Acute myocardial infarction in patients of nephrotic syndrome: a case series.

Thromboembolic complications have been frequently reported in patients with long-lasting nephrotic syndrome (NS).[1] Although thrombotic complications in the venous system are common in patients with NS, arterial thromboses associated with NS are much less common.[1] However, coronary thromboses are extremely rarely observed.[1],[2] So, NS is a rare cause of acute coronary syndrome (ACS). As such, the incidence, pathogenesis, and treatment of these patients have yet to be clearly defined. In the current literature, publications contain less than 15 patients, most of whom are young children.[3]

Serious clotting factor disturbances can be observed, such as changes in platelet hyperfunction, increased plasma fibrinogen, abnormalities of the fibrinolytic system, and acquired deficiencies of coagulation inhibitors.[2] However, increased platelet aggregation and antithrombin III (AT III) deficiency are the most important factors in this hypercoagulable state in the NS.[4] A hypothesis for hypercoagulable state in NS suggests a clinical correlation between thromboembolism and the underlying renal disease (especially minimal change glomerulopathy).[1],[2],[5],[6] Patients with chronic excess proteinuria and long-term exposure to abnormalities of hemostasis and lipid profiles appear to have a high risk of developing cardiovascular disease.[4]

In our study, we evaluated the characteristics of eight patients admitted to our hospital with a diagnosis of acute myocardial infarction (AMI) by ECG, clinical presentation and myocardial enzyme. They were all diagnosed NS before AMI. To our knowledge, this is the first study of multiple cases of NS associated with AMI.

In this case study, the cases presented here were retrospectively collected from a database of Jinling Hospital in which who had AMI. From 1800 patients who had been admitted to our Department for AMI, we found eight cases of combined NS. These patients were enrolled in the study from 2008 through 2016. All patients were diagnosed with NS and meanwhile AMI based on symptoms, electrocardiogram and myocardial enzyme. Follow-up at one year was achieved in 62.5% patients.

Two of the patients were female (25%) and six of the patients were male. The age range was between 29 and 72 years with a mean age of 55 years (54.5 years for men, 56.5 years for women). Seven patients (87.5%) are taking oral hormone therapy for a long time. Patients with specific pathologic diagnosis were membranous nephropathy (MN) while three of them have no data. The most infarcted area is inferior wall (62.5%). Three patients died during hospitalization. Severe hypoalbuminemia and proteinuria can be observed in most of the patients (Table 1).

Table 1.

Baseline clinical characteristics of patients.

Patients	1	2	3	4	5	6	7	8
Age, yrs	29	54	65	59	58	72	62	41
Gender	Male	Male	Male	Male	Male	Female	Male	Female
Hypertension	No	No	Yes	Yes	No	Yes	Yes	No
Diabetes	No	No	No	Yes	No	No	No	No
Dyslipidemia	Yes	No	No	No	No	No	No	No
Smoking	No	Yes	No	Yes	No	No	No	No
Previous heart disease	No	No	No	No	No	No	No	No
Troponin I, ng/L	ND	42.03	1.71	117.9	NA	NA	NA	50
Oral glucocorticoids treatment	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes
Pathological diagnosis	ND	MN	MN	ND	MN	MN	MN	ND
Albumin, g/L	ND	25.8	30.8	18.1	19.8	33.3	25.9	16.1
Proteinuria	No	Yes	Yes	Yes	NA	Yes	Yes	Yes
The interval between the diagnosis and the onset of the disease	21 years	5 months	3 years	1 year	ND	6 years	2 years	1 months
Infarction area	Anterior wall+side wall	Anteroseptal+ high lateral wall	Inferior wall+back wall+right ventricle	Anterior wall	Inferior wall+high lateral wall+ back wall	Inferior wall	Inferior wall	Inferior wall
Hospital ending	Discharged	Discharged	Death	Discharged	Death	Discharged	Death	Discharged
Follow-up	No events	No events	ND	No events	ND	Death	ND	No events

MN: membranous nephropathy; NA: not available; ND: no data.

Three people had coronary angiography and stent implantation. Two patients were treated with percutaneous transluminal coronary angioplasty (PTCA) only and two with thrombus spiration or thrombolysis. The incidence of cardiogenic shock was 3/8 (37.5%). The rate of no reflow or slow blood flow 3/8 (37.5%). In most patients, thrombosis is seen in coronary angiography, rather than in coronary atherosclerosis. Some people only do PTCA or thrombus and take the medicine in the coronary artery. The lesion of the blood vessel is dominated by the left anterior descending (LAD) and the right coronary artery (RCA). Most patients are found with either no reflow or slow blood flow (Table 2).

Table 2.

Angiography characteristics.

Patients	1	2	3	4	5	6	7	8
Culprit vessel	LAD	LAD	RCA	LAD	ND	RCA	ND	RCA
Multi-vessel lesions	Yes	No	Yes	Yes	ND	Yes	ND	No
Severe calcification	No	No	Yes	No	ND	No	ND	No
Diffuse lesion	Yes	No	Yes	Yes	ND	Yes	ND	No
Treatment	PTCA	Thrombus spiration	PTCA	Stent	Thrombolysis	stent	ND	Stent+thrombus Spiration+PTCA
Number of stents	0	0	0	2	0	3	ND	1
Length of stents	ND	ND	ND	52 mm	ND	63 mm	ND	23 mm
Thrombus spiration	No	Yes	No	No	ND	No	ND	Yes
Cardiac shock	No	No	Yes	Yes	Yes	No	ND	No
No reflow or slow blood flow	No	Yes	Yes	No	ND	No	ND	Yes
Intravascular medicine	No	Yes	No	No	ND	No	ND	Yes

LAD: left anterior descending; ND: no data; PTCA: percutaneous transluminal coronary angioplasty; RCA: right coronary artery.

The first report on coronary heart disease complicating NS was published 1969 by Berlyne and Mallick, who described the occurrence of AMI in four patients with NS due to glomemlonephritis. Now the combination of these diseases is still rare. Previous reports of such diseases are mostly case reports, and are mostly about young people.

We presented a case series of AMI secondary to NS mostly due to MN. In our cases, the age distribution is between 29 and 72 years old, It's interesting that the AMI occurs in patients of NS at all ages, not only young people. We also summarized the treatment of these patients. Most of the patients were treated with percutaneous coronary intervention and recovered well.

Most patients with coronary angiography can see a thrombosis, which can be identified as an acute coronary thrombosis, rather than an atheromatous plaque. In the treatment, some patients had a PTCA and did not implant stent, and the blood clots were taken from the blood clot. Coronary thrombosis can be seen in hypercoagulable states such as in the antiphospholipid syndrome, NS, and factor XII and protein S deficiencies, etc.[7]–[10] The possible pathogenesis of AMI in NS has been discussed in the former study.[11] The underlying mechanisms of the “thrombophilia” of the NS are multiple but seem related with an imbalance of prothrombotic factors. Firstly, factors associating with coagulation are enhanced. The proteinuria associated with NS leads to the loss of low molecular weight protein, such as factors IX, XI, and XII, as the liver tries to compensate for the hypoalbuminaemic state, there is an increased synthesis of factors II, VII, VIII, X, XIII, and fibrinogen.[12]–[14] Thrombocytosis and increased platelet aggregation and adhesiveness also contribute to the hypercoagulable state. Platelet hyperaggregability correlates with serum cholesterol concentrations. Secondly, factors associating with anticoagulation are weakened. Antithrombin III, a coagulation inhibitor significant reductions can be observed especially when the serum albumin concentration is below 20 g/L.

However, protein C and protein S are coagulation inhibitors whose decline has not been clearly implicated in arterial thrombosis in the NS. Thirdly, the imbalance of fibrinolytic system, with decreased concentrations of plasminogen and raised levels of plasminogen activator, contributes to the “thrombophilia”.[15] There is evidence of decreased fibrinolytic activity with hypertriglyceridemia, which often occurs in the NS.[16] And the extent of alterations in imbalance of prothrombotic factors correlate with the degree of hypoalbuminaemia. A serum albumin of less than 25 g/L is a significant risk factor for combined arterial and venous thrombosis in the NS.[17] Other factors that contribute to the hypercoagulable state are a thrombocytosis and increased platelet aggregation and adhesiveness. Platelet hyperaggregability correlates with serum cholesterol concentrations.[18],[19] Many of these abnormalities were evident in our patient and may have caused coronary thrombosis without atherosclerotic plaque rupture.

Most of our patients are MN, which is a glomerular disease characterized by NS and typical changes on renal biopsy. Most patients present with a NS (80%). In the past, MN was considered as a presentation of chronic serum sickness. With research evolvement, MN like other glomerular diseases is now thought to be an autoimmune disease.[20] Oral hormone therapy is considered beneficial in the medium risk group (normal plasma creatinine, proteinuria between 4 and 8 g on a maximal conservative treatment).

In conclusion, the cases report indicates that AMI is probably due to arterial thrombosis that can be attributed to a hypercoagulable state resulting from the NS, which may be an independent risk factor of AMI. Although rare, AMI should be considered even without traditional risk factors. A detailed clinical history may help to identify the aetiology, and guide subsequent management, but diagnostic coronary angiography is essential. Aspirin is recommended in most cases. Anticoagulation should be considered in the NS if serum albumin is less than 20 g/L.[12] Careful risk factor modification and treatment of the underlying cause should reduce the incidence of recurrent cardiac events. In summary, NS is a rare cause of AMI. However, special attention should be paid to the high coagulation state. And anticoagulation should be considered as a prophylactic therapy.