What not to ignore when diabetes interacts with acute and chronic kidney diseases: A local case sharing
While they may not necessarily have a causal relationship, both chronic kidney disease (CKD) and diabetes mellitus (DM) have become increasingly more prevalent worldwide.1 As these conditions could be risk factors for developing acute kidney injury (AKI),2 CKD and DM must be carefully managed to prevent disease progression and the eventual risk of mortality in end-stage renal disease patients.1 Dr. Cheung, Siu-Fai, Specialist in Nephrology, shared his management strategies of a patient who had pre-existing CKD and DM complicated by AKI during hospitalization.
Chronic kidney disease (CKD) is one of the most important contributors to mortality and morbidity among patients with non-communicable diseases.3 In 2017, there were 697.5 million cases of CKD, representing a global prevalence of 9.1%.3 The all-age mortality rate of CKD had increased by 41.5% from 1990 to 2017, with 1.2 million death in 2017 alone.3 Similarly, in Hong Kong, the number of incident CKD patients with end-stage renal disease had risen from 615 in 1996 to over 1,300 in 2017.4 CKD has become a more pressing public health issue around the world.4
While CKD is a growing health problem, diabetes mellitus (DM) is another tremendous health situation that a substantial increase in prevalence has been seen in recent years, reaching 8.3% in 2014.5 End-stage renal disease (ESRD) requiring renal replacement therapy (RRT) is frequently attributable to DM and the prognosis is poor since the combination of ESRD and DM can result in an increased risk of cardiovascular events.5 In fact, DM has been associated with CKD with data suggesting that 46.3% of diabetics developed CKD versus 17.1% in non-diabetics.2
DM is characterized by hyperglycemia, which is a known risk factor for microvascular dysfunction that could lead to renal hypoperfusion and ischemia, resulting in AKI.6 AKI is a condition that induces abrupt structural and functional failure in kidneys.7,8 Pathologically, the causes of AKI can be classified as prerenal, intrarenal and postrenal insults: Prerenal AKI is due to impaired kidney perfusion as in cardiogenic or hemorrhagic shock; intrarenal causes refer to intrinsic kidney pathologies associated with conditions such as glomerular, tubulointerstitial and vascular diseases; and postrenal AKI is caused by urinary outflow obstruction.8 A study showed that the rates of AKI were 4.7-fold higher in diabetic patients than those without DM.2
Once AKI is developed, the patient’s kidney function may be impaired and may not fully recover even after appropriate treatment, promoting the development of subsequent CKD.2 Conversely, CKD is also a well-known risk factor for AKI due to the patient’s inherently impaired renal function that is vulnerable to acute injury when exposed to sufficiently severe insults.2,9 From experience, Dr. Cheung noted that diabetic CKD patients with coronary artery diseases are at risk of AKI due to jeopardized kidney function from cardiac decompensation. Cardiac stenting, which requires injection of nephrotoxic contrast, could also promote AKI development in diabetic CKD patients. Based on the close interactions and dependent contributions between CKD, DM and AKI (Figure 1), Dr. Cheung shared his management approach and treatment insights in a patient with pre-existing CKD and DM who developed an episode of AKI during his hospital stay.
In September 2017, a 54-year-old male patient was admitted to hospital due to a sudden onset of chest discomfort, which was later confirmed to be inferior ST segment elevated myocardial infarction (MI). Patient was an ex-smoker and a social drinker, with diagnosis of T2DM, hypertension and hyperlipidemia since 2004. Previous blood tests in 2013 indicated suboptimal DM control with HbA1c of 7.9%, and the urine microalbumin creatinine ratio was elevated to 14.5mg/mmol. However, serum creatinine (sCr) level remained normal at 77μmol/L.
Initial diagnosis from echocardiogram revealed focal wall hypokinesia, diastolic dysfunction and impaired left ventricular function. Blood tests returned a spot glucose at 23mmol/L, an HbA1C of 9.9% and an elevated sCr at 203μmol/L, which was diagnosed as AKI based on clinical judgment. A kidney ultrasound scan was also performed, which showed no obstruction. Urine microscopy did not show active sediments, so acute nephritic syndrome was unlikely.
Thrombolytic therapy was initiated for his acute MI. Revascularization of the myocardium was later accomplished by cardiac stenting at the right coronary artery and the distal left circumflex artery. During hospital stay, patient showed mild fluid overload, which was successfully managed by diuretic therapy. Overall, the pharmacological therapies the patient received included insulin, angiotensin-converting-enzyme inhibitors (ACEi), statin, aspirin, and clopidogrel. With all the supportive therapy, the AKI was tied over with improvement in kidney function after discharge.
In a subsequent metabolic risk assessment within the same year, patient’s body mass index (BMI) was found to be 27.7kg/m², indicating overweight. The waist circumference was 94cm, suggesting central obesity. Laboratory tests showed HbA1c remained suboptimal at 9.9%, sCr had been reduced back to a lower level at 132μmol/L and the corresponding eGFR was 48ml/min/1.73m², which was clinically assessed as G3a CKD, and urine protein/Cr ratio was 4.7mg/mmol, which was an indication of albuminuria. Examination of the fundi showed moderate non-proliferative diabetic retinopathy (NPDR).
In 2018, patient’s HbA1c was 8.1%. His sCr had already surged to 354μmol/L and his renal function deteriorated to an eGFR of 15ml/min/1.73m².
In 2019, patient’s sCr further climbed to 535μmol/L and eGFR dwindled to 9ml/min/1.73m² only. In view of his progressive condition, the patient was referred to the renal team. A kidney ultrasound scan demonstrated increased cortical echogenicity. Patient had reached ESRD with clinical diabetic nephropathy.
Performing kidney biopsy to rule out other potentially reversible pathology was offered but declined by patient. As there was no potential kidney donor at the moment, RRT was then proposed to patient who eventually opted for Automated Cycler Assisted Peritoneal Dialysis. While on dialysis, the patient managed to resume his work. Since then, he also started on erythropoiesis-stimulating agents (ESAs). A multi-disciplinary team encompassing renal nurse, social worker, dietician, pharmacist, and occupational therapist was also arranged to facilitate patient’s rehabilitation. Overall, the patient well accepted his illness and the comprehensive management provided.
In the above case, as the cause of AKI was believed to be declined renal perfusion secondary to impaired cardiac output resulting from the ischemic insult to the myocardium, the primary therapy for the observed AKI was the revascularization of the heart by cardiac stenting. To further increase the cardiac output and renal perfusion, an inotrope was also given to this patient. Once the myocardial stunting was alleviated, renal perfusion was expected to resume normal and thus helped resolve the AKI.
Given the long clinical history of DM and deteriorating renal function, this patient was diagnosed of diabetic nephropathy. There are data suggesting that diabetic nephropathy develops in approximately 40% of diabetics and is now one of the leading causes of CKD worldwide.10 In Hong Kong, diabetic nephropathy accounts for approximately 50% of patients newly started on RRT.11 In this patient, his pre-existing T2DM, hypertension, albuminuria, and poor baseline renal function, coupled with the AKI induced by acute MI, had placed him in a relatively unfavorable position with respect to his long-term kidney condition. This observation was proven correct when subsequent follow-up evaluation showed that his renal function had been declining progressively since his AKI recovery.
When managing diabetic patients with CKD, Dr. Cheung remarked that adequate blood pressure and glycemic control, correction of metabolic acidosis and lifestyle modifications including smoking cessation and protein restriction would help control CKD development. Should drug therapies be needed, sodium-glucose co-transporter-2 (SGLT2) inhibitors and ACEi/angiotensin II receptor blocker (ARB) should be considered while easily accessible nephrotoxic agents such as NSAIDs should be avoided. However, the subsidence of AKI did not mean this patient was completely free from any complications, as studies have already demonstrated that AKI is strongly implicated in the risk of developing subsequent CKD.12 Dr. Cheung explained, “Many patients who recover from AKI may not return to their baseline kidney condition and therefore pose a risk of developing de novo CKD or worsening their existing CKD in the future.“
To rectify the interactions between CKD, DM and AKI, the metabolic risk profile of a patient should be considered as a whole. In patients who have experienced AKI, subsequent CKD can develop with risk factors of advanced age, greater severity of AKI, and presence of comorbidities such as diabetes and hypertension.12,13 A study revealed that patients with pre-existing CKD who had superimposed AKI were at 30% higher long-term risk of death or progression to ESRD.14 AKI also appears to recur more frequently within 12 months after discharge in DM patients.15 Apart from nephropathy, DM patients are also at risk of other microvascular and macrovascular complications that can result in wide-spread organ and tissue damage.16 Therefore, DM has a negative effect on survival with ESRD diabetic patients having higher mortality rate than those without DM (Figure 2).17,18,19
In retrospect to this shared case, the patient’s renal prognosis could be much improved if his metabolic risk factors were controlled at an earlier stage. With a history of DM since 2004 and suboptimal HbA1c control of 7.9% despite normal creatinine level from laboratory findings in 2013, Dr. Cheung commented that earlier intervention on glycemic control could lower the risk of deteriorating renal function. Moreover, the patient should have stopped smoking to remove this independent risk factor towards CKD. At this patient stage, Dr. Cheung commented that while the AKI can be controlled, the patient has already observed marked renal function decline and ESRD is almost inevitable in the future. “Had this patient endeavored on his metabolic risk factors at an earlier stage, his renal prognosis would have been much better. But it is too late now as the patient has already developed full blown macrovascular and microvascular complications of DM. So, his renal prognosis is guarded,“ Dr. Cheung added.
To provide timely intervention, the underlying cause of nephropathy should be ascertained before a treatment is given. This is particularly important as the prevalence of DM and CKD are both high in the general population, and patients who are presented with CKD and DM can indeed have true diabetic nephropathy while some CKD cases may not be directly related to DM or a combination of both.1 While the patient in this shared case had declined renal biopsy, this procedure is still recommended if a patient presents with atypical symptoms in order to determine the best treatment option.
Overall, the mainstay of AKI recovery depends on the identification and removal of underlying etiologies.7 Dr. Cheung thus summarized, “The medical records should be reviewed in detail to identify the baseline renal function. A careful review of potentially nephrotoxic medications is indispensable since withholding the culprit agent may resolve AKI. An ultrasound examination of the kidneys is almost a must to exclude obstructive uropathy, assess for kidney sizes, perfusion and to pick up possible renal vein thrombosis.“
AKI is a common condition that often develops in patients during hospitalization, particularly for CKD and DM patients. Understanding the underlying cause of AKI is conducive to devising a targeting approach that facilitates early recovery. It is common that many CKD patients are presented with DM concurrently, which is a common risk factor for renal complications. Optimal DM management lies in its early intervention, especially at the stage where complications or symptoms are still potentially reversible. By seizing this prime opportunity to control DM more stringently, the metabolic risk to progress to ESRD can be thereby reduced. As many patients are still the economic pillars of their families, every possible effort should be made to empower and facilitate patients to reintegrate into the society so that they can dedicate themselves to the workforce and live a normal life once again.
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