Reduction in microalbuminuria as an integrated indicator for renal and cardiovascular risk reduction in patients

WSTĘP. Mikroalbuminuria u chorych na cukrzycę typu 2 jest predyktorem nefropatii cukrzycowej oraz chorób układu sercowo-naczyniowego. Celem niniejszego badania obserwacyjnego była ocena efektu klinicznego redukcji mikroalbuminurii u chorych na cukrzycę typu 2. MATERIAŁ I METODY. W ciągu pierwszych 2 lat badania do projektu włączono 216 chorych na cukrzycę typu 2 z mikroalbuminurią, których obserwowano przez następne 8 lat. Za remisję lub 50-procentowe zmniejszenie mikroalbuminurii przyjęto odpowiednio powrót do wartości prawidłowych lub zmniejszenie poziomu mikroalbuminurii o połowę w porównaniu z poziomem wyjściowym. Analizowano zależność między redukcją poziomu mikroalbuminurii a czasem wystąpienia pierwszych objawów zaburzeń nerkowych lub sercowo-naczyniowych oraz oznaczanym co roku wskaźnikiem estymowanej filtracji kłębuszkowej (eGFR). WYNIKI. W grupie 93 chorych z 50-procentowym zmniejszeniem poziomów mikroalbuminurii odnotowano 12 incydentów nerkowych lub sercowo-naczyniowych w porównaniu z 35 w grupie 123 chorych bez takiej redukcji. Skumulowany wskaźnik częstości wspomnianych powikłań cukrzycy był istotnie mniejszy w grupie chorych z 50-procentową redukcją poziomów mikroalbuminurii. Analiza przy użyciu sumarycznej regresji logistycznej wykazała skorygowane ryzyko powikłań 0,41 (95% CI: 0,15-0,96) u chorych z 50-procentową redukcją mikroalbuminurii. Oznaczany co roku wskaźnik spadku eGFR u tych osób pogarszał się wolniej w porównaniu z grupą bez 50-procentowej redukcji mikroalbuminurii. Podobne dane uzyskano, analizując dane dotyczące okresów remisji. WNIOSKI. W przedstawionym badaniu dowiedziono, że redukcja mikroalbuminurii u chorych na cukrzycę typu 2 istotnie wpływa na zmniejszenie ryzyka powikłań nerkowych i sercowo-naczyniowych cukrzycy.OBJECTIVE. Microalbuminuria in diabetic patients is a predictor for diabetic nephropathy and cardiovascular disease. The aim of this study is to investigate the clinical impact of reducing microalbuminuria in type 2 diabetic patients in an observational follow-up study. RESEARCH DESIGN AND METHODS. We enrolled 216 type 2 diabetic patients with microalbuminuria during an initial 2-year evaluation period and observed them for the next 8 years. Remission and a 50% reduction of microalbuminuria were defined as a shift to normoalbuminuria and a reduction < 50% from the initial level of microalbuminuria. The association between reducing microalbuminuria and first occurrence of a renal or cardiovascular event and annual decline rate of estimated glomerular filtration rate (eGFR) was evaluated. RESULTS. Twelve events occurred in 93 patients who attained a 50% reduction of microalbuminuria during the follow-up versus 35 events in 123 patients without a 50% reduction. The cumulative incidence rate of events was significantly lower in patients with a 50% reduction. A pooled logistic regression analysis revealed that the adjusted risk for events in subjects after a 50% reduction was 0.41 (95% CI: 0.15-0.96). In addition, the annual decline rate of eGFR in patients with a 50% reduction was significantly slower than in those without such a reduction. The same results were also found in the analysis regarding whether remission occurred. CONCLUSIONS. The present study provides clinical evidence implying that a reduction of microalbuminuria in type 2 diabetic patients is an integrated indicator for renal and cardiovascular risk reduction

Role of dietary amino acid balance in diet restriction-mediated lifespan extension, renoprotection, and muscle weakness in aged mice.

Extending healthy lifespan is an emerging issue in an aging society. This study was designed to identify a dietary method of extending lifespan, promoting renoprotection, and preventing muscle weakness in aged mice, with a focus on the importance of the balance between dietary essential (EAAs) and nonessential amino acids (NEAAs) on the dietary restriction (DR)-induced antiaging effect. Groups of aged mice were fed ad libitum, a simple DR, or a DR with recovering NEAAs or EAAs. Simple DR significantly extended lifespan and ameliorated age-related kidney injury; however, the beneficial effects of DR were canceled by recovering dietary EAA but not NEAA. Simple DR prevented the age-dependent decrease in slow-twitch muscle fiber function but reduced absolute fast-twitch muscle fiber function. DR-induced fast-twitch muscle fiber dysfunction was improved by recovering either dietary NEAAs or EAAs. In the ad libitum-fed and the DR plus EAA groups, the renal content of methionine, an EAA, was significantly higher, accompanied by lower renal production of hydrogen sulfide (H2 S), an endogenous antioxidant. Finally, removal of methionine from the dietary EAA supplement diminished the adverse effects of dietary EAA on lifespan and kidney injury in the diet-restricted aged mice, which were accompanied by a recovery in H2 S production capacity and lower oxidative stress. These data imply that a dietary approach could combat kidney aging and prolong lifespan, while preventing muscle weakness, and suggest that renal methionine metabolism and the trans-sulfuration pathway could be therapeutic targets for preventing kidney aging and subsequently promoting healthy aging

Protective role of podocyte autophagy against glomerular endothelial dysfunction in diabetes.

To examine the cell-protective role of podocyte autophagy against glomerular endothelial dysfunction in diabetes, we analyzed the renal phenotype of tamoxifen (TM)-inducible podocyte-specific Atg5-deficient (iPodo-Atg5-/-) mice with experimental endothelial dysfunction. In both control and iPodo-Atg5-/- mice, high fat diet (HFD) feeding induced glomerular endothelial damage characterized by decreased urinary nitric oxide (NO) excretion, collapsed endothelial fenestrae, and reduced endothelial glycocalyx. HFD-fed control mice showed slight albuminuria and nearly normal podocyte morphology. In contrast, HFD-fed iPodo-Atg5-/- mice developed massive albuminuria accompanied by severe podocyte injury that was observed predominantly in podocytes adjacent to damaged endothelial cells by scanning electron microscopy. Although podocyte-specific autophagy deficiency did not affect endothelial NO synthase deficiency-associated albuminuria, it markedly exacerbated albuminuria and severe podocyte morphological damage when the damage was induced by intravenous neuraminidase injection to remove glycocalyx from the endothelial surface. Furthermore, endoplasmic reticulum stress was accelerated in podocytes of iPodo-Atg5-/- mice stimulated with neuraminidase, and treatment with molecular chaperone tauroursodeoxycholic acid improved neuraminidase-induced severe albuminuria and podocyte injury. In conclusion, podocyte autophagy plays a renoprotective role against diabetes-related structural endothelial damage, providing an additional insight into the pathogenesis of massive proteinuria in diabetic nephropathy

GW501516, a PPARδ Agonist, Ameliorates Tubulointerstitial Inflammation in Proteinuric Kidney Disease via Inhibition of TAK1-NFκB Pathway in Mice

Peroxisome proliferator-activated receptors (PPARs) are a nuclear receptor family of ligand-inducible transcription factors, which have three different isoforms: PPARα, δ and γ. It has been demonstrated that PPARα and γ agonists have renoprotective effects in proteinuric kidney diseases; however, the role of PPARδ agonists in kidney diseases remains unclear. Thus, we examined the renoprotective effect of GW501516, a PPARδ agonist, in a protein-overload mouse nephropathy model and identified its molecular mechanism. Mice fed with a control diet or GW501516-containing diet were intraperitoneally injected with free fatty acid (FFA)-bound albumin or PBS(−). In the control group, protein overload caused tubular damages, macrophage infiltration and increased mRNA expression of MCP-1 and TNFα. These effects were prevented by GW501516 treatment. In proteinuric kidney diseases, excess exposure of proximal tubular cells to albumin, FFA bound to albumin or cytokines such as TNFα is detrimental. In vitro studies using cultured proximal tubular cells showed that GW501516 attenuated both TNFα- and FFA (palmitate)-induced, but not albumin-induced, MCP-1 expression via direct inhibition of the TGF-β activated kinase 1 (TAK1)-NFκB pathway, a common downstream signaling pathway to TNFα receptor and toll-like receptor-4. In conclusion, we demonstrate that GW501516 has an anti-inflammatory effect in renal tubular cells and may serve as a therapeutic candidate to attenuate tubulointerstitial lesions in proteinuric kidney diseases

Ketone bodies : A double-edged sword for mammalian life span.

Accumulating evidence suggests health benefits of ketone bodies, and especially for longevity. However, the precise role of endogenous ketogenesis in mammalian life span, and the safety and efficacy of the long-term exogenous supplementation of ketone bodies remain unclear. In the present study, we show that a deficiency in endogenous ketogenesis, induced by whole-body Hmgcs2 deletion, shortens life span in mice, and that this is prevented by daily ketone body supplementation using a diet containing 1,3-butanediol, a precursor of β-hydroxybutyrate. Furthermore, feeding the 1,3-butanediol-containing diet from early in life increases midlife mortality in normal mice, but in aged mice it extends life span and prevents the high mortality associated with atherosclerosis in ApoE-deficient mice. By contrast, an ad libitum low-carbohydrate ketogenic diet markedly increases mortality. In conclusion, endogenous ketogenesis affects mammalian survival, and ketone body supplementation may represent a double-edged sword with respect to survival, depending on the method of administration and health status

Successful Renal Replacement Therapy for a Patient with Severe Hemophilia after Surgical Treatment of Intracranial Hemorrhage and Hydrocephalus

A 21-year-old Japanese male with severe hemophilia A was developed end-stage renal failure. He was placed on combination therapy with peritoneal dialysis (PD) and hemodialysis (HD). Eight months later, he developed a hypertensive cerebral hemorrhage. After emergency surgery, he was managed with PD without HD to avoid cerebral edema. One month later, his renal replacement therapy was switched to HD (three times a week) from PD, since a ventriculoperitoneal shunt catheter was placed to treat his hydrocephalus. HD could be performed safety without anticoagulant agents on condition that factor VIII is given after every HD

Stearoyl-CoA Desaturase-1 Protects Cells against Lipotoxicity-Mediated Apoptosis in Proximal Tubular Cells

Saturated fatty acid (SFA)-related lipotoxicity is a pathogenesis of diabetes-related renal proximal tubular epithelial cell (PTEC) damage, closely associated with a progressive decline in renal function. This study was designed to identify a free fatty acid (FFA) metabolism-related enzyme that can protect PTECs from SFA-related lipotoxicity. Among several enzymes involved in FFA metabolism, we identified stearoyl-CoA desaturase-1 (SCD1), whose expression level significantly decreased in the kidneys of high-fat diet (HFD)-induced diabetic mice, compared with non-diabetic mice. SCD1 is an enzyme that desaturates SFAs, converting them to monounsaturated fatty acids (MUFAs), leading to the formation of neutral lipid droplets. In culture, retrovirus-mediated overexpression of SCD1 or MUFA treatment significantly ameliorated SFA-induced apoptosis in PTECs by enhancing intracellular lipid droplet formation. In contrast, siRNA against SCD1 exacerbated the apoptosis. Both overexpression of SCD1 and MUFA treatment reduced SFA-induced apoptosis via reducing endoplasmic reticulum stress in cultured PTECs. Thus, HFD-induced decrease in renal SCD1 expression may play a pathogenic role in lipotoxicity-induced renal injury, and enhancing SCD1-mediated desaturation of SFA and subsequent formation of neutral lipid droplets may become a promising therapeutic target to reduce SFA-induced lipotoxicity. The present study provides a novel insight into lipotoxicity in the pathogenesis of diabetic nephropathy

Establishment of a novel mouse model of renal artery coiling-based chronic hypoperfusion-related kidney injury

Renal artery stenosis-induced chronic renal ischemia is an important cause of renal dysfunction, especially in older adults, and its incidence is currently increasing. To elucidate the mechanisms underlying chronic renal hypoperfusion-induced kidney damage, we developed a novel mouse model of renal artery coiling-based chronic hypoperfusion-related kidney injury. This model exhibits decreased renal blood flow and function, atrophy, and parenchymal injury in the coiled kidney, along with compensatory hypertrophy in the non-coiled kidney, without chronic hypertension. The availability of this mouse model, which can develop renal ischemia without genetic modification, will enhance kidney disease research by serving as a new tool to investigate the effects of acquired factors (e.g., obesity and aging) and genetic factors on renal artery stenosis-related renal parenchymal damage