very limited quantity of plant-base foods.

[onemanatatime]

what about BPC-157? it has shown organ protecting effects, it may be helpful ? i also have constant foamy urine induced by what is almost certainly Mercury toxicity. i have micro and proteinuria but so far not out of range Kreatinin and eGFR, are your serum levels very bad ? 


Also photbiomodulation directly on the kidneys with a effective device, something like this : https://redlightman....ed-combo-light/

the 800 - 830-850nm would probably give the best penetration but i still think the combo like with the 600nm range 660nm spesifically would be good, and im trying this out myself. 

Edited by onemanatatime, 13 August 2017 - 10:34 PM.

[zen]

Hi zen,

 

I´m a CKD patient too and my doctor said that I must avoid high potassium/phosporus fruits and veggies (bananas, avocados, potatoes, spinach for example)..

 

So I´m very confused how to create a diet for my condition.

 

Frankly speaking, actually I think that I can eat very few fruits and veggies and some of them must be cooked and the water must be thrown down. 

 

That way I wil become weak because I can´t eat proteins and a very limited quantity of plant-base foods.

​Yes, there is a lot of confusing information on almost anything these days.
That is why it is very important to do your own thorough research, especially if the results are affecting ones health.

Here is one more link I think you may find interesting  https://www.kidney.o...isease-patients

HTH

[Ark]

Thoughts on Ibudilast and Cardarine for non diabetic renal failure?

[Rocket]

Why would cardarine help?

[airplanepeanuts]

Foamy urine does not necessarily mean there is anything wrong with your kidneys.

[zen]

I was doing some reading today on klotho and it seems to apply to be an important piece of the CKD puzzle
http://www.lifeexten...ws?NewsID=10850

[Evan Yang]

Klotho is another anti aging gene similar to Sirt1.  I suspect NAD+ precursors will increase Klotho expression, but I have not found a study on it.

If you have high blood pressure, you can take drugs that can also benefit Kidney. I doubt it is more effective than NAD+ precursors.

[Ark]

KLOTHO supplementation possible?

[YOLF]

There is a peptide, Pep1192? that was studied for this. It's the klotho precursor and it worked wonders. This stuff is an all around awesome rejuvenation peptide, so if you find anyone selling it at affordable prices, let me know. Klotho is made in the kidneys and gets used as a structural component throughout the body, likely maintaining youthful cellular formations. Heterozygous for the higher kloto gene is a 30%+ lifespan extension and 6% cognition increase, though having both blocks electrical signals in the brain, so it'll make you very strong, durable, and youthful with an even longer lifespan, but will also limit intelligence.  

 

Black bears regenerate their kidneys from near failure with testosterone levels over 6000 coming out of hibernation oslt!  Maybe testosterone raises klotho?

 

Other things that raise klotho:

IGF1

Vit D3 (also increases testosterone levels, so that might be why)

 

That preserve klotho:

Tocotrienols

Lignans?

Something from oats

avoiding tocopherols

 

They make kidney glandulars, not sure if that would help with CKD or not, but it's bound to have useful youth factors, and maybe even klotho in it. I'll have to try taking some in an enteric capsule and see if I feel any youth enhancement from it. Maybe their is a kidney derived Khavinson Peptide?

 

Also, I'm not sure why yet, but I'm feeling like there's a reason FGF1 would be good for regenerating kidneys.

 

[YOLF]

Actually, there are alot of kidney patients that could use pep-1192. Anyone interested in a group buy? See above post for klotho benefits. There has only been one study directly on pep-1192 up to the time I did my research on it. I think it'd be worth trying on a short term basis, the possibility of side effects should be pretty low and klotho reduces tons of adverse health risks... not to mention it would regenerate the organ that slowly reduces output of the stuff over our lifetimes meaning we'd be able to crank it out like we were young after taking it. 

 

Anyways, transplant patients needing kidneys are pretty much screwed, there is a massive kidney shortage, so this has alot of potential to reduce that burden.

 

Diabetes kills kidneys, and FGF1 looks to be able to fix that. Why not do a group buy for both?

[YOLF]

Klotho is another anti aging gene similar to Sirt1.  I suspect NAD+ precursors will increase Klotho expression, but I have not found a study on it.

If you have high blood pressure, you can take drugs that can also benefit Kidney. I doubt it is more effective than NAD+ precursors.

Klotho is a downstream product of HGH/IGF1, though HGH isn't a good option as that can do kidney damage in these cases. If NAD+ increases HGH, it might be partially or entirely counterproductive, in this case it would be important to intervene as close to the necessary molecule as possible. klotho can't be taken orally afaiaa, at least not without a revised formulation, but the pep1192 should do the trick. The risk though, is that at some point the kidneys may not be able to use the peptide to much of an extent leading to slow results and expensive studies. 

 

I'm definitely interested in running  a group buy.

[onemanatatime]

Actually, there are alot of kidney patients that could use pep-1192. Anyone interested in a group buy? See above post for klotho benefits. There has only been one study directly on pep-1192 up to the time I did my research on it. I think it'd be worth trying on a short term basis, the possibility of side effects should be pretty low and klotho reduces tons of adverse health risks... not to mention it would regenerate the organ that slowly reduces output of the stuff over our lifetimes meaning we'd be able to crank it out like we were young after taking it. 

 

Anyways, transplant patients needing kidneys are pretty much screwed, there is a massive kidney shortage, so this has alot of potential to reduce that burden.

 

Diabetes kills kidneys, and FGF1 looks to be able to fix that. Why not do a group buy for both?

set it up YOLF, im in ....

[YOLF]

PEP1192 and FGF1 Group Buy started:

Follow it here.

[aconita]

Endoluten is claimed to eradicate renal failure.

[Ark]

https://www.ncbi.nlm...les/PMC3148703/
Journal of the American Society of Nephrology : JASN
American Society of Nephrology
Nilotinib Attenuates Renal Injury and Prolongs Survival in Chronic Kidney Disease
Masayuki Iyoda, Takanori Shibata, [...], and Tadao Akizawa

Additional article information

Abstract
The tyrosine kinase inhibitor imatinib is beneficial in experimental renal diseases, but the effect of the new tyrosine kinase inhibitor nilotinib on the progression of renal failure is unknown. We administered either nilotinib or vehicle to Sprague–Dawley rats beginning 2 weeks after 5/6 nephrectomy (Nx) or laparotomy and continuing for 8 weeks. Serum creatinine levels were significantly lower in the nilotinib group after 6 and 8 weeks of treatment. Furthermore, nilotinib-treated rats had less proteinuria, attenuated glomerulosclerosis and tubulointerstitial damage, and reduced macrophage infiltration into the tubulointerstitium. Treatment with nilotinib also significantly decreased renal cortical expression of profibrogenic genes, such as IL-1β and monocyte chemotactic protein-1, which correlated closely with the tubulointerstitial damage score and ED1-positive macrophages score. In addition, nilotinib treatment significantly prolonged survival. Taken together, these results suggest that nilotinib may limit the progression of chronic kidney disease.

Imatinib (Gleevec, Novartis Pharmaceuticals, Co., Basel, Switzerland) is a selective tyrosine kinase inhibitor that inhibits the tyrosine kinase activity of Bcr-Abl, c-Kit, and PDGF receptors (PDGFRs) and has been demonstrated to be highly active in patients with chronic myeloid leukemia and gastrointestinal stromal tumors.1 The therapeutic benefit of imatinib in animal models of kidney diseases (e.g., mesangial proliferative glomerulonephritis,2 chronic allograft nephropathy,3 diabetic nephropathy,4 lupus nephritis,5,6 and unilateral obstructive nephropathy7) has been reported. In aggregate, these studies have shown that the beneficial effects of imatinib therapy are the result of its inhibitory action on PDGFRs, leading to reductions of glomerular cell proliferation and extracellular matrix accumulation. In addition, we recently demonstrated that its immunosuppressive actions on B cells and macrophages resulted in amelioration of cryoglobulinemic membranoproliferative glomerulonephritis in mice and nephrotoxic serum nephritis in rats, respectively.8,9

Nilotinib (Novartis Pharmaceuticals, Co.) is a new phenylaminopyrimidine with enhanced activity and selectivity against the Bcr-Abl tyrosine kinase compared with imatinib, whereas the cellular and biochemical IC50 values of nilotinib and imatinib for PDGFRs inhibition are similar; nilotinib promises to provide improved treatment of chronic myeloid leukemia and imatinib-resistant disease.10–13 Thus, it is presumable that nilotinib has beneficial effects in renal diseases comparable to imatinib. Although nilotinib has shown efficacy in models of liver fibrosis and oxidative stress in a thioacetamide rat model compared with imatinib,14 the effects of nilotinib on experimental models of renal disease have not yet been reported.

The pathogenesis of chronic kidney disease (CKD) involves a complex interaction between hemodynamic abnormalities (represented mainly by systemic and glomerular hypertension) and inflammatory events (e.g., macrophages infiltration) as well as exaggerated production of extracellular matrix.15–17 The interaction between all of these phenomena to promote CKD is heavily dependent on the production of cytokines, chemokines, and growth factors, including PDGF and TGF-β.18–20 Accordingly, it is plausible that nilotinib could attenuate the progression of CKD by inactivation of PDGFRs as well as through its immunomodulatory effects.

In the study presented here, the objective was to determine whether nilotinib treatment of rats with 5/6 nephrectomy (Nx), a commonly used model of CKD, would provide renal protection comparable to other experimental models of kidney disease treated by imatinib. Whether such renal protection would be reflected in the survival rate was also investigated.

RESULTS
Effects of Nilotinib on Biochemical Parameters in 5/6 Nx Rats
The experimental design is described in Figure 1. The 5/6-Nx-vehicle and 5/6-Nx-nilotinib rats had higher systolic BP and lower body weights (BWs) than the Sham rats throughout the study period. There were no significant changes in BP and BW in the 5/6-Nx-vehicle and 5/6-Nx-nilotinib rats throughout the study period (Figure 2, a and b). Figure 2, c and d, show the results of urinary total protein and the serum creatinine (Cr) level for each group. Urinary total protein and serum Cr levels were significantly higher in 5/6-Nx-vehicle rats than in Sham rats from 1 week after treatment and throughout the study period, respectively. The increased urinary total protein excretion in 5/6-Nx-vehicle rats was significantly reduced by nilotinib treatment from 1 week after treatment to the end of the study (Figure 2c). After 6 and 8 weeks of treatment, serum Cr levels were significantly lower in the 5/6-Nx-nilotinib rats than in the 5/6-Nx-vehicle rats (Figure 2d). Nilotinib treatment also decreased remnant kidney hypertrophy (2.09 ± 0.06 g versus 1.90 ± 0.08 g, P < 0.05).

Figure 1.
Figure 1.
Schematic presentation of the experimental protocol.
Figure 2.
Figure 2.
Nilotinib preserves renal function in 5/6-nephrectomized rats. Changes in (a) systolic BP, (b) BW, © urinary total protein excretion, and (d) serum Cr of Sham-operated rats (Sham) and 5/6-nephrectomized rats treated with either vehicle (5/6-Nx-vehicle) ...
Effects of Nilotinib on Renal Histologic Findings in 5/6 Nx Rats
Figure 3 shows the representative periodic acid–Schiff (PAS), silver, and Masson trichrome stainings of the kidneys from the study groups. Renal histologic findings in 5/6-Nx-vehicle rats were characterized by hypertrophy, glomerular sclerosis, and tubulointerstitial fibrosis. The quantitative analysis of the glomerular tuft area is presented in Table 1. Nilotinib treatment significantly reduced glomerular hypertrophy in rats with remnant kidney (P < 0.05). The glomerular sclerosis score increased significantly in 5/6-Nx-vehicle rats compared with Sham rats (P < 0.001), and this increase was significantly reduced by nilotinib treatment (P < 0.01) (Table 1). The tubulointerstitial damage score was greater in 5/6-Nx-vehicle rats than in Sham rats (P < 0.001). Nilotinib treatment significantly improved the tubulointerstitial damage in 5/6 Nx rats (P < 0.01) (Table 1).

Figure 3.
Figure 3.
Nilotinib attenuates renal histological changes in 5/6-nephrectomized rats. Light microscopic findings in the study groups. Representative pictures stained with (a through c) PAS, (d through f) silver, and (g through i) Masson trichrome in (a, d, g) a ...
Table 1.
Table 1.
Morphologic evaluation of glomerular size, glomerular sclerosis, and tubulointerstitial damage at the end of study
Effects of Nilotinib on Profibrogenic Genes and Proteins in 5/6 Nx Rats
The gene expression level of collagen type I was much higher in 5/6-Nx-vehicle than in Sham rats, as assessed by real-time reverse transcriptase (RT)-PCR. Nilotinib treatment significantly decreased collagen type I gene expression in 5/6 Nx rats (Figure 4a). There was an increase in fibronectin and plasminogen activator inhibitor-1 (PAI-1) gene expressions in 5/6-Nx-vehicle rats compared with Sham rats. Fibronectin and PAI-1 gene expressions in the kidneys of 5/6 Nx rats were attenuated by nilotinib treatment (Figure 4, b and c). As shown in Figure 4, d and e, there was a significant increase in PDGF-B and TGF-β gene expressions in the kidneys of 5/6-Nx-vehicle rats compared with Sham rats that was significantly reversed by nilotinib treatment. For examination of the effect of nilotinib on TGF-β1 protein synthesis in 5/6 Nx rats, kidney tissue homogenate was measured using the TGF-β1 ELISA kit (Figure 5). The TGF-β1 level was significantly higher in 5/6 Nx rats than in Sham rats (P < 0.05). There was a 26% (P < 0.05) reduction of TGF-β1 by nilotinib treatment in 5/6 Nx rats (Figure 5). To verify the decrease of collagen gene expressions by nilotinib treatment, immunohistochemical staining for collagen type IV was performed. As shown in Figure 6, nilotinib treatment was associated with a significant decrease in the glomerular extracellular matrix as assessed by the percentage of the glomerular tuft area occupied by the collagen type IV-stained matrix (P < 0.05).

Figure 4.
Figure 4.
Nilotinib decreases profibrogenic gene expression levels in 5/6-nephrectomized rats. Real-time RT-PCR for (a) collagen type I, (b) fibronectin, © PAI-1, (d) PDGF-B, and (e) TGF-β in each group. The horizontal dotted lines show the expression ...
Figure 5.
Figure 5.
Nilotinib decreases renal cortical TGF-β1 protein level in 5/6-nephrectomized rats. Renal cortical homogenate TGF-β1 protein levels of each group measured by ELISA. Data are expressed as means ± SEM. Mann–Whitney test: ...
Figure 6.
Figure 6.
Nilotinib decreases urinary collagen level in 5/6-nephrectomized rats. Urinary collagen levels of each group measured as described in Concise Methods. Data are expressed as means ± SEM. Mann–Whitney test: **P < 0.01: 5/6-Nx-vehicle ...
Effects of Nilotinib on Tubulointerstitial Macrophage Infiltration in 5/6 Nx Rats
Quantitative evaluation of tubulointerstitial macrophage infiltration was performed by measurement of ED1-positive cells in 5/6-Nx-vehicle rats and Sham rats. There was a 4.27-fold increase in ED1-positive macrophages in the tubulointerstitium in 5/6-Nx-vehicle rats compared with Sham rats (Figure 7). The increase in ED1-positive macrophages in the tubulointerstitium in 5/6-Nx-vehicle rats was reduced to 57% by nilotinib treatment (Table 2). Immunostaining for ED1 in glomeruli was faint in each study group (data not shown).

Figure 7.
Figure 7.
Nilotinib reduces tubulointerstitial macrophage infiltration in 5/6-nephrectomized rats. Immunohistochemistry for ED1 in the study groups. (a through c) Representative pictures stained with immunohistochemistry for ED1 of (a) a 5/6-Nx-vehicle rat, (b) ...
Table 2.
Table 2.
Semiquantitative evaluation of immunohistochemistry for ED1 in tubulointerstitium at the end of study
Effects of Nilotinib on Proinflammatory Genes in 5/6 Nx Rats
Because macrophage-derived proinflammatory cytokines are fundamental in the pathogenesis of progressive CKD, they were examined by real-time RT-PCR. The gene expression levels of IL-6, IFN-γ, IL-1β, TNF-α, and monocyte chemotactic protein-1 (MCP-1), which are known as macrophage-associated proinflammatory cytokines, were much higher in 5/6-Nx-vehicle than in Sham rats. Consistent with the reduction of macrophage infiltration, nilotinib treatment significantly decreased gene expression levels of IL-6 (P < 0.01), IFN-γ (P < 0.05), IL-1β (P < 0.05), TNF-α (P < 0.05), and MCP-1 (P < 0.05) in 5/6 Nx rats (Figure 8). The gene expression levels of IL-1β in the 5/6 Nx rats correlated closely with the ED1-positive macrophages score (r = 0.65) and the tubulointerstitial damage score (r = 0.70). Similarly, the gene expression levels of MCP-1 in the 5/6 Nx rats were significantly correlated with the ED1-positive macrophages score (r = 0.60) and the tubulointerstitial damage score (r = 0.61) (Figure 9). Double immunostaining of ED1-positive macrophages with IL-1β and MCP-1 was performed to confirm that a significant reduction of IL-1β and MCP-1 in the kidneys is associated with inhibition of macrophage accumulation by nilotinib treatment. Many ED1-positive macrophages showed double staining for IL-1β and MCP-1 in 5/6-Nx-vehicle rats (Figure 10). In 5/6-Nx-nilotinib rats, there was a significant reduction of macrophage accumulation in the tubulointerstitium, along with inhibition of IL-1β and MCP-1 protein expressions that was co-localized with ED1-positive macrophages (Figure 10).

Figure 8.
Figure 8.
Nilotinib decreases proinflammatory gene expression levels in 5/6-nephrectomized rats. Real-time RT-PCR for IL-6, IFN-γ, IL-1β, and TNF-α in the study groups. Data are expressed as means ± SEM. The values were normalized ...
Figure 9.
Figure 9.
Proinflammatory genes correlated with tubulointerstitial macrophage infiltration and damage. The gene expression levels of IL-1β in the 5/6 Nx rats are closely correlated with (a) the ED1 score and (b) the tubulointerstitial damage score. Similarly, ...
Figure 10.
Figure 10.
Many ED1-positive macrophages in the tubulointerstitium are double stained by IL-1β and MCP-1. Double immunostaining for ED1 with IL-1β and MCP-1 in 5/6 Nx rats. Kidney sections were stained using two-color immunohistochemistry with ED1 ...
Effects of Nilotinib on the Survival Rate in 5/6 Nx Rats
The survival rate was analyzed at 18 weeks after the start of nilotinib treatment. Kaplan–Meier survival analysis showed that nilotinib treatment significantly prolonged the survival time of 5/6 Nx rats (P < 0.05) (Figure 11). Eight of 13 5/6-Nx-vehicle rats and 3 of 13 5/6-Nx-milotinib rats died during 18 weeks of treatment, mainly in the fourth month of follow-up. Mortality was associated with lower BW, high BP, and marked renal insufficiency including increased proteinuria, high serum Cr levels, and histologic injury. Thus, nilotinib treatment attenuated renal insufficiency, and that resulted in improving survival rate.

Figure 11.
Figure 11.
Nilotinib treatment significantly prolongs survival compared with vehicle treatment in rats with renal ablation (P < 0.05).
Effects of Nilotinib on PDGFRβ Phosphorylation Induced by Angiotensin II or PDGF-BB in Cultured Mesangial Cells and Renal Fibroblasts
Whether PDGFRβ phosphorylation is increased in mesangial cells and renal fibroblasts stimulated with angiotensin II (AT-II) or PDGF-BB was investigated. Stimulation with PDGF-BB for 5 minutes increased PDGFRβ phosphorylation, which was significantly inhibited by pretreatment with nilotinib in cultured mesangial cells and renal fibroblasts. On the other hand, the transactivation of PDGFRβ with AT-II stimulation was faint on Western blot analysis (Figure 12).

Figure 12.
Figure 12.
Nilotinib inhibits PDGFRβ phosphorylation induced by AT-II or PDGF-BB in (a) cultured mesangial cells and (b) renal fibroblasts. The cells were preincubated with nilotinib (10 μmol/L) or medium alone for 30 minutes, followed by stimulation ...
DISCUSSION
This study demonstrated that nilotinib, a clinically available, second-generation, selective tyrosine kinase inhibitor, attenuated renal disease progression and prolonged survival in rats with remnant kidney through its effects against fibrosis and inflammation.

The major finding of the study presented here is that nilotinib treatment had a significant protective effect against CKD progression, with reductions in proteinuria and renal dysfunction and amelioration of histologic changes in remnant kidney. These effects occurred independently of any change in BP, which was consistent with previous reports in which imatinib was administered in hypertensive rats.21,22 There was also no toxicity in this model, and there was no difference in BW or behavior between the nilotinib- and vehicle-treated rats. The renal pathology of remnant kidney is characterized by progressive glomerulosclerosis and interstitial fibrosis, which were significantly ameliorated by nilotinib treatment in this study. Furthermore, nilotinib reduced the upregulation of fibrosis-related genes (e.g., collagen type I, fibronectin, PAI-1, TGF-β, and PDGF-B) in remnant kidneys. This was reflected in the protein levels of total collagen in urine and TGF-β in kidney homogenate. Several lines of evidence show that imatinib has therapeutic benefits in animal models of renal disease via inhibiting PDGFRβ activation.2–6,8,9 The activity of nilotinib against the PDGFRs is similar to that of imatinib.12 Indeed, we verified that nilotinib suppressed PDGFRβ phosphorylation in PDGF-BB-stimulated glomerular mesangial cells and renal fibroblasts in vitro. The involvement of PDGF-B/PDGFRβ signaling in the development of glomerulosclerosis and tubulointerstitial fibrosis in 5/6 Nx rats has been reported.19,20 Floege et al.19 reported that the proliferation of renal intrinsic glomerular cells precedes glomerulosclerosis and that it may be sustained by PDGF released from intrinsic glomerular cells. Kliem et al.20 reported that tubular and interstitial PDGF-B/PDGFRβ signaling might play a role in mediating fibroblast migration and/or proliferation in tubulointerstitial injury. Thus, the inhibitory effect of nilotinib against PDGFRβ in glomerular mesangial cells and renal fibroblasts may potentially contribute to the observed attenuation of renal injury.

On the other hand, AT-II is known to play a crucial role in the pathogenesis of this experimental model of progressive CKD. AT-II transactivates receptor tyrosine kinases, including PDGFRβ23 and EGF receptor.24 PDGFRβ transactivation by AT-II has been reported in cardiac fibroblasts22 and vascular smooth muscle cells,21 and it was inhibited by imatinib treatment. However, the AT-II-PDGFR pathway in renal intrinsic cells has rarely been reported. In the study presented here, significant AT-II-mediated PDGFRβ transactivation could not be detected in mesangial cells or renal fibroblasts in vitro, which indicates that the renoprotective effect of nilotinib in remnant kidney was independent of the interruption of the AT-II-PDGFR pathway. Similarly, Escano et al.25 showed the differences in AT-II-mediated signaling between thoracic aorta smooth muscle cells and renal microvascular smooth muscle cells: AT-II activates extracellular signal-regulated kinase in thoracic aorta smooth muscle cells, but not renal microvascular smooth muscle cells, through transactivation of EGF and PDGFRs.

It has been reported that one of the possible mechanisms by which imatinib attenuates renal disease is related to its effects on inflammatory cells. We recently reported that renal and systemic injuries in thymic stromal lymphopoietin transgenic mice, a model of cryoglobulinemia and cryoglobulin-associated membranoproliferative glomerulonephritis, are dramatically attenuated by imatinib treatment.8 This protective effect seems to be largely due to the effects of imatinib on B cell development, which, in turn, diminishes cryoglobulin production. We also reported that imatinib treatment had renal preventive and therapeutic effects in rats with nephrotoxic nephritis, with a dramatic reduction of glomerular macrophage infiltration, possibly by M-CSF/c-fms signaling inactivation.9 Reductions of serum IgG levels, anti-ds-DNA antibody, lymph node swelling, and immune complex deposition in lupus model mice suggest that imatinib has inhibitory effects on T cells and/or B cells.5,6 Indeed, several in vitro studies have reported that imatinib suppresses various kinds of inflammatory cells, including T cells,26–28 B cells,8,29 macrophages/monocytes,29–31 dendritic cells,32,33 and mast cells.29 These lines of evidence suggest that nilotinib would have some effects on inflammatory cells in rats with remnant kidney in which monocyte/macrophage infiltration is involved in disease progression.19,20,34,35 In this study, nilotinib attenuated the tubulointerstitial infiltration of macrophages in remnant kidney. This was accompanied by reduction of proinflammatory cytokine gene expression in the renal cortex, including IL-6, IFN-γ, IL-1β, TNF-α, and MCP-1, in addition to protein levels of IL-1β and MCP-1, which were co-localized with ED1-positive macrophages, as indicated by double immunostaining. IL-1β and MCP-1 are two of the most important cytokines for renal fibrosis36–41 and are expressed in the remnant kidney model.41 Inhibition of IL-1β and MCP-1 has also been found to ameliorate progressive renal fibrosis.40,42–44 Therefore, the attenuation of tubulointerstitial fibrosis by nilotinib may be in part due to the suppression of macrophage recruitment and concomitant downregulation of these proinflammatory cytokines in remnant kidney. Consistent with this hypothesis, gene expression levels of MCP-1 and IL-1β were significantly correlated with the ED1-positive macrophage score and the tubulointerstitial damage score.

A difference in the therapeutic effects between imatinib and nilotinib in progressive renal failure was not verified in this study. In addition to Bcr-Abl, nilotinib has stronger binding affinity to the Abl family, including the abelson nonreceptor tyrosine kinase (c-Abl) and v-Abl (a mutated form of c-Abl), than imatinib. c-Abl is known as a noncanonical (non-Smad) TGF-β signaling pathway in mesenchymal cells, specifically in fibroblasts but less in epithelial cells.45 Wang et al.7,45 reported that imatinib effectively blocks c-Abl in the kidney of obstructive nephropathy and diminishes the number of interstitial fibroblasts and myofibroblasts and the interstitial accumulation of extracellular matrix proteins. Thus, it is likely that potent c-Abl inactivation by nilotinib might have also contributed to attenuating fibrosis in remnant kidney.

In conclusion, nilotinib treatment significantly attenuates renal injury and decreases mortality after subtotal renal ablation in rats. The effects may be mediated by inactivation of PDGFRs and inhibition of macrophage accumulation and subsequent cytokine production, resulting in less vigorous fibrotic and inflammatory responses. The results presented here suggest that nilotinib may prove useful in limiting the progression of CKD to end-stage renal failure.

CONCISE METHODS
Experimental Protocol
The experimental protocol for this study was reviewed and approved by the Animal Care Committee of Showa University in Tokyo. Ten-week-old male Sprague-Dawley rats weighing 270 to 320 g were purchased from Sankyo Labo Service Corporation, Inc. (Tokyo, Japan) and used in all of the experiments. The animals were housed in the animal care facility of Showa University (25°C, 50% humidity, 12-hour dark/light cycle) with free access to food and water. Fifty-six rats were subjected to 5/6 Nx (right Nx with surgical resection of the lower and upper thirds of the left kidney).46 Sham-operated rats (Sham Corporation, n = 9) underwent the same procedure without surgical reduction of the kidney. In experiment 1 (therapeutic study) (Figure 1), 30 rats with 5/6 Nx were then administered either nilotinib (45 mg/kg, Novartis Pharmaceuticals) (5/6-Nx-nilotinib, n = 15) or vehicle (5/6-Nx-vehicle, n = 15) via daily oral gavage from 2 weeks after surgery and for a period of 8 weeks. Vehicle-treated groups received an equal volume of sterile water. At the end of the study, the rats were anesthetized, their blood was collected by cardiac puncture, and their remnant kidneys were collected. Renal tissue was divided; some portions were snap-frozen in liquid nitrogen and some portions were fixed in 2% paraformaldehyde/PBS for later use. In experiment 2 (survival study) (Figure 1), 26 rats with 5/6 Nx (5/6-Nx-nilotinib, n = 13; 5/6-Nx-vehicle, n = 13) were used. Animals were carefully monitored, and deaths were recorded every day. Survival rates were compared between the groups at 18 weeks after the start of drug treatment.

Proteinuria and Cr Determination
For the analysis of proteinuria, rats were housed individually in metabolic cages for 24-hour urine collection. Urine samples were collected on the day before sacrifice. Urinary protein was determined using the Biuret method. Serum and urinary Cr levels were measured using an automated analyzer (Hitachi Corporation, Tokyo, Japan) according to the manufacturer's instructions.

Measurement of Urinary Total Collagen Levels
Urinary total collagen levels were determined by analysis of urinary hydroxyproline content as described by Kivirikko et al.47 Hydroxyproline values were converted to collagen content by multiplying by a factor of 6.94 (because hydroxyproline represents approximately 14.4% of the amino acid composition of collagen48) and expressed further as a proportion of the urinary Cr levels (μmol of collagen levels/mg of urinary Cr levels).

Light Microscopic Study
Tissues fixed in 2% paraformaldehyde/PBS were embedded in paraffin using routine protocols. Paraffin-embedded materials were sectioned at 4 μm for routine staining with PAS and Masson trichrome. Sections (2 μm thick) were used for periodic acid-methenamine silver stains (silver). The glomerular tuft area was quantified in 50 full-sized glomeruli (PAS stain) using WinROOF image processing software (Mitani Corporation, Tokyo, Japan). Glomerulosclerosis was assessed in 50 glomeruli on silver-stained sections under ×400 magnification using a semiquantitative score from 0 to 4 (0, no sclerosis; 1, sclerosis up to 25% of glomeruli; 2, sclerosis from 25% to 50% of glomeruli; 3, sclerosis from 50% to 75% of glomeruli; 4, sclerosis >75% of glomeruli), and the results were averaged. For evaluating tubulointerstitial damage, 15 fields for each section (Masson trichrome stain) were evaluated at ×200 magnification using WinROOF image processing software (Mitani Corporation). The extent of tubulointerstitial damage was evaluated by counting the percentage of areas with tubular dilation, interstitial infiltration, and fibrosis per field of cortex. Scores from 0 to 5 were used (0, normal interstitium; 1, <10% of areas injured; 2, 11% to 25% of areas injured; 3, 26% to 50% of areas injured; 4, 51% to 75% of areas injured; 5, >75% of areas injured), and the results were averaged. All histologic analyses were performed by two investigators without knowledge of the origin of the slides, and the mean values were calculated.

Immunohistochemistry
The mouse anti-rat ED1 monoclonal antibody, a macrophage marker, was purchased from BMA (Augst, Switzerland). Biotinylated rabbit anti-mouse IgG and peroxidase-conjugated streptavidin (LSAB 2 kit/horseradish peroxidase [HRP]) were purchased from Dako (Glostrup, Denmark). Immunohistochemical staining for ED1 was performed as follows. The paraffin sections of renal tissues were dewaxed, washed in PBS, drained, and incubated with the anti-ED1 antibody as the primary antibodies overnight at 4°C. For antigen retrieval, sections were treated twice for 5 minutes in a conventional household microwave (500 W; Sharp, Osaka, Japan) using citrate buffer (0.01 M, pH 6.0). They were then washed 3 times in PBS and incubated with a secondary antibody. After endogenous peroxidase was inactivated by incubation with 0.3% hydrogen peroxide in methanol, the sections were incubated with LSAB 2 kit/HRP and developed using diaminobenzedine (DAKO) as the substrate to produce a brown stain. The quantification of ED1-positive cells in the tubulointerstitium was performed by grading on a 5-point scale (0, absent; 1, weak; 2, moderate; 3, severe; 4, very severe) in 15 consecutive renal cortical fields at ×200 magnification. The mean score was then calculated as the ED1 staining score. Two-color immunostaining for IL-1β/ED1 and MCP-1/ED1 was performed as described previously.9

Cell Culture Studies
Normal human mesangial cells in primary culture were purchased from Lonza (Basel, Switzerland). Normal rat kidney fibroblast cells were purchased from the American Type Culture Collection (Manassas, VA). Cells were grown in DMEM containing 5% FBS, 1% streptomycin-penicillin mixture, 44 mM sodium bicarbonate, and 14 mM HEPES in an atmosphere of 5% carbon dioxide and 95% air at 37°C in a humidified incubator.

Western Blot Analysis
Cells were preincubated with nilotinib or medium for 30 minutes, followed by stimulation with PDGF-BB, AT-II, or medium for 5 minutes. Cells were then washed with PBS, and total protein was extracted in M-PER Mammalian Protein Extraction Reagent (Pierce Biotechnology, Rockford, IL) containing 1% (vol/vol) protease inhibitor cocktail (Sigma) and 1% (vol/vol) phosphatase inhibitor cocktail (Sigma). Harvested lysates were then centrifuged for 10 minutes at 4°C to remove cellular debris. The supernatants were collected and stored at −80°C. Protein concentration was measured using the BCA protein assay reagent kit (Pierce Biotechnology). For Western blotting, 10 μg of protein from each sample were then separated on a 4% to 20% gradient gel (Invitrogen) using SDS-PAGE and transferred to a polyvinylidene membrane. The blots were blocked with TBST buffer (20 mM Tris-HCl [pH 7.4], 140 mM sodium chloride, and 0.05% Tween 20) containing 5% skim milk at room temperature for 1 hour, washed 3 times in TBST buffer, and incubated with primary antibody (phosphorylated-PDGFRβ and total-PDGFRβ, 1:1000 [Cell Signaling Technology, Danvers, MA]) overnight at 4°C. The membranes were then incubated with secondary antibody (HRP-conjugated anti-rabbit IgG antibody, 1:3000; Cell Signaling Technology) at room temperature for 1 hour. The reaction products were detected using the enhanced chemiluminescence detection system.

Real-Time RT-PCR
Gene expressions of rat collagen type I, fibronectin, PAI-1, PDGF-B, TGF-β, IL-6, IFN-γ, IL-1β, TNF-α, MCP-1, and glyceraldehyde-3-phosphate dehydrogenase were analyzed using real-time RT-PCR. Briefly, kidney tissues (cortex) were homogenized using a TissueLyser (QIAGEN, Hilden, Germany), and total RNA was isolated using an RNeasy fibrous tissue mini kit (QIAGEN) in accordance with the manufacturer's instructions. cDNA synthesis was carried out using the SuperScript first-strand synthesis system for RT-PCR (Invitrogen, Carlsbad, CA). Predesigned TaqMan probe sets for the targets indicated above were purchased from Applied Biosystems (Foster City, CA). Each probe has a fluorescence reporter dye (FAM) linked to its 5′ end and a downstream quencher dye (TAMRA) linked to its 3′ end. Each reaction consisted of 25 μl containing 2× Universal Master Mix (Applied Biosystems), primers, labeled probes, and cDNA. The amplification conditions consisted of 40 cycles of 95°C for 15 seconds and 60°C for 1 minute after incubation at 95°C for 10 minutes. Amplification and fluorescence measurements were performed using the MicroAmp optical 96-well reaction plate on the ABI PRISM 7700 sequence detection system (Applied Biosystems). mRNA expressions were normalized using glyceraldehyde-3-phosphate dehydrogenase as an endogenous control to correct for the differences in the amount of total RNA added to each reaction.

Homogenization of Kidney Tissues
Kidney tissues (cortex) were homogenized with T-PER mammalian protein extraction reagent (20 ml/g renal tissues; Pierce Biotechnology) containing 1% (vol/vol) protease inhibitor cocktail (Sigma-Aldrich) using a TissueLyser (QIAGEN). Harvested lysates were then centrifuged for 10 minutes at 4°C to remove the cellular debris. The supernatants were collected and stored at −80°C. Protein concentration was measured using the BCA protein assay reagent kit (Pierce Biotechnology).

Measurement of TGF-β1 Protein Levels in Kidney Tissue Homogenate
Total TGF-β1 protein levels were measured in kidney tissue homogenates from each sample using the TGF-β1 ELISA kit (R&D Systems, Abingdon, Oxfordshire, United Kingdom) following the manufacturer's instructions. To control for the difference between samples, the concentration was corrected based on the amount of total tissue protein.

Statistical Analysis
Data were recorded as means ± SEM. The Mann–Whitney test was performed, and values of P < 0.05 were considered significant. Data were analyzed using the Kaplan–Meier life table method for survival curves.

DISCLOSURES
None.

Acknowledgments
This work was supported by a Grant-in-Aid for young scientists from the Japanese Ministry of Education, Culture, Sports, Science and Technology (KAKENHI). T.A. is supported by a research grant from Kyowa Hakko Kirin, Co., Ltd., and Chugai Pharmaceutical, Co., Ltd. The authors thank Ms. Tomoko Suzuki, Ms. Naoko Ono, and Ms. Fumiko Kondo for their excellent technical assistance. Nilotinib was a gift from Novartis Pharmaceuticals (Basel, Switzerland), which did not otherwise participate in the design, execution, or funding of this study.

Footnotes
Published online ahead of print. Publication date available at www.jasn.org.

See related editorial, “Fibrosis, Regeneration, and Aging: Playing Chess with Evolution,” on pages 1393–1396.

Article information
J Am Soc Nephrol. 2011 Aug; 22(8): 1486–1496.
doi: 10.1681/ASN.2010111158
PMCID: PMC3148703
Masayuki Iyoda,corresponding author Takanori Shibata, Yuki Hirai, Yoshihiro Kuno, and Tadao Akizawa
Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
corresponding authorCorresponding author.
Correspondence: Masayuki Iyoda, Division of Nephrology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan., Phone: +81-3-3784-8533; Fax: +81-3-3784-5934; E-mail: pj.ca.u-awohs.dem@adoyi
Received 2010 Nov 13; Accepted 2011 Feb 23.
Copyright © 2011 by the American Society of Nephrology
See commentary "Fibrosis, regeneration, and aging: playing chess with evolution." in volume 22 on page 1393.
This article has been cited by other articles in PMC.
Articles from Journal of the American Society of Nephrology : JASN are provided here courtesy of American Society of Nephrology
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[Soalian]

I'm digging up this thread, any new reports? Specifically in regards to improvements in kidney damage with the use of sartans or other purportedly renoprotective agents such as cardarine?

 

To my knowledge, there are two studies linking the use of GW-501516 with a reduction in renal inflammation:

 

https://www.ncbi.nlm...les/PMC4653448/

 

https://www.ncbi.nlm...pubmed/21966476

 

 

[Rocket]

Dasatanib (one 2 day round) improved my kidney function in pre and post blood tests. I don't have kidney disease but my numbers aren't of a teenager anymore. I saw a 3 or 4 point improvement in Egfr after my numbers being rock steady for several tests.

Edited by Rocket, 30 October 2018 - 12:39 AM.

[FrankEd]

I have only one working kidney and I´m struggling to find something that can ameliorate its function or reverse bad EGFR. My uro said that Cardarine is very dangerous at least for now. There are not much studies in humans. As for sartans I didn´t found much information too related to my problem.

[Ark]

.

Edited by Ark, 13 February 2020 - 09:43 AM.

[Ark]

Anyone have any Nilotinib left, msg me.

Thanks

[Believer]

Fasting. 100% fasting.

[Soalian]

Any updates on this?

I have symptoms of CKD, GFR 65 at 28 years old.

[Rocket]

Any updates on this?

I have symptoms of CKD, GFR 65 at 28 years old.

Slow down there tiger! GFR is based on ESTIMATED hence the e in eGFR. My doc thought I had kidney issues developing because of lowish eGFR.

1. eGFR numbers are based on a person with average muscle mass eating an average diet and something like 170 bodyweight.

2. Body bodybuilders with a lot of muscle over the average person have lower eGFR because of all the protein turnover naturally occurring.

3. Lifting weights even a few days before an eGFR test will show lower eGFR values.

4.forgive my spelling but you need a cystatin-c test that my doc gave me and cleared me of issues. I am over 210. Muscular. Lift weights and eat far more protein than in an average diet.

Also if you find a online calculator that takes bodyweight into account then run the numbers. I did and my much more accurate numbers for eGFR were not in the red zone taking into account age and muscle mass.

So slow your roll there a little bit tiger.

I have even seen creatine supplementing negatively affect eGFR despite all the bro science that says it doesn't work that way.... Well I seen my blood work on creatine and not on creatine and it was significant

Kidney failure will affect literally EVERYONE who lives past 60... Your nuMBERS get worse every year. Rather depressing to think about it.

All these people trying to live to 140 have some huge hurdles to leap over like kidneys and prostates. Take a room full of men in their 50s and 20% have prostate cancer with increasing numbers every year of age.

Edited by Rocket, 01 December 2020 - 02:38 AM.

[Gal220]

Renadyl is a probiotic that consumes waist your kidneys would normally have to deal with, almost like a 3rd kidney.

 

Life extension is a big proponent of P5P.  They recommend a few others as well.  They dont mention glutathione, but worth adding as well.

Edited by Gal220, 01 December 2020 - 04:14 AM.