| Abstract|| |
Diabetic kidney disease (DKD), one of the most frequent microvascular complications of diabetes mellitus (DM), is the leading cause of end-stage kidney disease worldwide. We reviewed all kidney biopsies performed at the Royal Hospital, Muscat, Oman, between January 2005 and December 2016, and data of 51 DM patients were analyzed. Of the 51 patients, 54.9% were male and 45.1% were female. The mean age was 50.8 (47.1–55.2) years; 86% were between 25 and 64 years old. Edema was the main clinical presentation (70.6%) with clinical urine changes in 84.3%. Diabetic retinopathy was present in 62.2% in ophthalmological examination of 44 patients. Majority (67.5%) of patients were in advanced chronic kidney disease Stages III, IV, and V. About one-quarter underwent hemodialysis at the time of admission. Majority (76.9%) were obese and hypertensive (78.4%). Low hemoglobin (51%), high triglyceride (35.7%), high total cholesterol (56.8%), low serum albumin (78.4%), nephrotic-range proteinuria (75.6%), and microscopic hematuria (77.1%) were the main laboratory findings. In addition, immunological investigations were examined and immunoglobulin A was the most common findings (35.7%) of serological investigations. About 24.4% had positive antinuclear antibody, 20.8% had positive anti-dsDNA, and 23.3% had positive extractable nuclear antigens. Also, p-antineutrophil cytoplasmic antibody (p-ANCA) was positive in 30% and c-ANCA was positive in 9.7%. This study represents the findings of the whole country for more than 10 years. It showed that only a small percentage of patients with DM undergo kidney biopsy. These patients have many clinical and laboratory abnormalities including those of specific immuno-logical investigations. Progression of DM nephropathy seems to be further aggravated by many coexisting risk factors of dyslipidemia and/or obesity. The prevalence of non-DKD is remarkably frequent in diabetics in whom nephrologists should consider kidney biopsy as an appropriate measure to enable better management.
|How to cite this article:|
Mohammed E, Atris A, Al Salmi I, Al-Menawi L, Shaheen F, Hannawi S. Clinical and laboratory findings of patients with diabetes undergoing kidney biopsy. Saudi J Kidney Dis Transpl 2018;29:1290-302
|How to cite this URL:|
Mohammed E, Atris A, Al Salmi I, Al-Menawi L, Shaheen F, Hannawi S. Clinical and laboratory findings of patients with diabetes undergoing kidney biopsy. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2019 Mar 18];29:1290-302. Available from: http://www.sjkdt.org/text.asp?2018/29/6/1290/248287
| Introduction|| |
The number of people with diabetes has risen from 6.4% affecting 285 million adults in 2010 to 7.7% affecting 349 million adults by 2030,, and between 2010 and 2030, there will be a 69% increase in numbers of adult with diabetes in developing countries and a 20% increase in developed countries., Diabetes prevalence has been rising more rapidly in middle-and low-income countries. Six of the top 10 countries with the highest prevalence of diabetes in adults are in the Middle East,, which are Kuwait (21.1%), Lebanon (20.2%), Qatar (20.2%), Saudi Arabia (20.0%), Bahrain (19.9%), and the UAE (19.2%).,,
The prevalence of diabetes is considered high (11.6%) in Oman, where nowadays its total population is approximately 3.174 million, of which 2.018 million are Omanis. In 2000, the age-adjusted prevalence of diabetes among Omanis aged 30–64 years reached 16.1% compared with 12.2% in 1991, indicating an increasing prevalence. Similarly, diabetes prevalence in Turkey was 7.2% in 2000, and it had increased to 13.7% by 2010., In Iran, a national survey was conducted in 2011, 11.4% [95% confidence interval (CI), 9.86–12.89] of Iranian adults aged 25–70 years had diabetes, and it is estimated that by the year 2030, 9.2 million Iranian individuals will have diabetes.
The cost burden of diabetes in the Gulf has the potential to rise even further if the condition goes undiagnosed or untreated, increasing the likelihood of complications. Accordingly, in the UAE, the cost of direct treatment is 2.2 times higher for those with diabetes-related microvascular complications, 6.4 times higher for patients with macrovascular complications, and 9.4 times higher for diabetes patients with both microvascular and macrovascular complications. A study conducted for Iranian patients in 2009 found that the total cost associated with type 2 diabetes amounts to approximately US$ 3.78 billion annually. It has been concluded that the direct and indirect annual health-care costs for an Iranian patient with diabetes are about 2.5 times higher than a healthy Iranian citizen.
Diabetic nephropathy (DN) is a clinical syn-drome in a patient with diabetes mellitus (DM) that is characterized by persistent albuminuria, worsening proteinuria, hypertension, and progressive kidney dysfunction., Approximately, a third of patients with type 1 insulin-dependent DM (T1DM) and type 2 noninsulin-dependent DM (T2DM) develop DN. The pathologic hallmark of DN is diabetic glome-rulosclerosis (DGS) that results from a progressive increase in extracellular matrix in the glomerular mesangium and glomerular basement membrane. DGS is the leading cause of end-stage kidney disease in the United States, Europe, and Japan. However, nondiabetic kidney disease (NDKD) may be present among these patients with or without DGS.
Only a few sporadic studies from different parts of our region or across the globe reported various clinical and laboratory findings in patients with diabetes that underwent kidney biopsies. These studies have reported variable frequencies of wide range of clinical and laboratory findings. The study aims to evaluate diabetic patients by utilizing clinical and laboratory data during time of deterioration of diabetes clinical syndrome.
| Patients and Methods|| |
The Royal Hospital has an internationally recognized electronic medical record system called AL SIFFA that uses the International Classification of Diseases. It is the only center where all cases undergo kidney biopsy from all hospitals and regions of the Ministry of Health (MOH) in Oman. The pathology department at Sultan Qaboos University Hospital (SQUH) is the only center in the country to interpret and analyze all the histological specimens, in addition to Royal Hospital.
The following data were collected at the time of kidney biopsy: age (years), height (cm) (was measured without shoes), body weight (kg) (while wearing outdoor clothing), body mass index (BMI) (weight in kg divided by height in meter squared – kg/m2) which were calculated. The WHO classification for BMI was used to estimate the degree of obesity, duration of symptoms and signs (months), duration of DM (years), clinical evidence of retinopathy, and blood pressure (BP) (mm Hg).
Laboratory investigations done were serum creatinine, blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), serum albumin, hemoglobin level, total white cell count, fasting serum glucose level, glycated hemoglobin (HbA1c) and HbA1c%, and lipid profile. Urine investigations included urinary protein/creatinine ratio (UPCR) (mg/mmol, normal <20, overt proteinuria 20–200, nephrotic >200), total protein in the urine (mg/dL), and total blood in the urine (ERY/pL).
Specific immunological tests carried out were complement level C3 and C4, antinuclear antibody (ANA), antineutrophil cytoplasmic antibodies (c-ANCA and p-ANCA), and immunoglobulin A (IgA). We collected data for virology screen including hepatitis B surface antigen, done by chemiluminescence semi-quantitative ELISA (cutoff of 1.0 S/O ratio, negative <1.0, positive ≥1.0), hepatitis C anti-bodies (ratio, reactive or nonreactive), and HIV (ratio, reactive or nonreactive).
In addition, radiological data regarding kidney ultrasound and chest X-ray, at the time of biopsy, were collected. Kidney ultrasound examination was done at the diagnostic radiology department to identify the kidney size, detect, and grade kidney parenchymal echogenicity and to exclude the presence of associated kidney disorders such as stones, masses, and hydronephrosis. It was done by expert sono-graphers with the patient in supine position. Axial and sagittal images were taken. The length of each kidney was measured in the sagittal plan. The kidney parenchymal echogenicity was estimated compared to the hepatic and splenic echogenicity.
The definitions followed is shown in [Table 1].,,,
|Table 1: Various clinical and laboratory parameters and their definitions used in our study.|
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Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines 2012 was used in our study to define acute kidney injury (AKI). The KDIGO defines AKI as any of the following:
- - Increase in serum creatinine by 0.3 mg/dL or more within 48 h or
- - Increase in serum creatinine to 1.5 times baseline or more within the last seven days or
- - Urine output <0.5 mL/kg/h for 6 h.
Furthermore, we followed the KDIGO staging system for the severity of the AKI:
- - Stage 1: serum creatinine 1.5–1.9 times baseline and/or urine output <0.5 mL/kg/h for 6 h
- - Stage 2: serum creatinine 2–2.9 times baseline and or urine output <0.5 mL/kg/h for 12 h
- - Stage 3: serum creatinine is 3 times baseline or equal or more than 4 mg/dL or initiation of renal replacement therapy and/or urine output <0.3 mL/kg/h for 24 h or anuria for 12 h.
The study was approved by the Medical Ethics and Research Committee at the hospital. The data entry was rechecked by two researchers. Quality control data were done as per our institute research guidelines. Data were analyzed using the STATA statistical software package, version 13.1 (StataCorp LP, College Station, Texas).
Data were described as frequencies and percentages for categorical variables. Continuous variables were reported as median and ranges or as mean and standard deviations (SDs). Age data are presented as mean ± SD (SD or 95% CI).
| Results|| |
The Royal Hospital is the only public hospital of MOH that provides kidney biopsy as private hospitals do not provide such a service in Oman. Furthermore, military and police hospitals do not provide this service, and the University Hospital (SQUH), an educational hospital, is the only one that admits selected patients for educational purposes and provide biopsy services. The Royal Hospital is the only hospital operated by MOH provides native and transplant kidney biopsies from all over the country as shown in [Figure 1]. The majority (60.8%) were from Muscat region, Northern (Batinah) region (15.7%), Interior region (9.8%), Eastern region (7.8%), and Southern region (5.9%).
|Figure 1: Patient’s distribution according to different regional areas in Oman.|
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During the period from January 2005 to the end of December 2016, a total of 51 T2DM/ T1DM patients, males – 54.9% and females – 45.1%, underwent native kidney biopsy. Only 88% of study patients had professional ophthalmological examinations, and diabetic retinopathy was present in 62.2%. The mean (95% CI) of age was 50.8 (47.1–55.2) years for all patients, ranged between 15 and –65 years, and was 51.8 (46.8–56.9) and 49.6 (43.7–55.5) for males and females, respectively. Majority (86.3%) of patients were in the age group of 25–64 years, 11.7% were 65 years and over, and only 2% were in the age group of 15–24 years. The majority (90.2%) of the patients were citizens, 5.9% were from the Indian subcontinent, and 3.9% were African.
At the time of admission for native kidney biopsy, the mean (95% CI) for body weight was 81.7 kg (75.3–88.2) for all patients, males – 86.6 kg (76.5–96.7) and females – 76.1 kg (68.2–83.8), of which 23.1% of patients were with normal (BMI: 18.5–24.9), no patient (0%) was underweight (BMI <18.5), while 26.9% of patients were overweight (BMI: 25–29.9), 23.1% with Class I obesity (BMI: 30–34.9), 15.4% with Class II obesity (BMI: 35–39.9), and 11.5% with Class III obesity (BMI >40).
The duration of symptoms was 4.7 months (2.7–4.4) for all patients, males – 5.8 months (2.1–9.5) and females – 3.5 months (2.6–4.4). The systolic BP was 139.9 mm Hg (135.3–144.5) for all patients, 142.1 mm Hg (136.1–148.1) in male patients, and 137.3 mm Hg (129.8–144.7) in female patients. Majority (70.6%) of patients presented had swelling in their lower limbs (clinical edema). Furthermore, majority (84.3%) of patients reported recent changes in their urine. The majority (90.2%) had T2DM on oral hypoglycemic therapy and 9.8% were labeled as T1DM on insulin therapy. Furthermore, majority (78.4%) were known to have high BP or being on anti-hypertensive therapy. About 55% of patients denied having any symptoms of uremia and 45% claim to have at least one symptom of uremia.
Routine laboratory data for all participants and by gender are mentioned in [Table 2]. When we analyzed patients’ data on the basis of normal and abnormal range, we found that 49%, 72.6%, and 74.5% had normal range hemoglobin, platelets, and white cell counts, respectively. Furthermore, majority (78.4%) of patients had low serum albumin, 56.8% had high total cholesterol, 69% had high low-density lipoprotein (LDL), 40% had low high-density lipoprotein (HDL), and 36% had high triglyceride levels. Furthermore, majority (91.7%) of patients had proteinuria and 77.1% had hematuria by urinary dipstick. UPCR test showed that 75.6% had nephrotic-range pro-teinuria, 22.2% had subnephrotic-range protei-nuria, and only 2.2% had normal range UPCR. When eGFR categorized into stages of CKD, it showed that majority of patients were in Stages III and IV, as shown in [Figure 2].
|Table 2: Mean (95% confidence interval) of various laboratory investigations for all participants and by gender.|
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|Figure 2: Stages of chronic kidney disease (I-V) in our participants at time of biopsy.|
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The specific immunological investigations showed that mean C3 complement level was 1269.7 mg/L (1167.7–1371.7) for all patients, 1202.7 mg/L (1092.4–1313) for males and 1351.6 mg/L (1162.9–1540.2) for females; mean C4 complement level was 325.7 mg/L (289.5–361.9) for all patients, 347.2 mg/L (299.9–394.5) for males and 299.4 mg/L (240.5–358.4) for females; and both C3 and C4 were low in 17.4% of total patients; and the mean IgA level was 3.6 g/L (2.7–4.5) for all patients, 3.4 g/L (2.7–4.1) for males and 3.8 g/L (2–5.7) for females. A 24.4% had positive ANA, 20.8% had positive anti-dsDNA, and 23.3% had positive extractable nuclear antigens (ENA) meanwhile p-ANCA was positive in 30% and c-ANCA positive in 9.7%.
Chest X-ray revealed no lung infection in 96.9% of patients, while pleural effusions were there in 28.1% and cardiomegaly in 12.5%. US examination showed that 13.64% had a kidney size >11 cm, 72.7% of patients had a kidney size between 10 and 11 cm in length, 11.4% of patients had kidney size between 9 and <10 cm, and only 2.3% had a kidney size of 8 cm. Kidney echogenicity was increased in 22 patients (44%). Kidney cysts were present in two patients (3.9%). Kidney stones were present in three patients (5.9%), and kidney scars were present in only one patient (1.96%).
| Discussion|| |
This is the first study from Oman that reports findings for more than 10 years for the country since the study hospital was the center reporting all biopsies. It showed that only a small percentage of patients with diabetes, with acute deterioration in function, undergo kidney biopsy. These patients have many clinical and laboratory abnormalities including the specific immunological investigations. Diabetic patients who underwent kidney biopsy were young with symptoms of short duration. Progression of DN seems to be further increased by many coexisting risk factors such as dyslipidemia and/or obesity. The most common clinical presentations were edema (70.6%) and urine changes in the form of frothy urine in 84.3% of patients. About 45.1% of patients had uremic signs and symptoms at time of biopsy, and 23.5% of patients were in need for hemodialysis at time of biopsy.
Diabetic kidney disease (DKD) is under diagnosed clinical identity. The risk for the development of DKD is low in a normo-albuminuric patient with diabetes duration of >30 years. Patients who have no proteinuria after 20–25 years have a risk of developing overt kidney disease of only approximately 1% per year.
The indications for kidney biopsy in these diabetic patients were as follow: heavy protei-nuria in about 75.6%, microscopic hematuria in 77.1% and proteinuria with an absence of clinical presence of diabetic retinopathy in 37.8%. Furthermore, laboratory findings of rapid decline in kidney function as defined by AKI criteria were present in 78.4%. Further-more, there were other indications such as recently diagnosed DM within <3 months in patients with CKD (52.9%) and positive immunological findings such as IgA, low C3/C4, positive ANA/ENA, and ANCA.
Similar to our indications for biopsy in diabetes, two studies from the Republic of Korea found that the clinical features to predict kidney involvement in the diabetic patient are sudden onset of proteinuria, proteinuria in the absence of retinopathy or neuropathy, short duration of diabetes, AKI, and hematuria.,
Furthermore, in a retrospective analysis study from Malaysia of all T2DM patients in whom kidney biopsies were performed from January 2004 to March 2008 in the University Malaya Medical Centre found that the indications for kidney biopsy included uncertain causes of AKI (with no obvious prerenal or obstructive disorders), chronic kidney dysfunction with relatively short duration of diabetes or without retinopathy, heavy proteinuria (>1 g/day), and microscopic hematuria. It has been reported that atypical clinical features of kidney involvement, especially in those with short duration of diabetes which warrant kidney biopsy, are determined due to the absence of diabetic retinopathy, rapidly decreasing kidney function, briskly rising proteinuria or acute onset of nephrotic syndrome, and active urinesediment.,
KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 Update decided that kidney biopsy is indicated in diabetic patients with an atypical presentation of kidney disease that could be attributed to other kidney entities different from DN. Atypical presentation of kidney disease in diabetic patients include microalbuminuria without diabetic retinopathy, rapid decline of glomerular filtration rate, rapid increase of proteinuria, sudden appearance of the nephrotic syndrome, active sediment or the appearance of signs and symptoms of systemic diseases. Shorter duration of diabetes (≤5 years), absence of retinopathy, and presence of glomerular hematuria were independent indicators associated with NDKDs, indicating the need for kidney biopsy. These indications are similar to our patients’ features and laboratory findings.
Many of our studied patients were over-weight and only 23.1% had normal BMI. 23.1% had mild obesity, 15.4% were moderately obese, and 11.5% had morbid obesity. Similarly, Chinese patients with biopsy-confirmed DN, 22.3% presented with obesity and 53.7% with overweight/obesity. The prevalence of obesity was as high as 24.8% in patients with early-stage DN compared with the prevalence in the general Chinese popu-lation. Another study, obesity and DKD, concluded that obesity and diabetes are major causes of CKD and ESKD and are thus one of the health concerns worldwide. Both obesity and diabetes, along with other elements of the metabolic syndrome including hypertension, are highly interrelated and contribute to the development and progression of kidney disease. These findings were similar to our where all components of metabolic syndrome exist in our diabetic patients.
A Swedish study, quantified the possible link between obesity and CKD, found that the excess risk for CKD among obese people seems to be driven mainly by a high prevalence of hypertension and/or type 2 diabetes. Our study, similarly, found that majority of patients have high BP. A study from Madrid, Spain, found that proteinuria decreased by 31.2% ± 37% in the diet group whereas it tended to increase in the control group.
Our study population was relative of younger age group and only 11.8% of patients aged 65 years and above. Male represented 54.9% of patients while 45.1% of patients were females. In a similar study from Izmir, the average age of the patients was 58.9 ± 9.7 years and 59% of the patients were female while male patients were 41%. In another study from the United Arab Emirates, the age groups were mainly around 50–59 years in 30.1% of patients, 27.3% were 60 or above, 26.8% were between age of 41 and 49, and 15.85 were 40 or less; males represented 51.55 of all patients while females were 48.5%.
Similar to our finding of short duration of diabetes in patients with DN, Indian patients with DN were found to have shorter duration of diabetes on biopsy compared with Malays and Chinese. This observation suggests that ethnic or genetic factors may play a role in the pathogenesis of DN, and similar observations of increased susceptibility in certain ethnic group have been reported previously in the American black population.,
The most common clinical presentations were with edema (70.6%) and high BP (78.4%). Clinical urine changes in the form of frothy urine were there in 84.3%. A 45.1% of patients had uremic signs and symptoms at time of biopsy. One published study could be found on DN in Oman, conducted in 2005. It showed a prevalence of microalbuminuria of 27% and also found that HbA1c, serum creatinine, and presence of hypertension were the most significant predictors for microalbuminuria. Data from the renal dialysis center show increasing incidence of DN on dialysis.
Our patients had short duration of DM and diabetic retinopathy, while Chong et al suggested that the presence of diabetic retinopathy and longer duration of diabetes may be predictors of DN, whereas AKI and microscopic hematuria may be predictors of non-DN. Kim et al and Soni et al suggested that a shorter duration of diabetes, absence of retinopathy, and absence of nephritic proteinuria may be predictors of non-DN. In other studies, DN and non-DN were found to be associated with similar durations of disease, as well as incidences of retinopathy and neuropathy.,
One study from Ankara, Turkey, showed diabetes duration of patients with NDKD was shorter than that of patients with DN. However, type 2 diabetes may have developed long before these patients were diagnosed. Therefore, the known diabetes duration does not accurately predict the presence or severity of DN. HbA1c was lower in patients with NDKD than those with DN.
Hypertension is common among patients with chronic kidney disease and DM. In this population, hypertension increases risk for kidney disease onset and progression and cardiovascular morbidity and mortality. The possible role of BP reduction in the treatment of DKD has been shown by several studies., In our study, the majority have high BP with mean of the systolic BP of 139.9 mmHg. Furthermore, majority (78.4%) were known to have high BP or being on anti-hypertensive therapy. A study by Van Buren and Toto concluded that hypertension is highly prevalent in patients with type 1 and type 2 diabetes and nephro-pathy, and BP treatment goals should be aimed at a BP <130/80 mm Hg. The KDIGO clinical practice guideline for the management of BP in CKD recommends a BP target of <140/90 mm Hg in patients with diabetes and CKD. Tkachenko and Schrier from the USA concluded that the main therapies for primary and secondary prevention of DKD are management of BP and blood glucose. In the RENAAL study, the risk of end-stage kidney disease or death was increased by 38% among patients with initial systolic BP of 140–159 mm Hg compared to patients with systolic BP <130 mm Hg.
Blood tests for BUN and creatinine are the simplest way to monitor kidney function. eGFR is the best measure of kidney function since it accounts for age, BMI, and sex. The normal value for GFR in a normal-sized person is 110–150 mL/min. In our study, kidney functions at the time of biopsy revealed that most of the patients had high serum creatinine in 78.4% of all patients with mean eGFR of 37.7 mL/min/m2. In addition, 23.5% of patients were in need for renal replacement therapy and hemodialysis, at the time of biopsy. Stage I CKD was present in 13.7%, 9.8% were in Stage II CKD, 9.8% in Stage IIIA CKD, 11.8% in Stage IIIB CKD, 23.5% of patients in Stage IV CKD, and 31.4% of patients in Stage V CKD. Berhane et al studied albuminuria and eGFR as predictors of diabetic end-stage kidney disease and death, and they concluded that albuminuria and eGFR are each significant predictor of ESKD and of mortality in T2DM, and the combination of albuminuria and eGFR is significantly better than either measure alone.
Like many other studies, the most common laboratory findings were nephrotic proteinuria (75.6%) with hypoalbuminemia (78.4%) and dyslipidemia. Microscopic hematuria was also there in 77.1%, and urine protein was there in 91.7%. Patients with DKDs often have multiple lipoprotein abnormalities (diabetic dyslipidemia); LDL was high in most of the patients (69%), while HDL was low in 40.5% with trend for more dyslipidemia in female patients. It has been recognized that lipid nephrotoxicity is involved in the development of DN since the 1970s. Lipid may induce kidney injury. Triglyceride-rich lipoproteins can activate monocytes, degrade glycocalyx, and increase permeability of the glomerular filtration barrier, which may contribute to the progression of DN. Clinical studies have demonstrated that lipid-lowering therapy shows a protective effect of the kidney function, and it is well known that statins reduce albuminuria in patients with DN. The prevalence of high LDL in patients with diabetes appears to be similar to that of general population, as demonstrated by the Framingham study and the United States National Health and Nutritional Examination Survey. The United Kingdom prospective diabetes study showed no differences in total cholesterol levels between diabetic and nondiabetic participants. The heart protection study showed that the prevalence of low HDL was higher in diabetic individuals (21% in males and 25% in females) compared to nondiabetic individuals (12% in males and 10% in females).
Hemoglobin was lower than normal level in 51% of patients at the time of biopsy. Antwi-Bafour et al in a study from Ghana found a high incidence of anemia in patients with DN, where 84.8% had a hemoglobin concentration that was significantly less than normal range. Earlier research studies have reported that anemia mostly occurs in patients who also have kidney dysfunction. Anemia occurs early and at a greater degree in patients presenting with DN than those presenting with other causes of kidney dysfunction. A study from Greece by Loutradis et al concluded that the prevalence of anemia progressively increases with advancing stages of CKD and is higher in diabetes than matched nondiabetic CKD patients and diabetes is independently associated with anemia occurrence. Detection and treatment of anemia in diabetic CKD patients should be performed earlier than nondiabetic counterparts.
In metabolic diseases such as DM, the implication of complement activation has been poorly appreciated in the development of kidney involvement. Recently, the complement system has been shown to be causally involved in tissue injury in patients with DN including obesity, dyslipidemia, and hypertension as well as in patients with autoimmune or infective diseases., In our study, complements C3 and C4 were low in 17.4%, indicating another or additionally possible patho-genesis rather than diabetes-induced CKD. Furthermore, a Danish study concluded that not all patients with DM will develop DN and that an increasing evidence points toward a role of the complement system in the patho-genesis of DN which may accelerate the kidney dysfunction. Hence, new approaches to modulate the complement system might lead to the development of new agents to prevent or slow the progression of DN.
Many studies investigated the relation between IgA and DN. In our study, IgA level was high in 35.7% of patients with mean (95% Cl) of 3.6 g/L (2.7–4.5) in all patients which may play role in the kidney dysfunction in patients with worsening DKD. However, other researchers concluded that the superimposed IgA does not significantly alter the medium-term clinical outcome of patients with DGS.
An early study in Japan about the presence of anti-DNA antibody in DM found that the antibody in patients with DM might be produced as a result of tissue destruction due to diabetic angiopathy or it may be an index of immune abnormality causally related to the development of diabetic complications. In our study, we had positive ANA in 24.4%, positive anti-dsDNA in 20.8%, and positive ENA in 23.3%, while p-ANCA was positive in 30% and c-ANCA was positive in 9.7% of patients. All these positive autoimmune diseases may play role in the worsening of kidney function of diabetic patients. Pauci-immune necrotizing and crescentic glomerulonephritis (PNCGN) superimposed on DGS in a rare occurrence. PNCGN may occur superimposed on DGS. The realization that type 1 diabetes is an auto-immune disease and that some of the antigens expressed by islets are also expressed by kidney glomerular cells supports the immunologic factors contributing to secondary complications. The prognosis of this dual glomerulopathy is poor despite aggressive therapy.
Ultrasound examination revealed that 2.3% had small kidney size, but the majority of patients had normal kidney size of 9–11 cm. Fifty percent of the patients had increased echogenicity, and kidney cysts were present in 0.045% of patients. Kidney stones were present in 6.52% of patients. These factors also may have contributed to kidney dysfunction in our population in a hot weather with poor water intake.
There are limitations in our study. It is a single-center retrospective study, and sample size is small. It is known that DM and DKD are notoriously underdiagnosed, and therefore, the results might reflect only the tip of iceberg. Obesity in the study was defined using BMI rather than waist circumference, which if measured would have correlated more with albuminuria. Finally, many Omani peoples travel outside Oman for the second opinion including kidney biopsy which is not registered in our system.
| Conclusion|| |
This is the first study from Oman that reports clinical and laboratory findings among DKD patients who underwent kidney biopsy for more than 10 years for the whole country. Although it is a single-centered study, it reflects the whole country for more than 10 years since renal biopsy is not carried out in any other center in Oman.
The high prevalence of DM and DKDs among Omani patients is a devastating human and social problem incurring heavy economic burden. The situation is similar in other GCC countries and other Middle East regions. Education of diabetic patients about the risks and complications of poor glycemic control is a critical component of clinical practice to avoid this as far as possible.
The clinical features to predict nondiabetic kidney involvement in our diabetic patients are short duration of DM, sudden onset of protei-nuria, proteinuria in the absence of retino-pathy, AKI, hematuria, and positive immuno-logical findings. The prevalence of NDKD is remarkably frequent in Omani diabetic patients in whom nephrologists should consider kidney biopsy as an appropriate measure.
Conflict of interest: None declared.
| References|| |
NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in diabetes since 1980: A pooled analysis of 751 population-based studies with 4.4 million participants. Lancet 2016;387:1513-30.
Zhang P, Zhang X, Brown J, et al. Global healthcare expenditure on diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010;87: 293-301.
Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010; 87:4-14.
Rahim HF, Sibai A, Khader Y, et al. Non-communicable diseases in the Arab world. Lancet 2014;383:356-67.
Al-Lawati JA. Diabetes mellitus: A local and global public health emergency! Oman Med J 2017;32:177-9.
Al-Lawati JA, Panduranga P, Al-Shaikh HA, et al. Epidemiology of diabetes mellitus in Oman: Results from two decades of research. Sultan Qaboos Univ Med J 2015;15:e226-33.
Satman I, Yilmaz T, Sengül A, et al. Population-based study of diabetes and risk characteristics in Turkey: Results of the Turkish diabetes epidemiology study (TURDEP). Diabetes Care 2002;25:1551-6.
Satman I; TURDEP II Working Group 47. Ulusal Diayabet Kongrei-TURDEP II Sonuplari-Turkiye Diyabet Prevalans. Istanbul Tip Fakultesi-Istanbul Universitesi, 11-15 Mayis; 2011.
Esteghamati A, Etemad K, Koohpayehzadeh J, et al. Trends in the prevalence of diabetes and impaired fasting glucose in association with obesity in Iran: 2005-2011. Diabetes Res Clin Pract 2014;103:319-27.
Javanbakht M, Mashayekhi A, Baradaran HR, Haghdoost A, Afshin A. Projection of diabetes population size and associated economic burden through 2030 in Iran: Evidence from micro-simulation markov model and Bayesian meta-analysis. PLoS One 2015;10:e0132505.
Al-Maskari F, El-Sadig M, Nagelkerke N. Assessment of the direct medical costs of diabetes mellitus and its complications in the United Arab Emirates. BMC Public Health 2010;10:679.
Javanbakht M, Baradaran HR, Mashayekhi A, et al. Cost-of-illness analysis of type 2 diabetes mellitus in Iran. PLoS One 2011;6:e26864.
Tervaert TW, Mooyaart AL, Amann K, et al. Pathologic classification of diabetic nephro-pathy. J Am Soc Nephrol 2010;21:556-63.
Fioretto P, Steffes MW, Brown DM, Mauer SM. An overview of renal pathology in insulindependent diabetes mellitus in relationship to altered glomerular hemodynamics. Am J Kidney Dis 1992;20:549-58.
WHO Expert Consultation. Appropriate body-mass index for asian populations and its implications for policy and intervention strategies. Lancet 2004;363:157-63.
Kaspersak-Zajac A, Grzanka A, Machura E, Misiolek M, Mazur B, Jochem J. Increased serum complement C3 and C4 concentrations and their relation to severity of chronic spontaneous urticaria and CRP concentration. J Inflamm (London, England) 2013;10(1):22.
Patient Fact Sheet Antinuclear Antibodies (ANA). Kelly Weselman K. American College of Rheumatology, Updated March 2017 by Kelly Weselman, MD, and reviewed by the American college of rheumatology communications and marketing committee. https://www.rheumatology.org
Savige J, Pollock W, Trevisin M. What do antineutrophil cytoplasmic antibodies (ANCA) tell us? Best Pract Res Clin Rheumatol 2005; 19:263-76.
Mehta RL, Kellum JA, Shah SV, et al. Acute kidney injury network: Report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31.
Floege J, Feehally J. Introduction to glomerular disease. In: Feehally J, Floege J, Johnson RJ, editors. Clinical Presentations: Comprehensive Clinical Nephrology. 3rd
ed. Philadelphia: Mosby Elsevier; 2007. p. 193-207.
Cotran RS. The kidney. In: Cotran RS, Kumar V, Robbins SL, editors. The Pathologic Basis of Disease. 5th
ed. Philadelphia: W. B. Saunders; 1994. p. 932.
Huyhes PJ, Desai T, Lerna EV. Classification Systems for Acute Kidney Injury. Medscape, Drug & Diseases April 27, 2017.
Acute Kidney Injury Work Group. Kidney disease: Improving global outcomes – Clinical practice guideline for acute kidney injury. Kidney Int 2012;2:1-138.
Pham TT, Sim JJ, Kujubu DA, Liu IL, Kumar VA. Prevalence of nondiabetic renal disease in diabetic patients. Am J Nephrol 2007;27:322-8.
Chang TI, Park JT, Kim JK, et al. Renal outcomes in patients with type 2 diabetes with or without coexisting non-diabetic renal disease. Diabetes Res Clin Pract 2011;92:198-204.
Chong YB, Keng TC, Tan LP, et al. Clinical predictors of non-diabetic renal disease and role of renal biopsy in diabetic patients with renal involvement: A single centre review. Ren Fail 2012;34:323-8.
Huang F, Yang Q, Chen L, et al. Renal pathological change in patients with type 2 diabetes is not always diabetic nephropathy: A report of 52 cases. Clin Nephrol 2007;67:293-7.
Nelson RG, Tuttle KR. The new KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and CKD. Blood Purif 2007;25:112-4.
Wu Y. Overweight and obesity in China. BMJ 2006;333:362-3.
Maric-Bilkan C. Obesity and diabetic kidney disease. Med Clin North Am 2013;97:59-74.
Ejerblad E, Fored CM, Lindblad P, et al. Obesity and risk for chronic renal failure. J Am Soc Nephrol 2006;17:1695-702.
Praga M. Obesity – A neglected culprit in renal disease. Nephrol Dial Transplant 2002;17: 1157-9.
Celepholu T, Tansriverdi M, Celik SB; Rakize Gamze Erten Bucarktepe. The evaluation of nephropathy risk factors in type 2 diabetes. Acta Med Mediterr 2014;30:221.
Al-Maskari F, El-Sadig M, Obineche E. Prevalence and determinants of microalbumi-nuria among diabetic patients in the United Arab Emirates. BMC Nephrol 2008;9:1.
Brancati FL, Whittle JC, Whelton PK, Seidler AJ, Klag MJ. The excess incidence of diabetic end-stage renal disease among blacks. A population-based study of potential explanatory factors. JAMA 1992;268:3079-84.
Cowie CC, Port FK, Wolfe RA, et al. Disparities in incidence of diabetic end-stage renal disease according to race and type of diabetes. N
Engl J Med 1989;321:1074-9.
Al-Futaisi A, Al-Zakwani I, Almahrezi A, et al. Prevalence and predictors of microalbuminuria in patients with type 2 diabetes mellitus: A cross-sectional observational study in Oman. Diabetes Res Clin Pract 2006;72:212-5.
Renal Data System, Oman Renal Dialysis Center, DGHS, Muscat: Ministry of Health; [Last accessed February 2018].
Kim BS, Chang YK, Song HC, et al. The clinical differentiations between diabetic nephropathy and non-diabetic renal disease in type 2 diabetic patients. Korean J Nephrol 2009;28:588-94.
Soni SS, Gowrishankar S, Kishan AG, Raman A. Non diabetic renal disease in type 2 diabetes mellitus. Nephrology (Carlton) 2006; 11:533-7.
Lin YL, Peng SJ, Ferng SH, Tzen CY, Yang CS. Clinical indicators which necessitate renal biopsy in type 2 diabetes mellitus patients with renal disease. Int J Clin Pract 2009;63:1167-76.
Mak SK, Gwi E, Chan KW, et al. Clinical predictors of non-diabetic renal disease in patients with non-insulin dependent diabetes mellitus. Nephrol Dial Transplant 1997;12: 2588-91.
Tone A, Shikata K, Matsuda M, et al. Clinical features of non-diabetic renal diseases in patients with type 2 diabetes. Diabetes Res Clin Pract 2005;69:237-42.
United Kingdom Prospective Diabetes Study. 13: Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. BMJ 1995;310:83-8.
Van Buren PN, Toto R. Hypertension in diabetic nephropathy: Epidemiology, mechanisms, and management. Adv Chronic Kidney Dis 2011;18:28-41.
KDIGO clinical practice guidelines for the management of blood pressure in chronic kidney disease. Kidney Int Suppl 2012;2:363-9.
Tkachenko O, Schrier RW. Blood pressure control in diabetic nephropathy. J Nephrol Ther 2014:148.
Bakris GL, Weir MR, Shanifar S, et al. Effects of blood pressure level on progression of diabetic nephropathy: Results from the RENAAL study. Arch Intern Med 2003;163: 1555-65.
Berhane AM, Weil EJ, Knowler WC, Nelson RG, Hanson RL. Albuminuria and estimated glomerular filtration rate as predictors of diabetic end-stage renal disease and death. Clin J Am Soc Nephrol 2011;6:2444-51.
Prakash J. Dyslipidemia in diabetic kidney disease. Clin Queries Nephrol 2012;1:115-8.
Wellmann KF, Volk BW. Renal changes in experimental hypercholesterolemia in normal and in subdiabetic rabbits. II. Long term studies. Lab Invest 1971;24:144-55.
Kawanami D, Matoba K, Utsunomiya K. Dyslipidemia in diabetic nephropathy. Ren Replace Ther 2016;2:16.
Jacobs MJ, Kleisli T, Pio JR, et al. Prevalence and control of dyslipidemia among persons with diabetes in the United States. Diabetes Res Clin Pract 2005;70:263-9.
Parish S, Offer A, Clarke R, et al. Lipids and lipoproteins and risk of different vascular events in the MRC/BHF heart protection study. Circulation 2012;125:2469-78.
Antwi-Bafour S, Hammond S, Adjei JK, et al. A case-control study of prevalence of anemia among patients with type 2 diabetes. J Med Case Rep 2016;10:110.
El-Achkar TM, Ohmit SE, McCullough PA, et al. Higher prevalence of anemia with diabetes mellitus in moderate kidney insufficiency: The kidney early evaluation program. Kidney Int2005;67:1483-8.
Bosman DR, Winkler AS, Marsden JT, Macdougall IC, Watkins PJ. Anemia with erythropoietin deficiency occurs early in diabetic nephropathy. Diabetes Care 2001;24: 495-9.
Loutradis C, Skodra A, Georgianos P, et al. Diabetes mellitus increases the prevalence of anemia in patients with chronic kidney disease: A nested case-control study. World J Nephrol 2016;5:358-66.
Qin X, Goldfine A, Krumrei N, et al. Glycation inactivation of the complement regulatory protein CD59: A possible role in the pathogenesis of the vascular complications of human diabetes. Diabetes 2004;53:2653-61.
Uesugi N, Sakata N, Nangaku M, et al. Possible mechanism for medial smooth muscle cell injury in diabetic nephropathy: Glycoxidation-mediated local complement activation. Am J Kidney Dis 2004;44:224-38.
Flyrbjerg A. The role of the complement system in diabetic nephropathy. Nephrology 2017;13:311-8.
Mak SK, Wong PN, Lo KY, Tong GM, Wong AK. Prospective study on renal outcome of IgA nephropathy superimposed on diabetic glomerulosclerosis in type 2 diabetic patients. Nephrol Dial Transplant 2001;16:1183-8.
Yokokawa N, Aizawa T, Ishihara M, et al. Presence of anti-DNA antibody in diabetes mellitus: Its relation to the duration of diabetes and diabetic complications. Metabolism 1989; 38:891-4.
Dr. Issa Al Salmi
Department of Renal Medicine, Royal Hospital, P. O. Box 1331, Code 111, Muscat
[Figure 1], [Figure 2]
[Table 1], [Table 2]