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Acute kidney injury impacts ∼13.3 million individuals and causes ∼1.7 million deaths per year globally. Numerous injury pathways contribute to acute kidney injury, including cell cycle arrest, senescence, inflammation, mitochondrial dysfunction, and endothelial injury and dysfunction, and can lead to chronic inflammation and fibrosis. However, factors enabling productive repair versus nonproductive, persistent injury states remain less understood. The (Re)Building a Kidney (RBK) consortium is a National Institute of Diabetes and Digestive and Kidney Diseases consortium focused on both endogenous kidney repair mechanisms and the generation of new kidney tissue. This short review provides an update on RBK studies of endogenous nephron repair, addressing the following questions: (i) What is productive nephron repair? (ii) What are the cellular sources and drivers of repair? and (iii) How do RBK studies promote development of therapeutics? Also, we provide a guide to RBK's open access data hub for accessing, downloading, and further analyzing data sets.

Alterations in renal microperfusion play an important role in the development of acute kidney injury with long-term consequences. Here we used contrast-enhanced ultrasonography as a novel method for depicting intra-renal distribution of blood flow. After infusion of microbubble contrast agent, bubbles were collapsed in the kidney and post-bubble destruction refilling was measured in various regions of the kidney. Local perfusion was monitored in vivo at 15, 30, 45, 60 minutes and 24 hours after 28 min of bilateral ischemia in 12 mice. High-resolution, pixel-by-pixel, analysis was performed on each imaging clip using customized software, yielding parametric perfusion maps of the kidney, representing relative blood volume in each pixel. These perfusion maps revealed that outer medullary perfusion decreased disproportionately to the reduction in the cortical and inner medullary perfusion after ischemia. Outer medullary perfusion was significantly decreased by 69% at 60 minutes post-ischemia and remained significantly less (40%) than pre-ischemic levels at 24 hours post-ischemia. Thus, contrast-enhanced ultrasonography with high-resolution parametric perfusion maps can monitor changes in renal microvascular perfusion in space and time in mice. This novel technique can be translated to clinical use in man.

Progressively decreasing glomerular filtration rate (GFR), or renal decline, is seen in patients with type 1 diabetes (T1D) and normoalbuminuria or microalbuminuria. Here we examined the associations of kidney injury molecule-1 (KIM-1) in plasma and urine with the risk of renal decline and determine whether those associations are independent of markers of glomerular damage. The study group comprised patients with T1D from the 2nd Joslin Kidney Study of which 259 had normoalbuminuria and 203 had microalbuminuria. Serial measurements over 4 to 10 years of follow-up (median 8 years) of serum creatinine and cystatin C were used jointly to estimate eGFRcr-cys slopes and time of onset of CKD stage 3 or higher. Baseline urinary excretion of IgG2 and albumin were used as markers of glomerular damage, and urinary excretion of KIM-1 and its plasma concentration were used as markers of proximal tubular damage. All patients had normal renal function at baseline. During follow-up, renal decline (eGFRcr-cys loss 3.3% or more per year) developed in 96 patients and 62 progressed to CKD stage 3. For both outcomes, the risk rose with increasing baseline levels of plasma KIM-1. In multivariable models, elevated baseline plasma KIM-1 was strongly associated with risk of early progressive renal decline, regardless of baseline clinical characteristics, serum TNFR1 or markers of glomerular damage. Thus, damage to proximal tubules may play an independent role in the development of early progressive renal decline in non-proteinuric patients with T1D.

Kidney organoids, derived from human pluripotent stem cells, have the potential to greatly facilitate drug development. Borestrom et al. have used CRISPR/Cas9 to create kidney fluorescent lineage markers for SIX2 and NPHS1 to monitor the differentiation process to tubular and glomerular structures and optimize maturity. The convergence of "personalized" kidney organoids with genome editing and single-cell sequencing technology hold great promise to result in better insight to disease, better human cell disease models, more predictive toxicology, and potentially "clinical trials in a dish."

Vascular inflammation is a major contributor to the severity of acute kidney injury. In the context of vasospasm-independent reperfusion injury we studied the potential anti-inflammatory role of the Gα-related RGS protein, RGS4. Transgenic RGS4 mice were resistant to 25 minute injury, although post-ischemic renal arteriolar diameter was equal to the wild type early after injury. A 10 minute unilateral injury was performed to study reperfusion without vasospasm. Eighteen hours after injury blood flow was decreased in the inner cortex of wild type mice with preservation of tubular architecture. Angiotensin II levels in the kidneys of wild type and transgenic mice were elevated in a sub-vasoconstrictive range 12 and 18 hours after injury. Angiotensin II stimulated pre-glomerular vascular smooth muscle cells (VSMC) to secrete the macrophage chemoattractant, RANTES; a process decreased by angiotensin II R2 (AT2) inhibition. However, RANTES increased when RGS4 expression was suppressed implicating Gα protein activation in an AT2-RGS4-dependent pathway. RGS4 function, specific to VSMC, was tested in a conditional VSMC-specific RGS4 knockout showing high macrophage density by T2 MRI compared to transgenic and non-transgenic mice after the 10 minute injury. Arteriolar diameter of this knockout was unchanged at successive time points after injury. Thus, RGS4 expression, specific to renal VSMC, inhibits angiotensin II-mediated cytokine signaling and macrophage recruitment during reperfusion, distinct from vasomotor regulation.

Few investigations have evaluated the incremental usefulness of tubular injury biomarkers for improved prediction of chronic kidney disease (CKD) progression. As such, we measured urinary kidney injury molecule-1, neutrophil gelatinase–associated lipocalin, N -acetyl-s-D-glucosaminidase and liver fatty acid binding protein under highly standardized conditions among 2466 enrollees of the prospective Chronic Renal Insufficiency Cohort Study. During 9433 person-years of follow-up, there were 581 cases of CKD progression defined as incident end-stage renal disease or halving of the estimated glomerular filtration rate. Levels of the urine injury biomarkers, normalized for urine creatinine, were strongly associated with CKD progression in unadjusted Cox proportional hazard models with hazard ratios in the range of 7 to 15 comparing the highest with the lowest quintiles. However, after controlling for the serum creatinine–based estimated glomerular filtration rate and urinary albumin/creatinine ratio, none of the normalized biomarkers was independently associated with CKD progression. None of the biomarkers improved on the high (0.89) C-statistic for the base clinical model. Thus, among patients with CKD, risk prediction with a clinical model that includes the serum creatinine–based estimated glomerular filtration rate and the urinary albumin/creatinine ratio is not improved on with the addition of renal tubular injury biomarkers.

Chronic kidney disease (CKD) remains one of the leading causes of death in the developed world, and acute kidney injury (AKI) is now recognized as a major risk factor in its development. Understanding the factors leading to CKD after acute injury are limited by current animal models of AKI, which concurrently target various kidney cell types including epithelial, endothelial, and inflammatory cells. Here, we developed a mouse model of kidney injury using the Six2-Cre-LoxP technology to selectively activate expression of the simian diphtheria toxin (DT) receptor in renal epithelia derived from the metanephric mesenchyme. By adjusting the timing and dose of DT, a highly selective model of tubular injury was created to define the acute and chronic consequences of isolated epithelial injury. The DT-induced sublethal tubular epithelial injury was confined to the S1 and S2 segments of the proximal tubule rather than being widespread in the metanephric mesenchyme-derived epithelial lineage. Acute injury was promptly followed by inflammatory cell infiltration and robust tubular cell proliferation, leading to complete recovery after a single toxin insult. In striking contrast, three insults to renal epithelial cells at 1-week intervals resulted in maladaptive repair with interstitial capillary loss, fibrosis, and glomerulosclerosis, which was highly correlated with the degree of interstitial fibrosis. Thus, selective epithelial injury can drive the formation of interstitial fibrosis, capillary rarefaction, and potentially glomerulosclerosis, substantiating a direct role for damaged tubule epithelium in the pathogenesis of CKD.

Pre-renal acute kidney injury (AKI) is assumed to represent a physiological response to underperfusion. Its diagnosis is retrospective after a transient rise in plasma creatinine, usually associated with evidence of altered tubular transport, particularly that of sodium. In order to test whether pre-renal AKI is reversible because injury is less severe than that of sustained AKI, we measured urinary biomarkers of injury (cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), γ-glutamyl transpeptidase, IL-18, and kidney injury molecule-1 (KIM-1)) at 0, 12, and 24 h following ICU admission. A total of 529 patients were stratified into groups having no AKI, AKI with recovery by 24 h, recovery by 48 h, or the composite of AKI greater than 48 h or dialysis. Pre-renal AKI was identified in 61 patients as acute injury with recovery within 48 h and a fractional sodium excretion

Elevated urinary albumin excretion in patients with type 1 diabetes reverts to normoalbuminuria in a majority of patients but advances toward proteinuria in some. In order to gain valuable insights into the early pathophysiology of diabetic nephropathy we evaluated the association of kidney tubular injury biomarkers with changes in albuminuria in patients with type 1 diabetes mellitus. Urine levels of kidney injury molecule-1 (KIM-1), N-acetyl-β-D-glucosaminidase (NAG), and some inflammatory markers were determined in 38 healthy individuals and 659 patients with type 1 diabetes mellitus having varying degrees of albuminuria. Urinary interleukin-6, CXCL10/IP-10, NAG, and KIM-1 levels were very low in healthy individuals, increased in type 1 patients with normoalbuminuria, and were highest in diabetic patients that had microalbuminuria. Low baseline concentrations of urinary KIM-1 and NAG both individually and collectively were significantly associated with the regression of microalbuminuria over the subsequent 2 years; an effect independent of clinical characteristics. Progression and regression of microalbuminuria were unrelated to urinary levels of interleukins 6 and 8, CXCL10/IP-10, and monocyte chemoattractant protein-1. Thus our results show that lower urinary KIM-1 and NAG levels were associated with the regression of microalbuminuria in type 1 diabetes mellitus. Hence, tubular dysfunction is a critical component of the early course of diabetic nephropathy.

Acute kidney injury (AKI) is a common condition with significant associated morbidity and mortality. The insensitivity and non-specificity of traditional markers of renal dysfunction prevent timely diagnosis, estimation of the severity of renal injury, and the administration of possible therapeutic agents. Here, we determine the prognostic ability of urinary liver-type fatty acid-binding protein (L-FABP), and further characterize its sensitivity and specificity as a biomarker of AKI. Initial western blot studies found increased urinary L-FABP in patients with confirmed AKI. A more extensive cross-sectional study found significant increases in urinary L-FABP, normalized to urinary creatinine, in 92 patients with established AKI compared with 62 patients without clinical evidence of AKI. In hospitalized patients, the diagnostic performance of urinary L-FABP for AKI, assessed by the area under the receiver operating characteristic curve, was 0.93. This compares favorably with other established biomarkers of AKI such as kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, N-acetyl-beta-glucosaminidase, and interleukin-18. Our study shows that age-adjusted urinary L-FABP levels were significantly higher in patients with poor outcome, defined as the requirement for renal replacement therapy or the composite end point of death or renal replacement therapy.

Kidney injury molecule-1 (Kim-1) has been qualified by the Food and Drug Administration and European Medicines Agency as a highly sensitive and specific urinary biomarker to monitor drug-induced kidney injury in preclinical studies and on a case-by-case basis in clinical trials. Here we report the development and evaluation of a rapid direct immunochromatographic lateral flow 15-min assay for detection of urinary Kim-1 (rat) or KIM-1 (human). The urinary Kim-1 band intensity using the rat Kim-1 dipstick significantly correlated with levels of Kim-1 as measured by a microbead-based assay, histopathological damage, and immunohistochemical assessment of renal Kim-1 in a dose- and time-dependent manner. Kim-1 was detected following kidney injury induced in rats by cadmium, gentamicin, or bilateral renal ischemia/reperfusion. In humans, the urinary KIM-1 band intensity was significantly greater in urine from patients with acute kidney injury than in urine from healthy volunteers. The KIM-1 dipstick also enabled temporal evaluation of kidney injury and recovery in two patients who developed postoperative acute kidney injury following cytoreductive surgery for malignant mesothelioma with intraoperative local cisplatin administration. We hope that future, more extensive studies will confirm the utility of these results, which show that the Kim-1/KIM-1 dipsticks can provide a sensitive and accurate detection of Kim-1/KIM-1, thereby providing a rapid diagnostic assay for kidney damage and facilitating the rapid and early detection of kidney injury in preclinical and clinical studies.

Kidney injury molecule-1 (KIM-1) is a specific histological biomarker for diagnosing early tubular injury on renal biopsies. In this study, KIM-1 expression was quantitated in renal transplant biopsies by immunohistochemistry and correlated with renal function. None of the 25 protocol biopsies showed detectable tubular injury on histologic examination, yet 28% had focal positive KIM-1 expression. Proximal tubule KIM-1 expression was present in all biopsies from patients with histological changes showing acute tubular damage and deterioration of kidney function. In this group, higher KIM-1 staining predicted a better outcome with improved blood urea nitrogen (BUN), serum creatinine, and estimated glomerular filtration rate (eGFR) over an ensuing 18 months. KIM-1 was expressed focally in affected tubules in 92% of kidney biopsies from patients with acute cellular rejection. By contrast, there was little positive staining for Ki-67, a cell proliferation marker, in any of the groups. KIM-1 expression significantly correlated with serum creatinine and BUN, and inversely with the eGFR on the biopsy day. Our study shows that KIM-1 staining sensitively and specifically identified proximal tubular injury and correlated with the degree of renal dysfunction. KIM-1 expression is more sensitive than histology for detecting early tubular injury, and its level of expression in transplant biopsies may indicate the potential for recovery of kidney function.

Fibroblast growth factor 23 (FGF23) is elevated in chronic kidney disease and associated with increased mortality, but data on FGF23 in humans with acute kidney injury (AKI) are limited. Here we tested whether FGF23 levels rise early in the course of AKI following cardiac surgery, and if higher postoperative FGF23 levels are independently associated with severe AKI and adverse outcomes. Plasma C-terminal FGF23 (cFGF23) levels were measured preoperatively, at the end of cardiopulmonary bypass, and on postoperative days 1 and 3 in 250 patients undergoing cardiac surgery. We also measured intact FGF23 (iFGF23), parathyroid hormone, phosphate, and vitamin D metabolites in a subgroup of 18 patients with severe AKI and 18 matched non-AKI controls. Beginning at the end of cardiopulmonary bypass, cFGF23 levels were significantly and consistently higher in patients who developed AKI compared to those who did not. The early increase in cFGF23 predated changes in other mineral metabolites. The levels of iFGF23 also increased in patients who developed severe AKI, but the magnitude was lower than cFGF23. In analyses adjusted for age, preoperative eGFR, and cardiopulmonary bypass time, higher cFGF23 levels at the end of cardiopulmonary bypass were significantly associated with greater risk of severe AKI and the need for renal replacement therapy or death. Thus, cFGF23 levels rise early in AKI following cardiac surgery, and are independently associated with adverse postoperative outcomes.

Polymorphism of host response genes: Implications in the pathogenesis and treatment of acute renal failure. Acute inflammatory disorders are the result of an interaction between genetic and environmental factors, and are often characterized by an imbalance between pro- and anti-inflammatory host immune responses. Over the past decade, polymorphisms of host response genes have been explored as genetic risk and prognostic markers in the course and severity of acute inflammatory disorders. Increasing evidence supports an important role for inflammatory mechanisms in the pathogenesis of acute renal failure (ARF) following both ischemic and nephrotoxic injury. The use of genetic epidemiology may become a useful tool to identify patients with an altered susceptibility to developing hospital-acquired ARF, and stratify those who may benefit from preventive therapies that modulate host immune responses in a favorable way. This review summarizes the existing experimental and clinical studies supporting the role of inflammation in ARF and critically appraises studies that have examined polymorphism of immune response genes as potential determinants of susceptibility to and severity of acute inflammatory disorders. Conclusions are drawn on the application of genetic epidemiology to the field of ARF and the rationale for further research on the role of genetic markers in ARF.

The T-cell immunoglobulin mucin 1 (Tim-1) modulates CD4(+) T-cell responses and is also expressed by damaged proximal tubules in the kidney where it is known as kidney injury molecule-1 (Kim-1). We sought to define the role of endogenous Tim-1 in experimental T-cell-mediated glomerulonephritis induced by sheep anti-mouse glomerular basement membrane globulin acting as a planted foreign antigen. Tim-1 is expressed by infiltrating activated CD4(+) cells in this model, and we studied the effects of an inhibitory anti-Tim-1 antibody (RMT1-10) on immune responses and glomerular disease. Crescentic glomerulonephritis, proliferative injury, and leukocyte accumulation were attenuated following treatment with anti-Tim-1 antibodies, but interstitial foxp3(+) cell accumulation and interleukin-10 mRNA were increased. T-cell proliferation and apoptosis decreased in the immune system along with a selective reduction in Th1 and Th17 cellular responses both in the immune system and within the kidney. The urinary excretion and renal expression of Kim-1 was reduced by anti-Tim-1 antibodies reflecting diminished interstitial injury. The effects of anti-Tim-1 antibodies were not apparent in the early phase of renal injury, when the immune response to sheep globulin was developing. Thus, endogenous Tim-1 promotes Th1 and Th17 nephritogenic immune responses and its neutralization reduces renal injury while limiting inflammation in cell-mediated glomerulonephritis.

Protection from toxicant-mediated renal injury in the rat with anti-CD54 antibody.BackgroundThe benefit of the potent chemotherapeutic agent cisplatin in treating neoplasms is limited by nephrotoxicity. We tested the hypothesis that CD54 [intercellular adhesion molecule-1 (ICAM-1)] is an important mediator in cisplatin-mediated renal failure.MethodsThe effect of a monoclonal anti-CD54 antibody was evaluated in a rat model of cisplatin toxicity. Renal function, histopathology, renal myeloperoxidase activity, and mortality were determined in the anti-CD54 and placebo groups.ResultsRenal CD54 mRNA expression was markedly increased by 24 hours after exposure to cisplatin in mice. An improvement in renal function, mortality, and histological abnormalities was evident in animals exposed to cisplatin and treated with anti-CD54 antibody (mAb). Seven days after the administration of cisplatin, the mean creatinine was 0.65 ± 0.05 mg/dl in the rats that received anti-CD54 mAb and 4.76 ± 1.42 in control animals (P < 0.02). Mortality was lower in experimental animals (0 vs. 29% in control rats seven days following cisplatin, P < 0.04). Histological evidence of cell injury was markedly attenuated (P < 0.04) in the treated compared with the control rats.ConclusionCD54 may be critical in the pathophysiology of renal injury following cisplatin, perhaps by its effects on leukocyte–endothelial interactions.

To better understand the diagnostic and predictive performance of urinary biomarkers of kidney injury, we evaluated γ-glutamyltranspeptidase (GGT), alkaline phosphatase (AP), neutrophil-gelatinase-associated lipocalin (NGAL), cystatin C (CysC), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18) in a prospective observational study of 529 patients in 2 general intensive care units (ICUs). Comparisons were made using the area under the receiver operator characteristic curve (AUC) for diagnosis or prediction of acute kidney injury (AKI), dialysis, or death, and reassessed after patient stratification by baseline renal function (estimated glomerular filtration rate, eGFR) and time after renal insult. On ICU entry, no biomarker had an AUC above 0.7 in the diagnosis or prediction of AKI. Several biomarkers (NGAL, CysC, and IL-18) predicted dialysis (AUC over 0.7), and all except KIM-1 predicted death at 7 days (AUC between 0.61 and 0.69). Performance was improved by stratification for eGFR or time or both. With eGFR60 ml/min, CysC and KIM-1 had AUCs of 0.69 and 0.73, respectively, within 6 h of injury, and between 12 and 36 h, CysC (0.88), NGAL (0.85), and IL-18 (0.94) had utility. With eGFR60 ml/min, GGT (0.73), CysC (0.68), and NGAL (0.68) had the highest AUCs within 6 h of injury, and between 6 and 12 h, all AUCs except AP were between 0.68 and 0.78. Beyond 12 h, NGAL (0.71) and KIM-1 (0.66) performed best. Thus, the duration of injury and baseline renal function should be considered in evaluating biomarker performance to diagnose AKI.

Arachidonic acid and its metabolites play important roles in renal tubular function. This overview will review general characteristics of arachidonic acid metabolism, focus on the characterization and regulation of renal acylhydrolases that generate arachidonic acid from phospholipids, examine what is known about the production of arachidonic acid metabolites along the nephron, and explore what the potential roles of these metabolites are in physiological and pathophysiological states. Due to space limitations it is not possible to review this extensive topic including the glomerulus as well as the rest of the nephron, renal interstitium, and vasculature. Since this monograph is focused upon the tubulointerstitium, we will not discuss the various aspects of arachidonic acid metabolism in the glomerulus but only refer to glomerular cells when a mechanism pertinent to the tubulointerstitium is best illustrated by work done on a glomerular cell.

Kidney tubular epithelium is restored without replacement with bone marrow-derived cells during repair after ischemic injury. The kidney has the ability to restore the structural and functional integrity of the proximal tubule, which undergoes extensive epithelial cell death after prolonged exposure to ischemia. In order to study the role that adult bone marrow-derived stem cells might play in kidney remodeling after injury, we employed a murine model of ischemia/reperfusion (I/R) injury in which the degree of injury, dysfunction, repair, tubular cell proliferation and functional recovery have been characterized [Park KM, et al, J Biol Chem 276:11870-11876, 2001]. We generated chimeric mice using marrow from mice expressing the bacterial LacZ gene, or the enhanced green fluorescence protein ( eGFP ) gene, or from male mice transplanted into female mice. The establishment of chimerism was confirmed at 6 weeks following transplantation in each case. I/R injury was induced in chimeric mice by occluding the renal arteries and veins with microaneurysm clamps for 30 minutes. After functional recovery in the eGFP chimeras, although there were many interstitial cells, no tubular cells were derived from bone marrow cells. In the bacterial β-galactosidase (β-gal) chimeric mice we found evidence of mammalian (endogenous) β-gal by 5-bomo-4-chloro-3-indolyl-β-D-galactopyranoside (X-gal) staining, but not bacterial β-gal in tubule cells. Detection of the Y chromosome by fluorescence in situ hybridization (FISH) in the postischemic kidneys of gender-mismatched chimeras revealed Y chromosome positivity only in the nuclei of interstitial cells, when scrutinized by deconvolution microscopy. In our model of I/R injury there was a large amount of proliferation of surviving, injured tubular cells indicating that the injured tubule is repopulated by daughter cells of surviving tubular cells. Analysis of the phenotype of interstitial and vascular cells following I/R injury revealed small numbers of peritubular endothelial cells to be derived from bone marrow cells that may serve in the repair process.

Kidney Injury Molecule-1 (KIM-1): A novel biomarker for human renal proximal tubule injury. Background Traditional blood and urine markers for the diagnosis of various renal diseases are insensitive and nonspecific. Kidney Injury Molecule-1 (KIM-1) is a type 1 transmembrane protein, with an immunoglobulin and mucin domain, whose expression is markedly up-regulated in the proximal tubule in the post-ischemic rat kidney. The ectodomain of KIM-1 is shed from cells. The current studies were carried out to evaluate whether KIM-1 is present in human acute renal failure and might serve as a urinary marker of acute renal tubular injury. Methods Kidney tissue samples from six patients with biopsy-proven acute tubular necrosis (ATN) were evaluated by immunohistochemistry for expression of KIM-1. Urine samples were collected from an additional thirty-two patients with various acute and chronic renal diseases, as well as from eight normal controls. Urinary KIM-1 protein was detected by immunoassay and was quantified by ELISA. Results There was extensive expression of KIM-1 in proximal tubule cells in biopsies from 6 of 6 patients with confirmed ATN. The normalized urinary KIM-1 levels were significantly higher in patients with ischemic ATN (2.92 ± 0.61; N = 7) compared to levels in patients with other forms of acute renal failure (0.63 ± 0.17, P N = 16) or chronic renal disease (0.72 ± 0.37, P N = 9). Adjusted for age, gender, length of time delay between the initial insult and sampling of the urine, a one-unit increase in normalized KIM-1 was associated with a greater than 12-fold (OR 12.4, 95% CI 1.2 to 119) risk for the presence of ATN. Concentrations of other urinary biomarkers, including total protein, γ-glutamyltransferase, and alkaline phosphatase, did not correlate with clinical diagnostic groupings. Conclusions A soluble form of human KIM-1 can be detected in the urine of patients with ATN and may serve as a useful biomarker for renal proximal tubule injury facilitating the early diagnosis of the disease and serving as a diagnostic discriminator.

Evidence for genetic factors in the development and progression of IgA nephropathy. Background IgA nephropathy (IgAN) is the most common glomerulonephritis in the world among patients undergoing renal biopsy. Once considered a relatively benign condition, longitudinal follow-up studies have revealed that in fact 9 to 50% of patients progress to end-stage renal disease within 20 years of disease onset. In the three decades since its first description by Jean Berger and Nicole Hinglais, clinical, epidemiologic, and immunologic studies of the pathogenesis of primary (idiopathic) mesangial glomerulonephritis with predominant IgA deposits have characterized the features of IgAN as a distinct glomerular disease entity. However, the basic molecular mechanism(s) underlying abnormal IgA deposition in the mesangium with ensuing extracellular matrix expansion and mesangial cell proliferation remains poorly understood. The task of elucidating the molecular basis of IgAN is made especially challenging by the fact that both environmental and genetic components likely contribute to the development and progression of IgAN. Methods and Results We review here the evidence for genetic factors in the development and progression of IgAN, including a reappraisal of earlier conflicting results from small immunogenetic case-control studies, the evidence for racial differences in the prevalence of IgAN, a detailed summary of all reported occurrences of familial IgAN worldwide, and an exhaustive review of new insights gained through the study of two murine models of hereditary IgAN: the ddY and the uteroglobin-deficient mouse. Conclusions With the development of powerful molecular genetic approaches to the study of both Mendelian and complex human genetic diseases, and the successful efforts of investigators to identify and clinically characterize large IgAN multiplex families, we propose that genetic analysis of familial IgAN is the most promising approach to the identification of IgAN disease/susceptibility genes. Alternatively, if the case-control study design is employed to identify associations between particular candidate genes or markers and the development of IgAN, spurious associations caused by the effects of population stratification should be ruled out by confirming the findings using powerful and sensitive family-based methodologies such as the transmission/dysequilibrium test (TDT).

State University of New York at Stony Brook and Tufts University School of Medicine one liter/day. On day 13, the BUN was 78 mg/dl and the serum creatinine was 3.5 mg/dl. A blood culture grew methicillin-resistant Staphylococcus aureus. Recurrent episodes of bradycardia required placement of a cardiac pacemaker; his blood pressure decreased from 130/80 mm Hg to 100/60 mm Hg. The serum albumin was 1.5 g/dl. The BUN and serum creatinine began to increase again, although he remained nonoliguric with a urine output greater than one liter/day. Urinalysis revealed numerous granular casts and epithelial cells. Urine osmolality was 370 mOsm/liter. The urine contained no white blood cells and an insignificant amount of protein. The BUN and serum creatinine increased to 154 mg/dl and 7.4 mg/dl respectively on the 17th hospital day, and peritoneal dialysis was initiated. The urine output decreased to 10 mI/hr. Peritoneal dialysis was continued until the 36th hospital day. On the 43rd hospital day, the BUN was 28 mgldl and the serum creatinine was 1.2 mg/dl. The hospital course was complicated by anoxic encephalopathy, recurrent sepsis, and respiratory failure. The patient was discharged to his home two months later with a BUN of 10 mg/dl and a serum creatinine of 1.1 mgldl.

Cytosolic calcium and protein kinase C reduce complement-mediated glomerular epithelial injury. In rat membranous nephropathy, proteinuria is due to formation of the C5b-9 membrane attack complex of complement (C), and is associated with morphological evidence of glomerular epithelial cell (GEC) injury. Analogous morphological changes are induced by C5b-9 in cultured GEC. In addition, in cultured GEC C5b-9 induces Ca 2+ influx, as well as Ca 2+ mobilization and increased 1,2-diacylglycerol due to the activation of phospholipase C. In this study we investigated how this GEC activation pattern might influence C-mecliated GEC injury. We demonstrate that the C5b-9-induced increase in cytosolic Ca 2+ concentration ([Ca 2+ ] i ) did not impair ATP generation by mitochondria, suggesting that it does not contribute to cytotoxicity. Moreover, this increase in [Ca 2+ ] i protected GEC from C-mediated cytolysis. However, a large increase in [Ca 2+ ] i (produced by the Ca 2+ ionophore A23187) impaired ATP generation and aggravated C-mediated cytotoxicity, suggesting that intact mitochondrial activity is necessary for GEC to withstand C attack. Activation of protein kinase C (PKC) by phorbol myristate acetate (PMA) also decreased C-mediated cytolysis. Conversely, C lysis was enhanced in GEC that had been pretreated for 18 hours with a high dose of PMA to deplete PKC, and following PKC inhibition with H-7. Therefore, PKC activation, possibly resulting from C5b-9-induced increase in 1,2-diacylglycerol, triggered mechanisms that protected GEC from C-mediated injury. Thus, as a consequence of C5b-9-induced phospholipase activation, the amount of C-induced GEC injury is diminished.

One of the events that is most vital to organ and organism function is that of a hormone acting upon a cell to evoke a physiological response. The hormone evoking the cellular response is the “first messenger”. The activation of a cellular response, however, involves “secondary messengers” that are generated in the cell as a result of hormone-receptor cell interaction and that are crucial to the expression of hormone action. The two most well-studied secondary messenger systems in hormone physiology are cyclic adenosine monophosphate (cAMP) and calcium. In this present chapter we will describe the biochemical mechanisms in which vasopressin interacts with its V1 and V2 receptors generating, in specific cells, cAMP and/or calcium as second messengers. We will focus on two cell culture models that have been utilized to identify vasopressin signaling: 1) the LLC-PK1 cell which contains the V2 receptor and 2) the glomerular mesangial cell which contains the V1 receptor.

A role for oxygen free radicals in aminonucleoside nephrosis. The cellular processes responsible for the proteinuria induced by the aminonucleoside of puromycin (PA) remain inadequately defined. Hypoxanthine is both a metabolic breakdown product of PA as well as a substrate for xanthine oxidase, which catalyzes its enzymatic conversion to xanthine and uric acid, yielding the superoxide anion in the process. We examined whether oxygen free radical production contributes to the development of proteinuria in this model. Seven groups of male Sprague-Dawley rats were studied. Proteinuria was quantitated and histology examined 7 days after rats were treated with PA intravenously over 5min. PA-treated animals received either saline, dimethyl sulfoxide, superoxide dismutase, or catalase over 30min prior to and 30min following PA administration. Another group received allopurinol over 4hr prior to PA. The superoxide dismutase and allopurinol treatment groups had a significant suppression of urinary protein excretion compared to the PA control group. There were also less severe glomerular morphologic changes in the superoxide dismutase group vs. the PA controls, which demonstrated a pathologic pattern that included epithelial cell blebbing, segmental mesangial cell proliferation and matrix expansion, loss of glomerular capillary lumina, and occasional adhesions between the glomerular tuft and Bowman's capsule. The allopurinol group exhibited normal glomerular morphology on light microscopy, with the exception of occasional epithelial cell blebs. All groups showed spreading of the epithelial cell cytoplasm along the glomerular basement membrane with loss of foot processes, focal areas of lifting of the epithelial cell from the glomerular basement membrane, cytoplasmic vacuolization, and protein reabsorption droplets; however, allopurinol-treated animals demonstrated these changes to a lesser extent. The protective effects of superoxide dismutase and allopurinol provide indirect evidence that oxygen free radicals generated by xanthine oxidase are important mediators of PA-induced proteinuria.

Urinary biomarkers, such as albumin and other markers of kidney injury, are frequently reported as a normalized ratio to urinary creatinine (UCr) concentration [UCr] to control for variations in urine flow rate. The implicit assumption is that UCr excretion is constant across and within individuals, such that changes in the ratio will reflect changes in biomarker excretion. Using computer simulations of creatinine kinetics, we found that normalized levels of a biomarker reflecting tubular injury can be influenced by dynamic changes in the UCr excretion rate when the glomerular filtration rate changes. Actual timed urine collections from hospitalized patients with changing glomerular filtration rates and/or critical illness exhibited variability in UCr excretion rates across and within individuals. Normalization by [UCr] may, therefore, result in an underestimation or overestimation of the biomarker excretion rate depending on the clinical context. Lower creatinine excretion in the setting of acute kidney injury or poor renal allograft function may amplify a tubular injury biomarker signal, thereby increasing its clinical utility. The variability of creatinine excretion, however, will complicate the determination of a threshold value for normalized biomarkers of acute or chronic kidney disease, including albumin. Thus, we suggest that the most accurate method to quantify biomarkers requires the collection of timed urine specimens to estimate the actual excretion rate, provided that the biomarker is stable over the period of collection. This ideal must be balanced, however, against practical considerations.

Ischemic acute renal failure: An inflammatory disease? Inflammation plays a major role in the pathophysiology of acute renal failure resulting from ischemia. In this review, we discuss the contribution of endothelial and epithelial cells and leukocytes to this inflammatory response. The roles of cytokines/chemokines in the injury and recovery phase are reviewed. The ability of the mouse kidney to be protected by prior exposure to ischemia or urinary tract obstruction is discussed as a potential model to emulate as we search for pharmacologic agents that will serve to protect the kidney against injury. Understanding the inflammatory response prevalent in ischemic kidney injury will facilitate identification of molecular targets for therapeutic intervention.

In a recent editorial printed in this Journal [1], it was proposed that total body sodium was regulated around a set point by a feedback-control system. The set point was postulated to be "…that amount of sodium chloride in the patient's body when he is in balance on a no-salt intake". We would like to present an alternative description of sodium homeostasis that we feel is more consistent with the available experimental data. Regulation of sodium in the body can be best described by a series of steady states determined by many factors, one of which is the intake of sodium.

Let us try to state concisely the difference between the view we present and that proposed by Hollenberg. He regards the regulation of sodium excretion as focused on a single level of body sodium, namely that attained on a sodium-free intake. This he regards as the set point about which sodium excretion is regulated. We think the evidence is consistent with regulation of renal sodium excretion through a continuous range of steady states and that the capacity to excrete sodium is a function of body sodium content which in turn is related directly to the sodium intake; there is no single set point.