Cardiorenal syndrome not a good start

Given the diverse mechanisms of HF pathophysiology, renal and cardiac functions have close
and complementary interconnections. Communication between these organs through
bidirectional pathways causes pathological changes in kidneys and hearts [1,2]. Renal
impairment in patients with HF is common due to renal ischemia after low cardiac output and
renal congestion resulting from generalized edema. Renal dysfunction is being increasingly
recognized as an independent risk factor for morbidity and mortality in patients with HF.
Volume overload in patients with renal impairment predisposes to progression of congestive
HF. Conversely, low cardiac output predisposes to renal hypoperfusion, resulting in renal
dysfunction in patients with HF[3]. Recognition of the bi-directional links between cardiac and
renal function, and the understanding that dysfunction of one organ affects the other, led to
coining of the term cardio-renal syndrome. Although use of cardio-renal syndrome terminology
is helpful when describing the interactions between the heart and kidneys, it is important to
realize that the current classification of cardio-renal syndrome encompasses all forms of
bi-directional links and is not specific for heart failure[4–7].

Classification of CRS
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Recognizing a wider clinical spectrum that may represent cardiorenal dysregulation, the Acute
Dialysis Quality Initiative outlined a consensus approach in 2008 that phenotyped CRS into 2
major groups, cardiorenal and renocardiac syndromes, based on the primum movens of the
disease process[5,6]. This was further grouped into 5 subtypes based on disease acuity and
sequential organ involvement, which are outlined in Table 1. This classification system aims
to take into account important interactions between the pivotal organ systems (the heart and
the kidney). Although the classification is not widely applied in the clinic, it can provide a
clinically oriented definition as a basis to better understand the complex interactions between
the heart and kidney; guide future research into the respective underlying mechanisms; and
guide the development of therapeutic strategies to target the complex bidirectional
pathophysiology[8–11].

Table 1: classification of cardiorenal syndrome[12,13].

Type Name Description Clinical
examples
Type 1 Acute Cardiorenal Acute HF leading to AKI ACS leading to
CRS syndrome (Altered cardiac and/or renal haemodynamics cardiogenic
might be of particular importance) shock
 Type 2 Chronic Chronic HF leading to CKD Chronic HF
CRS Cardiorenal (Accelerated renal cell apoptosis and
syndrome replacement fibrosis might be of particular
importance)

Type 3 Acute Acute kidney injury resulting HF HF in the setting

CRS Renocardiac (Salt and water imbalance, uraemia-induced of AKI from
syndrome effects and neuro-hormonal dysregulation volume overload,
might be key in this setting) inflammatory
surge
Type 4 Chronic CKD causing Chronic HF and LVH and HF
CRS Renocardiac progression of CKD from CKD-
syndrome (CKD-induced myopathy might be of associated
particular importance in this setting) cardiomyopathy

Type 5 Secondary Systemic process resulting kidney Amyloidosis,

CRS Cardiorenal failure and HF sepsis, cirrhosis
syndrome (Microcirculatory dysfunction, altered innate
and adaptive immune responses and cytokine
release, and other effects result in
simultaneous organ injury)

ACS: Acute coronary syndrome, HF: Heart failure, AKI: Acute kidney injury, CKD: Chronic kidney
disease

Pathophysiology of Heart failure and kidney dysfunction

As mentioned, interactions between the heart and kidneys are complex and bi-directional. The
direct effect of kidney dysfunction on HF progression is strikingly illustrated by studies of
kidney transplant recipients. Data show that left ventricular hypertrophy is present in about
75% of patients at commencement of dialysis[14] and that uraemia promotes interstitial cardiac
fibrosis[15]. In patients with dialysis-dependent CKD stage 5 and HF with reduced left
ventricular ejection fraction (LVEF) <40%, kidney transplantation can result in a considerable
increase in mean LVEF, and even normalization of LVEF in a considerable number of
patients[16]. This improvement in cardiac function highlights the key role of kidney
dysfunction in cardiac remodelling, independent of classic CVD risk factors[4]. ah para ok

Three key pathophysiological categories are currently thought to contribute to the

development and progression of cardio-renal and reno-cardiac interactions: haemodynamic
alterations due to low cardiac output and/or altered venous return; dysregulation of the (neuro)
hormonal axis via sympathetic nerve activation and/or triggering of the renin–angiotensin–
aldosterone system (RAAS); and other factors that contribute to the accelerated progression of
HF and CKD. The overview of these mechanisms are illustrated in Fig 1.

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 pehli line ch edha likh
skda ki haemodynamic
1 Heamodynamic alterations alterations like reduced
renal bf, cvp syste
Numerous studies have suggested the importance of reduced renal blood flow, increased central
venous pressure (CVP), and systemic blood pressure as primary effectors of renal impairment
in patients with CRS. Initially, much of the progressive decline in renal function observed with
HF was thought to be secondary to poor renal perfusion from a reduced cardiac output. Cardiac
output may be reduced in heart failure for various reasons, such as atrial fibrillation, myocardial
infarction, or other processes[17]. At first, several studies have reported that higher blood
pressure on admission is related to a greater risk of worsening of renal function (WRF). In
contrast, hypotension is also an important risk factor for WRF, leading to renal hypoperfusion.
However, in the association with longstanding hypertension, a blunted dilatory ability of the
preglomerular circulation is often observed in response to a drop in blood pressure, which
might be related to an exaggerated decrease in intraglomerular pressure. This explanation
supports the findings that both higher blood pressure at baseline and drop in blood pressure are
associated with the higher risk of WRF[18]. As the kidneys receive about 25% of cardiac
output, the traditional understanding (the so-called ‘low-flow’ theory) was that hypoperfusion
of the kidneys followed by triggering of baroreceptors, juxtaglomerular renin release, and
RAAS activation might lead to renal vasoconstriction affecting both the glomerulus and tubular
apparatus. This leads to:

• the retention of sodium,

• increased vascular congestion, and
• further worsening of renal function due to renal afferent arteriolar vasoconstriction.

HF with significant cardiac-output decline (clinically referred to as ‘forward failure’), can lead
to renal tubule hypoxia and acute tubular necrosis, due to the sensitivity of renal tubular cells
to hypoxia. Moreover, tubulointerstitial injury in this clinical setting might be further
aggravated by the presence of comorbidities, such as diabetes mellitus, which is associated
with chronic tubular hypoxia, inflammation, and tubulointerstitial fibrosis[19–21].

In contrast to role of cardiac output in CRS, recent studies have suggested that
congestion of the venous system is one of the most important hemodynamic determinants of
CRS. The relationship between blood pressure, cardiac output, and systemic vascular resistance
is summarized by the Poiseuille law. According to Poiseuille’s law, blood flow through the
kidneys depends on the pressure gradient—high pressure on the arterial side, low pressure on
the venous side[22]. HF results in volume overload leading to elevation in central venous
pressure/right atrium pressure, constitute the lowest pressures in the circulation, as eventually
all blood flow goes to the right atrium (except for in the thebesian veins). To maintain blood
flow through the vascular system an adequate pressure gradient is required across the capillary
network. Elevated venous pressures attenuate the gradient for forward blood flow across the
renal vasculature resulting in sluggish flow and causing congestion, glomerular dysfunction
and a decrease in urine output. The ability of renal venous pressure to reduce renal blood flow
was shown in animal models more than 60 years ago[23,24]. Renal venous hypertension can
induce a decline in GFR via mechanisms that include reduced renal blood flow via increased
efferent pressures, decreased transrenal perfusion pressure, increased intraglomerular
hydrostatic pressure, increased intratubular pressure, and reduced net filtration pressure. In
cases of persisting renal venous hypertension, both glomeruli and tubules are affected, which
can induce tubular hypertrophy, tubulointerstitial renal fibrosis, and intraglomerular sclerosis,
resulting in progression of kidney disease[6,13].

Other important manifestations of systemic congestion are splanchnic and

intestinal congestion, which may lead to intestinal edema and less often to ascites. This leads
to increased intra-abdominal pressure, which can further compromise renal function by
compressing the renal veins and ureters[25,26].

2 Neurohormonal Responses
[1] L.G. Bongartz, B. Braam, C.A. Gaillard, M.J. Cramer, R. Goldschmeding, M.C.
Verhaar, P.A. Doevendans, J.A. Joles, Target organ cross talk in cardiorenal
syndrome: animal models, Am. J. Physiol. Renal Physiol. 303 (2012).
https://doi.org/10.1152/AJPRENAL.00392.2012.
[2] C. Ronco, M. Cicoira, P.A. McCullough, Cardiorenal syndrome type 1:
pathophysiological crosstalk leading to combined heart and kidney dysfunction in the
setting of acutely decompensated heart failure, J. Am. Coll. Cardiol. 60 (2012) 1031–
1042. https://doi.org/10.1016/J.JACC.2012.01.077.
[3] H. Takahama, M. Kitakaze, Pathophysiology of cardiorenal syndrome in patients with
heart failure: Potential therapeutic targets, Am. J. Physiol. - Hear. Circ. Physiol. 313
(2017) 715–721.
https://doi.org/10.1152/AJPHEART.00215.2017/ASSET/IMAGES/LARGE/ZH40091
723180001.JPEG.
[4] I.R. Whitman, H.I. Feldman, R. Deo, CKD and Sudden Cardiac Death: Epidemiology,
Mechanisms, and Therapeutic Approaches, J. Am. Soc. Nephrol. 23 (2012) 1929–
1939. https://doi.org/10.1681/ASN.2012010037.
[5] C. Ronco, M. Haapio, A.A. House, N. Anavekar, R. Bellomo, Cardiorenal Syndrome,
J. Am. Coll. Cardiol. 52 (2008) 1527–1539.
https://doi.org/10.1016/J.JACC.2008.07.051.
[6] P.A. McCullough, J.A. Kellum, M. Haase, C. Müller, K. Damman, P.T. Murray, D.
Cruz, A.A. House, K.M. Schmidt-Ott, G. Vescovo, S.M. Bagshaw, E.A. Hoste, C.
Briguori, B. Braam, L.S. Chawla, M.R. Costanzo, J.A. Tumlin, C.A. Herzog, R.L.
Mehta, H. Rabb, A.D. Shaw, K. Singbartl, C. Ronco, Pathophysiology of the
cardiorenal syndromes: executive summary from the eleventh consensus conference of
the Acute Dialysis Quality Initiative (ADQI), Contrib. Nephrol. 182 (2013) 82–98.
https://doi.org/10.1159/000349966.
[7] H. S, K. SP, Cardiorenal syndrome: review of our current understanding, J. R. Soc.
Med. 109 (2016) 12–17. https://doi.org/10.1177/0141076815616091.
[8] A.A. House, I. Anand, R. Bellomo, D. Cruz, I. Bobek, S.D. Anker, N. Aspromonte, S.
Bagshaw, T. Berl, L. Daliento, A. Davenport, M. Haapio, H. Hillege, P. McCullough,
N. Katz, A. Maisel, S. Mankad, P. Zanco, A. Mebazaa, A. Palazzuoli, F. Ronco, A.
Shaw, G. Sheinfeld, S. Soni, G. Vescovo, N. Zamperetti, P. Ponikowski, C. Ronco,
Definition and classification of Cardio-Renal Syndromes: workgroup statements from
the 7th ADQI Consensus Conference, Nephrol. Dial. Transplant. 25 (2010) 1416–
1420. https://doi.org/10.1093/NDT/GFQ136.
[9] S.M. Bagshaw, D.N. Cruz, N. Aspromonte, L. Daliento, F. Ronco, G. Sheinfeld, S.D.
Anker, I. Anand, R. Bellomo, T. Berl, I. Bobek, A. Davenport, M. Haapio, H. Hillege,
A. House, N. Katz, A. Maisel, S. Mankad, P. McCullough, A. Mebazaa, A. Palazzuoli,
P. Ponikowski, A. Shaw, S. Soni, G. Vescovo, N. Zamperetti, P. Zanco, C. Ronco,
Epidemiology of cardio-renal syndromes: workgroup statements from the 7th ADQI
Consensus Conference, Nephrol. Dial. Transplant. 25 (2010) 1406–1416.
https://doi.org/10.1093/NDT/GFQ066.
[10] L. Segall, I. Nistor, A. Covic, Heart failure in patients with chronic kidney disease: a
systematic integrative review, Biomed Res. Int. 2014 (2014).
https://doi.org/10.1155/2014/937398.
[11] K. Tsuruya, M. Eriguchi, Cardiorenal syndrome in chronic kidney disease, Curr. Opin.
Nephrol. Hypertens. 24 (2015) 154–162.
https://doi.org/10.1097/MNH.0000000000000099.
[12] J. Rangaswami, V. Bhalla, J.E.A. Blair, T.I. Chang, S. Costa, K.L. Lentine, E. V.
Lerma, K. Mezue, M. Molitch, W. Mullens, C. Ronco, W.H.W. Tang, P.A.
Mccullough, Cardiorenal Syndrome: Classification, Pathophysiology, Diagnosis, and
Treatment Strategies: A Scientific Statement From the American Heart Association,
Circulation. 139 (2019) E840–E878. https://doi.org/10.1161/CIR.0000000000000664.
[13] J.C. Schefold, G. Filippatos, G. Hasenfuss, S.D. Anker, S. Von Haehling, Heart failure
and kidney dysfunction: epidemiology, mechanisms and management, Nat. Rev.
Nephrol. 12 (2016) 610–623. https://doi.org/10.1038/NRNEPH.2016.113.
[14] C. Evans-Molina, J.C. Garmey, R. Ketchum, K.L. Brayman, S. Deng, R.G. Mirmira,
Glucose Regulation of Insulin Gene Transcription and Pre-mRNA Processing in
Human Islets, Diabetes. 56 (2007) 827. https://doi.org/10.2337/DB06-1440.
[15] G. Mall, W. Huther, J. Schneider, P. Lundin, E. Ritz, Diffuse intermyocardiocytic
fibrosis in uraemic patients, Nephrol. Dial. Transplant. 5 (1990) 39–44.
https://doi.org/10.1093/NDT/5.1.39.
[16] R.K. Wali, G.S. Wang, S.S. Gottlieb, L. Bellumkonda, R. Hansalia, E. Ramos, C.
Drachenberg, J. Papadimitriou, M.A. Brisco, S. Blahut, J.C. Fink, M.L. Fisher, S.T.
Bartlett, M.R. Weir, Effect of kidney transplantation on left ventricular systolic
dysfunction and congestive heart failure in patients with end-stage renal disease, J.
Am. Coll. Cardiol. 45 (2005) 1051–1060. https://doi.org/10.1016/J.JACC.2004.11.061.
[17] U. Kumar, N. Wettersten, P.S. Garimella, Cardiorenal Syndrome: Pathophysiology,
Cardiol. Clin. 37 (2019) 251–265. https://doi.org/10.1016/J.CCL.2019.04.001.
[18] I. Kohno, H. Iwasaki, M. Okutani, Y. Mochizuki, S. Sano, Y. Satoh, T. Ishihara, H.
Ishii, S. Mukaiyama, H. Ijiri, S. Komori, K. Tamura, Administration-time-dependent
effects of diltiazem on the 24-hour blood pressure profile of essential hypertension
patients, Chronobiol. Int. 14 (1997) 71–84.
https://doi.org/10.3109/07420529709040543.
[19] D.K. Singh, P. Winocour, K. Farrington, Mechanisms of disease: the hypoxic tubular
hypothesis of diabetic nephropathy, Nat. Clin. Pract. Nephrol. 4 (2008) 216–226.
https://doi.org/10.1038/NCPNEPH0757.
[20] K. Manotham, T. Tanaka, M. Matsumoto, T. Ohse, R. Inagi, T. Miyata, K. Kurokawa,
T. Fujita, J.R. Ingelfinger, M. Nangaku, Transdifferentiation of cultured tubular cells
induced by hypoxia, Kidney Int. 65 (2004) 871–880. https://doi.org/10.1111/J.1523-
1755.2004.00461.X.
[21] J.T. Norman, I.M. Clark, P.L. Garcia, Hypoxia promotes fibrogenesis in human renal
fibroblasts, Kidney Int. 58 (2000) 2351–2366. https://doi.org/10.1046/J.1523-
1755.2000.00419.X.
[22] J.S. Bock, S.S. Gottlieb, Cardiorenal syndrome: New perspectives, Circulation. 121
(2010) 2592–2600. https://doi.org/10.1161/CIRCULATIONAHA.109.886473.
[23] F.R. Winton, The influence of venous pressure on the isolated mammalian kidney, J.
Physiol. 72 (1931) 49. https://doi.org/10.1113/JPHYSIOL.1931.SP002761.
[24] C.W. GOTTSCHALK, M. MYLLE, Micropuncture study of pressures in proximal
tubules and peritubular capillaries of the rat kidney and their relation to ureteral and
renal venous pressures, Am. J. Physiol. 185 (1956) 430–439.
https://doi.org/10.1152/AJPLEGACY.1956.185.2.430.
[25] F.H. Verbrugge, M. Dupont, P. Steels, L. Grieten, M. Malbrain, W.H.W. Tang, W.
Mullens, Abdominal contributions to cardiorenal dysfunction in congestive heart
failure, J. Am. Coll. Cardiol. 62 (2013) 485–495.
https://doi.org/10.1016/J.JACC.2013.04.070.
[26] W. Mullens, Z. Abrahams, H.N. Skouri, G.S. Francis, D.O. Taylor, R.C. Starling, E.
Paganini, W.H.W. Tang, Elevated intra-abdominal pressure in acute decompensated
heart failure: a potential contributor to worsening renal function?, J. Am. Coll. Cardiol.
51 (2008) 300–306. https://doi.org/10.1016/J.JACC.2007.09.043.