Type 4 cardiorenal syndrome: diagnosis and treatment


Type 4 cardiorenal syndrome: diagnosis and treatment
eISSN 2059-3007
Nephrology @ Point of Care 2015; 1 (1): e20-e23
DOI: 10.5301/NAPOC.2015.14678
Type 4 cardiorenal syndrome: diagnosis and treatment
Luca Di Lullo1, Alberto Santoboni1, Claudio Ronco2
Department of Nephrology and Dialysis, L. Parodi–Delfino Hospital, Colleferro, Rome - Italy
International Renal Research Institute, S. Bortolo Hospital, Vicenza - Italy
The clinical presentation of, and diagnostic approach taken for, a 63-year-old man with worsening dyspnea, chest
heaviness and widespread lower limb edema, leading to a diagnosis of type 4 cardiorenal syndrome, is presented.
The most appropriate approach at point of care is thoroughly discussed.
Keywords: Chronic kidney disease, Heart failure, Renal replacement therapy, Type 4 cardiorenal syndrome
Case presentation
The patient was a 63-year-old white male who was referred to the emergency room (ER) with worsening dyspnea,
chest heaviness and widespread lower limb edema. Three
days before he had attended a wedding party during the
week, eating and drinking much more he was used to, with a
weight increase of about 3.2 kg.
macological treatment with angiotensin-converting enzyme
inhibitors (ACEi), angiotensin II receptor blockers (ARBs),
beta-blockers and calcium channel blockers.
The patients had also suffered an acute myocardial infarction treated with triple coronary artery bypass grafting followed by antiaggregation therapy (clopidogrel 75 mg twice/
daily and aspirin 100 mg/daily). Home therapy was furosemide
(80 mg/day) and pantoprazole (40 mg/day).
Clinical history
Physical examination
The patient was a retired school teacher with a family
history of diabetes, hypertensive disease and chronic kidney
disease (CKD). He did not refer to any alcohol abuse but was
a smoker with a half a pack per day habit for 20 years. The
patient had a history of CKD secondary to diabetic nephropathy; his last estimated glomerular filtration rate (eGFR) evaluation (by Chronic Kidney Disease Epidemiology Collaboration
[eGFR-EPI] equation), had been 3 months before admission
to the ER unit and was then about 24 ml/min (with serum
creatinine of 2.8 mg/dL). Recent laboratory results showed
proteinuria (2 g/24 hours), mild hyperuricemia (7.1 mg/dL)
and secondary anemia partially corrected by epoetin therapy
(hemoglobin [Hb] level of 10.6 g/dL).
The patient’s history of diabetic disease had started
15 years earlier; he was on metformin treatment (2.1 g/
day) until 2 years ago, when insulin treatment was started,
and metformin was discontinued due to worsening of kidney function. Our patient also presented with hypertensive
disease for the previous 10 years and was undergoing phar-
When admitted to the ER, the patient appeared to
be suffering, and he was visibly short of breath. Systemic
blood pressure was 170/85 mm Hg with a heart rate of
80 bpm. He was apyretic with an oxygen saturation percentage of 87%. External jugular vein distension was well
rendered together with posterior coarse rales up to one
half of the chest and marked use of accessory respiratory
muscles. On heart examination, a systolic ejection murmur
on the centrum cordis was found. The patient also present
with pitting edema in the lower limbs, and he was oliguric
with 200-mL urine output in previous 24 hours.
Accepted: March 18, 2015
Published online: April 28, 2015
Corresponding author:
Luca Di Lullo
Department of Nephrology and Dialysis
L. Parodi–Delfino Hospital
00034 Colleferro, Roma, Italy
[email protected]
Laboratory and Instrumental data at admittance
Laboratory results showed an increase in serum creatinine
levels (3.2 mg/dL) with mild hyperkalemia (5.6 mEq/L) and
normochromic, normocytic anemia (Hb levels of 10.1 g/dL).
Brain natriuretic peptide (BNP) levels were slightly increased (3,530 mg/dL), while urinalysis showed proteinuria
without white or red blood cells in the sediment. A chest
X-ray pointed out moderate interstitial edema (Fig. 1), while
renal ultrasound highlighted small kidneys (longitudinal diameters of 88 and 82 mm for right and left kidney, respectively). Echocardiography showed left atrial enlargement
(left atrium area by 33.79 cm2) (Fig. 2), increased left ventricular end-diastolic diameter (60 mm) and area (189 cm2),
left ventricular diastolic dysfunction (E/E ratio 0.65), widespread aortic and mitral valve calcifications with mild mitral
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Di Lullo et al
Fig. 1 - Chest X-ray showing diffuse interstitial edema at emergency
room admittance.
pressure dropped to 120/70 mm Hg, but respiratory distress
did not improve.
Renal replacement therapy (RRT) was started with continuous venovenous hemofiltration (CVVH) and was extended
for the following 3 days together with i.v. furosemide therapy
and metolazone 5 mg/day. On day 2, urine output rose to
100 mL/hour, and serum creatinine levels dropped to 2.9 mg/
dL. ProBNP and NGAL serum levels also dropped (1,600 ng/mL
and 110 pg/mL, respectively). On day 3, serum creatinine was
2.3 mg/dL, K was 3.9 mEq/L and urine output was 80 ml/hour.
On day 4, CVVH treatment was stopped, urine output was
90 ml/hour, blood pressure was 130/80 mm Hg and serum
creatinine was 2.4 mg/dL. On day 6, serum creatinine remains
2.4 mg/dL, K was 4.1 mEq/L and i.v. furosemide was discontinued with a return to 80-mg oral furosemide therapy together with 5 mg/day of metolazone. Beta-blocker therapy
was restarted (carvedilol 6.25 mg/twice a day). Chest X-ray
showed marked reduction of interstitial edema, and echocardiography pointed up a reduction in left atrium size and
volume with contemporary increase in ejection fraction and
decrease of left ventricular end-systolic and end-diastolic
On day 8, the patient was discharged from the nephrology unit to return home with follow-up therapy: metolazone
5 mg/day, furosemide 80 mg/day, carvedilol 6.25 mg/twice a
day, amlodipine 10 mg/day, clopidogrel 75 mg/twice a day,
pantoprazole 40 mg/day and insulin according to glycemic
Fig. 2 - Echocardiogram showing left atrium enlargement at
emergency room admittance.
Hospital course
The patient was admitted to a monitored bed in the nephrology unit, and intravenous furosemide therapy was started (125 mg i.v. at 30 ml/hour); ACEi and ARBs were suspended. Initial urine output was 800 ml/2 hours, but it fell to 10
ml/hour in next 2 hours, and serum creatinine was raised to
5.6 mg/dL, while laboratory results also showed an increase
in proBNP levels (4,500 ng/mL) and neutrophil gelatinaseassociated lipocalin (NGAL; up to 451 pg/mL). Metoprolol
therapy was also discontinued after cardiology survey. Blood
© 2015 The Authors. Published by Wichtig International
This case report gives a typical picture of cardiac involvement in CKD patients, also known as type 4 cardiorenal syndrome, according to a well-established classification (1). Key
points to be underlined are those regarding pharmacological therapy and timing of RRT. We need to be concerned that
early RRT start could preserve renal function (2) although
there is no general consensus for this at present. We also
have to be sure that diuretic therapy is properly conducted
even with an association schedule (loop diuretic associated
with thiazides, for example). It is crucial to stop any ACEi
and ARBs if eGFR falls below 25 ml/min and beta-blocker
therapy if respiratory distress is prominent. Once patient is
compensated, beta-blocker therapy can be restarted before
discharging him to an outpatient unit. ACEi and/or ARBS can
be administrated according to eGFR levels.
It is well established that renal dysfunction is an independent risk factor for cardiovascular disease; CKD patients
show higher mortality risk for myocardial infection and sudden cardiac death (3). To better understand the pathophysiological pathways underlying type 4 cardiorenal syndrome,
we have to consider various aspects of it – from atherosclerotic damage and development of vascular calcifications,
to development of left ventricular hypertrophy (LVH) and
cardiomyocyte remodeling. Finally FGF-23 and vitamin D receptor (VDR) roles have to be cleared based on last experimental evidences.
Cardiovascular risk for patients with eGFR less than 30 ml/
min per 1.73 m2 is tenfold greater than that for patients with
eGFR above 60 ml/min per 1.73 m2. These higher rates are in
Type 4 cardiorenal syndrome
contrast with the risk expected from typical risk factors present in CKD patients (hypertension, diabetes, dyslipidemia and
so on); CKD is probably able to directly contribute to cardiovascular complications (4, 5).
Secondary hyperparathyroidism involves osteoblastic transformation of smooth muscle cells, representing a key point in
the pathogenesis of vascular and valvular calcification during
CKD. Coronary calcifications can predict major cardiac events
contributing to reduced coronary reserve in CKD patients and
higher risk of coronary acute syndromes (6, 7) increasing with
progression of renal disease. Secondary hyperparathyroidism
is also accountable for LVH in CKD patients, due to hypertension, atherosclerosis, pressure overload and renin-angiotensinaldosterone system (RAAS) activation.
CKD patients also present various degree of intermyocardial fibrosis quite different from those of hypertensive and
chronic ischemic heart disease patients, in whom endocardial
and epicardial fibrosis predominate (8).
During CKD progression, phosphate accumulation leads to
an increase of FGF-23 levels contributing to LVH and cardiac
remodeling. New data have shown that modest reduction in
GFR can stimulate FGF-23 production; echocardiographic assays have demonstrated a 5% left ventricular mass index rise
for every log increase in plasma FGF-23 levels (9).
Several studies have indicated a relationship among vitamin D, survival, vascular calcification and inflammation
(10, 11). Vitamin D is also involved in the regulation of immune, cardiovascular and endocrine systems through the
activation of the high-affinity VDR. The association between
LVH and VDR gene polymorphisms has recently been investigated, and it has been reported that the VDR BsmI gene
polymorphism is involved in LVH in end-stage renal disease
patients and independently related to LVH and LVH progression in dialysis patients and in stage IIIb CKD patients (12, 13).
Type 4 cardiorenal syndrome diagnosis is based on serological and instrumental diagnosis of both chronic heart and kidney
disease. Cardiac function is more widely assessed by NT-proBNP
serum levels, while eGFR represents the most widely employed
biochemical test to evaluate kidney function.
Kidney ultrasound evaluation usually shows classic features
of chronic nephropathy such as thin and hyperechogenic cortex with reduced corticomedullary ratio. It is quite common
to observe small dilations of the urinary tract and parapyelic
cysts. Echocardiographic assay shows signs of volume overload, left ventricular dysfunction and right ventricular dysfunction especially in end-stage renal disease and hemodialysis patients. On echocardiographic evaluation, we can find increased
atrial volumes or areas, pleural or pericardial effusion and lung
comets (all signs of volume overload) (14). Cardiac ultrasound
also allows the discovery of the presence of valvular calcifications (related to secondary hyperparathyroidism) (14) and possible right heart dysfunction features (high pulmonary artery
pressure, low tricuspid annulus plane systolic excursion or right
chamber dilation) (15).
For whom to concerning therapeutic approach, correction
of traditional (hypertension, dyslipidemia, diabetes, obesity)
and nontraditional (anemia, chronic inflammation, secondary
hyperparathyroidism, LVH, oxidative stress, RAAS and sympathetic nervous system hyperactivity, RRT complications) cardiovascular risk factors is crucial.
While there is a clearly established role for secondary
anemia correction (16), controversy remains regarding other risk factor corrections such as secondary hyperparathyroidism, hypertension and dyslipidemia. The EVOLVE and
SHARP studies have, respectively, investigated the roles of
cinacalcet and ezetimibe/simvastatin therapy in CKD patients (17, 18).
Blood pressure control represents a cornerstone in preventing CKD-related cardiovascular disease: predialysis patients are strongly recommended to maintain blood pressure
levels below 130/80 mm Hg, while those on hemodialysis
should keep their blood pressure below 140/90 before starting a dialytic session and below 130/80 after a session (19).
Finally, treatment of arrhythmias and sudden cardiac prevention is still a challenge for nephrologists and cardiologists;
together with prior attention to electrolyte disorder prevention
(low potassium dialysate), the use of beta-blockers appears to
be beneficial (20).
Financial support: None.
Conflict of interest: None.
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