Discussion and conclusion
Diabetic nephropathy (DN) or diabetic kidney disease is characterized by its unique functional and structural changes. During the initial phase of clinically silent period, important structural changes occur. These include glomerular basement membrane thickening, mesangial proliferation, podocyte injury, and glomerular sclerosis. These histopathologic abnormalities are noted to be presence before the onset of moderately increased albuminuria. On the other hand, functional changes include hyperfiltration, micro and macroalbuminuria, with incipient progressive proteinuria that slowly progressed into chronic kidney disease and eventually ESRD.
In a study of carried out in San Francisco outpatient dialysis units, 7.6 to 12.7% of the patients were noted to have suffered from rapid declined in kidney function prior to the initiation of permanent dialysis [
4]. Unfortunately, the author did not provide much information about causes of the rapid declined in kidney function or any remedial step was taken. The definition of “rapid decline in kidney function” was also arbitrary [
4]. In a logistic regression model with rapid decline as the outcome, the Spanish researchers has reported that previous cardiovascular disease and higher proteinuria were the main predictors of rapid kidney decline (odd ratio 1.8–1.9) [
5]. In the same study, the rapid decliners consisted of more diabetic patients. In the Cardiovascular Health Study done by Shlipak et al. which included 4380 individuals older than 65 years of age, the rapid kidney function decliner group are mainly made up of diabetic patients [
6].
We summarized here 3 cases of T2DM patients with rapidly declining renal function (46 to 60 mL/min/year) and all had undergone renal biopsies for unexplained reduction in eGFR (Table
4). All three patients were noted to have overt proteinuria at diagnosis. Only one patient had respectable Hba1c at 7.4% while the rest had poorly controlled diabetes with Hba1c ranged more than 10%. However, it is important to note that the patient with better Hba1c had anemia at presentation and this may have led to a falsely low A1c reading. All patients had poorly controlled BP during follow up, and 2 patients had acute kidney injuries secondary to infections that have accelerated the renal deterioration. 2 patients admitted taking alternative treatment for diabetes mellitus beside being non-compliant to their diabetic medications. Their renal biopsies showed diabetic nephropathy with chronic, severe tubulointerstitial damage and interstitial nephritis (Figs.
1 and
2).
Table 4
Summary of the patients’ data
Gender | Female | Male | Female |
Ethnicity | Female | Malay | Malay |
Age | 45 | 41 | 33 |
Diabetes (Years) | 15 | < 1 year | 12 |
Hypertension (Year) | 1 | 1 | 3 |
Drop in GFR in mL/min/year | 46 | 46 | 60 mL |
Renal ultrasound | Normal | Increased parenchymal echogenicity | Normal |
Renal biopsy | Diabetic nephropathy, hypertensive changes with interstitial nephritis | Diabetic nephropathy, hypertensive changes with interstitial nephritis | Diabetic nephropathy, hypertensive changes and interstitial nephritis |
Hbaic (%) | 6.2 | 7.4 | 10.2 |
Albumin (g/L) | 24 | 12 | 29 |
Proteinuria g/day | 14.8 | 18.7 | 13.8 |
Tried supplements | Yes | Yes | Yes |
Proteinuria has long been recognized as an independent risk factor for renal function loss. It is the cardinal feature of acute and chronic kidney disease. The presence and severity of proteinuria has been shown to be a reliable strategy to identify rapid renal decline in community-based prospective cohort study [
7]. Measurement of total protein in urine is an inexpensive and well-established marker for kidney injury. The failing kidney is characterized histologically by tubulointerstitial inflammation, tubular cell apoptosis, tubular atrophy and fibrosis, and these changes correlate with the severity of proteinuria. Heavy tubular proteinuria also predicts a longer duration of interim dialysis support in patient with kidney injury in our population [
8].
In healthy kidneys, proximal tubules epithelial cells (PTEC) can reclaim proteins that have managed to pass the glomerular filtration barrier via endocytosis. The complex mechanisms of PTEC protein handling involve the much studied megalin-cubilin complex [
9]. However, this process is compromised in diseased glomeruli, where excess filtration of bioactive proteins into the tubular fluid can dysregulated PTEC signaling pathways in response to protein leakage from the glomeruli. As a consequence, there are abnormal PTEC growth, apoptosis, gene transcription and inflammatory cytokine production [
9].
Traditional supplement has been known to contain various herbal compounds that are nephrotoxic to kidneys. Aristolochic acids, anthraquinones, flavonoids, and glycosides from herbs have all been implicated for causing nephropathy. The exact pathogenesis of supplement related AKI has not been well established. Most of the time, the diagnosis is made via history of consumption of the supplement and demonstration of acute tubular necrosis and acute interstitial nephritis as per our case [
10]. It has been our experience that the renal functions of patients who have heavy proteinuria tends to suffer the most when they also taking herbal compounds concurrently. The magnitude of deterioration is as high as 60 mL/min per year in our case series.
Two of the patients (Madam A and Mr. B) have recurrent infections and needed courses of antibiotics. None of them have received non-steroidal anti-inflammatory drugs or contrast agents. However, all of them did receive diuretics. The prescribed medicines and the rapid fluctuation in their extracellular water compositions may have inadvertently cause some degree of interstitial nephritis or pre-renal acute kidney injuries.
DN patients are the one of the most common nephropathies being referred to our instituation [
11]. In our experience, patients who has proteinuria of more than 3 g per day do experience rapid deterioration of renal function over years, however the magnitude of deterioration will be less than 10 ml/min/year. It was the rapid deterioration of the renal function that has prompted to perform diagnostic renal biopsies.
There are many ways to retard diabetic nephropathy progression. Current management practices advocate that the best way to reduce microvascular and macrovascular complications is by treating the sugar control to target. In addition, as the rate of progression DN is also closely related to blood pressure control at baseline, a good blood pressure control plays an equally important role in retarding DN progression. As a matter of fact, it has been demonstrated that for DN patient with a background of hypertension, glycemic control may have little independent predictive value [
12]. This is further strengthened by the findings from the United Kingdom Diabetes Prospective Study (UKPDS), whereby a sustained reduction in blood pressure came out as the most important single intervention that could slow down the progression of diabetic nephropathy in both Type 1 and type 2 DM patients [
13].
Current guideline suggests a blood pressure goal of less than 140/90 mmHg in T2 DM patients and in addition it emphasis on good control of glycemia, obesity management, lowering lipids and cessation of smoking. Achieving this target is also associated with renoprotective effects, although there may be particular advantages conferred following blockade of the renin- angiotensin system (RAS) [
14]. Novel treatment strategies targeting different pathway, such as inflammation, fibrosis, and oxidative stress— are on-going for treatment of DN [
15].
Data from the Japan Diabetes Complications Study (JDCS) showed that in normo- and micro albuminuric patients with type 2 diabetes, patients with hyperfiltration (eGFR ≥120 ml/min/1.73 m2) have high risk of rapid renal function deterioration [
16]. It is also important to retard the microalbuminuria as once overt proteinuria develop, it is almost difficult to retard the CKD progression.
Currently there is no one-off investigations that can distinguishing fast decliners from slow decliners. Serial measurements of serum creatinine performed in the clinic often detect late stages of the fast decliners. The traditional end points used in clinical trials such as doubling of serum creatinine level or ESRD are not suitable to detect rapid decliners and this has hamper the effective evaluation of clinical trials in rapid decliners. A more suitable outcome measurement should include the rate of annual renal function declined over 2 to 3 years. Massive interest is underway to find an effective prognostic marker that identifies decliners at a single clinical encounter. Until recently 30 biomarkers showed significant associations with rapid progression after adjusted for clinical characteristics. Some of the well-known biomarkers identified are β2-microglobulin, Kidney injury molecule-1 and cystatin-C, whereas others have little or no prior data (for example, Symmetric dimethylarginine/asymmetric dimethylarginine ratio, Fibroblast growth factor-21 and uracil) [
17]. Elevated serum TNF receptor 1 and 2 have shown early promise to become effective predictors of fast renal decline to ESRD in diabetic population [
18].
Understanding the mechanisms underlying heavy proteinuria in T2DN that leads to rapid renal deterioration is desired to halt this undesirable event. Future studies will include identifying bio-markers, understanding individual variation in rate of decline, designing novel treatment targets and perhaps individualizing treatment for T2DN.