Urinary kidney injury molecule-1 in renal disease
Moresco RN, Bochi GV, Stein CS, De Carvalho JAM, Cembranel BM, Bollick YS. Clin Chim Acta 2018; 487: 15–21
Kidney injury molecule-1 (KIM-1), a type l transmembrane glycoprotein, is recognized as a potential biomarker for detection of tubular injury in the main renal diseases. Urinary KIM-1 increases rapidly upon the tubular injury, and its levels are associated with the degree of tubular injury, interstitial fibrosis, and inflammation in the injured kidney. Currently, the investigation of kidney diseases is usually performed through the assessment of serum creatinine and urinary albumin. However, these biomarkers are limited for the early detection of changes in renal function. Besides, the tubular injury appears to precede glomerular damage in the pathophysiology of renal diseases. For these reasons, the search for sensitive, specific and non-invasive biomarkers is of interest. Therefore, the purpose of this article is to review the physiological mechanisms of KIM-1, as well to present clinical evidence about the association between elevated urinary KIM-1 levels and the main renal diseases such as chronic kidney disease, diabetic kidney disease, acute kidney injury, and IgA nephropathy.
Prognostic impact of tumour-infiltrating CD276/Foxp3-positive lymphocytes and associated circulating cytokines in patients undergoing radical nephrectomy for localized renal cell carcinoma
Iida K, Miyake M, Onishi K, Hori S, Morizawa Y, et al. Oncol Lett 2019;17(4): 4004–4010
Renal cell carcinoma (RCC) is an immunogenic tumour and pathological specimens generally contain large quantities of tumour-infiltrating lymphocytes (TILs). Numerous cell types and cytokines could affect the immune escape mechanism of tumour cells. The aim of the present study was to investigate the prognostic impact of TILs and the associated circulating cytokines on localized clear cell RCC following radical nephrectomy. A total of 87 patients who had undergone radical nephrectomy and were pathologically diagnosed with localized clear cell RCC were included. The present study evaluated the profile of TILs with immunohistochemical analysis of tumour specimens using a panel of antibodies [cluster of differentiation (CD)-4, CD8, CD80, CD86, CD276, and Forkhead box p3 (Foxp3)]. Counts of each TIL were compared with clinicopathological variables. Based on the results of immunohistochemical analyses, putative cytokines, including interleukin (IL)-6, IL-10, IL-17, interferon-γ, tumour necrosis factor (TNF)-α, and transforming growth factor (TGF)-β, were selected, and their levels in preoperative serum were measured by ELISA. The levels were compared with TIL counts in tumour specimens. High counts of the CD276+ and Foxp3+ TILs were identified as independent factors for poor prognosis for metastasis and local recurrence following radical nephrectomy (P=0.033 and 0.006, respectively). A high CD276+ TIL count was associated with preoperative serum levels of TNF-α and IFN-γ (P=0.027 and P=0.035, respectively), whereas a high count of Foxp3+ TILs was associated with preoperative serum levels of TGF-β (P=0.021). High levels of TNF-α and TGF-β were associated with recurrence-free survival (P=0.035 and P=0.031, respectively). Topical intra-tumoral immunoreaction and systemic immune status may be associated with patients with localized RCC. The topical induction of the CD276+ and Foxp3+ TILs was suggested to be associated with high levels of serum TNF-α and IFN-γ. Preoperative serum levels of TNF-α and TGF-β could be simple and non-invasive biomarkers for risk stratification before radical surgery.
Mesangial C4d deposition may predict progression of kidney disease in pediatric patients with IgA nephropathy
Fabiano RCG, de Almeida Araújo S, Bambirra EA, Oliveira EA, Simões E Silva AC, Pinheiro SVB. Pediatr Nephrol 2017; 32(7): 1211–1220
BACKGROUND: Data on the risk factors for chronic kidney disease in children with immunoglobulin A nephropathy (IgAN) are scarce. This study was aimed at investigating whether glomerular C4d immunostaining is a prognostic marker in pediatric IgAN.
METHODS: In this retrospective cohort study, 47 patients with IgAN biopsied from 1982 to 2010 were evaluated. Immunohistochemistry for C4d was performed in all cases. For analysis, patients were grouped according to positivity or not for C4d in the mesangial area. Primary outcome was a decline in baseline estimated glomerular filtration rate (eGFR) by 50 % or more.
RESULTS: Median follow-up was 8.3 years. Median renal survival was 13.7 years and the probability of a 50 % decline in eGFR was 13 % over 10 years. Nine children exhibited the primary outcome and four developed end-stage renal disease (ESRD). Compared with C4d-negative patients (n=37), C4d-positive patients (n=10) presented higher baseline proteinuria (1.66 ± 0.68 vs 0.47 ± 0.19 g/day/1.73 m2, P<0.001), a progressive decline in eGFR (−10.04 ± 19.38 vs 1.70 ± 18.51 mL/min/1.73 m2/year; P=0.045), and more frequently achieved the primary outcome (50.0 vs 10.8 %, P=0.013), and ESRD (30.0 vs 2.7 %, P=0.026). No difference was observed in Oxford classification variables. Baseline proteinuria, endocapillary hypercellularity and mesangial C4d deposition were associated with primary outcome in univariate analysis. Proteinuria and mesangial C4d deposition at baseline independently predicted the decline in eGFR. Renal survival was significantly reduced in C4d-positive patients (8.6 vs 15.1 years in C4d-negative patients, P<0.001).
CONCLUSIONS: In this exclusively pediatric cohort, positivity for C4d in the mesangial area was an independent predictor of renal function deterioration in IgAN.
Non-invasive biomarkers of acute rejection in kidney transplantation: novel targets and strategies
Eikmans M, Gielis EM, Ledeganck KJ, Yang J, Abramowicz D, Claas FFJ. Front Med (Lausanne) 2019; 5: 358
Kidney transplantation is considered the favoured treatment for patients suffering from end-stage renal disease, since successful transplantation is associated with longer survival and improved quality of life compared to dialysis. Alloreactive immune responses against the donor kidney may lead to acute rejection of the transplant. The current diagnosis of renal allograft rejection mainly relies on clinical monitoring, including serum creatinine, proteinuria, and confirmation by histopathologic assessment in the kidney transplant biopsy. These parameters have their limitations. Identification and validation of biomarkers, which correlate with or predict the presence of acute rejection, and which could improve therapeutic decision making, are priorities for the transplantation community. There is a need for alternative, less invasive but sensitive markers to diagnose acute graft rejection. Here, we provide an overview of the current status on research of biomarkers of acute kidney transplant rejection in blood and urine. We specifically discuss relatively novel research strategies in biomarker research, including transcriptomics and proteomics, and elaborate on donor-derived cell-free DNA as a potential biomarker.
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, /in Featured Articles /by 3wmediaReducing the impact of multiple sclerosis
, /in Featured Articles /by 3wmediaRecently I heard on BBC Radio 4 a fascinating interview of Professor George Jelineck by Caroline Quentin, both of whom suffer from multiple sclerosis (MS). MS, as no doubt you know, is a condition caused by the demyelination of neurons as the result of attack by the body’s own Th1 cells, usually resulting in progressive debilitation. There are a number of ‘types’ of MS that people can be classified as having, commonly: relapsing–remitting MS, secondary progressive MS, primary progressive MS; but also including progressive relapsing MS and benign MS. However, diagnosis is not straightforward and people can move between types as the condition progresses. It is estimated that there are perhaps around 2.5 million people worldwide living with MS and the incidence is higher in people living in colder climates. George Jelineck MBBS, MD is professor and founder of the Neuroepidemiology Unit, Melbourne School of Population and Global Health, which expressly evaluates modifiable risk factors that predict the progression of MS, as well as having set up the Overcoming Multiple Sclerosis charity and being author of the Overcoming Multiple Sclerosis book. George was diagnosed with MS in 1999 at the age of 45, having seen his mother’s progressive deterioration because of the disease. Initially devastated at the diagnosis, he quickly turned his medical knowledge and capabilities to researching the literature about MS and created an evidence-based wellness programme for himself, to which he credits his continuing good health and apparent symptom-free life. The programme includes modifications to diet [following the striking results of Swank and Duggan (Lancet 1990; 336(8706): 37–39)], ensuring adequate vitamin D levels as well as care of general physical and mental health. It seems to be becoming generally accepted that MS is caused by a coincidence of a number of environmental factors (including low vitamin D levels) on top of a genetic predisposition. The impact of this for clinical diagnostics has been the upsurge of interest in testing vitamin D levels in the last decade. Interestingly, George mentioned in the interview that when mothers with MS give birth at the end of the winter, their child is much more likely to develop MS also. The solution is simply to supplement vitamin D levels, which could easily be done across the population, similarly to folic acid. Currently there is no simple genetic test for predisposition to MS, but perhaps further work with genome-wide association, such as that published recently by the International Multiple Sclerosis Genetics Consortium (Nat Commun 2019; 10(1): 2236), will eventually lead to a genetic screen for MS risk, allowing those predisposed to it to alter their modifiable risk factors and so reduce the development/impact of the condition before the appearance of symptoms.
Biomarkers for improving the diagnosis of acute interstitial nephritis
, /in Featured Articles /by 3wmediaAcute interstitial nephritis (AIN) may be the cause of more than 15 % of instances of acute loss of kidney function. Diagnosed early, it can often be successfully treated; however, lack of obvious symptoms means it can be easily missed. Left untreated, AIN can progress to chronic kidney disease. Currently, clinical diagnosis is confirmed by invasive biopsy. The development of noninvasive biomarkers is needed for improving early AIN diagnosis and therapeutic outcomes.
Background
Acute interstitial nephritis (AIN) is the inflammation of the kidney interstitium, an area surrounding the renal tubules consisting of fluid and extracellular matrix cells [1]. AIN is generally uncommon (<1 % incidence) in people with no symptoms but is thought to be the cause of more than 15 % of instances of acute loss of kidney function [2, 3].
Causes and symptoms
AIN can be caused by a variety of factors including environmental factors, infection and systemic disease. However, it is most usually seen as a result of adverse reaction to certain medications, such as antibiotics, antivirals, analgesics, gastrointestinal medications, antiseizure medication, diuretics and chemotherapy. When first described, the classic triad of AIN symptoms involved rash, joint pain and eosinophilia, similar to that of an allergic reaction. Fever was also present in 30–50 % of patients. A number of general and vague symptoms, such as nausea, vomiting, fatigue and lack of appetite, were also associated. However, more recently, AIN is more often caused by modern drugs, such as proton pump inhibitors and immune checkpoint inhibitors used in chemotherapy [3] and symptoms, if present, can be very subtle.
Treatment and prognosis
AIN can be treated (unlike other causes of acute loss of kidney function) if detected early by removal of the cause – such as the medication or treatment of the infection. Early treatment results in complete regain of kidney function in approximately 65% of cases, partial resolution in around 20% and irreversible damage in the remainder [4]. Although definitions have been developed and adopted into routine use for acute kidney injury (AKI: abrupt decrease in kidney function occurring over 7 days or less) and chronic kidney disease (CKD: persistence of kidney disease for a period of more than 90 days), there is an increasing awareness that AKI and CKD are not necessarily separate but may represent different stages along a continuum. For patients who develop AKI but then have ongoing pathology, the term acute kidney disease (AKD) has been developed [5]. AIN is an example of this as delayed diagnosis of this condition is more likely to result in incomplete recovery of kidney function and progression to CKD. It has been estimated that 40–60 % of AIN cases progress to CKD and that 2–3 % of CKD cases could be from undiagnosed AIN caused by proton pump inhibitor use [6, 7].
Methods of diagnosis
As we have seen, early diagnosis of AIN is crucial for the best prognosis; however, drug-induced AIN can develop over several days or weeks and the previously described ‘typical’ triad of symptoms is often absent. Physicians need to be aware of a range of more mild and varied symptoms such as flank pain, blood in the urine and joint pain. The main differential diagnosis is acute tubular necrosis (ATN) and the distinguishing features can be seen in Table 2 in Raghavan and Eknoyan’s 2014 paper [4]. Current laboratory tests include testing for markers of tubular dysfunction, which vary depending on the main site of injury; microscopic analysis of urine for the presence of protein, blood and eosinophils; and imaging studies. However, none of these tests are specific for AIN, with the only definitive diagnosis being given by kidney biopsy and even then histological examination needs to be performed by several pathologists.
Biomarkers for AIN
A number of biomarkers are available for the detection of AKI, such as monocyte chemotactic protein-1 (MCP-1), neutrophil gelatinase-associated lipocalin (NGAL), transforming growth factor beta 1 (TGF-β), etc; however, as mentioned by Raghavan and Eknoyan, these have been developed to diagnose AKI based on its definition of increased serum creatinine, which for AIN is too late for the best hope of regaining good kidney function [4 and references therein]. Recently, though, a new study by Moledina and colleagues has identified two new urine biomarkers that improve prebiopsy diagnosis of AIN [7]. The authors postulated that as AIN is caused by certain T-cell subsets, specific T-cell cytokine levels might serve as biomarkers to distinguish AIN from other causes of AKD. Of 218 participants in the study, who had all had kidney biopsy for the evaluation of AKD, 32 were confirmed with AIN and the remaining 186 who did not have AIN were used as controls. After testing 22 selected urine and plasma cytokines, they found two, tumour necrosis factor alpha (TNF-α) and interleukin (IL)-9, that were present at consistently higher levels in the urine of AIN patients and were diagnostic of AIN. The authors conclude “inclusion of urinary TNF-α and IL-9 improves discrimination over clinicians’ prebiopsy diagnosis and currently available tests for AIN diagnosis” [7]. In another recent paper from the same group, the authors demonstrate that the use of urinary TNF-α and IL-9 biomarkers also allows the differentiation of AIN over ATN [8].
Summary
Diagnosis of drug-induced AIN at a stage early enough to limit irreversible kidney damage is challenging because of a lack of conclusive symptoms and the gold standard diagnosis of kidney biopsy is invasive, not suitable for all patients and fraught with low inter-rater agreement. The results of the study by Moledina et al. demonstrate that testing for urine biomarkers TNF-α and IL-9 is a useful addition to a clinician’s prebiopsy diagnosis and might be able to eventually replace the need for kidney biopsy. The use of these biomarkers may be a welcome step for maximizing the chances of complete kidney function recovery and limiting the number of patients who progress to CKD.
References
1. Zeisberg M, Kalluri R. Physiology of the renal interstitium. Clin J Am Soc Nephrol 2015; 10(10): 1831–1840.
2. Brewster UC, Rastegar A. Acute Interstitial Nephritis. In: National Kidney Foundation’s primer on kidney diseases, eds Gilbert SJ, Weiner DE, Bomback AS, Parazella MA, Tonelli M, 7th edn; pp320–325. Elsevier 2017. ISBN 978-0323477949.
3. Mamlouk O, Selamet U, Machado S, Abdelrahim M, Glass WF, et al. Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: single-center experience. J Immunother Cancer 2019; 7(1): 2.
4. Raghavan R, Eknoyan G. Acute interstitial nephritis – a reappraisal and update. Clin Nephrol 2014; 82(3): 149–62.
5. Chawla LS, Bellomo R, Bihorac A, Goldstein SL, Siew ED, et al. Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup. Nat Rev Nephrol 2017; 13(4): 241–257.
6. Lazarus B, et al. Proton pump inhibitor use and the risk of chronic kidney disease. JAMA Intern Med 2016; 176(2): 238–246.
7. Moledina DG, Wilson FP, Pober JS, Perazella MA, Singh N, et al. Urine TNF-α and IL-9 for clinical diagnosis of acute interstitial nephritis. JCI Insight 2019; 4(10): pii: 127456.
8. Moledina DG, Parikh CR. Differentiating acute interstitial nephritis from acute tubular injury: a challenge for clinicians. Nephron 2019; doi: 10.1159/000501207 [Epub ahead of print].
Could H-FABP have potential benefit in diagnostics beyond cardiac health problems?
, /in Featured Articles /by 3wmediaThe rising incidence of Acute Kidney Injury (AKI) comes at a price. Patients tend to survive intensive care (ICU) but will be discharged with various degrees of chronic kidney disease (CKD), placing an increasing strain on the healthcare system. At present, the cost to the NHS is estimated to be between £434 and £620 million (€490-700 mil), which is more than the costs associated with breast cancer, or lung and skin cancer combined. However, this increased cost and strain could be unnecessary, as research has shown that 30% of the reported 100,000 deaths in the UK could have been prevented with the right care and treatment.1,2 These unfavourable statistics are the result of late detection of AKI, as to date, a superior method of detection has not been found.
www.randox.comRecent research has supported the use of Heart Type Fatty Acid Binding Protein (H-FABP), a traditional cardiac biomarker, and its potential utility as a clinical diagnostic biomarker for cardiac surgery-associated AKI. Cardiac surgery associated acute kidney injury (CSA-AKI) is a serious complication affecting approximately 33% – 94% of patients undergoing heart surgery, it is also associated with a high incidence of mortality and morbidity.3
A number of studies have been conducted focusing on measuring the levels of H-FABP before and after surgery. It was found that patients who developed AKI had higher levels of H-FABP both pre and postoperatively compared to patients who did not have AKI. Figure 1 shows the perioperative H-FABP levels based on AKI status. Day 1 represents 0 – 6 hours after surgery, Day 2 represents 24 – 48 hours after surgery and Day 3 represents 48 – 72 hours after surgery. As illustrated by the box plots, patients with severe AKI had the highest levels of H-FABP across all 3 days compared to those with any and no AKI.4
Researchers found that post-operative (Day 1) H-FABP levels in patients with severe AKI increased by 13-fold and an increase of 8 -fold was observed for the same time point in patients who experienced any AKI. In day 2 and 3, H-FABP levels began to decline, however, a slower rate of decline was observed in patients who experienced AKI.4
In the follow-up of this study, 10.8% of the patient cohort died which was found to have associations with preoperative levels. Patients with elevated preoperative log (H-FABP) were significantly more likely to die compared to patients with normal or low levels. They concluded that H-FABP explained <10% of the variability in known kidney injury biomarkers and that it is possible that H-FABP is capturing a different aspect of the pathophysiology of AKI when compared to traditional kidney biomarkers.4
Further studies conducted looked at the prognostic value of H-FABP levels collected on admission and found that a level of ≥ 15.7 ng/ml and the presence of AKI were independent predictors of 180-day mortality. Figure 2 is a Kaplan-Meier survival curve which shows that prognosis, including all-cause death, had a significantly poorer outcome for mortality in the high serum H-FABP with AKI group.4
Patients with H-FABP levels of less than 15.6 ng/ml and no AKI had nearly a 100% chance of event free survival over the 180 days. In comparison, patients with levels greater than 15.7 ng/ml, with AKI had a steady decrease in event free survival over the 180 days levelling out at just above 40%.4
Randox Laboratories are manufacturers of an automated biochemistry H-FABP assay exhibiting clinical utility for the early risk assessment of AKI including cardiac surgery-associated AKI. Applications detailing instrument-specific settings are available for a wide range of biochemistry analysers.
References
1. Kidney Care UK. [Online] [Cited: February 15, 2019.] https://www.kidneycareuk.org/news-and-campaigns/facts-and-stats/.
2. Centers for Disease Control and Prevention. [Online] March 16, 2018. [Cited: February 22, 2019.] https://www.cdc.gov/mmwr/volumes/67/wr/mm6710a2.htm.
3. Prediction and Prevention of Acute Kidney Injury after Cardiac Surgery. Shin, Su, et al. s.l. : Hindawi, 2016.
4. Perioperative heart-type fatty acid binding protein is associated with acute kidney injury after cardiac surgery. Schaub, J, et al. 3, s.l. : NCBI, 2015, Vol. 88.
LITERATURE REVIEW: Renal disease
, /in Featured Articles /by 3wmediaUrinary kidney injury molecule-1 in renal disease
Moresco RN, Bochi GV, Stein CS, De Carvalho JAM, Cembranel BM, Bollick YS. Clin Chim Acta 2018; 487: 15–21
Kidney injury molecule-1 (KIM-1), a type l transmembrane glycoprotein, is recognized as a potential biomarker for detection of tubular injury in the main renal diseases. Urinary KIM-1 increases rapidly upon the tubular injury, and its levels are associated with the degree of tubular injury, interstitial fibrosis, and inflammation in the injured kidney. Currently, the investigation of kidney diseases is usually performed through the assessment of serum creatinine and urinary albumin. However, these biomarkers are limited for the early detection of changes in renal function. Besides, the tubular injury appears to precede glomerular damage in the pathophysiology of renal diseases. For these reasons, the search for sensitive, specific and non-invasive biomarkers is of interest. Therefore, the purpose of this article is to review the physiological mechanisms of KIM-1, as well to present clinical evidence about the association between elevated urinary KIM-1 levels and the main renal diseases such as chronic kidney disease, diabetic kidney disease, acute kidney injury, and IgA nephropathy.
Prognostic impact of tumour-infiltrating CD276/Foxp3-positive lymphocytes and associated circulating cytokines in patients undergoing radical nephrectomy for localized renal cell carcinoma
Iida K, Miyake M, Onishi K, Hori S, Morizawa Y, et al. Oncol Lett 2019;17(4): 4004–4010
Renal cell carcinoma (RCC) is an immunogenic tumour and pathological specimens generally contain large quantities of tumour-infiltrating lymphocytes (TILs). Numerous cell types and cytokines could affect the immune escape mechanism of tumour cells. The aim of the present study was to investigate the prognostic impact of TILs and the associated circulating cytokines on localized clear cell RCC following radical nephrectomy. A total of 87 patients who had undergone radical nephrectomy and were pathologically diagnosed with localized clear cell RCC were included. The present study evaluated the profile of TILs with immunohistochemical analysis of tumour specimens using a panel of antibodies [cluster of differentiation (CD)-4, CD8, CD80, CD86, CD276, and Forkhead box p3 (Foxp3)]. Counts of each TIL were compared with clinicopathological variables. Based on the results of immunohistochemical analyses, putative cytokines, including interleukin (IL)-6, IL-10, IL-17, interferon-γ, tumour necrosis factor (TNF)-α, and transforming growth factor (TGF)-β, were selected, and their levels in preoperative serum were measured by ELISA. The levels were compared with TIL counts in tumour specimens. High counts of the CD276+ and Foxp3+ TILs were identified as independent factors for poor prognosis for metastasis and local recurrence following radical nephrectomy (P=0.033 and 0.006, respectively). A high CD276+ TIL count was associated with preoperative serum levels of TNF-α and IFN-γ (P=0.027 and P=0.035, respectively), whereas a high count of Foxp3+ TILs was associated with preoperative serum levels of TGF-β (P=0.021). High levels of TNF-α and TGF-β were associated with recurrence-free survival (P=0.035 and P=0.031, respectively). Topical intra-tumoral immunoreaction and systemic immune status may be associated with patients with localized RCC. The topical induction of the CD276+ and Foxp3+ TILs was suggested to be associated with high levels of serum TNF-α and IFN-γ. Preoperative serum levels of TNF-α and TGF-β could be simple and non-invasive biomarkers for risk stratification before radical surgery.
Mesangial C4d deposition may predict progression of kidney disease in pediatric patients with IgA nephropathy
Fabiano RCG, de Almeida Araújo S, Bambirra EA, Oliveira EA, Simões E Silva AC, Pinheiro SVB. Pediatr Nephrol 2017; 32(7): 1211–1220
BACKGROUND: Data on the risk factors for chronic kidney disease in children with immunoglobulin A nephropathy (IgAN) are scarce. This study was aimed at investigating whether glomerular C4d immunostaining is a prognostic marker in pediatric IgAN.
METHODS: In this retrospective cohort study, 47 patients with IgAN biopsied from 1982 to 2010 were evaluated. Immunohistochemistry for C4d was performed in all cases. For analysis, patients were grouped according to positivity or not for C4d in the mesangial area. Primary outcome was a decline in baseline estimated glomerular filtration rate (eGFR) by 50 % or more.
RESULTS: Median follow-up was 8.3 years. Median renal survival was 13.7 years and the probability of a 50 % decline in eGFR was 13 % over 10 years. Nine children exhibited the primary outcome and four developed end-stage renal disease (ESRD). Compared with C4d-negative patients (n=37), C4d-positive patients (n=10) presented higher baseline proteinuria (1.66 ± 0.68 vs 0.47 ± 0.19 g/day/1.73 m2, P<0.001), a progressive decline in eGFR (−10.04 ± 19.38 vs 1.70 ± 18.51 mL/min/1.73 m2/year; P=0.045), and more frequently achieved the primary outcome (50.0 vs 10.8 %, P=0.013), and ESRD (30.0 vs 2.7 %, P=0.026). No difference was observed in Oxford classification variables. Baseline proteinuria, endocapillary hypercellularity and mesangial C4d deposition were associated with primary outcome in univariate analysis. Proteinuria and mesangial C4d deposition at baseline independently predicted the decline in eGFR. Renal survival was significantly reduced in C4d-positive patients (8.6 vs 15.1 years in C4d-negative patients, P<0.001).
CONCLUSIONS: In this exclusively pediatric cohort, positivity for C4d in the mesangial area was an independent predictor of renal function deterioration in IgAN.
Non-invasive biomarkers of acute rejection in kidney transplantation: novel targets and strategies
Eikmans M, Gielis EM, Ledeganck KJ, Yang J, Abramowicz D, Claas FFJ. Front Med (Lausanne) 2019; 5: 358
Kidney transplantation is considered the favoured treatment for patients suffering from end-stage renal disease, since successful transplantation is associated with longer survival and improved quality of life compared to dialysis. Alloreactive immune responses against the donor kidney may lead to acute rejection of the transplant. The current diagnosis of renal allograft rejection mainly relies on clinical monitoring, including serum creatinine, proteinuria, and confirmation by histopathologic assessment in the kidney transplant biopsy. These parameters have their limitations. Identification and validation of biomarkers, which correlate with or predict the presence of acute rejection, and which could improve therapeutic decision making, are priorities for the transplantation community. There is a need for alternative, less invasive but sensitive markers to diagnose acute graft rejection. Here, we provide an overview of the current status on research of biomarkers of acute kidney transplant rejection in blood and urine. We specifically discuss relatively novel research strategies in biomarker research, including transcriptomics and proteomics, and elaborate on donor-derived cell-free DNA as a potential biomarker.
New microfluidics device can detect cancer cells in blood
, /in Featured Articles /by 3wmediaResearchers at the University of Illinois at Chicago and Queensland University of Technology of Australia have developed a device that can isolate individual cancer cells from patient blood samples. The microfluidic device works by separating the various cell types found in blood by their size. The device may one day enable rapid, cheap liquid biopsies to help detect cancer and develop targeted treatment plans.
“This new microfluidics chip lets us separate cancer cells from whole blood or minimally-diluted blood,” said Ian Papautsky, the Richard and Loan Hill Professor of Bioengineering in the UIC College of Engineering and corresponding author on the paper. “While devices for detecting cancer cells circulating in the blood are becoming available, most are relatively expensive and are out of reach of many research labs or hospitals. Our device is cheap, and doesn’t require much specimen preparation or dilution, making it fast and easy to use.”
The ability to successfully isolate cancer cells is a crucial step in enabling liquid biopsy where cancer could be detected through a simple blood draw. This would eliminate the discomfort and cost of tissue biopsies which use needles or surgical procedures as part of cancer diagnosis. Liquid biopsy could also be useful in tracking the efficacy of chemotherapy over the course of time, and for detecting cancer in organs difficult to access through traditional biopsy techniques, including the brain and lungs.
However, isolating circulating tumour cells from the blood is no easy task, since they are present in extremely small quantities. For many cancers, circulating cells are present at levels close to one per 1 billion blood cells. “A 7.5-milliliter tube of blood, which is a typical volume for a blood draw, might have ten cancer cells and 35-40 billion blood cells,” said Papautsky. “So we are really looking for a needle in a haystack.”
Microfluidic technologies present an alternative to traditional methods of cell detection in fluids. These devices either use markers to capture targeted cells as they float by, or they take advantage of the physical properties of targeted cells — mainly size — to separate them from other cells present in fluids.
Papautsky and his colleagues developed a device that uses size to separate tumour cells from blood. “Using size differences to separate cell types within a fluid is much easier than affinity separation which uses ‘sticky’ tags that capture the right cell type as it goes by,” said Papautsky. “Affinity separation also requires a lot of advanced purification work which size separation techniques don’t need.”
The device Papautsky and his colleagues developed capitalizes on the phenomena of inertial migration and shear-induced diffusion to separate cancer cells from blood as it passes through ‘microchannels’ formed in plastic. “We are still investigating the physics behind these phenomena and their interplay in the device, but it separates cells based on tiny differences in size which dictate the cell’s attraction to various locations within a column of liquid as it moves.”
Papautsky and his colleagues ‘spiked’ 5-milliliter samples of healthy blood with 10 small-cell-lung cancer cells and then ran the blood through their device. They were able to recover 93 percent of the cancer cells using the microfluidic device. Previously-developed microfluidics devices designed to separate circulating tumour cells from blood had recovery rates between 50 percent and 80 percent.
When they ran eight samples of blood taken from patients diagnosed with non-small-cell lung cancer, they were able to separate cancer cells from six of the samples using the microfluidic device.
In addition to the high efficiency and reliability of the devices, Papautsky said the fact that little dilution is needed is another plus. “Without having to dilute, the time to run samples is shorter and so is preparation time.” They used whole blood in their experiments as well as blood diluted just three times, which is low compared to other protocols for cell separation using devices based on inertial migration.
University in Illinois at Chicagohttps://tinyurl.com/y6roxnur