Key Words:
cardiorenal syndrome
For a long time, physicians have recognized that the kidney
and the heart are related especially when there is severe
dysfunction of either of them. Dysfunction of one of these
organs seldom occurs in isolation. [1]. Of late the cardio
renal syndrome is assuming significance because of its
increasing incidence, awareness and complications. There is no
definite definition of the cardio renal syndrome. However, an
attempted definition states that it is a "decline in renal
function in the setting of advanced heart failure". This
definition does not cover the whole gamut of the cardio renal
syndrome. Cardiac diseases are associated independently with a
decrease in renal function and progression of existing renal
disease. Chronic Kidney disease (CKD) is an independent risk
factor for cardiovascular events and outcome. This
bidirectional nature of cardiac and renal interaction is
called Cardio Renal Syndrome (CRS).
In the Acute Decompensated Heart Failure National Registry
(ADHERE) comprising of more than 1,05,000 patients admitted
for acute decompensated heart failure, 30% had a history of
renal insufficiency, 21% had serum creatinine concentration of
> 2.0 mg/ dL and 9% had creatinine concentration of
>3.0 g/dL. [2]
Pathophysiology
The decrease in cardiac output in cardiac diseases reduces
renal perfusion. The Renin Angiotensin Aldosterone System
(RAAS) produces vasoconstriction, sodium overload and water
retention causing an increasing in preload and afterload. The
effects of endothelin which is produced in excess consequent
to these pathophysiological changes are vasoconstriction,
increased secretion of adrenaline and nor adrenaline. These
cause hypertrophy of the cardiomyocytes in a chronic setting.
The effect of arginine vasopressin which is also increased is
to cause fluid retention, myocyte hypertrophy and potentiation
of the effects of angiotensin II and noradrenaline. Increased
activity of the Sympathetic Nervous system (SNS) causes
cardiomyocyte apoptosis, focal myocardial necrosis and myocyte
hypertrophy. This is increased by the fact that in heart
failure with advanced renal insufficiency there is reduced
clearance of catecholamines by the kidney. [3]
The CRS has been classified into five types depending on the
pathophysiology. They are as follows: [4]
1. CRS type 1 (Acute Cardio renal syndrome).
It is acute worsening of cardiac function (e.g. Acute
decompensated heart failure or acute coronary syndrome)
leading to an acute kidney injury.
2. CRS type 2 (Chronic Cardio renal syndrome).
A chronic cardiac dysfunction (e.g. chronic heart failure or
congenital heart disease) leads to a progressive and
potentially permanent chronic kidney disease.
3. CRS type 3 (Acute Reno Cardiac syndrome).
Acute kidney injury (e.g. Acute tubular necrosis or
interstitial or glomerular diseases) leads to acute cardiac
dysfunction (e.g. Acute heart failure, arrhythmia or
ischemia)
4. CRS type 4. (Chronic Reno Cardiac syndrome).
Chronic kidney disease (e.g. Chronic glomerular or
interstitial disease) leads to progressive cardiac
dysfunction.
5. CRS type 5. (Secondary Cardio renal syndrome).
Systemic conditions (e.g. Sepsis, Amyloidosis, Vasculitis or
Diabetes mellitus) causing simultaneous cardiac and renal
dysfunction.
Risk Factors for the Cardio Renal Syndrome
A few risk factors increase the propensity of a patient to
develop the CRS. These are:
1. Old age increases the chances of developing
CRS.
2. Other co morbid conditions like diabetes mellitus,
uncontrolled hypertension and anemia are factors which
contribute to the development of CRS.
3. Drugs like anti-inflammatory agents, diuretics
(thiazides, loop diuretics), angiotensin converting enzyme
inhibitors (ACEI) and angiotensin Receptor blockers (ARB)
and aldosterone receptor antagonists can accelerate the
development of CRS.
4. In the heart, a history of heart failure or impaired left
ventricular ejection fraction, prior myocardial infarction,
poor functional class and elevated cardiac troponin
contribute to the development of CRS.
5. In the kidney, chronic kidney disease with reduced
glomerular filtration rate (GFR), elevated blood urea
nitrogen and elevated creatinine and cystatin contribute to
the development of CRS.
Biomarkers for the Detection of Kidney and Heart Injury
Various biomarkers have been identified for the detection
of Kidney and Cardiac injury in CRS. Cystatin-C, Neutrophil
Gelatinase Associated Lipocalin (NGAL), L-type fatty acid
binding protein (L-FABP), Glutathione S-Transferase (GST) and
Interleukin are some of the common protein biomarkers which
can be used in the early detection of Acute Kidney Injury
[5],[6],[7].
The biomarkers identified for the detection of cardiac injury
are Troponin I, Myoglobin, B-Natriuretic Peptide (BNP)
Ischemia Modified Albumin, S-Amyloid Protein A and the C -
reactive protein (CRP).
Renal Failure - Cardiac Effects
The cardiac effects of chronic renal failure are multiple. The
left ventricle shows hypertrophy which subsequently leads to
'diastolic heart failure' or 'heart failure with preserved
ejection fraction'. There is development of early and
progressive atherosclerotic coronary artery disease. High
levels of inflammation and oxidative stress cause negative
inotropic and vascular effects. When the patient goes for a
dialysis program, the arteriovenous fistula created may
contribute to a high output state and high output heart
failure subsequently.
In acute renal failure, the main cardiac problems are due to a
volume overload and electrolyte disturbances. Increased volume
overload may stress the left ventricle to cause acute left
ventricular failure presenting as acute pulmonary edema. The
commonest electrolyte disturbance seen is hyperkalemia which
can lead to various arrhythmias which may be fatal.
The GFR and Cardiac Output
There is no linear correlation between the serum creatinine
and the Glomerular Filtration Rate. Approximately two-thirds
of patients with heart failure have a low GFR. In these the
serum creatinine may be normal. The GFR affects the prognosis
in patients with congestive heart failure. The cardiac output
is also not a very reliable indicator to assess the severity
of CRS. The cardiac output may be normal in patients with CRS.
Diuretic Resistance in CRS
Patients with CRS may develop resistance to diuretics and
hence may not respond to adequate therapeutic doses of
diuretics. This may be due to various factors. There may
be a delayed intestinal absorption of drugs. The GFR decrease
along with a decreased renal perfusion. There is also a
decreased diuretic excretion in urine. Inadequate diuretic
dose, concomitant use of NSAID's and hypoalbunemia may also
contribute to the diuretic resistance. There may be increased
re-absorption of sodium due to distal tubular hypertrophy
causing a phenomenon of diuretic "braking" [8].
Treatment of diuretic resistance or refractoriness may be by
many methods. A continuous infusion of frusemide or torsemide
rather than bolus injections may be effective in many. An
infusion of frusemide in a dose of 5 - 10 mg /hour is given.
Metazolone may increase the response of other diuretics. An
oral dose of 5 - 10 mg per day often is beneficial. A change
from oral to intravenous diuretics also helps in many
patients. If the patient is resistant to frusemide, bumetanide
or torsemide may be tried as they are better absorbed from the
intestines.
Management of Cardio Renal Syndrome - Heart Failure
The management of CRS caused by heart failure centers mainly
on the use of oral or intravenous diuretics in adequate
therapeutic doses. Low dose infusion of dopamine may be useful
in some patients both to improve the renal perfusion and
improve myocardial function [9]. Other inotropes like
milrinone, levosimendan and dobutamine have been used with
variable results. If the serum creatinine is less than 2.5
mg/dL, ACEI or ARB's may be used. Ultrafiltration
(aquapheresis) or other renal replacement strategies may be
employed in patients who need them [10]. Vasopressin
antagonists like conivaptan or tolvaptan have recently been
used in patients with heart failure with salutary results
[11].
Management of Reno Cardiac Syndrome - Acute and Chronic
Renal Failure
The management of reno cardiac syndrome mainly revolves around
managing the fluid and electrolyte balance. Volume overload
may be tackled by restricting fluid intake and employing renal
replacement therapy when needed. The management of electrolyte
disturbance is mainly the management of hyperkalemia with
sodium bicarbonate, intravenous calcium and when needed renal
replacement. Other electrolytes like sodium also need to be
addressed. In addition, one has to look for factors which
precipitate CRS like, hypertension, infections and anemia.
Prevention of Cardio Renal Syndrome
The prevention of CRS varies depending on the type of CRS that
the patient is suffering from.
Type 1 CRS
In type 1 CRS acute decompensated heart failure or acute
coronary syndrome leads to decrease in left ventricular
function and subsequently to acute renal failure. The mainstay
in preventing acute renal failure in this setting is the
adequate treatment of the acute left ventricular failure and
acute coronary syndrome. Prompt treatment of the precipitating
factors like infections, drugs, atrial fibrillation and
hypertension is absolutely essential in the prevention of CRS.
When acute coronary syndrome is associated with shock, prompt
revascularization, using intra-aortic balloon pump and
inotropic agents are needed to get adequate results.
Type 2 CRS
In chronic congestive heart failure the strategies to prevent
CRS are those that will improve the congestive heart failure.
Drugs like ACEI, ARB, or a combination of nitrate with
hydralazine are useful in reducing the afterload and improving
left ventricular function. Optimal management of sodium and
fluid volume is mandatory in controlling the symptoms of
chronic heart failure. To maintain adequate hemodynamics the
lowest dose of loop diuretics that give the best results are
used. Anemia, if present should be corrected. Added insults to
the kidney like contrast agents, NSAIDs and nephrotoxic agents
are to be avoided. In extreme cases, ultrafiltration or other
forms of renal replacement therapy may be resorted to. Those
patients who may benefit from Cardiac resynchronization
therapy may benefit from the increase in cardiac output that
follows.
Type 3 CRS
In the acute reno cardiac syndrome due to acute renal failure,
cardiac decompensation may be prevented by aggressive
avoidance of hypervolemia. Electrolyte imbalance like
hyperkalemia need to be addressed immediately. Contrast
induced acute kidney injury also needs to be prevented by the
judicious use of contrast when and if needed along with
adequate hydration and n-acetyl cysteine.
Type 4 CRS
Chronic reno cardiac syndrome where cardiac complications
follow chronic kidney disease (CKD) may be prevented by
adequate management of CKD. Reducing the rate of progression
of CKD delays cardiac complications. Patients during
hemodialysis may develop acute cardiac ischemia with chest
pain, ECG changes and increase in cardiac biomarkers. It
has been found that cooling of the dialysate solution can
reduce the transient left ventricular dysfunction that may
occur during dialysis. Both overdosing and under dosing of
cardiac drugs are to be avoided in patients with CKD. Drugs
should be prescribed based on the calculated GFR and not on
serum creatinine alone. In addition treatment of other cardiac
risk factors like dyslipidemia, diabetes mellitus,
hypertension and life style factors have to be addressed in
the prevention of type 4 CRS.
Type 5 CRS
Secondary CRS is caused by a disease that causes both cardiac
and renal complications. Hence the important preventive
measure in them is to adequately treat the primary illness
which could be sepsis, diabetes mellitus, amyloidosis,
hemorrhagic shock etc. If the primary disease is
adequately treated, the renal and cardiac complications can be
postponed though in many cases cannot be totally prevented.
Lacune in the Knowledge of CRS
In spite of the large volume of literature available regarding
the CRS, there are still lacunae in our knowledge regarding
this syndrome. Some of these are just listed below and the
future may hold the answers to these questions.
- It is not known as to what is the optimal target
blood pressure needed to prevent CRS.
- What methods and technology can be developed to assess the
intra / extra vascular sodium content?
- What is the ideal timing and mode of renal replacement
therapy to achieve optimal results?
- Will the treatment of other responses in CKD like
hyperparathyroidism, renal bone disease and
hyperphosphatemia change the development and progression of
CRS?
Concluding, the cardio renal syndrome is an interdependent
involvement of both the kidney and the heart, one leading to
the dysfunction of the other. Considering the pathophysiology
and the ubiquitous nature of the disorder, prevention of the
syndrome is of the utmost importance in patients who have
cardiac or renal disease, especially in an acute setting. Many
questions remain unanswered and are still out there. The
future probably with hold the answers to these and the
treatment of CRS may be more crystallized in future.
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