Major Renal Diseases Research Articles

A glimpse of recent advances in the research of acute kidney injury

AbstractAcute kidney injury (AKI) is a major renal disease that affects 13 million people and is associated with almost 1.7 million deaths each year around the world. Previously referred to as acute renal failure, AKI is defined not only by a rapid functional decline of the kidney but also by pathological damages in kidney tissue. This updated definition contributes to modern renal medicine in at least two ways. First, the definition of AKI includes an early, preventable and treatable stage of the disease, which implies an urgent need for sensitive biomarkers for early diagnosis and treatment. Second, the AKI definition is proposed with clear criteria for diagnosis and severity grading, which are beneficial for clinical studies and the meta‐analysis of different datasets.

Autophagy in acute kidney injury and maladaptive kidney repair.

Acute kidney injury (AKI) is a major renal disease characterized by a sudden decrease in kidney function. After AKI, the kidney has the ability to repair, but if the initial injury is severe the repair may be incomplete or maladaptive and result in chronic kidney problems. Autophagy is a highly conserved pathway to deliver intracellular contents to lysosomes for degradation. Autophagy plays an important role in maintaining renal function and is involved in the pathogenesis of renal diseases. Autophagy is activated in various forms of AKI and acts as a defense mechanism against kidney cell injury and death. After AKI, autophagy is maintained at a relatively high level in kidney tubule cells during maladaptive kidney repair but the role of autophagy in maladaptive kidney repair has been controversial. Nonetheless, recent studies have demonstrated that autophagy may contribute to maladaptive kidney repair after AKI by inducing tubular degeneration and promoting a profibrotic phenotype in renal tubule cells. In this review, we analyze the role and regulation of autophagy in kidney injury and repair and discuss the therapeutic strategies by targeting autophagy.

Vision transformer and explainable transfer learning models for auto detection of kidney cyst, stone and tumor from CT-radiography

Renal failure, a public health concern, and the scarcity of nephrologists around the globe have necessitated the development of an AI-based system to auto-diagnose kidney diseases. This research deals with the three major renal diseases categories: kidney stones, cysts, and tumors, and gathered and annotated a total of 12,446 CT whole abdomen and urogram images in order to construct an AI-based kidney diseases diagnostic system and contribute to the AI community’s research scope e.g., modeling digital-twin of renal functions. The collected images were exposed to exploratory data analysis, which revealed that the images from all of the classes had the same type of mean color distribution. Furthermore, six machine learning models were built, three of which are based on the state-of-the-art variants of the Vision transformers EANet, CCT, and Swin transformers, while the other three are based on well-known deep learning models Resnet, VGG16, and Inception v3, which were adjusted in the last layers. While the VGG16 and CCT models performed admirably, the swin transformer outperformed all of them in terms of accuracy, with an accuracy of 99.30 percent. The F1 score and precision and recall comparison reveal that the Swin transformer outperforms all other models and that it is the quickest to train. The study also revealed the blackbox of the VGG16, Resnet50, and Inception models, demonstrating that VGG16 is superior than Resnet50 and Inceptionv3 in terms of monitoring the necessary anatomy abnormalities. We believe that the superior accuracy of our Swin transformer-based model and the VGG16-based model can both be useful in diagnosing kidney tumors, cysts, and stones.

Association of retinopathy severity with cardiovascular and renal outcomes in patients with type 1 diabetes: a multi-state modeling analysis

This study aimed to assess the impact of diabetic retinopathy (DR) severity on the incidence of major adverse cardiac events (MACE) and end-stage renal disease (ESRD) in T1D patients. Patients diagnosed with T1D between 1999 and 2013 were identified from patient-level data of Taiwan’s National Health Insurance Research database. A total of 1135 patients were included and classified into mild DR (n = 454), severe DR (n = 227), or non-DR (n = 454) by using propensity score matching. Multi-state model analyses, an extension of competing risk models with adjustment for transition-specific covariates for prediction of subsequent MACE and ESRD, were performed. MACE and ESRD risks were significantly higher in the severe DR patients; a 2.97-fold (1.73, 5.07) and 12.29-fold (6.50, 23.23) increase in the MACE risk among the severe DR patients compared to the mild DR and DR-free patients, respectively; and, a 5.91-fold (3.50, 9.99) and 82.31-fold (29.07, 233.04) greater ESRD risk of severe DR patients than that of the mild DR and DR-free groups, respectively (p < 0.001). Severity of DR was significantly associated with the late diabetes-related vascular events (i.e., MACE, ESRD) among T1D patients.

Quantification of molecular heterogeneity in kidney tissue by targeted proteomics

Renal diseases are driven by alterations in the entity of proteins within the kidney, at the level of single cells, nephron subunits (such as glomerulus and tubule), tissues and body fluids. Histologically, kidney diseases are extremely heterogeneous. Mass-spectrometry based proteomics provides a unique opportunity to interrogate heterogeneity and dynamics of various proteome layers within the kidney to better understand physiology and pathophysiology, and to translate signaling networks into therapies. Yet, the success of this endeavor will largely depend on improving proteomic data acquisition methods toward increased reproducibility. Here, we provide an overview of targeted proteomics studies in renal tissue and their insights into major renal diseases such as diabetic nephropathy, acute kidney injury and chronic kidney disease. The technical approaches currently include antibody-based and mass spectrometry based approaches, range from single-cells to single-nephrons to bulk tissue proteomic acquisitions, and are applied to physiological studies and translational approaches in biomarker discovery. Within this context, we identify key challenges in proteomics of kidney biopsies. We also suggest that novel models of translational nephrology have increased need for targeted acquisition of proteomics data with focus on primary urinary cells, organoids and induced renal epithelial cells (IRECs). In conclusion, targeted proteomics will be very beneficial to identify heterogenic disease mechanisms that drive renal disease and further emerge as an important tool in translational kidney research. SignificanceImproved targeted proteomics technologies will be an important cornerstone of renal systems medicine in order to identify and tackle the heterogenic disease mechanisms driving renal disease.

Exploratory Analysis for the Evaluation of Estimated Glomerular Filtration Rate, Cholesterol and Triglycerides after Switching from Tenofovir/Emtricitabine plus Atazanavir/Ritonavir (ATV/r) to Abacavir/Lamivudine plus ATV/r in Patients with Preserved Renal Function.

Background and Objectives:Renal toxicity due to tenofovir (TDF) has been largely described in patients with HIV infection. However, other antiretroviral drugs (such as atazanavir [ATV], especially when boosted by ritonavir, ATV/r) could perpetuate some degrees of renal impairment with or without TDF co-administration. Also, possible benefits of stopping TDF in patients without renal diseases is not well known. This study aimed at exploring evolution of renal function and lipid profile after switching from tenofovir/emtricitabine (TDF/FTC) to abacavir/lamivudine (ABC/3TC), maintaining the ATV/r component of the regimen.Methods:Patients in the Italian MASTER Cohort, who switched from TDF/FTC plus ATV/r to ABC/3TC plus ATV/r were included, provided that major renal diseases were not diagnosed before switching (i.e., baseline). Serum creatinine, estimated glomerular filtration rate (eGFR), total cholesterol, HDL and triglycerides were evaluated at baseline and at month 18 after switching.Results:126 patients were selected (80% males). Patients were mostly Italians (92%). 79% had undetectable HIV-RNA and 44% were co-infected by HBV and/or HCV. Median age at switch was 47 years (IQR 43-55). A small but significant decrease in serum creatinine [from 1.06 mg/dl (SD: 0.3) to 0.94 mg/dl (SD: 0.2); p<0.001] with an improvement in eGFR [from 86.8 ml/min (SD: 33) to 96.4 ml/min (SD: 37); p<0.001] were observed in per protocol analysis at month 18. Also ITT analysis showed a decrease in mean serum creatinine [from 1.08 mg/dl (SD: 0.35) to 0.95 mg/dl (SD: 0.24); p<0.001] with an improvement in mean eGFR [from 86.9 ml/min/1.73m2 (SD: 24.11) to 95.8 ml/min/1.73m2 (SD: 19.99); p<0.001]. Total cholesterol increased [from 188 mg/dl (SD: 42) to 206 mg/dl (SD: 44); p<0.001] but also HDL increased as well [from 46 mg/dl (SD: 14) to 54 mg/dl (SD: 19); p=0.015]. An increase in triglycerides concentration was observed [from 162 mg/dl (SD: 144) to 214 mg/dl (SD: 109); p=0.027] in per protocol analysis. Also ITT analysis showed increases of both total cholesterol [from 187 mg/dl (SD: 43.69) to 203 mg/dl (SD: 44.10); p<0.001] and HDL fraction [from 46 mg/dl (SD: 15.49) to 52 mg/dl (SD: 17.13); p=0.002] at month 18.Conclusion:This analysis reports an improvement in eGFR and an increase in total cholesterol and HDL fraction at month 18 after switching to ABC/3TC plus ATV/r. Given the fact that renal function was not significantly affected at baseline, our findings may suggest the utility of a proactive switch from TDF to ABC, when otherwise indicated, in patients who cannot avoid using a nucleoside backbone.

Renoprotective approaches and strategies in acute kidney injury.

Acute kidney injury (AKI) is a major renal disease associated with high mortality rate and increasing prevalence. Decades of research have suggested numerous chemical and biological agents with beneficial effects in AKI. In addition, cell therapy and molecular targeting have been explored for reducing kidney tissue damage and promoting kidney repair or recovery from AKI. Mechanistically, these approaches may mitigate oxidative stress, inflammation, cell death, and mitochondrial and other organellar damage, or activate cytoprotective mechanisms such as autophagy and pro-survival factors. However, none of these findings has been successfully translated into clinical treatment of AKI. In this review, we analyze these findings and propose experimental strategies for the identification of renoprotective agents or methods with clinical potential. Moreover, we propose the consideration of combination therapy by targeting multiple targets in AKI.

Kidney diseases in Roma and non-Roma children from eastern Slovakia: are Roma children more at risk?

To compare the occurence of primary renal diseases (PRD) in Roma and non-Roma children. Data on all outpatients (n = 921) from a tertiary pediatric nephrology centre (<19 years) in eastern Slovakia were collected. We assessed early signs and symptoms and PRD for Roma and non-Roma children. The proportion of Roma among patients was relatively small regarding early signs like proteinuria but large regarding PRD with gross clinically apparent symptoms (e.g. Alport syndrome, p < 0.01 and systemic lupus erythematosus, p < 0.05). The overall proportion of Roma children in outpatients with kidney problems is smaller than the estimated proportion of Roma in all children in Slovakia, in particular for early signs, but not for major renal diseases.

Growth Hormone, Insulin-Like Growth Factor-1, and the Kidney: Pathophysiological and Clinical Implications

Besides their growth-promoting properties, GH and IGF-1 regulate a broad spectrum of biological functions in several organs, including the kidney. This review focuses on the renal actions of GH and IGF-1, taking into account major advances in renal physiology and hormone biology made over the last 20 years, allowing us to move our understanding of GH/IGF-1 regulation of renal functions from a cellular to a molecular level. The main purpose of this review was to analyze how GH and IGF-1 regulate renal development, glomerular functions, and tubular handling of sodium, calcium, phosphate, and glucose. Whenever possible, the relative contributions, the nephronic topology, and the underlying molecular mechanisms of GH and IGF-1 actions were addressed. Beyond the physiological aspects of GH/IGF-1 action on the kidney, the review describes the impact of GH excess and deficiency on renal architecture and functions. It reports in particular new insights into the pathophysiological mechanism of body fluid retention and of changes in phospho-calcium metabolism in acromegaly as well as of the reciprocal changes in sodium, calcium, and phosphate homeostasis observed in GH deficiency. The second aim of this review was to analyze how the GH/IGF-1 axis contributes to major renal diseases such as diabetic nephropathy, renal failure, renal carcinoma, and polycystic renal disease. It summarizes the consequences of chronic renal failure and glucocorticoid therapy after renal transplantation on GH secretion and action and questions the interest of GH therapy in these conditions.

Implementation and first results of a German Chronic Kidney Disease Registry

Advanced chronic kidney disease (CKD) is gaining increasing medical and economical importance, but little information exists about treatment variation and the impact of routine clinical treatments on survival, quality of life, and cost. We demonstrate the first results of a national electronic registry of nephrology clinic data that will serve as a resource for the prospective observation of CKD patients in Germany. A large network of German nephrologist practices is currently joining the project. Routinely obtained clinical data for non-dialysis dependent CKD patients are documented in health records electronically, and elements from these data are extracted using QuaNT (Qualitätssicherung Nephrologie und Transplantation) to create a centralized database. Here, we report cross-sectional data from 59 participating nephrology clinics and 6,187 patients with CKD Stage 3 - 5 in 2011. Mean age ± standard deviation (SD) was 72 ± 12 years. The distribution of CKD 3, 4, and 5 (non-dialysis) was 60%, 33%, and 8%, respectively. The major renal diseases were hypertension/vascular nephropathy (47%) and diabetic nephropathy (26%). Reninangiotensin-system inhibitor prescription was 78%. Vitamin D prescription was 50%, phosphate binders 6%, iron (oral or i.v.) 19%, and erythropoietin-stimulating agents 14%. This electronic registry follows clinical nephrology care and outcomes for CKD patients in Germany, and increased participation is anticipated. As a component of the initiative, variation in patient care will be studied to identify best treatment practices in analyses integrated into the international CKD Outcomes and Practice Patterns Study (CKDopps).

Clinicopathological features of paediatric renal biopsies in Shanghai over a 31 year period

To identify the variations in paediatric renal biopsy pathology and clinicopathological features during the past 31 years. A retrospective analysis of paediatric renal biopsies performed at a single institution in Shanghai from January 1979 to December 2009 was conducted. The major pathologies included minor glomerular abnormalities (MGA, 26.1%), IgA nephropathy (IgAN, 17%) and mesangial proliferative glomerulonephritis (MsPGN) without IgA deposition (11.3%). The major clinical presentations included nephrotic syndrome (NS, 39.4%), haematuria with proteinuria (24.4%) and persistent microscopic haematuria (15.1%). MGA accounted for 46.9% of the cases in NS. IgAN and HSN accounted for 24% and 28.9% of patients with concomitant haematuria and proteinuria, and thin basement membrane nephropathy accounted for 51.2% of cases with persistent microscopic haematuria. The frequency of IgAN (78.6%) was much higher than that of TBMN (29.0%) in patients with persistent microscopic haematuria with abnormal urinary albumin. Minor glomerular abnormalities and IgAN were the major renal diseases in our study population, and the focus of our paediatric nephrologists. The high proportion of TBMN suggested that there should be limited use of renal biopsy for patients with persistent microscopic haematuria and renal biopsy should be performed in the presence of proteinuria or abnormal levels of urinary albumin.

MicroRNAs in kidneys: biogenesis, regulation, and pathophysiological roles

MicroRNAs (miRNA) are endogenously produced, short RNAs that repress and thus regulate the expression of almost half of known protein-coding genes. miRNA-mediated gene repression is an important regulatory mechanism to modulate fundamental cellular processes such as the cell cycle, growth, proliferation, phenotype, and death, which in turn have major influences on pathophysiological outcomes. In kidneys, miRNAs are indispensable for renal development and homeostasis. Emerging evidence has further pinpointed the pathogenic roles played by miRNAs in major renal diseases, including diabetic nephropathy, acute kidney injury, renal carcinoma, polycystic kidney disease, and others. Although the field of renal miRNA research is still in its infancy and important questions remain, future investigation on miRNA regulation in kidneys has the potential to revolutionize both the diagnosis and treatment of major renal diseases.

Rituximab versus cyclophosphamide for ANCA-associated vasculitis.

Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen. We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months. Nine centers enrolled 197 ANCA-positive patients with either Wegener's granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P=0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events. Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.)

Contribution of metabolic and anthropometric abnormalities to cardiovascular disease risk factors.

Patients with human immunodeficiency virus (HIV) infection have sustained alterations in metabolism (lipids and insulin/glucose homeostasis) and body composition (fat distribution) that are proatherogenic (the Figure). HIV infection itself and/or its therapies may contribute to these alterations (the Table); although most effects are reversible, there are some possibly irreversible consequences of treatment. With the relative restoration to health seen in the era of highly active antiretroviral therapy (HAART), many traditional risk factors and promoters of dyslipidemia and diabetes also are present; they interact with HIV-specific inducers to worsen dyslipidemia and to increase the prevalence of insulin resistance and diabetes. Figure. Overview of the effects of HIV and its therapies on CVD risk. The contribution of traditional risk factors must be kept in mind, and they may occur with increased prevalence in people with HIV infection (eg, smoking). HIV, likely through the inflammatory response, and antiretroviral therapies independently affect many of the mediators of CVD risk. The effects on lipids are a prominent but complex example; HIV infection lowers LDL levels, but antiretroviral therapy raises LDL back up to normal levels. The bidirectional arrows indicate associations, but there is not yet adequate proof of causality. The dotted arrow between body composition and CVD indicates that body fat is known to affect the mediators such as dyslipidemia and insulin resistance but may also have a direct effect. FFA indicates free fatty acids; ARV, antiretroviral. View this table: Table. Effects of HIV Treatment These disturbances in lipid and glucose metabolism and renal disease may contribute, at least in part, to the excess cardiovascular disease (CVD) morbidity and mortality observed in HIV-infected individuals (the Figure). However, the relative contribution to excess CVD risk of traditional CVD risk factors, especially smoking, compared with these infection- and treatment-specific complications requires clarification. More prospective data with multivariable modeling are needed. …

Cardiovascular Risk in Hypertension – Can We Ask for More?

The burden of cardiovascular (CV) disease remains high nowadays, despite the tremendous development in the therapeutic strategies that has occurred during the last 30 years. The growing focus on pharmacological strategies capable of interacting with key pathophysiological mechanisms has resulted in a better control of CV disease. The renin-angiotensin system (RAS) is involved in many pathophysiological processes underlying the development of major CV and renal diseases and, thus, it represents an 'ideal' target for the pharmacological treatment of these clinical conditions. Recently, in addition to the traditional therapeutic approaches, mostly based on the use of ACE inhibitors and/or angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]), the scientific and medical community have focused on a new therapeutic possibility to interfere with RAS activity. Indeed, the first compound of the new drug class of direct renin inhibitors, aliskiren, has been made available for clinical use. The therapeutic properties of aliskiren are of particular interest, since it interferes with the enzymatic activities of renin, the key rate-limiting step of the RAS cascade. This unique mechanism of action, e.g. occupation of the renin active site, provides an 'upstream' modulation in the RAS enzymatic-proteic cascade. This results in an inhibition of the biological properties of renin to promote the cleavage of the angiotensin I peptide from the angiotensinogen substrate.Clinical studies have demonstrated that the use of aliskiren provides antihypertensive efficacy comparable with, or even superior to, that observed with other classes of antihypertensive drugs. Also, the addition of aliskiren to different antihypertensive strategies results in a further significant increase in blood pressure (BP) reduction than those achieved with monotherapy based on diuretics, calcium-channel antagonists, ACE inhibitors and ARBs. The overall safety and tolerability of aliskiren are comparable with other classes of antihypertensive drugs and almost overlap with placebo. Recent evidence also demonstrates that aliskiren is effective in promoting the regression of organ damage (e.g. microalbuminuria and left ventricular hypertrophy), beyond its BP-lowering properties and in addition to standard therapies, including ARBs. An ambitious programme of clinical development of this modern antihypertensive drug will investigate whether aliskiren may further limit the incidence of major CV and renal events in hypertensive patients with co-morbidities, treated with the available therapeutic strategies, including ACE inhibitors and ARBs.

Urinary excretion of endothelin-1 (ET-1), transforming growth factor- 1 (TGF- 1) and vascular endothelial growth factor (VEGF165) in paediatric chronic kidney diseases: results of the ESCAPE trial

The severity and dynamics of renal tissue damage in chronic kidney disease (CKD) may be reflected by the urinary excretion of vasoactive and growth factors released by the damaged kidney. Urinary excretion of ET-1, TGF-beta1 and VEGF(165) was evaluated in 303 children with CKD stage II-IV (GFR 48 +/- 22 ml/min/1.73 m(2)) and 81 age-matched healthy controls. Major renal disease groups were hypo-/dysplastic kidney disease (N = 183), obstructive uropathies (N = 47), glomerulopathies (N = 34), nephronophthisis (N = 19) and polycystic kidney disease (N = 20). The mean urinary excretion rates of each of the three putative biomarkers were significantly elevated in CKD patients compared to controls: 965 +/- 2042 vs 216 +/- 335 fmol/g creatinine for ET-1; 252 +/- 338 vs 155 +/- 158 ng/g for VEGF; 31.6 +/- 37.0 vs 10.9 +/- 9.8 ng/g for TGF-beta1 (each P < 0.0001). The excretion of ET-1 and TGF-beta1 was highest in patients with obstructive uropathies. In the patients, ET-1, TGF-beta1 and VEGF excretion rates were inversely correlated with age (r = -0.22, -0.32 and -0.17, all P < 0.005) and renal function (r = -0.21, -0.13 and -0.15; P < 0.001; < 0.05; < 0.01; respectively) VEGF and TGF-beta1 excretion rates were positively correlated both in patients and controls. Children with CKD exhibit significantly elevated urinary excretion of ET-1, TGF-beta1 and VEGF(165) in comparison to healthy children. Urinary excretion of these biomarkers was most enhanced in patients with obstructive uropathies. A positive correlation between urinary TGF-beta1 and VEGF(165) excretion, shown both in patients and healthy controls, indicates an interdependent nature of their generation.

Immunofluorescence on pronase-digested paraffin sections: A valuable salvage technique for renal biopsies

Direct immunofluorescence (IF) on frozen tissue is the method of choice for the study of medical renal diseases. When no glomeruli are available, IF can be performed on the formalin-fixed paraffin-embedded tissue allocated for light microscopy after antigen retrieval with proteases. In this study, the results of IF on frozen tissue (IF-F) and on deparaffinized, pronase-treated tissue (IF-P) were compared in 71 renal biopsies representing 12 major renal diseases. Using IF-P, diagnostic findings were obtained in 100% of cases of lupus nephritis, acute post-infectious glomerulonephritis, cryoglobulinemic glomerulonephritis, fibrillary glomerulonephritis, primary amyloidosis, myeloma cast nephropathy, and light-chain Fanconi syndrome (LCFS), 88% of cases of immunoglobulin (Ig)A nephropathy, 80% of cases of light-chain deposition disease, 60% of cases of membranoproliferative glomerulonephritis type 1, 50% of cases of idiopathic membranous glomerulopathy (MGN) and 20% of cases of anti-glomerular basement membrane (GBM) disease. IF-P was less sensitive than IF-F for the detection of C3 in all disease categories and for the detection of IgG in cases of MGN and anti-GBM disease. The diagnostic kappa light-chain staining was demonstrated in 100% of cases of LCFS by IF-P versus 40% by IF-F. We conclude that IF-P is a valuable salvage immunohistochemical technique for renal biopsies lacking adequate cortical sampling for IF-F, and is superior to IF-F for the diagnosis of LCFS.

Mapping a locus for susceptibility to HIV-1-associated nephropathy to mouse chromosome 3.

HIV-1-associated nephropathy (HIVAN) is a major complication of HIV-1 infection with distinct pathologic features. Introduction of the HIV-1 genome into mice results in a renal disease with all of the histologic and clinical hallmarks of HIVAN on the FVB/N genetic background (TgFVB). We assessed the influence of genetic background on the development or progression of HIVAN by making F1 hybrids of TgFVB with five other inbred strains (CBA, DBA/2, CAST/Ei, C3H/He, BALB/c) and determining phenotypes relevant to renal failure among transgenic offspring (histology, blood urea nitrogen, proteinuria, serum albumin, and serum cholesterol). We found striking variation in phenotypes among F1s, ranging from severe renal disease to no renal disease whatsoever (P<0.001 for ANOVA across all groups). To map genes responsible for this variation, we produced a backcross of TgFVB/CAST F1 x TgFVB. By genome-wide analysis of linkage in 185 heterozygous transgenic backcross mice, we identified a locus on chromosome 3A1-3, HIVAN1, that showed highly significant linkage to renal disease [logarithm of odds (lod) score 4.9 at D3Mit203, accounting for 15% of the variance in renal disease]. Other loci on chromosomes 11, 14, and 16 were suggestive of linkage to renal disease, and a locus on chromosome 9 influenced serum cholesterol but not nephropathy. Interestingly, HIVAN1 is syntenic to human chromosome 3q25-27, an interval showing suggestive evidence of linkage to various nephropathies. These findings demonstrate a strong genetic influence on HIVAN and demonstrate a major renal disease susceptibility locus on mouse chromosome 3A1-3.

Salt intake and the progression of chronic renal diseases

To what extent dietary salt intake is involved in the pathogenesis of progressive renal diseases has never been fully understood in humans. To this aim, we investigated the relationship between urinary sodium excretion (under a low salt & low protein diet) and urinary protein excretion/renal function in patients with three major renal diseases: chronic glomerulonephritis(GN), diabetic nephropathy(DN) and nephrosclerosis(NS). The results were as follows; 1) A significant positive correlation was found between urinary sodium excretion (equivalent to the daily salt intake) and daily urinary protein excretion in patients with a GN and DN. However, no relationship was found between the two parameters in patients with NS. 2) Reduction in salt intake led to a significant decrease in daily protein excretion, the effect of which was prominent in patients with GN and DN. 3) A significant positive correlation was found between urinary sodium excretion and estimated protein intake(EPI) in all three groups. 4) There was a significant positive correlation between EPI and urinary protein excretion in DN, but not in GN. 5) Reduction in salt and protein intake(calculated as an EPI) ameliorates the slope of reciprocal creatinine concentration(1/Cr) in patients with GN and DN. These results indicate that slat restriction is strongly associated with the preservation of renal function in patients with GN and DN, suggesting that this dietary strategy can be a useful measure for retarding the progressive nature of these diseases. Of note is that both salt and protein restriction was renoprotective only in patients with DN. Thus, patients with GN and DN must be followed-up on the basis of a salt-restricted diet throughout their clinical course.

Infectious disease

PURPOSE: To elucidate socio-demographic and clinical determinants for hospitalization among “low-risk” community acquired pneumonia (CAP) patients. “Low-risk” patients are HIV negative, non-nursing home residents with no major renal, neoplastic or hepatic diseases, and with a Pneumonia Severity Index (PSI) less than 90. METHODS: A retrospective analysis was conducted of 296 low-risk community acquired pneumonia patients examined from January 1999 to January 2000. All patients were assigned a PSI score. 208 (70%) of patients were discharged from the emergency room while 80 (30%) were hospitalized. All patients were assigned to classes I-V according to PSI score. A comparison was made between PSI class II patients discharged from the emergency department and those hospitalized. RESULTS: Predictors for hospitalization were female gender (p < 0.01), African American race (p < 0.05), having medical insurance coverage (p < 0.001), elevated temperature (p < 0.001), and tachycardia (p < 0.001). No statistically significant differences were observed for altered mental status, hypotension, tachypnea, laboratory, and radiologic parameters, and social indicators (e.g., substance abuse). CONCLUSION: Socio-demographic parameters, including age, gender and insurance coverage, are important determinants for hospitalization among “low-risk” patients with community-acquired pneumonia. Clinical predictors for hospitalization were high fever, and tachycardia. The average length of stay for in-patient care was 3.5 days (Range = 3 to 5 days), at ten times higher the cost of out-patient care. This study supports the recommendation of using the PSI for ED evaluation of patients.