Non-diabetic renal disease in patients with type-2 diabetes mellitus

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in diabetics worldwide, yet most patients with type-2 diabetes mellitus are not formally evaluated with a renal biopsy. The diagnosis is almost always based on clinical grounds. A wide spectrum of non-diabetic renal disease (NDRD) is reported to occur in patients with type-2 diabetes. It has been estimated that up to one-third of all diabetic patients who present with proteinuria are suffering from NDRD. The aim of this analysis was to evaluate the prevalence and etiology of NDRD in patients with type-2 diabetes. We retrospectively reviewed the medical records of patients with type-2 diabetes who underwent kidney biopsy on clinical suspicion of NDRD (absence of diabetic retinopathy and/or neuropathy; short duration of diabetes, i.e. less than five years) from January 2003 through December 2007 at the Aga Khan University Hospital, Karachi. Based on the biopsy findings, patients were grouped as Group-I, isolated NDRD; Group-II, NDRD with underlying DN; and Group-III, isolated DN. Of 68 patients studied, 75% were males and the mean age was 56 years. The mean duration of diabetes was nine years. Group-I included 34 patients (52%), Group-II included 11 patients (17%) and Group-III included 23 patients (31%). Among the Group-I patients, the mean age was 56 years (41-77 years). The most common NDRDs were acute interstitial nephritis (32%), diffuse proliferative glomerulonephritis (17%); membranous nephropathy (12%) and crescentic glomerulonephritis (12%). Among Group-II, the mean age was 60 years (46-71 years), and the most common lesion was interstitial nephritis superimposed on underlying DN (63% cases). Among Group-III, the mean age was 53 years (42- 80 years). The mean proteinuria was 5, 6.3 and 7.3 g/24 h of urine collection in Groups I, II and III, respectively (P = NS). The mean duration of diabetes was 7.3, 11.7 and 10.7 years in Groups I, II and III, respectively. The duration of diabetes was significantly less in Group-I compared with Group-II and Group-III (P = 0.04). Our study suggests that the prevalence of NDRD (either isolated or superimposed on underlying DN) is high in appropriate clinical settings. Performing renal biopsy in diabetics with no extrarenal end organ damage other than nephropathy helps to diagnose and treat NDRD. This is the first report from Pakistan documenting the prevalence of NDRD in patients with type-2 diabetes

Two Congenital Left-to-Right Shunt Anomalies in a Septuagenarian: ARare Occurrence

Atrial septal defect (ASD) and patent ductus arteriosus (PDA) are common congenital anomalies presenting in childhood. Life expectancy of an uncorrected PDAis shortened to half; and ASD of a significant size has increased morbidity and mortality. Their co-existence in an elderly patient with first presentation at 70 years of age is a rarity. We present the case of a 70-year woman with one-week history of dyspnea with high blood pressure and signs of heart failure. She was found to have a PDA and an ASD with left-to-right shunt. She was managed conservatively. She was offered cardiac catheterization, but she refused. This is the first documented case in local literature with two such congenital heart defects presenting in a septuagenarian. In a country where average life expectancy is in the 60\u27s, the survival of the patient with two heart defects, beyond-average survival age, is interesting

Spot urine protein: creatinine ratio versus 24 hour urine protein at various levels of GFR patients referred to a tertiary care hospital of Pakistan

OBJECTIVE: To determine the correlation of random single voided urine protein: creatinine ratio to twenty four hour urine protein at different levels of glomerular filtration rate (GFR) in Pakistani population. METHODS: A total of 107 patients were included in this cross section study. Patients were divided into five groups according to the GFR. Spot urine protein: creatinine ratio and 24 hour urine protein was measured by the standard methods. The correlation coefficient ( r) between the two was calculated in each group separately. RESULTS: The GFR in groups 1 to 5 was \u3e or =90, 60-89, 30-59, 15-29, and /minute/1.73 m2 respectively. In group one correlation coefficient r was 0.96, in group two r was 0.81, in group three r was 0.94, in group four r was 0.82 and in group five r was 0.80. CONCLUSION: Random single voided urine protein: creatinine ratio may be used as an alternative to 24 hour urine collection for protein at all levels of GFR in Pakistani population

Complication rate and diagnostic yield of percutaneous native kidney biopsies: A 10-year experience at a Tertiary Care Hospital in Pakistan

The use of an automated biopsy device, and real-time ultrasound for percutaneous kidney biopsies (PKBs) has improved the likelihood of obtaining adequate tissue for diagnosis and also has reduced the complications associated with the procedure. We aimed to determine the frequency and type of complications associated with PKB and to determine the diagnostic yield. It was a retrospective file-based review of cases who underwent PKB of native kidney between January 2003 and December 2013 at the Aga Khan University Hospital in Karachi, Pakistan. PKBs were performed by trained nephrologists or radiologists using an automated device with a 16/18-gauge needle under real-time ultrasound. The data obtained included age, gender, clinical and histopathological diagnosis, and complications associated with the procedure (minor: hematuria, local infections, and hematoma; major: transfusions, severe infections, surgery, nephrectomy, arteriography, embolism, and death. Yield of the procedure was based on the number of glomeruli obtained. Patients having major complications were compared with the patients who had minor or no complications. A total of 433 native kidney biopsies were performed. The mean age of the patients was 41 ± 15.9 years, and 58% of the patients were male. The main histological findings were membranoproliferative glomerulonephritis (17.6%) followed by focal and segmental glomerulosclerosis (16.4%) and interstitial nephritis (13.9%). Majority of the procedures were performed by nephrologists (67.4%). The overall complication rate was 14.2%. Among those, 21 patients (4.8%) had a major complication while the others had minor complications. Of those who had a major complication, 17 patients required blood transfusion(s) and had hematuria or a major hematoma, three had prolonged hospitalization \u3e24 hours, and one patient required surgical intervention. Only 10 procedures (2.3%) had inadequate tissue to establish the histopathologic diagnosis. PKB under real-time ultrasound guidance is a safe and efficacious procedure to establish the histological diagnosis of the renal disease

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Acute Kidney Injury in Acute Stroke

Madam, Acute kidney injury (AKI) in acute stroke setting has recently gained importance as a relatively common complication and its associated adverse clinical outcomes in this population. Early diagnosis of AKI in its potentially reversible stages is of utmost importance, especially in a resource-limited setting like ours, and may improve outcomes in these patients. The lack of data on the burden of AKI and its risk factors in patients with acute stroke in Pakistan represents an important knowledge gap. We aimed to fill this gap by studying the frequency of AKI in patients with acute stroke and delineating associated risk factors. We performed a cross-sectional study of 215 acute stroke patients admitted to the stroke unit at our institution between December 2019 and June 2020. The mean age was 60 ± 14 years. One hundred and thirty-one patients (60.9%) were males. Hypertension and diabetes were found in 164 (76.3%) and 92 (42.8%) patients, respectively. Acute ischemic stroke (AIS) was seen in 130 patients (60.5%), while 85 (39.5%) had intracranial hemorrhage (ICH). Acute kidney injury was found in 73 patients (34%) of which 26 % (n=56) seen in patients 65 years, respectively. Males were more likely to experience AKI than females (72.6% vs 27.4%); odds ratio (OR) = 2.174 (95% CI: 1.18 – 4.007) p=0.012. Increasing severity of stroke was associated with an increased risk of AKI (p<0.001). However, no significant factors affecting the severity of AKI were found on subgroup analysis by age, gender, comorbidities, type and severity of stroke or admission blood pressure. Patients with ICH were more likely to suffer from AKI than to those with AIS (OR 1.429; 95% CI: 1.033 – 1.977; p=0.035). In our study, the frequency of A|KI in acute stroke   was much higher than previously reported from other parts of the world (1–3). This high burden of AKI has major implications in a resource-limited setting, given the demand for integrated long-term care required by stroke patients with renal dysfunction. Moreover, we observed male gender susceptibility to AKI, a finding reported by other studies from South Asia (3,4) but not from the western world. This might reflect gender biased access to health care in the subcontinent but multivariable analysis with larger database is needed to verify the independent link between gender and risk for AKI, if any. ---Continu

A comparison of definitions (RIFLE, AKIN, AND KDIGO) of acute kidney injury for prediction of outcomes in adults after isolated coronary artery bypass graft (CABG) surgery

Introduction: Acute kidney injury (AKI) occurs in as many as 40% of patients after cardiac surgery and is associated with an increased risk of mortality and morbidity, predisposes patients to a longer hospitalization, requires additional treatments, and increases the hospital costs. At present, there are three widely accepted consensus definitions providing uniform criteria for the diagnosis of AKI; RIFLE, AKIN and KDIGO. Each of these definition systems have their own benefits and limitations for predicting the degree of AKI as well as adverse outcomes (need for RRT, morbidity and mortality) in patients undergoing cardiac surgery. Having a standard definition for diagnosing and classifying AKI would enhance our ability to improve the management of patients and their clinical outcomes.The aim of this study is to compare the three AKI criteria (RIFLE (eGFR), AKIN and KDIGO) for their ability to predict all-cause mortality and morbidity after isolated CABG surgery in adult patients.Methods: A single center retrospective review was conducted on adults who had undergone isolated CABG surgery during January 2013- January 2017 at Aga Khan University Hospital Karachi, Pakistan. Patients with known chronic kidney disease or a baseline Serum Creatinine of \u3e1.1 and 1.3 mg/dL respectively for female and males were excluded. AKI was assessed on three definitions and estimated glomerular filtration rate (eGFR) was computed using standardized CKD-EPI-PK equations. Comparative ROC curves were built and Area under the Curve with sensitivity and specificity of each definitions were computed on percent change and the outcomes.Results: A total of 1508 patients were analyzed. Mean age of participants was 59.43 (±1.12) years and 82.6% were males. Patient with AKI were older and more likely to be diabetic and hypertensive. Their perfusion and cross clamp time and morbidities were higher than their counterpart. Incidence of AKI was 33.7%, 34.4% and 57.5% on AKIN, KDIGO and RIFLE (based on change in eGFR) respectively. Area under the curve for 30 day mortality was AKIN: [0.786 (0.764 to 0.806)], KDIGO: [0.796 (0.775 to 0.816)], and RIFLE [0.844 (0.825 to 0.862)]. However discrimination power for morbidity was \u3c0.7 and was undesirable.Conclusions: AKIN and KDIGO are comparable to estimate AKI, while RIFLE (eGFR based) definition though overestimates the incidence of AKI, however has excellent discriminatory power to predict mortality compared to other definitions. Since eGFR provides age and gender adjusted estimates of AKI rather absolute change in renal function over the course of recovery phase, it should be integrated for a subset of population undergoing surgical intervention