Renal function of rats in response to 37 days of head-down tilt

Spaceflight induces changes in human renal function, suggesting similar changes may occur in rats. Since rats continue to be the prime mammalian model for study in space, the effects of chronic microgravity on rat renal function should be clarified. Acute studies in rats using the ground-based microgravity simulation model, head-down tilt (HDT), have shown increases in glomerular filtration rate (GFR), electrolyte excretion, and a diuresis. However, long term effects of HDT have not been studied extensively. This study was performed to elucidate rat renal function following long-term simulated microgravity. Chronic exposure to HDT will cause an increase in GFR and electrolyte excretion in rats, similar to acute exposures, and lead to a decrease in the fractional excretion of filtered electrolytes. Experimental animals (HDT, n=10) were tail-suspended for 37 days and renal function compared to ambulatory controls (AMB, n=10). On day 37 of HDT, GFR, osmolal clearance, and electrolyte excretion were decreased, while plasma osmolality and free water clearance were increased. Urine output remained similar between groups. The fractional excretion of the filtered electrolytes was unchanged except for a decrease in the percentage of filtered calcium excreted. Chronic exposure to HDT results in decreased GFR and electrolyte excretion, but the fractional excretion of filtered electrolytes remained primarily unaffected.     

Association of high blood pressure with renal insufficiency: role of albuminuria, from NHANES, 1999-2006

Background

The relationship between hypertension and kidney disease is complicated. Clinical trials found intense blood pressure control was not associated with alterations in glomerular filtration rate (GFR) in all patients but did slow the rate of GFR decline among those with a higher baseline proteinuria. However, the underlying mechanism has been unclear.

Methods

We tested the hypothesis that the association between high blood pressure and renal function is modified by albuminuria status by conducting analyses in a cross-sectional study with 12,440 adult participants without known kidney diseases, diabetes or cardiovascular diseases, participating in the National Health and Nutrition Examination Survey (NHANES) 1999–2006.

Results

1226 out of 12440 were found to have unknown high blood pressure and 4494 were found to have reduced renal function. Overall, a moderate association was found between high blood pressure and renal function insufficiency in all participants analyzed. However, among participants with albuminuria, the prevalence of moderate-severe renal insufficiency substantially and progressively increased from normal subjects to prehypertensive and undiagnosed hypertensive subjects (1.43%, 3.44%, 10.96%, respectively, P for trend<0.0001); on the other hand, the prevalence of undiagnosed hypertension was also significantly higher among subjects with moderate-severe renal insufficiency than those with mild renal insufficiency (35.54% Vs 19.09%, P value <0.05), supporting an association between hypertension and renal function damage. In contrast, no association between hypertension and renal insufficiency was observed among those without albuminuria in this population. Similar findings were observed when the CKD-EPI equation was used.

Conclusions

The association between high blood pressure and reduced renal function could be dependent upon the albuminuria status. This finding may provide a possible explanation for results observed in clinical trials of intensive blood pressure control. Further studies are warranted to confirm our findings.     

Cystatin C--a paradigm of evidence based laboratory medicine

Cystatin C is a 13-kDa protein, of the cysteine proteinase inhibitor superfamily, produced by all nucleated cells. Its production rate is constant throughout the ages of 1 to 50 years. It is freely filtered at the glomerulus and then resorbed and fully catabolised by proximal renal tubules, making it an ideal marker of glomerular filtration rate (GFR). Serum creatinine, the most established marker of renal function, is affected by age, gender, muscle mass, nutritional status and analytical interference. The abbreviated Modifiation of Diet in Renal Diseases (MDRD) equation has recently been introduced in an attempt to overcome these shortcomings, but still has many limitations. Cystatin C is not affected by gender, muscle mass, malignancy, its production rate is usually constant and its plasma concentration therefore is dependent only on GFR. Cystatin C has been demonstrated to be more accurate than serum creatinine in the detection of early renal impairment and in specific populations may allow for early detection of renal disease. Cystatin C has also been found to be a strong predictor of long-term clinical outcomes in patients with cardiovascular diseases. Although cystatin C may have advantages in detection of early renal impairment there is a paucity of evidence that it significantly improves clinical decision making over creatinine. This coupled with assay cost may be the reason why cystatin C, although well recognised, has not been introduced into routine operational use, although that may eventuate with emerging evidence.     

The Influence of Postural Changes on the Glomerular Filtration Rate in Nephroptosis

The influence of postural changes on renal function was determined in 13 patients with nephroptosis and in 5 normal subjects by measuring GFR in the erect and supine positions. The results indicate that GFR was reduced in the erect position in 10 of 13 patients with either unilateral or bilateral nephroptosis whereas GFR was increased in the erect position in 4 of 5 patients without renal disease. One patient with bilateral nephroptosis and renovascular hypertension was studied before and after surgical correction of his disease. These observations indicate that patients with nephroptosis may have significant reductions in renal function when they assume an upright position, and suggest that GFR measurements in the supine and erect position in patients with nephroptosis can be helpful in evaluating this disease.     

Effects of short-term hypothermic perfusion and cold storage on function of the isolated-perfused dog kidney

The isolated-perfused dog kidney was used as a model to measure the effects of short-term hypothermic preservation on renal function and metabolism. Kidneys were cold-stored in Collins' solution, hypotonic citrate, or phosphate-buffered sucrose for 4 and 24 hr, or were continuously perfused for 4 and 24 hr with a synthetic perfusate. Following preservation kidneys were perfused with an albumin-containing perfusate at 37 degrees C for 60 min for determination of renal function. The results indicate that many of the effects of short-term preservation on renal function in dog kidneys are similar to results reported for rat and rabbit kidneys. Cold storage for 4 hr resulted in a large decrease in GFR (57%), but only a small decrease in Na reabsorption (from 97 to 87%). Cold storage for 24 hr caused a further decline in renal function (GFR = 95% decrease, Na reabsorption = 49-64%). Results were similar for all cold storage solutions tested. Perfusion for 4 hr was less damaging to renal function than cold storage. The GFR decreased only 14% and urine formation and Na reabsorption were practically normal. After 24 hr of hypothermic perfusion, the GFR was reduced by 79%, urine flow was normal, and Na reabsorption was 78%. There were no obvious biochemical correlates (adenine nucleotides, tissue edema, or electrolyte concentration) with the loss of renal function during short-term preservation. The results suggest that the isolated-perfused dog kidney can be used to test the effects of preservation on renal function, and yields results similar to those obtained using small animal models.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms

When the kidney is subjected to acute increases in blood pressure (BP), renal blood flow (RBF) and glomerular filtration rate (GFR) are observed to remain relatively constant. Two mechanisms, tubuloglomerular feedback (TGF) and the myogenic response, are thought to act in concert to achieve a precise moment-by-moment regulation of GFR and distal salt delivery. The current view is that this mechanism insulates renal excretory function from fluctuations in BP. Indeed, the concept that renal autoregulation is necessary for normal renal function and volume homeostasis has long been a cornerstone of renal physiology. This article presents a very different view, at least regarding the myogenic component of this response. We suggest that its primary purpose is to protect the kidney against the damaging effects of hypertension. The arguments advanced take into consideration the unique properties of the afferent arteriolar myogenic response that allow it to protect against the oscillating systolic pressure and the accruing evidence that when this response is impaired, the primary consequence is not a disturbed volume homeostasis but rather an increased susceptibility to hypertensive injury. It is suggested that redundant and compensatory mechanisms achieve volume regulation, despite considerable fluctuations in distal delivery, and the assumed moment-by-moment regulation of renal hemodynamics is questioned. Evidence is presented suggesting that additional mechanisms exist to maintain ambient levels of RBF and GFR within normal range, despite chronic alterations in BP and severely impaired acute responses to pressure. Finally, the implications of this new perspective on the divergent roles of the myogenic response to pressure vs. the TGF response to changes in distal delivery are considered, and it is proposed that in addition to TGF-induced vasoconstriction, vasodepressor responses to reduced distal delivery may play a critical role in modulating afferent arteriolar reactivity to integrate the regulatory and protective functions of the renal microvasculature.     

Determination of the glomerular filtration rate (GFR): methodological problems, age-dependence, consequences of various surgical interventions, and the influence of different drugs and toxic substances

Determinations of renal clearance of fluorescein isothiocyanate (FITC)-inulin were used for assessing the glomerular filtration rate (GFR) in rats and to characterize factors influencing the glomerular filtration capacity. In anesthetized rats, GFR develops after birth up to day 30. Thereafter, GFR remains relatively constant for up to 3 months of age and drops continuously until the 8th month. GFR can be determined in utero, already one day before birth, however, only at a very low level. It increases significantly on the first day of life. Even at this time the effect of furosemide on GFR can be proven. After reduction of renal mass, GFR is decreased in dependence on the extent of kidney tissue removal. However, within 2 days after unilateral nephrectomy (NX) or one week after 5/6 NX, GFR reaches values about 3/4 of the controls with two intact kidneys. Furthermore, the compensation of GFR after renal ischemia reaches 80% of baseline values after one week. On the other hand, GFR is enhanced after bile duct ligation as a model of hepato-renal failure. It has been shown in previous experiments that pretreatment with hormones can stimulate renal tubular transport processes. Pretreatment with dexamethasone or triiodothyronine after 5/6 NX improves glomerular filtration capacity whereas in animals with ligated bile ducts dexamethasone seems to prevent the increase in GFR. After subchronic treatment with epidermal growth factor (EGF) GFR is significantly reduced. A continuous infusion of amino acids does not change GFR in the controls but enhances the filtration capacity in EGF-treated rats. But immediately after bolus injection of amino acids GFR also increases significantly in the controls. Diuretics such as furosemide, most nephrotoxic agents (cyclosporine A [CsA], heavy metals) and imidazole reduce the GFR significantly. Diltiazem reported to act nephroprotectively in CsA nephrotoxicity in human beings was without beneficial effect in rats. This could be due to species differences in GFR because the rat is one of the species with the highest glomerular filtration capacity.     

Effects of dipyridamole and furosemide on renal function during adenine dinucleotide infusion in rats

In anaesthetized rats kept on normal diet an i.v. infusion of NAD (200 nmole X kg-1 X X min-1) induced a decrease in renal plasma flow (CPAH), glomerular filtration rate (GFR) and electrolyte excretion accompanied by an increase in plasma adenosine concentration. Separate infusions of a small dose of NAD (50 nmole X kg-1 X min-1) or dipyridamole (25 micrograms X kg-1 X min-1) did not affect renal function or plasma adenosine concentration. However, when the above small doses of both agents were given simultaneously, GFR, CPAH and electrolyte excretion fell significantly, indicating potentiation of NAD action by dipyridamole, associated with increased plasma adenosine level. An i.v. infusion of furosemide failed to abolish the depression of renal function in response to NAD. The data suggest that the causal factor of this depression was adenosine and not NAD itself.     

Relationship Between Orcadian Changes in Renal Hemodynamics and Circadian Changes in Urinary Glycosaminoglycan Excretion in Normal Rats

Circadian changes in renal hemodynamics and urinary glycosaminogly-can (GAG) excretion were studied in normal Sprague-Dawley rats to further investigate rhythms in kidney function. Urinary water, protein, and GAG excretion, as well as glomerular filtration rate (GFR) and renal plasma flow (RPF), were determined every 4h over the 24h cycle in an attempt to characterize any temporal changes. Urinary flow rate and proteinuria peaked during the dark activity period of the animals, consistently at the same hour, whereas the lowest values were detected during the resting phase. GAG are mucopolysaccharides entering the constitution of the glomerular basement membrane (GBM), which is the key component in the process of glomerular filtration. Similarly, the urinary excretion rate of GAG showed a circadian rhythmicity in phase with urinary water and protein excretion, with markedly increased values observed during the nocturnal phase of the animals. Moreover, GFR and RPF were demonstrated to exhibit large circadian variations in phase with renal excretory rhythmicity, showing nighttime values significantly greater compared to daytime ones. Strong correlations were found between GFR and RPF rhythms, as well as between GAG and GFR, and GAG and RPF rhythms, although the latter were not statistically significant. This pattern suggests that the circadian rhythmicity in urinary excretion rate of GAG in physiological conditions could presumably be secondary to the temporal changes in renal hemodynamics. In this respect, knowledge of renal chronobiology helpfully contributes to increase our understanding of renal physiology.     

Estimating renal function for drug dosing decisions

In order to adjust the dose of renally excreted drugs in response to reduced renal function, it is necessary to make a quantitative estimate of the glomerular filtration rate (GFR) of the patient. Traditionally this has been done with the use of the Cockcroft and Gault equation or a measured creatinine clearance. More recently the MDRD (Modification of Diet in Renal Disease) formula has become available, providing an estimate of GFR readily available on routine pathology reports. The presence of these different methods of assessing renal function has created some confusion for healthcare workers as to the best approach. In this paper the two methods are compared, together with a newer formula CKD-EPI (named after the Chronic Kidney Disease Epidemiology Collaborative), and a proposal is made for future practice.     

Is Increased Echogenicity Related to a Decrease in Glomerular Filtration Rate? Objective Measurements in Pediatric Solitary Kidney Patients—A Retrospective Analysis

Quantitative measurements of renal echogenicity using a graphic program show close correlation with renal histology in adult patients, but this has neither been applied in pediatric patients nor correlated with glomerular filtration rate (GFR). To determine the direct relationship between echogenicity and GFR, we retrospectively analyzed 91 patients with a solitary functioning kidney under the age of 10, who underwent ultrasonography and serum cystatin C evaluation on a single day between January 2013 and December 2014. Echogenicity was quantified as previously reported. Echogenicity and kidney length were correlated with age-matched values of serum cystatin C-based GFR. Evaluation was performed at a median age of 17.1 months. GFR was low for age in eight of 54 right solitary kidney patients and four of 37 left solitary kidney patients. The right kidney-liver ratio was significantly elevated in the right decreased GFR group, while the left kidney-spleen ratio was not different in the left decreased GFR group. Age-matched longitudinal kidney length ratios were similar between the decreased and normal GFR groups for both sides. This is the first report to objectively prove the relationship between echogenicity and renal function in patients with a right solitary kidney. The right kidney-liver echogenicity ratio, measured objectively, showed feasibility in clinical practice as it showed a close relationship with decreased renal function when increased. However, absolute kidney echogenicity values, or the left kidney-spleen echogenicity ratio, were not independent markers for decreased renal function.     

Estimating glomerular filtration rate in diabetes using serum cystatin C

Chronic kidney disease (CKD) is a major public health problem, especially for people with diabetes. Not only is it a risk factor for end-stage renal disease (ESRD) but it is also a major cardiovascular disease (CVD) risk factor. Methods that accurately and simply estimate glomerular filtration rate (GFR) are therefore needed to optimise the detection and management of CKD in people with diabetes. One of the main failures of commonly used creatinine-based methods for estimating renal function is that they lack applicability across the full range of GFR values and underestimate GFR levels >60 mL/min/1.73m(2). Methods for accurately estimating an early pathological decline in GFR (i.e. ΔGFR >3.3 mL/min/year before reaching a GFR <60 mL/min/1.73m(2)) are especially needed as appropriate interventions have been shown to retard progression to ESRD and reduce CVD risk in people with diabetes. In contrast, recent studies have suggested that estimates of GFR based on serum cystatin C concentration might provide a simple and accurate method for detecting and monitoring an early decline in renal function.     

Inhibition by angiotensin II of some vasopressin effects on renal function in sheep.

The effects of intravenous infusions of arginine vasopressin (AVP) alone and with angiotensin II (AII) on renal function were studied in conscious Merino ewes. AVP at 11.5 pmol.min-1 caused an increase in water and electrolyte output which was associated with a rise in glomerular filtration rate (GFR), solute clearance, solute-free water reabsorption and tubular sodium reabsorption. Addition of AII of 100 ng.min-1 generally reversed all of these effects. The filtration fraction, which rose during AVP infusion, increased further when AII was added due to a greater fall in renal plasma flow than in GFR. The diuretic and electrolyte-excreting effects of infused AVP appeared to be brought about by an increase in GFR. It is suggested that this inappropriate effect of AVP, which is secreted in response to water deprivation, could be countered by the simultaneous production of AII.     

Relationships among endogenous digitalis-like factors in essential hypertension

Elements of a hypothesis that relate endogenous digitalis-like factors to both natriuretic hormone and hypertension are briefly reviewed. The stimulus for secretion of these factors appears to involve a tendency toward a state of extracellular fluid volume expansion as a consequence of an inherited or an acquired defect in renal function. Several studies implicate the brain and, in particular, the hypothalamus in the control of the secretion. The digitalis-like factors are thought to act by partial inhibition of active sodium transport, thereby promoting increased intracellular levels of Na+ and Ca2+ in a variety of cell types. In the kidney, inhibition of sodium transport leads to a compensatory natriuresis to correct the tendency for volume overload. In smooth muscle, the inhibition of sodium transport will indirectly increase intracellular calcium levels. The increased availability of Ca2+ will elevate muscle tone and increase peripheral vascular resistance. Also presented are criteria that may be used to characterize digitalis-like activity in samples and extracts obtained from purification procedures. Finally, we review our measurements of the 6-h integrated plasma levels of digitalis-like factors and other hormones for normotensive subjects and patients with essential hypertension. The data indicate the presence of two classes of digitalis-like factors with potentially different roles in electrolyte metabolism and hypertension.     

Soluble RAGE, diabetic nephropathy and genetic variability in the AGER gene

Diabetes mellitus, especially when complicated with decline of renal function due to diabetic nephropathy (DN), is associated with accumulation of advanced glycation end products (AGEs) exerting their adverse effects via receptor of AGE (RAGE). Soluble RAGE (sRAGE) is a truncated form of RAGE functioning as an inhibitor of AGE-mediated signalling. We studied relationships between sRAGE, renal function and genetic variability in the AGER gene in diabetic subjects. Study comprised a total of 265 diabetics (type 1 or 2 or LADA) with normoalbuminuria (n = 94) or DN (n = 171). sRAGE (assessed by ELISA) was significantly higher in DN than normoalbuminuria subjects (P = 0.007) and positively correlated with age, S-urea, S-creatinine and albuminuria and AGEs (determined spectrofluorimetrically), negatively with GFR (all P < 0.05); however, multivariate regression revealed that GFR was the only independent variable associated with sRAGE (P = 0.047). sRAGE did not correspond with carrier state of risk-haplotype copies (RAGE2) (P > 0.05). In conclusion, GFR is a principal determinant of sRAGE concentration and gradual sRAGE increase in subjects with advancing impairment of renal function is paralleled by AGEs.     

Vascular, renal, and endocrine responses to low-dose atrial natriuretic peptide in the fluid-balanced New Zealand genetically hypertensive rats with and without endogenous arginine vasopressin.

In hypertension, the relationship between atrial natriuretic peptide (ANP) and vasopressin (AVP) is not yet clear, although their renal actions are effectively autoregulation. To examine the possible interaction further, the responses to ANP infusion (75 ng x min (-1), i.v.) have been investigated in both hypertensive and normotensive AVP-replete (HT and NT) and AVP-deficient (HTDI and NTDI) rats. This study aimed to assess the renal function and the plasma hormone concentrations of AVP, angiotensin II (AII), ANP, aldosterone, and corticosterone in the conscious, chronically catheterized, fluid-balanced rats, and to examine the cardiovascular, renal, and endocrine responses to a constant infusion of a low-dose ANP. Data gained from the present study showed, for the first time, the hormone profile, plasma electrolyte composition, and detailed renal function of the servo-controlled, fluid-balanced rats. The similarities of plasma electrolyte composition between servo-controlled and untreated rats indicated that the servo-controlled fluid replacement technique maintained the differences between the strains and maintained body fluid balance during the experimental periods. Following ANP administration, there were no changes in glomerular filtration rate (GFR) in all groups, but an enduring diuresis and natriuresis were observed in HT and NT, which were milder in HTDI rats. However, the hypotensive effect of ANP was of a similar magnitude in all rat strains. HTDI rats exhibited an inhibition of the renin-angiotensin system (RAS), which may have participated in the reduced mean arterial blood pressure (MAP) and natriuresis observed in these rats. The renal actions of ANP appear to rely upon renal tubular events, as indicated by increased fractional electrolyte excretions in the AVP-replete rats. This study highlights the importance of AVP to the profile of the renal actions of ANP in normal rats.     

Inhibitors of poly (ADP-ribose) synthetase reduce renal ischemia-reperfusion injury in the anesthetized rat in vivo.

The activation of poly (ADP-ribose) synthetase (PARS) subsequent to DNA damage caused by reactive oxygen or nitrogen species has been implicated in several pathophysiological conditions, including ischemia-reperfusion injury and shock. The aim of this study was to investigate whether PARS inhibitors could provide protection against renal ischemia-reperfusion injury in the rat in vivo. Male Wistar rats were subjected to 45 min bilateral clamping of the renal pedicles, followed by 6 h reperfusion (control animals). Animals were administered the PARS inhibitors 3-aminobenzamide, 1, 5-dihydroxyisoquinoline, or nicotinamide during the reperfusion period. Ischemia, followed by reperfusion, produced significant increases in plasma concentrations of urea, creatinine, and fractional excretion of Na(+) (FE(Na)) and produced a significant reduction in glomerular filtration rate (GFR). However, administration of the PARS inhibitors significantly reduced urea and creatinine concentrations, suggesting improved renal function. The PARS inhibitors also significantly increased GFR and reduced FE(Na), suggesting the recovery of both glomerular and tubular function, respectively, with a more pronounced recovery of tubular function. In kidneys from control animals, histological examination revealed severe renal damage and immunohistochemical localization demonstrated PARS activation in the proximal tubule. Both renal damage and PARS activation were attenuated by administration of PARS inhibitors during reperfusion. Therefore, we propose that PARS activation contributes to renal reperfusion injury and that PARS inhibitors may be beneficial in renal disorders associated with oxidative stress-mediated injury.     

Early renal hemodynamic modifications following the ablation of the controlateral kidney]

Instantaneous measurements of renal blood flow (RBF) and glomerular filtration rate (GFR) have been performed in anesthetized dogs to determine if removal of one kidney induces early functional adaptation in the remaining kidney. Increases in RBF (10%) and GFR (20%) were observed within the first minutes after exclusion of controlateral kidney; these are the earliest events described until now. These observations favour the concept that a functional adjustement may contribute to development of compensatory renal hypertrophy.     

Renal amino acid excretion and aging

The urinary excretion and serum concentration of amino acids were studied in 62 healthy individuals aged 15 to 70 years. In elderly subjects (61-70 years), it was found that renal amino acid clearance per 100 ml GFR (fractional excretion, FE) rose significantly in the following amino acids: CYS, VAL, MET, ILE and LEU. Since the serum concentrations of these amino acids showed no significant changes, but the GFR was reduced, it can be concluded that the raised FE of these amino acids was due to a decrease in their effective tubular reabsorption. A significant correlation was found between FENa and FE of most amino acids including those mentioned above. The findings support the assumption that changes in tubular Na+ transport probably participate in the changes of tubular amino acid transport in elderly individuals.     

The Uremic Toxin Adsorbent AST-120 Abrogates Cardiorenal Injury Following Myocardial Infarction

An accelerated progressive decline in renal function is a frequent accompaniment of myocardial infarction (MI). Indoxyl sulfate (IS), a uremic toxin that accumulates from the early stages of chronic kidney disease (CKD), is contributory to both renal and cardiac fibrosis. IS levels can be reduced by administration of the oral adsorbent AST-120, which has been shown to ameliorate pathological renal and cardiac fibrosis in moderate to severe CKD. However, the cardiorenal effect of AST-120 on less severe renal dysfunction in the post-MI setting has not previously been well studied. MI-induced Sprague-Dawley rats were randomized to receive either AST-120 (MI+AST-120) or were untreated (MI+Vehicle) for 16 weeks. Serum IS levels were measured at baseline, 8 and 16 weeks. Echocardiography and glomerular filtration rate (GFR) were assessed prior to sacrifice. Renal and cardiac tissues were assessed for pathological changes using histological and immunohistochemical methods, Western blot analysis and real-time PCR. Compared with sham, MI+Vehicle animals had a significant reduction in left ventricular ejection fraction (by 42%, p<0.001) and fractional shortening (by 52%, p<0.001) as well as lower GFR (p<0.05) and increased serum IS levels (p<0.05). A significant increase in interstitial fibrosis in the renal cortex was demonstrated in MI+Vehicle animals (p<0.001). Compared with MI+Vehicle, MI+AST-120 animals had increased GFR (by 13.35%, p<0.05) and reduced serum IS (p<0.001), renal interstitial fibrosis (p<0.05), and renal KIM-1, collagen-IV and TIMP-1 expression (p<0.05). Cardiac function did not change with AST-120 treatment, however gene expression of TGF-β1 and TNF-α as well as collagen-I and TIMP-1 protein expression was decreased in the non-infarcted myocardium (p<0.05). In conclusion, reduction of IS attenuates cardio-renal fibrotic processes in the post-MI kidney. KIM-1 appears to be a sensitive renal injury biomarker in this setting and is correlated with serum IS levels.