PeerJ Preprints: Nephrologyhttps://peerj.com/preprints/index.atom?journal=peerj&subject=5300Nephrology articles published in PeerJ PreprintsAllogenic stem cell transplant in a patient with classical Kaposi's sarcomahttps://peerj.com/preprints/482019-08-042019-08-04Richard Barchas
A 68 year old male with a history of classical Kaposi's sarcoma (KS) and precursor T-cell acute lymphoblastic leukemia (ALL) received an allogenic stem cell transplant from an unrelated donor to treat his ALL. He developed acute graft-vs.-host-disease (GVHD) which was treated by increasing immunosuppressants. KS, which had been in remission for years, then recurred aggressively. Tapering immunosuppressants to treat the KS was not possible because of GVHD. Chemotherapy could not be used because of its adverse effect on the bone marrow so soon after transplant. The only option was to use antiviral therapy (cidofovir) to lower the level of HHV-8, the virus that is a causal factor in KS. Although HHV-8 levels were significantly reduced, new KS lesions continued to appear. The patient developed acute kidney injury after the third cidofovir infusion and died from renal and respiratory failure soon afterward. Post-mortem revealed extensive internal KS lesions involving multiple organs. Based on the experience with this patient, allogenic transplant using an unrelated donor has been found to be a questionable treatment modality for classical KS patients requiring treatment for another condition such as leukemias and lymphomas. Post-transplant immunosuppression is required to prevent GVHD, and if it occurs, immunosuppression may have to be increased. Aggressive KS developed in this patient under these conditions, and could not be controlled by tapering immunosuppressants. Although the risk of GVHD is lower for an allogenic transplant using a matched sibling instead of an unrelated donor, the risk of both GVHD and aggressive KS both developing may still be unacceptably high.Alternative treatment modalities for these patients might include continuing with chemotherapy and autologous transplant. These avoid GVHD and lower the need for long term immunosuppression, but have a much higher risk of relapse of the underlying malignancy. Still, they could be preferable to an allogenic transplant for such cases.
A 68 year old male with a history of classical Kaposi's sarcoma (KS) and precursor T-cell acute lymphoblastic leukemia (ALL) received an allogenic stem cell transplant from an unrelated donor to treat his ALL. He developed acute graft-vs.-host-disease (GVHD) which was treated by increasing immunosuppressants. KS, which had been in remission for years, then recurred aggressively. Tapering immunosuppressants to treat the KS was not possible because of GVHD. Chemotherapy could not be used because of its adverse effect on the bone marrow so soon after transplant. The only option was to use antiviral therapy (cidofovir) to lower the level of HHV-8, the virus that is a causal factor in KS. Although HHV-8 levels were significantly reduced, new KS lesions continued to appear. The patient developed acute kidney injury after the third cidofovir infusion and died from renal and respiratory failure soon afterward. Post-mortem revealed extensive internal KS lesions involving multiple organs. Based on the experience with this patient, allogenic transplant using an unrelated donor has been found to be a questionable treatment modality for classical KS patients requiring treatment for another condition such as leukemias and lymphomas. Post-transplant immunosuppression is required to prevent GVHD, and if it occurs, immunosuppression may have to be increased. Aggressive KS developed in this patient under these conditions, and could not be controlled by tapering immunosuppressants. Although the risk of GVHD is lower for an allogenic transplant using a matched sibling instead of an unrelated donor, the risk of both GVHD and aggressive KS both developing may still be unacceptably high.Alternative treatment modalities for these patients might include continuing with chemotherapy and autologous transplant. These avoid GVHD and lower the need for long term immunosuppression, but have a much higher risk of relapse of the underlying malignancy. Still, they could be preferable to an allogenic transplant for such cases.Hibernation, puberty and chronic kidney disease in troglodytes from Spain half a million years agohttps://peerj.com/preprints/273702018-11-202018-11-20Antonis BartsiokasJuan Luis Arsuaga
Both animal hibernation (heterothermy) and human renal osteodystrophy are characterized by high levels of serum parathyroid hormone. To test the hypothesis of hibernation in an extinct human species, we examined the hominin skeletal collection from Sima de los Huesos, Cave Mayor, Atapuerca, Spain, for evidence of hyperparathyroidism. We studied the morphology of the fossilized bones by using macrophotography, microscopy, histology and CT scanning. We found trabecular tunneling and osteitis fibrosa, subperiosteal resorption,‘rotten fence post’ signs,brown tumours, subperiosteal new bone, chondrocalcinosis, rachitic osteoplaques and empty gaps between them, craniotabes, and beading in ribs mostly in the adolescent population of these hominins. Since many of the above lesions are pathognomonic, these extinct hominins suffered annually from renal rickets, secondary hyperparathyroidism, and renal osteodystrophy associated with Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). We suggest these diseases were caused by non-tolerated hibernation in dark cavernous hibernacula. This is evidenced by the rachitic osteoplaques and the gaps between them mainly in the adolescent individuals along with the evidence of healing mainly in the adults. The sublayers in the rachitic osteoplaques point to bouts of arousal from hibernation. The strong projection of the external lip of the femoral trochlea, the rachitic osteoplaques with the empty gaps between them,the “rotten fence post sign”, and the evidence of annual healing caused by non-tolerated hibernation in adolescent individuals, also point to the presence of annually intermittent puberty in this population. The hypothesis of hibernation is consistent with the genetic evidence and the fact that the SH hominins lived during a glacial period. The present work will provide a new insight into the physiological mechanism of early human metabolism which could help in determining the life histories and physiologies of extinct human species.
Both animal hibernation (heterothermy) and human renal osteodystrophy are characterized by high levels of serum parathyroid hormone. To test the hypothesis of hibernation in an extinct human species, we examined the hominin skeletal collection from Sima de los Huesos, Cave Mayor, Atapuerca, Spain, for evidence of hyperparathyroidism. We studied the morphology of the fossilized bones by using macrophotography, microscopy, histology and CT scanning. We found trabecular tunneling and osteitis fibrosa, subperiosteal resorption,‘rotten fence post’ signs,brown tumours, subperiosteal new bone, chondrocalcinosis, rachitic osteoplaques and empty gaps between them, craniotabes, and beading in ribs mostly in the adolescent population of these hominins. Since many of the above lesions are pathognomonic, these extinct hominins suffered annually from renal rickets, secondary hyperparathyroidism, and renal osteodystrophy associated with Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). We suggest these diseases were caused by non-tolerated hibernation in dark cavernous hibernacula. This is evidenced by the rachitic osteoplaques and the gaps between them mainly in the adolescent individuals along with the evidence of healing mainly in the adults. The sublayers in the rachitic osteoplaques point to bouts of arousal from hibernation. The strong projection of the external lip of the femoral trochlea, the rachitic osteoplaques with the empty gaps between them,the “rotten fence post sign”, and the evidence of annual healing caused by non-tolerated hibernation in adolescent individuals, also point to the presence of annually intermittent puberty in this population. The hypothesis of hibernation is consistent with the genetic evidence and the fact that the SH hominins lived during a glacial period. The present work will provide a new insight into the physiological mechanism of early human metabolism which could help in determining the life histories and physiologies of extinct human species.Cardiovascular manifestations of renovascular hypertension in diabetic micehttps://peerj.com/preprints/13232015-12-032015-12-03Sonu KashyapSean EngelMazen OsmanYousif Al-SaieghAsarn WongjarupongJoseph P Grande
Purpose. Type 2 diabetes is the leading cause of end stage renal disease in the United States. Atherosclerotic renal artery stenosis is commonly observed in diabetic patients and impacts the rate of renal and cardiovascular disease progression. We hypothesized that renal artery stenosis contributes to bilateral renal disease in diabetics. In our original study, we found that leptin-deficient diabetic (db/db) mice subjected to RAS developed severe and bilateral renal disease, with the contralateral (uncuffed) kidney showing features reminiscent of progressive diabetic nephropathy. In non-diabetic mice (WT), the cuffed kidney developed progressive atrophy, but the contralateral kidney showed minimal histopathologic alterations. In doing these studies, we observed increased sudden death in db/db mice with RAS, but not in WT mice with RAS. The objective of this study was to characterize the aortic and cardiac phenotype of db/db mice subjected to RAS. Methods. We developed a murine model of renal artery stenosis by placement of a polytetrafluoroethylene cuff on the right renal artery in db/db mice. We studied 109 WT and 95 db/db mice subjected to Renal artery stenosis (RAS) or sham surgery. Results. The mortality rate of db/db RAS mice was about 23.5%, whereas only 1.5% deaths were observed in WT RAS mice. Interestingly, 60% of mortality in the db/db mice occurred in the first two weeks following RAS surgery. Necropsy showed massive intrathoracic hemorrhage associated with aortic dissection. Aortas from db/db RAS mice showed more smooth muscle dropout, medial disruption, and hemorrhage than aortas from WT mice with RAS. Cardiac tissue from db/db RAS mice had more fibrosis than did cardiac tissue from WT RAS mice. Conclusions. Db/db mice subjected to RAS are prone to develop fatal aortic dissection, which is not observed in WT mice with RAS. The db/db RAS model provides the basis for future studies directed towards defining basic mechanisms underlying the interaction of hypertension and diabetes on the development of aortic lesions.
Purpose. Type 2 diabetes is the leading cause of end stage renal disease in the United States. Atherosclerotic renal artery stenosis is commonly observed in diabetic patients and impacts the rate of renal and cardiovascular disease progression. We hypothesized that renal artery stenosis contributes to bilateral renal disease in diabetics. In our original study, we found that leptin-deficient diabetic (db/db) mice subjected to RAS developed severe and bilateral renal disease, with the contralateral (uncuffed) kidney showing features reminiscent of progressive diabetic nephropathy. In non-diabetic mice (WT), the cuffed kidney developed progressive atrophy, but the contralateral kidney showed minimal histopathologic alterations. In doing these studies, we observed increased sudden death in db/db mice with RAS, but not in WT mice with RAS. The objective of this study was to characterize the aortic and cardiac phenotype of db/db mice subjected to RAS. Methods. We developed a murine model of renal artery stenosis by placement of a polytetrafluoroethylene cuff on the right renal artery in db/db mice. We studied 109 WT and 95 db/db mice subjected to Renal artery stenosis (RAS) or sham surgery. Results. The mortality rate of db/db RAS mice was about 23.5%, whereas only 1.5% deaths were observed in WT RAS mice. Interestingly, 60% of mortality in the db/db mice occurred in the first two weeks following RAS surgery. Necropsy showed massive intrathoracic hemorrhage associated with aortic dissection. Aortas from db/db RAS mice showed more smooth muscle dropout, medial disruption, and hemorrhage than aortas from WT mice with RAS. Cardiac tissue from db/db RAS mice had more fibrosis than did cardiac tissue from WT RAS mice. Conclusions. Db/db mice subjected to RAS are prone to develop fatal aortic dissection, which is not observed in WT mice with RAS. The db/db RAS model provides the basis for future studies directed towards defining basic mechanisms underlying the interaction of hypertension and diabetes on the development of aortic lesions.Exome sequencing and prediction of long-term kidney allograft functionhttps://peerj.com/preprints/8542015-09-272015-09-27Laurent MesnardThangamani MuthukumarMaren BurbachCarol LiHuimin ShangDarshana DadhaniaJohn R LeeVijay K SharmaJenny XiangCaroline SuberbielleMaryvonnick CarmagnatNacera OualiEric RondeauJohn J FriedewaldMichael M AbecassisManikkam SuthanthiranFabien Campagne
Current strategies to improve graft outcome following kidney transplantation consider information at the HLA loci. Here, we used exome sequencing of DNA from ABO compatible kidney graft recipients and their living donors to determine recipient and donor mismatches at the amino acid level over entire exomes. We estimated the number of amino acid mismatches in transmembrane proteins, more likely to be seen as foreign by the recipient’s immune system, and designated this tally as the allogenomics mismatch score (AMS). The AMS can be measured prior to transplantation with DNA for potential donor and recipient pairs. We examined the degree of relationship between the AMS and post-transplantation kidney allograft function by linear regression. In a discovery cohort, we found a significant inverse correlation between the AMS and kidney graft function at 36 months post-transplantation (n=10 recipient/donor pairs; 20 exomes) (r2>=0.57, P<0.05). The predictive ability of the AMS persists when the score is restricted to regions outside of the HLA loci. This relationship was validated using an independent cohort of 24 recipient donor pairs (n=48 exomes) (r2>=0.39, P<0.005). In an additional cohort of living and mostly intra-familial recipient/donor pairs (n=19, 38 exomes), we validated the association after controlling for donor age at time of transplantation. Finally, a model that controls for donor age, HLA mismatches and time post-transplantation yields a consistent AMS effect across these three independent cohorts (P<0.05). Taken together, these results show that the AMS is a strong predictor of long-term graft function in kidney transplant recipients.
Current strategies to improve graft outcome following kidney transplantation consider information at the HLA loci. Here, we used exome sequencing of DNA from ABO compatible kidney graft recipients and their living donors to determine recipient and donor mismatches at the amino acid level over entire exomes. We estimated the number of amino acid mismatches in transmembrane proteins, more likely to be seen as foreign by the recipient’s immune system, and designated this tally as the allogenomics mismatch score (AMS). The AMS can be measured prior to transplantation with DNA for potential donor and recipient pairs. We examined the degree of relationship between the AMS and post-transplantation kidney allograft function by linear regression. In a discovery cohort, we found a significant inverse correlation between the AMS and kidney graft function at 36 months post-transplantation (n=10 recipient/donor pairs; 20 exomes) (r2>=0.57, P<0.05). The predictive ability of the AMS persists when the score is restricted to regions outside of the HLA loci. This relationship was validated using an independent cohort of 24 recipient donor pairs (n=48 exomes) (r2>=0.39, P<0.005). In an additional cohort of living and mostly intra-familial recipient/donor pairs (n=19, 38 exomes), we validated the association after controlling for donor age at time of transplantation. Finally, a model that controls for donor age, HLA mismatches and time post-transplantation yields a consistent AMS effect across these three independent cohorts (P<0.05). Taken together, these results show that the AMS is a strong predictor of long-term graft function in kidney transplant recipients.Comparing two models that reduce the number of nephrology fellowship positions in the United Stateshttps://peerj.com/preprints/592v22014-12-182014-12-18Tejas Desai
There has been a steady decline in the number of applications to nephrology training programs. One solution is to decrease the number of available fellowship positions. Proponents believe that training programs have grown too big but the method for reduction has not been established. This investigation analyzes two models that decrease the number of available training positions and compares them head-to-head to identify the least burdensome method by which this reduction should occur. In the survival of the fittest model (SotFM) fellowship positions are eliminated if they were unfilled in the National Residency Match Program’s (NRMP) 2013 Specialty Match. In the equal proportions model (EPM) a formula is used to calculate a priority score using ESRD prevalence data from the 2013 USRDS Report and the geometric mean between a given jurisdiction’s current apportionment (n) and its next position (n+1). The least burdensome model is that which results in the 1) least number of jurisdictions losing fellow positions and 2) lowest percent reduction for any single jurisdiction. There were 416 nephrology positions offered and 47 unfilled in 2013. In the SotFM, 23 jurisdictions would sacrifice these 47 positions. In the EPM, 369 positions were apportioned (=416-47); only 9 jurisdictions would experience a reduction. The largest single-jurisdiction reduction in fellow positions was 67% (SotFM) and 50% (EPM). The EPM results in a less burdensome reduction of fellow positions nationwide. The EPM is a time-tested model that injects fairness into the painful process of reducing the total number of fellow positions across America.
There has been a steady decline in the number of applications to nephrology training programs. One solution is to decrease the number of available fellowship positions. Proponents believe that training programs have grown too big but the method for reduction has not been established. This investigation analyzes two models that decrease the number of available training positions and compares them head-to-head to identify the least burdensome method by which this reduction should occur. In the survival of the fittest model (SotFM) fellowship positions are eliminated if they were unfilled in the National Residency Match Program’s (NRMP) 2013 Specialty Match. In the equal proportions model (EPM) a formula is used to calculate a priority score using ESRD prevalence data from the 2013 USRDS Report and the geometric mean between a given jurisdiction’s current apportionment (n) and its next position (n+1). The least burdensome model is that which results in the 1) least number of jurisdictions losing fellow positions and 2) lowest percent reduction for any single jurisdiction. There were 416 nephrology positions offered and 47 unfilled in 2013. In the SotFM, 23 jurisdictions would sacrifice these 47 positions. In the EPM, 369 positions were apportioned (=416-47); only 9 jurisdictions would experience a reduction. The largest single-jurisdiction reduction in fellow positions was 67% (SotFM) and 50% (EPM). The EPM results in a less burdensome reduction of fellow positions nationwide. The EPM is a time-tested model that injects fairness into the painful process of reducing the total number of fellow positions across America.Effects of three commonly used diuretics on the urinary proteomehttps://peerj.com/preprints/102v12013-11-192013-11-19Xundou LiMindi ZhaoMenglin LiLulu JiaYouhe Gao
Biomarker is the measurable change associated with a physiological or pathophysiological process. Unlike blood which has mechanisms to keep the internal environment homeostatic, urine is more likely to reflect changes of the body. In other words, urine is likely to be a better biomarker source than blood. However, the urinary proteome are affected by many factors. In this study, the effects of three commonly used diuretics (furosemide, hydrochlorothiazide and spirolactone ) on the urinary proteome were analyzed in rats. Urine samples were collected before and after the intragastric administration of diuretics at therapeutic doses and analyzed using LC-MS/MS. Based on quantification by Progenesis LC-MS software, there are 7, 5 and 2 proteins with the p value ≤0.05, a fold change ≥2, a spectral count ≥5 and FDR ≤1%, respectively. Most their human orthologs were considered to be stable in the healthy human urinary proteome. 10 of the 14 proteins have been reported as disease biomarkers in previous studies. So the effects of diuretics should be given more attention in future urinary protein biomarkers studies. The effects of diuretics on urinary proteome are different which can provide clues to elucidate the mechanisms of the diuretics.
Biomarker is the measurable change associated with a physiological or pathophysiological process. Unlike blood which has mechanisms to keep the internal environment homeostatic, urine is more likely to reflect changes of the body. In other words, urine is likely to be a better biomarker source than blood. However, the urinary proteome are affected by many factors. In this study, the effects of three commonly used diuretics (furosemide, hydrochlorothiazide and spirolactone ) on the urinary proteome were analyzed in rats. Urine samples were collected before and after the intragastric administration of diuretics at therapeutic doses and analyzed using LC-MS/MS. Based on quantification by Progenesis LC-MS software, there are 7, 5 and 2 proteins with the p value ≤0.05, a fold change ≥2, a spectral count ≥5 and FDR ≤1%, respectively. Most their human orthologs were considered to be stable in the healthy human urinary proteome. 10 of the 14 proteins have been reported as disease biomarkers in previous studies. So the effects of diuretics should be given more attention in future urinary protein biomarkers studies. The effects of diuretics on urinary proteome are different which can provide clues to elucidate the mechanisms of the diuretics.Urimem, a membrane that can store urinary proteins simply and economically, makes the large-scale storage of clinical samples possiblehttps://peerj.com/preprints/37v12013-06-262013-06-26Lulu JiaXuejiao LiuLiu LiuMingxi LiYouhe Gao
Biological samples from patients are invaluable for both medical research and medical practice. Ideally, the samples should be preserved for the same period of time as the duration of their corresponding medical records. Urine is a body fluid that can be non-invasively acquired, and it contains important biological information about the patient. Unlike blood which has mechanisms to keep the internal environment homeostatic, urine is more likely to reflect changes of the body. In other words, urine is likely to be a better biomarker source than blood. Here, we propose a method to adsorb urinary proteins onto a polyvinylidene fluoride (PVDF) membrane called Urimem. The method is very simple and inexpensive and requires minimal sample handling. It does not use organic solvents, and it is environmentally friendly. The proteins on the membrane are dried and stored in vacuum bag, which keeps the protein pattern faithfully preserved. The membrane may even permit storage at room temperature for weeks. The quantity of eluted proteins from the membrane is sufficient for biomarker validation experiments. Using this simple and inexpensive urinary protein preservation method, it is possible to begin preserving urine samples from all consenting patients. Thus, medical research especially biomarker research can be conducted more economically, ultimately benefiting the patients who provided the samples. This sample storage approach can facilitate the biomarker research and potentially change the landscape of medical research and medical practice.
Biological samples from patients are invaluable for both medical research and medical practice. Ideally, the samples should be preserved for the same period of time as the duration of their corresponding medical records. Urine is a body fluid that can be non-invasively acquired, and it contains important biological information about the patient. Unlike blood which has mechanisms to keep the internal environment homeostatic, urine is more likely to reflect changes of the body. In other words, urine is likely to be a better biomarker source than blood. Here, we propose a method to adsorb urinary proteins onto a polyvinylidene fluoride (PVDF) membrane called Urimem. The method is very simple and inexpensive and requires minimal sample handling. It does not use organic solvents, and it is environmentally friendly. The proteins on the membrane are dried and stored in vacuum bag, which keeps the protein pattern faithfully preserved. The membrane may even permit storage at room temperature for weeks. The quantity of eluted proteins from the membrane is sufficient for biomarker validation experiments. Using this simple and inexpensive urinary protein preservation method, it is possible to begin preserving urine samples from all consenting patients. Thus, medical research especially biomarker research can be conducted more economically, ultimately benefiting the patients who provided the samples. This sample storage approach can facilitate the biomarker research and potentially change the landscape of medical research and medical practice.