The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

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Initial sequencing and analysis of the human genome.

The Modification of Diet in Renal Disease (MDRD) Study equation underestimates glomerular filtration rate (GFR) in patients with mild kidney disease. Levey and associates therefore developed and va...

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A New Equation to Estimate Glomerular Filtration Rate

Background End-stage renal disease substantially increases the risks of death, cardiovascular disease, and use of specialized health care, but the effects of less severe kidney dysfunction on these outcomes are less well defined. Methods We estimated the longitudinal glomerular filtration rate (GFR) among 1,120,295 adults within a large, integrated system of health care delivery in whom serum creatinine had been measured between 1996 and 2000 and who had not undergone dialysis or kidney transplantation. We examined the multivariable association between the estimated GFR and the risks of death, cardiovascular events, and hospitalization. Results The median follow-up was 2.84 years, the mean age was 52 years, and 55 percent of the group were women. After adjustment, the risk of death increased as the GFR decreased below 60 ml per minute per 1.73 m2 of body-surface area: the adjusted hazard ratio for death was 1.2 with an estimated GFR of 45 to 59 ml per minute per 1.73 m2 (95 percent confidence interval, 1....

https://www.nejm.org/doi/pdf/10.1056/NEJMoa041031

Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization

There is no consensus definition of acute renal failure (ARF) in critically ill patients. More than 30 different definitions have been used in the literature, creating much confusion and making comparisons difficult. Similarly, strong debate exists on the validity and clinical relevance of animal models of ARF; on choices of fluid management and of end-points for trials of new interventions in this field; and on how information technology can be used to assist this process. Accordingly, we sought to review the available evidence, make recommendations and delineate key questions for future studies. We undertook a systematic review of the literature using Medline and PubMed searches. We determined a list of key questions and convened a 2-day consensus conference to develop summary statements via a series of alternating breakout and plenary sessions. In these sessions, we identified supporting evidence and generated recommendations and/or directions for future research. We found sufficient consensus on 47 questions to allow the development of recommendations. Importantly, we were able to develop a consensus definition for ARF. In some cases it was also possible to issue useful consensus recommendations for future investigations. We present a summary of the findings. (Full versions of the six workgroups' findings are available on the internet at http://www.ADQI.net
 ) Despite limited data, broad areas of consensus exist for the physiological and clinical principles needed to guide the development of consensus recommendations for defining ARF, selection of animal models, methods of monitoring fluid therapy, choice of physiological and clinical end-points for trials, and the possible role of information technology.

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Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.

Background It is unknown whether either the angiotensin-II–receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure. Methods We randomly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan (300 mg daily), amlodipine (10 mg daily), or placebo. The target blood pressure was 135/85 mm Hg or less in all groups. We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration, the development of end-stage renal disease, or death from any cause. We also compared them with regard to the time to a secondary, cardiovascular composite end point. Results The mean duration of follow-up was 2.6 years. Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo gro...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa011303

Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes

https://www.kidney-international.org/article/S0085-2538(15)58422-6/pdf

Cell-mediated immune injury in the kidney: Acute nephritis induced in the rat by azobenzenearsonate

Introduction To investigate the role and mechanisms of indirect allorecognition in allograft rejection, we studied whether priming T cells with donor-derived MHC allopeptides could accelerate rejection in a vascularized allograft model. Methods Lewis recipients of fully mismatched Wistar Furth cardiac allografts were immunized before transplantation with donor MHC allopeptides. Results Animals immunized with immunogenic class II MHC allopeptides rejected their grafts in a significantly accelerated fashion compared with controls. Additional studies demonstrated that a single immunodominant RT1.D (HLA-DR like) allopeptide was responsible for accelerating the rejection process. Histological analysis of rejected allografts revealed marked vascular rejection in the accelerated, although not the control, group as well as severe cellular rejection. Peak production of IgM and IgG donor-specific alloantibodies was detected by flow cytometry 1 week earlier in the sera of the accelerated group compared with the control group. Immunohistological analysis of grafts from the accelerated compared with the control group showed increased endothelial deposition of IgG2b, C3, and fibrin, and up-regulation of class II MHC molecule expression. Increased intragraft expression of interferon-y and the interferon-gamma-induced chemokines, inducible protein-10 and Mig, and infiltration by activated mononuclear cells expressing CXCR3, the receptor for inducible protein-10 and Mig, was also seen. Conclusion These novel data provide evidence of a definitive link between indirect allorecognition of donor-derived MHC class II peptides and the cellular and humoral mechanisms of vascularized allograft rejection.

Cellular and humoral mechanisms of vascularized allograft rejection induced by indirect recognition of donor MHC allopeptides.

The role of glomerular hyperfiltration in the initiation and progression of diabetic nephropathy

Equilibrium binding studies with angiotensin II (AII) in isolated rat renal glomeruli indicate the presence of a single population of high-affinity AII receptors. Autoradiographic studies localize these receptors to glomerular mesangial cells, which are ideally positioned to modulate glomerular capillary patency and hence the glomerular capillary ultrafiltration coefficient. Modulation of AII receptor density occurs in response to alterations of circulating AII levels, with down-regulation of receptor number in the presence of salt depletion. Kinetic studies of the ligand dissociation rate performed in the presence and absence of MgCl2 and GTP indicate multiple affinity states and suggest that this receptor is coupled to a guanyl nucleotide regulatory unit. Such coupling may provide a basis for interaction with cyclase-activating hormones in modulating the contractile state of the mesangium.

Angiotensin II receptor regulation in isolated renal glomeruli.

Review of renal physiology regulation of salt and water balance disorders of water balance - hyponatremia, hypernatremia and polyuria edematous states and the use of diuretics acid-base physiology and metabolic alkalosis metabolic acidosis disorders of potassium balance urinalysis and approach to the patient with renal disease pathogenesis of major glomerular and vascular diseases acute renal failure progression of chronic renal failure signs and symptoms of chronic renal failure pathogenesis of major tubulointerstitial diseases and urinary tract obstruction.

Helmut G. Rennke

Papers

Cell-mediated immune injury in the kidney: Acute nephritis induced in the rat by azobenzenearsonate

Cellular and humoral mechanisms of vascularized allograft rejection induced by indirect recognition of donor MHC allopeptides.

The role of glomerular hyperfiltration in the initiation and progression of diabetic nephropathy

Angiotensin II receptor regulation in isolated renal glomeruli.

Renal Pathophysiology: The Essentials