despite the growing amount of literature concerning cardio - renal syndrome ( crs ) , certain stages of pathogenesis and the possibility of its diagnosis remain unclear .
suspicion of crs seems to be obvious in the presence of apparent kidney or heart damage with accompanying second organ dysfunction .
diagnostic difficulties arise at the stage preceding the clinical manifestation of disease , or in the case of dysfunction of only 1 of the organs , while function of the second organ does not arouse suspicion and does not require intervention . however , even minor sub - clinical pathological changes at the functional level in 1 of the organs can cause changes in the functioning of the other 1 .
renal perfusion disorders are an important element in the pathogenesis of cardio - renal syndrome .
both the reduction and excessive increase in renal perfusion result in the decrease of tissues oxygenation and the onset of fibrosis . left ventricular heart failure results in the reduction in renal perfusion and the launch of compensatory mechanisms , improving cardiac output in order to restore normal organ perfusion . on the other hand , pathological processes primarily concerning kidneys significantly modify the perfusion , leading to progressive organ function impairment .
chronic kidney disease ( ckd ) results in the impaired salt excretion , water retention , neurohormonal activation , and worsening of blood pressure control .
these factors are considered the main reasons for the development of chronic cardio - renal syndrome .
therefore , the evaluation of renal perfusion parameters may be important for the early diagnosis of the disorders in the cardio - renal axis .
so far , most of the attempts of non - invasive doppler assessment of renal perfusion were based on the measurement of renal resistive index ( ri ) .
although the renal resistive index assessed by doppler examination is an acknowledged marker of vascular - organ damage in cardiovascular diseases , in most cases its value does not match the organ perfusion . even though the usefulness of ri was proven in monitoring of the effectiveness of hypertension treatment , predicting a response to immunosuppressive treatment of glomerulonephritis as well as diagnosis of renal artery stenosis , the specificity of ri for the recognition of cardiovascular changes decreases with the progression of renal disease [ 69 ] .
another feature limiting the usefulness of ri is the measurement made in single and well - visualized segmental artery , which results in obvious omission of vessels with lower flow and often overestimates the result .
if this error is irrelevant to the determination of inflow reduction as it is in the diagnosis of renal artery stenosis , it may be important for other applications of ri .
in contrast , the method of dynamic tissue perfusion measurement ( dtpm ) reflects the size of renal perfusion and includes all of the blood flow in the tested area .
the aim of the study was to test a hypothesis whether renal perfusion index ( rpi ) could relate stronger to cardiac hemodynamics than to renal function and could differentiate etiology of chronic cardio - renal syndrome .
twenty - four patients with hypertension and stable chronic kidney disease at 24 stage were enrolled in the study .
patients were recruited from consecutive subjects who had been admitted to the nephrology department over an 18-month period .
exclusion criteria included : acute renal and cardiac diseases , history of renal artery stenosis , ckd stage 5 , heart failure in nyha iv stage , atrial fibrillation , hyperkinetic state , inflammation , connective tissue diseases , vasculitis , diabetes mellitus , amyloidosis , visceral obesity , hydronephrosis , systemic cancer , lack of good quality ultrasound imaging of renal or heart structures .
a total of 24 patients ( 4 f ; 20 m ; age 5017 , bmi 27.023.44 kg / m ) performed protocol of the study .
primary diagnosis of chronic kidney disease ( pckd ) was recognized in next 12 patients ( 9 due to glomerulonephritis , 3 of unknown etiology ) .
serum creatinine ( cr ) and cystatin c ( cys ) were examined to calculate glomerular filtration rate with the use of ckd - epi formula .
in addition , biochemical cardiac markers such as nt - probnp and troponin i were collected . in a random urine spot sample
albumin and creatinine were tested , then albumin to creatinine ratio ( mg / mg ) was calculated .
the 24-h ambulatory blood pressure monitoring ( abpm-04 , meditech , hungary ) was performed and the mean of 24-h systolic and diastolic blood pressure ( sbp , dbp ) , pulse pressure ( pp ) and mean arterial pressure ( map ) were recorded .
logiq p6 ( ge ) ultrasound equipment with a convex transducer 4l ( 25 mhz ) was used to perform kidney ultrasound measurements .
the right kidney was chosen because of better technical access to the mid - segment of renal cortex and to avoid alterations after renal biopsies .
mean value of ri was calculated from 2 or 3 measurements in the upper , middle and lower regions of the renal sinus .
a renal perfusion intensity , achieved from recorded images of color doppler signal , from at least 3 full heart cycles in the chosen region of examination ( roe ) was calculated automatically with the use of the software package pixelflux ( chameleon - software , leipzig , germany ) .
the roe was set in the mid - segment of renal cortex without focal abnormalities , in the area between the outer border of medullary pyramids and the kidney surface .
the roe contained vessels running in straight toward the transducer , avoiding angle error corrections .
a whole roe perfusion intensity was calculated as total cortex perfusion intensity ( tcp ) . to calculate renal perfusion index ( rpi )
the perfusion intensities of proximal ( pcp ) and distal ( dcp ) cortex were measured separately , then rpi was calculated as a decimal logarithm of pcp to dcp ratio . to determine arterial organ damage , left common carotid artery intima - media thickness ( imt )
the mean of 3 measurements of distal wall imt in the distance of at least 10 mm before carotid sinus was calculated .
for echocardiography the vivid s6 ( ge ) with m4s - rs transducer ( 1.53.6 mhz ) was used .
all m - mode measurements were made according to recommendations of the american society of echocardiography .
the left atrial ( la ) diameter was measured using m - mode methodology from the parasternal long - axis view . left ventricular mass ( lvm ) was derived from the devereux et al .
the left ventricular ejection fraction ( lvef ) was estimated by simpson s biplane method .
left ventricular stroke volume ( lvsv ) and cardiac index ( ci ) were collected using 2d / continuous doppler functions .
the examined variables were analyzed with pearson s or spearman s correlation test as determined by meeting the condition of normal distribution .
the t - test and u mann - whitney test were used to analyze the difference between the groups .
receiver operating characteristic ( roc ) analysis was performed to assess a diagnostic value of rpi in recognizing cardio - renal damage direction .
serum creatinine ( cr ) and cystatin c ( cys ) were examined to calculate glomerular filtration rate with the use of ckd - epi formula . in addition ,
in a random urine spot sample albumin and creatinine were tested , then albumin to creatinine ratio ( mg / mg ) was calculated .
the 24-h ambulatory blood pressure monitoring ( abpm-04 , meditech , hungary ) was performed and the mean of 24-h systolic and diastolic blood pressure ( sbp , dbp ) , pulse pressure ( pp ) and mean arterial pressure ( map ) were recorded .
logiq p6 ( ge ) ultrasound equipment with a convex transducer 4l ( 25 mhz ) was used to perform kidney ultrasound measurements .
the right kidney was chosen because of better technical access to the mid - segment of renal cortex and to avoid alterations after renal biopsies .
mean value of ri was calculated from 2 or 3 measurements in the upper , middle and lower regions of the renal sinus .
a renal perfusion intensity , achieved from recorded images of color doppler signal , from at least 3 full heart cycles in the chosen region of examination ( roe ) was calculated automatically with the use of the software package pixelflux ( chameleon - software , leipzig , germany ) .
the roe was set in the mid - segment of renal cortex without focal abnormalities , in the area between the outer border of medullary pyramids and the kidney surface .
the roe contained vessels running in straight toward the transducer , avoiding angle error corrections .
a whole roe perfusion intensity was calculated as total cortex perfusion intensity ( tcp ) . to calculate renal perfusion index ( rpi )
the perfusion intensities of proximal ( pcp ) and distal ( dcp ) cortex were measured separately , then rpi was calculated as a decimal logarithm of pcp to dcp ratio . to determine arterial organ damage , left common carotid artery intima - media thickness ( imt )
the mean of 3 measurements of distal wall imt in the distance of at least 10 mm before carotid sinus was calculated .
for echocardiography the vivid s6 ( ge ) with m4s - rs transducer ( 1.53.6 mhz ) was used .
all m - mode measurements were made according to recommendations of the american society of echocardiography .
the left atrial ( la ) diameter was measured using m - mode methodology from the parasternal long - axis view . left ventricular mass ( lvm ) was derived from the devereux et al .
the left ventricular ejection fraction ( lvef ) was estimated by simpson s biplane method .
left ventricular stroke volume ( lvsv ) and cardiac index ( ci ) were collected using 2d / continuous doppler functions .
the examined variables were analyzed with pearson s or spearman s correlation test as determined by meeting the condition of normal distribution .
the t - test and u mann - whitney test were used to analyze the difference between the groups .
receiver operating characteristic ( roc ) analysis was performed to assess a diagnostic value of rpi in recognizing cardio - renal damage direction .
patients with hypertensive nephropathy ( ht - ckd ) were older , had higher values of imt , lower diastolic blood pressure and uacr in comparison to patients with ckd of other origins ( table 1 ) .
although rpi was lower in the ht - ckd group than in pckd , this difference was not significant .
the number and classes of prescribed antihypertensive agents were similar in both groups ( table 2 ) .
considering the impact of cardiac and renal functions , and other factors on renal perfusion parameters , analysis of correlations was performed in both groups separately and in a group of all 24 patients .
after the examination of the model containing ckd - epi(cys - cr ) , lvsv , lvmi , lvef , troponin i , imt , map and pp , in the ht - ckd group , stepwise multiple regression analysis showed that rpi was independently influenced by ckd - epi(cys - cr ) ( b=0.500 ) , lvsv ( b=0.790 ) and map ( b=0.494 ) , ( r=0.84 ; p=0.002 ) .
the same regression analysis model was used in the pckd group , and we found that only lvsv ( b=0.888 ) significantly modified rpi value ( r=0.79 ; p<0.001 ) , ( figure 1 ) . when stepwise multiple regression analysis was repeated in the group of all 24 patients , ckd - epi(cys - cr ) ( b=0.360 ) , lvsv ( b=0.924 ) and map ( b=0.376 ) together independently modified rpi ( r=0.74 ; p<0.0001 ) .
prediction values of rpi based on this analysis are presented in table 4 . to assess a diagnostic value of rpi in recognizing cardio - renal damage direction , receiver operating characteristic ( roc ) analysis
the optimal rpi cut - off point was 0.567 , and rpi<0.567 allowed for the identification of patients with chronic cardio - renal syndrome with sensitivity of 41.7% and specificity of 83.3% ( area under curve 0.5970.122 ) .
the present work shows a significant impact of cardiac echocardiographic hemodynamic parameters on rpi . recently ,
significant correlations of renal cortex perfusion parameters with cardiac biochemical and echocardiographic parameters as well as renal function have been found . despite a strong dependence of distal renal cortex perfusion ( dcp ) on biochemical markers of cardiac function such as troponin
i and nt - probnp , and nearly significant correlation with lvmi were demonstrated , renal function turned out to be the main factor modifying the value of dpi . in the present study ,
the leading influence of left ventricular stroke volume assessed in echocardiography on rpi was shown in both considered groups as well as in the group of all patients . with the exception of lvsv , in the ht - ckd group rpi
more strongly correlates with lvef , in contrast to the pckd group , where only relations to troponin i and ci with rpi were more expressed .
as long as lvef is another parameter showing cardiac systolic function and ci is lvsv derivate , relations of these variables with rpi can be parallel to lvsv correlation .
based on the acquired data , it could not be explained by differences in renal or cardiac function and markers of organ damage ( lvmi , rri , imt ) . finally , troponin i did not appear to be an independent factor modifying rpi value . the concept that the etiology of ckd in considered groups could be distinguished by rpi can be supported by the various types of renal injury . in essential hypertension ,
preserved renal autoregulation protects glomerular capillaries , but hypertensive damage is more expressed in preglomerular vessels .
vascular damage is more evident than decrease in renal function . in hypertension and primary ckd ,
disrupted autoregulation promotes transmission of barotrauma to the glomeruli , which accelerates renal dysfunction , while preglomerular arteries could be preserved . in our study , with an agreement of described methodology , the proximal part of roi contains arcuate arteries  the biggest preglomerular arteries in the whole roi .
based on of roc analysis , we found that rpi<0.567 allowed for the identification of patients with cardio - renal direction of damage with sensitivity of 41.7% and specificity of 83.3% . at first
, it seems that rpi , with its rather poor sensitivity is not a good marker for recognition of cardiorenal direction damage .
disturbances in the cardiorenal axis can result in both , significant ( for the maintenance of normal renal perfusion ) decrease in cardiac output , and hypervolemia effecting in excessive increase of preload and increased tension of the ventricles , resulting in increased levels of natriuretic peptides in serum . examining data of right heart cauterization in 178 patients with heart failure exacerbation , guglin at al .
central venous pressure and renal perfusion pressure , but not with cardiac index or cardiac output , suggesting stronger dependence of renal dysfunction from congestion than cardiac output .
this could be one of the reasons that weaken predictive role of rpi in recognizing etiology of crs in our study . nevertheless , in the aforementioned study of guglin at al . , cr was higher in upper tertile of ci .
this data are consistent with our findings , where rpi is mainly influenced by lvsv ( b=0.924 ) , and less and negatively by renal function ( b=0.360 ) .
demonstrated by our study the positive correlation between rpi and lvsv despite ckd , rather corresponds with a compensatory increase in cardiac output induced by impaired renal perfusion , and not with an improvement in heart function as the organ .
compensatory mechanisms appear to be the next reason responsible for low sensitivity of rpi . on the other hand , despite various etiologies , both studied groups were not different in relation to renal and cardiac function .
thus , the study was performed in the early stage of cardio - renal axis disturbances . in these conditions
, we showed only mild , but significant , impact of renal function parameters on rpi .
the considered hypothesis seems to be confirmed by scholbach et al . , who studied 38 kidneys 1 year after transplantation and found a perfusion ratio ( pcp to dcp ) of 2.99 , rising up to 5.56 in the following years , with the progress of nephropathy , which could reflect the reduction in the perfusion of the distal cortex .
on the other hand , in the further observation , the authors found decreasing perfusion ratio values , explained by the reduction of the renal proximal cortex perfusion .
firstly , graft denervation impairs the response of cardiovascular system to hypoxemia and changes in perfusion . secondly , there may be a significant risk of renal perfusion modification by nephrotoxic drugs such as cyclosporine in patients after transplantation [ 1820 ] .
most of the patients were treated with vasodilators such as ace - i / arb , and almost half of them with ccb . in analysis of correlations
moreover , taking into account similar vasodilatory effect of these agents on proximal and distal cortex arteries , calculation of rpi as pcp to dcp ratio reduces effect of these drugs on rpi .
we present for the first time an influence of cardiac systolic function on rpi , which is only slightly related to renal function .
this finding enables probability of early , noninvasive detection of cardiac systolic abnormalities exactly at the time of kidney ultrasonography , when good quality ultrasound imaging of heart structures is impossible ( lack of method , emphysema , obesity ) . at last
, it is likely that rpi evaluation could be helpful in the early recognition of cardio - renal syndrome related to lowering cardiac output and , reversely , in the prediction of renal function improvement after cardiac transplantation .
nevertheless , applicability of rpi in diagnosing early abnormalities in the cardio - renal axis requires further investigation .
although the results of our study are promising , they are still a subject to a number of serious limitations . the small size of the study group with a majority of men does not allow for a generalization of the results .
in addition , the limited degree of kidney impairment in the studied group ( egfr>15 ml / min/1.73 m ) reduce the significance of our findings .
therefore , there is a need for further studies in larger groups of patients with all degrees of renal damage .
verification of our results is likely to allow for the use of ultrasound evaluation of renal perfusion in the diagnosis of cardio - renal axis disturbances .
renal perfusion index relates more strongly to cardiac output than to renal function , and could be helpful in recognizing the early stage of chronic cardio - renal syndrome .
nevertheless , applicability of rpi in diagnosing abnormalities in the cardio - renal axis requires further investigation .
 backgroundcardiac dysfunction can modify renal perfusion , which is crucial to maintain sufficient kidney tissue oxygenation . 
 renal cortex perfusion assessed by dynamic ultrasound method is related both to renal function and cardiac hemodynamics . 
 the aim of the study was to test the hypothesis that renal perfusion index ( rpi ) can more closely reflect cardiac hemodynamics and differentiate etiology of chronic cardio - renal syndrome.material/methodstwenty-four patients with hypertension and chronic kidney disease ( ckd ) at 24 stage ( 12 with hypertensive nephropathy and 12 with ckd prior to hypertension ) were enrolled in the study . 
 blood tests , 24-h abpm , echocardiography , and ultrasonography with estimation of total renal cortical perfusion intensity and renal perfusion index ( rpi ) were performed.resultsin the group of all patients , rpi correlated with left ventricular stoke volume ( lvsv ) , and cardiac index , but not with markers of renal function . in multiple stepwise regression analysis ckd - epi(cys - cr ) ( b=0.360 ) , lvsv ( b=0.924 ) and map ( b=0.376 ) together independently influenced rpi ( r2=0.74 ; p<0.0001 ) . 
 rpi<0.567 allowed for the identification of patients with chronic cardio - renal syndrome with sensitivity of 41.7% and specificity of 83.3%.conclusionsrenal perfusion index relates more strongly to cardiac output than to renal function , and could be helpful in recognizing chronic cardio - renal syndrome . 
 applicability of rpi in diagnosing early abnormalities in the cardio - renal axis requires further investigation . 
Background
Material and Methods
Blood tests
Urinary albumin excretion ratio
Blood pressure monitoring
Color Doppler sonography
Cardiac sonography
Statistical analysis
Results
Discussion
Conclusions