Randomized control trial of prednisolone and doxycycline in patients with acute interstitial nephritis of unknown aetiology.

BACKGROUND: Patients presenting with acute interstitial nephritis (AIN) of unknown aetiology, probably the earliest presentation of chronic kidney disease of unknown aetiology (CKDu), have been treated with oral prednisolone and doxycycline by physicians in Sri Lanka. This trial assessed the effectiveness of prednisolone and doxycycline based on eGFR changes at 6 months in patients with AIN of unknown aetiology. METHOD: A randomized clinical trial with a 2 × 2 factorial design for patients presenting with AIN of unknown aetiology (n = 59) was enacted to compare treatments with; A-prednisolone, B-doxycycline, C-both treatments together, and D-neither. The primary outcome was a recovery of patients' presenting renal function to eGFR categories: 61-90 ml/min/1.73m2 (complete remission- CR) to 31-60 ml/min/1.73m2 (partial remission- PR) and 0-30 ml/min/1.73m2 no remission (NR) by 6 months. A secondary outcome was progression-free survival (not reaching < 30 ml/min/1.73m2 eGFR), by 6-36 months. Analysis was by intention to treat. RESULTS: Seventy patients compatible with a clinical diagnosis of AIN were biopsied for eligibility; 59 AIN of unknown aetiology were enrolled, A = 15, B = 15, C = 14 and D = 15 randomly allocated to each group. Baseline characteristics were similar between groups. The number of patients with CR, PR and NR, respectively, by 6 months, in group A 3:8:2, group B 2:8:3 and group C 8:5:0 was compared with group D 8:6:1. There were no significant differences found between groups A vs. D (p = 0.2), B vs. D (p = 0.1) and C vs. D (p = 0.4). In an exploratory analysis, progression-free survival in prednisolone-treated (A + C) arms was 0/29 (100%) in comparison to 25/30 (83%) in those not so treated (B + D) arms, and the log-rank test was p = 0.02, whereas no such difference found (p = 0.60) between doxycycline-treated (B + C) arms 27/29 (93%) vs those not so treated (A + D) arms 27/30 (90%). CONCLUSION: Prednisolone and doxycycline were not beneficial for the earliest presentation of CKDu at 6 months. However, there is a potential benefit of prednisolone on the long-term outcome of CKDu. An adequately powered steroid trial using patients reaching < 30 ml/min/1.73m2 eGFR by 3 years, as an outcome is warranted for AIN of unknown aetiology. TRIAL REGISTRATION: Sri Lanka Clinical Trial Registry SLCTR/2014/007, Registered on the 31st of March 2014.

Could Consumption of Trace Element-Contaminated Rice Be a Risk Factor for Acute Interstitial Nephritis with Uncertain Etiology in the Dry Zone of Sri Lanka?

Ingestion of toxic trace elements in the human body has been considered one of the major reasons for renal dysfunction. Chronic kidney disease with uncertain etiological factors (CKDu) is a recently described clinical entity in which the disease is found in geographically isolated pockets in the dry zone of Sri Lanka. In CKDu regions, an increasing number of cases are reported with acute interstitial nephritis without any known reason (AINu). However, recent exposure to certain risk behaviors or nephrotoxins, or both, is suspected for the AINu. Consumption of foods that are contaminated with trace elements is one of the main pathways of human exposure to environmental toxins. The current study was carried out to assess the possibility of trace element-contaminated rice consumption on the etiopathogenesis of AINu. Samples of rice consumed by 32 clinically diagnosed AINu cases were collected and analyzed for possible nephrotoxic trace elements. Out of 32 patients, 26 were histologically confirmed with tubulointerstitial disease. The results revealed that the mean values of Cd, As, and Pb were 0.18, 0.055, and 0.135 mg/kg, with ranges of 0.020-1.06, 0.012-0.222, and 0.003-0.744 mg/kg (on dry weight basis), respectively. This study indicated that the investigated toxic trace element levels of rice consumed by AINu were reasonably below the recommended levels of the Codex Alimentarius Commission of FAO and WHO. Hence, it is less likely that rice consumption is to be a risk factor for the etiology of AINu.

Prevalence, risk factors and predicted risk of cardiac events in chronic kidney disease of uncertain aetiology in Sri Lanka: A tubular interstitial nephropathy.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with 'traditional' chronic kidney disease (CKD). However, chronic kidney disease of uncertain aetiology (CKDu), a tubular interstitial nephropathy is typically minimally proteinuric without high rates of associated hypertension or vascular disease and it is unknown if the rates of CVD are similar. This study aimed to identify the prevalence and the risk of CVD in patients with CKDu. This cross-sectional study included patients with confirmed CKDu who were attending two renal clinics in CKDu endemic-area. A detailed medical history, blood pressure, electrocardiogram (resting and six minutes vigorous walking), echocardiograms, appropriate laboratory parameters and medical record reviews were used to collect data at baseline. The WHO/Pan American Health Organization, cardiovascular risk calculator was employed to determine the future risk of CVD. The clinics had recorded 132 number of patients with CKDu, of these 119 consented to participation in the study. The mean age was 52 (± 9.5) years and mean eGFR was 51.1 (± 27.61); a majority (81.5% (n = 97)) were males. Thirty-four patients (28.6%) had evidence of ischaemic heart disease (IHD). Troponin-I (p = 0.02), Age >50 years (p = 0.01) and hyperuricemia (p = 0.01) were significantly associated with IHD in CKDu. Left ventricular hypertrophy was reported in 20.2% (n = 24). According to the risk calculator, 97% of the enrolled patients were at low risk (<10%) for experiencing a cardiovascular event within the next 10 years. Patients with CKDu have low prevalence and risk for CVD, implying that a majority are likely to survive to reach end-stage kidney disease. Our findings highlight the need for developing strategies to minimize the progression of CKDu to end-stage renal disease.

An Analysis of Rate of Progression and Associated Risk Factors of Chronic Kidney Disease of Uncertain Etiology in Sri Lanka.

Chronic kidney disease of uncertain etiology (CKD-u) is an important public health issue in Sri Lanka and around the world, but published evidence of the progression of this disease is scanty. Our aim is to analyze the progression patterns and the associated risk factors of definite and probable CKD-u cases. This observational study was based on records of CKD-u cohort from 2005-14 at Girandurukotte, an endemic area for CKD-u in Uva Province, Sri Lanka. Data (rate of progression, survival, and risk factors) were analyzed using R statistical software. CKD-u cases (379) were included in analyses based on the adequacy of variables. Mean age was 53 years, male-to-female ratio of 2.5:1, and smoking were significant risk factors (P <0.10) for CKD-u progression. Males had 2.3 times hazard for CKD-u survival than females, and males who smoked had 2.57 times risk of CKD-u progression than nonsmoking males. Faster eGFR decline rate of >5 mL/min/1.73 m2/year have been identified in 25% of the sample (n = 100); this group is significantly younger than the slower progression group (mean age 46 years) and was at an early stage at the time of presentation (mean eGFR 76.02). CKD-u progression was not equal in all patients but faster in young people who presented at earlier stages. Continuous exposure to environmental risk factors may influence the rate of progression. Females have higher CKD-u survival rates than males. Tobacco smoking was associated with a lower survival of CKD-u but could be a proxy indicative of other exposures.

Correction: Evaluation of biochemical profile of Chronic Kidney Disease of uncertain etiology in Sri Lanka.

[This corrects the article DOI: 10.1371/journal.pone.0232522.].

Evaluation of biochemical profile of Chronic Kidney Disease of uncertain etiology in Sri Lanka.

Chronic Kidney Disease of uncertain etiology (CKDu) is an endemic, disease that mostly affects young agricultural workers in the rural dry zone of Sri Lanka. This study was designed to identify specific biochemical manifestations of CKDu cases. All (119) non-dialysis definite CKDu patients in Girandurukotte and Wilgamuwa were selected. Blood and urine samples were collected and measured biochemical parameters. All analyses were performed in IBM SPSS statistics version 23 (IBM Corp, USA). The median blood pressure was normal though nearly half of the patients (45.4%) who were in the advanced stages (Stage 3b, 4 and 5) of CKDu. Patients without a history of hypertension before the diagnosis of CKDu (100%) and minimal proteinuria (26%) are similar to the previous findings. Patients without a history of diabetes before the CKDu diagnosis had high percentages of diabetes (15.7%) and pre-diabetes (59.8%) and hence indicated the possibility of uremia induced impaired glucose intolerance in the rural areas of the country. There were 62.2% patients who had low vitamin D and only a minority had evidence of bone mineral diseases. Out of liver disease markers serum glutamic pyruvic transaminases (SGPT), serum glutamic oxaloacetic transaminases (SGOT), gamma-glutamyl transferase (GGT), and Lactic acid degydrogenase (LDH) had an inverse correlation with the advancement of the disease indicating subclinical liver disease. Osmolality in serum and urine showed a discrepancy despite > 50% of CKDu patients had increased their serum osmolality. The current study supports most of the previously described manifestations of CKDu. Moreover, some specific patterns have been identified which need to be validated in a larger group.

Pilot Study of Renal Urinary Biomarkers for Diagnosis of CKD of Uncertain Etiology.

INTRODUCTION: Chronic kidney disease of uncertain etiology (CKDu), an emerging chronic kidney disease (CKD) subtype, contributes to significant morbidity and mortality in certain tropical countries. Although several indicators of CKDu have been previously suggested, sensitive and specific tests to detect early disease or predict disease progression are currently unavailable. This study focused on evaluating 8 renal urinary markers, namely neutrophil gelatinase-associated lipocalin (NGAL), Kidney Injury Molecule-1 (KIM1), cystatin C (CST3), beta 2 microglobulin (B2M), osteopontin (OPN), alpha 1 microglobulin (A1M), tissue inhibitor of metalloproteinase 1 (TIMP1), and retinol binding protein 4 (RBP4), with the hypothesis that these have distinct expression patterns in patients with CKDu. METHODS: A cross-sectional study was conducted with 5 study groups comprising subjects from CKDu, endemic CKD, nonendemic CKD, and endemic healthy and nonendemic healthy controls. The urinary levels of the 8 selected renal biomarkers were quantified using multiplex biomarker assay, and the data were subjected to systematic analysis using logistic regression algorithm aiming to extract the best marker combination that could distinctly identify the disease groups noninvasively from the healthy controls. RESULTS: A 3-marker signature panel comprising A1M, KIM1, and RBP4 was identified to represent the best minimum marker combination for differentiating all CKD categories, including CKDu, from healthy controls with an overall sensitivity of ≥0.867 and specificity ≥0.765. The marker combination comprising OPN, KIM1, and RBP4 showed high predictive performance for distinguishing patients with CKDu from patients with CKD with both sensitivity and specificity ≥0.93, which was superior to any existing noninvasive indicator. CONCLUSION: In all, our systematic evaluation of urinary markers previously linked to CKD, in general, allowed identification of exclusive marker panel combination for early diagnosis and confirmation of CKDu.

Prospective Biopsy-Based Study of CKD of Unknown Etiology in Sri Lanka.

BACKGROUND AND OBJECTIVES: A kidney disease of unknown cause is common in Sri Lanka's lowland (dry) region. Detailed clinical characterizations of patients with biopsy-proven disease are limited, and there is no current consensus on criteria for a noninvasive diagnosis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We designed a prospective study in a major Sri Lankan hospital servicing endemic areas to ascertain pathologic and clinical characteristics of and assess risk factors for primary tubulointerstitial kidney disease. We used logistic regression to determine whether common clinical characteristics could be used to predict the presence of primary tubulointerstitial kidney disease on kidney biopsy. RESULTS: From 600 new patients presenting to a tertiary nephrology clinic over the course of 1 year, 87 underwent kidney biopsy, and 43 (49%) had a biopsy diagnosis of primary tubulointerstitial kidney disease. On detailed biopsy review, 13 (30%) had evidence of moderate to severe active kidney disease, and six (15%) had evidence of moderate to severe chronic tubulointerstitial kidney disease. Patients with tubulointerstitial kidney disease were exclusively born in endemic provinces; 91% spent a majority of their lifespan there. They were more likely men and farmers (risk ratio, 2.0; 95% confidence interval, 1.2 to 2.9), and they were more likely to have used tobacco (risk ratio, 1.7; 95% confidence interval, 1.0 to 2.3) and well water (risk ratio, 1.5; 95% confidence interval, 1.1 to 2.0). Three clinical characteristics-age, urine dipstick for protein, and serum albumin-could predict likelihood of tubulointerstitial kidney disease on biopsy (model sensitivity of 79% and specificity of 84%). Patients referred for kidney biopsy despite comorbid diabetes or hypertension did not experience lower odds of tubulointerstitial kidney disease. CONCLUSIONS: A primary tubulointerstitial kidney disease occurs commonly in specific regions of Sri Lanka with characteristic environmental and lifestyle exposures.

Snap shot view on anaemia in chronic kidney disease of uncertain aetiology.

AIM: Anaemia is a well-known complication of chronic kidney disease but there are no published studies on the pattern of anaemia in chronic kidney disease of uncertain aetiology (CKDu). This study aims to find out the prevalence, causes and associations of anaemia in CKDu to identify any unique features which are different from already described anaemia in chronic kidney disease. METHOD: All (119) biopsy-confirmed CKDu patients in two endemic clinics (Girandurukotte and Wilgamuwa) were selected as cases. Blood samples (10 mL) were collected from the peripheral veins into Potassium-Ethylenediaminetetraacetic acid (K-EDTA) tubes, plain tubes and Na-citrated tubes. Serum was separated immediately by centrifugation at 3000 rpm for 10 min. Spot urine samples were collected into empty, sterile, polypropylene urine containers. All analyses were performed in IBM spss statistics version 23 (IBM Corp, Armonk, New York). RESULTS: The overall prevalence of anaemia in 119 non-dialysis CKDu patients was 72.3% with the highest prevalence seen in females compared to males (P < 0.001). The prevalence of anaemia in CKDu patients with progression to renal failure was 66.7% - stage 1, 60% - stage 2, 50% - stage 3a, 95% - stage 3b, 79.2% - stage 4 and 100% - stage 5 (P = 0.005). Of CKDu patients, 44.3% had anaemia of chronic disease with iron deficiency. CKDu patients with anaemia had a high inflammatory score were seen in both early and late stages of CKDu. There were a similar proportion of patients with both early and late CKDu having unexplained anaemia. CONCLUSION: The current study showed a significant association of anaemia with disease severity among CKDu patients. Iron deficiency is a crucial aetiology factor of anaemia in CKDu and inflammation likely to effects adversely on anaemia of CKDu.

Screening for chronic kidney disease of uncertain aetiology in Sri Lanka: usability of surrogate biomarkers over dipstick proteinuria.

BACKGROUND: The use of dipstick proteinuria to screen Chronic Kidney Disease of uncertain aetiology (CKDu) in Sri Lanka is a recently debated matter of dispute. The aim of this study was to assess the suitability of biomarkers: serum creatinine, cystatin C and urine albumin to creatinine ratio (ACR) for screening CKDu in Sri Lanka. METHODS: Forty-four male CKDu patients and 49 healthy males from a CKDu-endemic region were selected. Meanwhile, 25 healthy males from a non-endemic region were selected as an absolute control. The diagnostic accuracy of each marker was compared using the above three study groups. RESULTS: In receiver operating characteristics (ROC) plots for creatinine, cystatin C and ACR, values of area under the curve (AUC) were 0.926, 0.920 and 0.737 respectively when CKDu was compared to non-endemic control. When CKDu was compared to endemic control, AUCs of above three analytes were distinctly lower as 0.718, 0.808 and 0.678 respectively. Cystatin C exhibited the highest sensitivity for CKDu when analyzed against both control groups where respective sensitivities were 0.75 against endemic control and 0.89 against non-endemic control. ROC-optimal cutoff limits of creatinine, cystatin C and ACR in CKDu vs non-endemic control were 89.0 µmol/L, 1.01 mg/L and 6.06 mg/g-Cr respectively, whereas in CKDu vs endemic control the respective values were 111.5 µmol/L, 1.22 mg/L and 12.66 mg/g-Cr. CONCLUSIONS: Amongst the three biomarkers evaluated in this study, our data suggest that Cystatin C is the most accurate functional marker in detecting CKDu in endemic regions, yet the high cost hinders its usability on general population. Creatinine is favorable over dipstick proteinuria owing to its apparent accuracy and cost efficiency, while having the ability to complement the kidney damage marker (ACR) in screening. ACR may not be favorable as a standalone screening marker in place of dipstick proteinuria due to its significant decline in sensitivity against the CKDu-endemic population. However, creatinine and ACR in a complementary manner could overcome current shortcomings of dipstick proteinuria and such a dual marker tool could be commodious in screening CKDu-type tubulointerstital diseases. Furthermore, use of ACR may also increase the ability to clinically discriminate CKDu from other glomerular nephropathies.

Chronic kidney disease of uncertain etiology in Sri Lanka is a possible sequel of interstitial nephritis!

INTRODUCTION: The majority of published data on chronic kidney disease of uncertain etiology (CKDu) is on asymptomatic patients who were detected in screening programs. The clinicopathological profile of a group of patients presenting with acute symptoms and renal dysfunction from CKDu endemic regions in Sri Lanka was studied. METHODS: 59 patients > 10 years of age with backache, feverish fatigue feeling, dysuria, joint pain, or dyspepsia, singly or in combination with elevated serum creatinine (> 116 and > 98 µmol/L for male and females, respectively) were included in the study. Those patients who had normal-sized kidneys were biopsied after excluding clinically detectable causes for renal dysfunction. Histology was scored with activity and chronicity indices. These patients' urinary sediment and inflammatory markers were checked. Patients were stratified into three groups based on duration of symptom onset to the time of biopsy. The natural course of the disease was described using serial mean serum creatinine and histological activity as well as chronicity indices in these 3 groups. RESULTS: These patients' mean age, occupation, and sex ratio were 44 (9) years, 57 farmers, and male : female 55 : 4, respectively. Mean serum creatinine at biopsy was 143.8 (47.9) µmol/L. Elevated inflammatory markers and active urine sediment were reported. Histology was compatible with an interstitial nephritis with a mixture of acute and chronic tubulointerstitial lesions and glomerular scarring. In the natural course of an acute episode of CKDu, serum creatinine and histological activity were reduced while histological chronicity increased. CONCLUSION: CKDu may be preceded by an acute episode of tubulointerstitial nephritis (TIN).