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This Month’s Highlights

The Calcimimetic AMG 073 as a Potential Treatment for Secondary Hyperparathyroidism of End-Stage Renal Disease
A Pill for Secondary Hyperparathyroidism.

Hyperparathyroidism is associated with an increased risk of death, whereas hypoparathyroidism has been associated with low-turnover bone disease and vascular calcification. Suppression of PTH with vitamin D and calcium has been associated with hypercalcemia, whereas surgical approaches produce hypoparathyroidism. In this issue of JASN, Quarles et al. report in a randomized clinical trial design the efficacy of adding a calcimimetic agent to standard therapy for the suppression of PTH in patients with hyperparathyroidism. The mechanism is to increase the sensitivity of the parathyroid-sensing calcium receptor to calcium. The dose of AMG 073 was titrated up to 100 mg daily over 18 wk. The PTH values decreased by 33% in treatment group compared with an increase of 3% in the standard-therapy group. The serum calcium, phosphorous, and their product were lower in the treatment compared with the standard-therapy group. The treatment was tolerated well, with vomiting being the only significant side effect. Calcimimetic agents offer a new approach to the management of secondary hyperparathyroidism with the potential to titrate the PTH values to desired target ranges without inducing hypercalcemia.FIGURE

CTGF Mediates TGF--Induced Fibronectin Matrix Deposition by Upregulating Active 51 Integrin in Human Mesangial Cells
Another Link in the Process from High Glucose to Scarred Glomeruli.

The mesangial cell has long been regarded as central to the pathogenesis of diabetic nephropathy because mesangial matrix expansion correlates well with loss of renal function. Studies in the 1990s by Border and others clearly established TGF-, which is overexpressed in diabetes, as the key molecule driving mesangial synthesis of matrix components such as fibronectin. More recently, other components of this pathway have been appreciated, such as the SMAD and connective tissue growth factor (CTGF), through which TGF seems to act. Also involved in this process is 51 integrin, a cell surface receptor that binds to fibronectin. In this study, Weston et al. from Imperial College in London further explore the interrelationships between TGF, CTGF, and 51 in the mesangial cell. Using molecular technology, they establish that both TGF and CTGF increase 51 expression and mesangial adhesion to fibronectin, that the TGF effect is mediated through CTGF, and that selective blockade of 51 diminishes fibronectin deposition. Thus the critical effects of high glucose and TGF on matrix expansion seem to be mediated by CTGF through effects on 51 integrin expression. Although efforts to target TGF- therapeutically have been in progress for some time, observations such as this add two additional molecules to the list of potential targets for therapeutic intervention in the critical efforts to reduce the effects of the epidemic of diabetes on the expanding population of diabetic patients with end-stage renal disease.FIGURE

Hemodynamics, Hypertension, and Vascular Regulation

Development of Renal Disease in People at High Cardiovascular Risk: Results of the HOPE Randomized Study
Microalbuminuria — It’s Not Just Diabetic Patients Who Are at Increased Risk.

Microalbuminuria predicts nondiabetic renal injury. The role of microalbuminuria as a risk factor for renal injury in nondiabetic patients remains uncertain. The secondary analysis of the HOPE (Heart Outcomes and Prevention Evaluation) study by Mann et al. in this issue of JASN provides evidence that microalbuminuria is as strong a predictor of subsequent renal injury for nondiabetic patients as for diabetic patients. HOPE was a randomized clinical trial that included 9297 participants (3577 were diabetic). Subjects were selected for the presence of either existing cardiovascular disease (CVD) or high risk of subsequent CVD. Among subjects with microalbuminuria at the onset of the study, the risk of clinical proteinuria was 17-fold higher than among those without baseline microalbuminuria. The magnitude of the risk was comparable for both nondiabetic (HR, 19.4; 95% CI, 10.0 to 38.0) and diabetic subjects (HR, 14.8; 95% CI, 10.3 to 21.5). Finally, after accounting for other risk factors, angiotensin-converting enzyme (ACE) inhibitor therapy was associated with reduced risk for progression (HR, 0.87; 95% CI, 0.78 to 0.97). Although it remains to be established that treatment strategies that reduce the risk of development and progression of microalbuminuria are renoprotective and cardioprotective, these results clearly support the importance of ACE therapy for both diabetic and nondiabetic patients at risk for cardiovascular disease.FIGURE

Immunology and Pathology

Administration of a Soluble Recombinant Complement C3 Inhibitor Protects against Renal Disease in MRL/lpr Mice
Can Complement Inhibition Benefit a Chronic Autoimmune Disease Like Lupus?

Understanding of the pathophysiology of immune renal injury supports the concept that tissue injury is mediated by complement activation in all forms of glomerulonephritis induced with antibodies. Once believed to reflect primarily neutrophil chemotaxis by C5a, it is now clear that the principal mediator of complement-dependent tissue injury in the glomerulus is not C5a but the terminal membrane attack complex, C5b-9. Of even greater importance to treatment considerations, it now appears that the interstitial fibrosis leading to progressive loss of renal function in most chronic proteinuric renal diseases is also mediated by C5b-9. Blocking complement activation is thus a very attractive objective in developing new therapies for progressive renal disease. In this issue of JASN, Bao et al. from the University of Chicago, utilize a soluble form of the complement regulatory protein Crry to substantially reduce both structural and functional renal injury in the MRL/lpr model of lupus nephritis in mice. Although other studies have also demonstrated beneficial effects from acute administration of soluble regulatory proteins, the importance of this study lies in the observation that a beneficial effect can be obtained in a chronic autoimmune disease akin to human lupus and that therapy was effective, even when given after disease development. This provides the best evidence so far for optimism that complement regulatory proteins, which are already in clinical trial in human disease, may represent an important and soon-available addition to the aging therapeutic armamentarium in antibody-mediated kidney disease. See also the editorial by Couser in this issue of JASN.FIGURE

Pathophysiology of Renal Disease

Cyclosporine A Slows the Progressive Renal Disease of Alport Syndrome (X-Linked Hereditary Nephritis): Results from a Canine Model
A Role for Cyclosporin in Non-Immune Renal Disease Too?

Cyclosporine A has been reported to improve renal function in humans with Alport syndrome, but carefully controlled studies of using this agent for this purpose are lacking. In this issue of JASN, a well-characterized animal model of Alport syndrome with progression to proteinuria, renal failure, and characteristic glomerular basement membrane alterations is used to examine the efficacy of cyclosporine therapy for this disease. Chen et al. show that cyclosporine A slows the progression of renal disease in the animals exhibiting Alport syndrome, but they also show that, contrary to what has been reported in humans, cyclosporine slows but does not arrest the disease in the dog model. Several unexpected findings also emerged from this study; for instance, cyclosporine did not have an effect on proteinuria, despite its effect on disease progression. This study provides a sound basis for continuing studies in humans on the efficacy of cyclosporine treatment for what is generally considered to be an untreatable disorder. The findings provide a measure of hope for patients affected by this disorder, as well as the clinicians who care for them.FIGURE

The Lack of Cyclin Kinase Inhibitor p27^Kip1 Ameliorates Progression of Diabetic Nephropathy
Does the Answer to Diabetic Nephropathy Lie in the Cell Cycle?

Cell-cycle regulatory proteins are intracellular molecules that regulate the progression of cells from quiescence through the cell cycle to mitosis and proliferation. Cyclin-dependent kinases favor moving through the cell cycle, whereas their partners, cyclin kinase inhibitors (CKI), prevent proliferation and favor other responses like apoptosis and hypertrophy. In diabetes, of course, everything is hypertrophied — individual cells, the glomeruli, the whole kidney, even the GFR initially. In this fascinating study, Awazu et al. ask what would happen if a creature that lacked an important CKI (p27, which is known to be increased in diabetic nephropathy) got diabetes. The answer: They are protected from diabetic nephropathy! In contrast to wild-type controls, p27 knockout mice given diabetes developed no renal hypertrophy, no glomerular hypertrophy, no albuminuria, and no mesangial matrix expansion. Of course, we do not yet know how to manipulate CKI levels in humans, but that day comes closer as understanding of the role of these proteins in disease rapidly expands. Once the exclusive domain of oncologists, nephrologists are also now finding new ways in which dysregulation of the cell cycle can lead to disease, or, as in this case, prevent development of the most common cause of ESRD. This is not the end of this important story. Stay tuned! See also the editorial by Wolf and Shankland in this issue of JASN.FIGURE

Clinical Nephrology

Pharmacokinetics of Mycophenolate Mofetil in Patients with Autoimmune Diseases Compared with Renal Transplant Recipients
Mycophenolate Mofetil (MMF) — The Dose Depends on the Disease.

We are regularly presented with new immunosuppressive drugs that emerge from the battle against transplant rejection. Not uncommonly, the use of effective immunosuppressants is then extended to nontransplant diseases of immune dysfunction — in nephrology, glomerulonephritis, and vasculitis. Of additional interest to us are the several observations that MMF may also be effective in progressive renal diseases of non-immune etiology, a finding still poorly understood. Usually we simply use drugs in the same doses and protocols worked out in transplant patients, where the large numbers make pharmacokinetic studies easy. However, the transplant setting with a single kidney and multidrug protocols is clearly unique and raises the question of how safe and effective such extrapolations really are. In this study, Neumann et al. provide good evidence that such extrapolations are not optimal and may be dangerous. Careful pharmacologic studies of MMF in patients with lupus and other forms of vasculitis found the vasculitic patients particularly exhibited different pharmacokinetics than transplant patients, particularly much lower maximal drug concentrations that could result in undertreatment. The study does not address the optimal dosing or efficacy of MMF in the nontransplant setting, but the authors make a strong case for considering and carefully measuring drug levels in different clinical settings, where significant differences are important to appreciate.FIGURE

Dialysis

Restriction of Dietary Glycotoxins Reduces Excessive Advanced Glycation End Products in Renal Failure Patients
Dietary Measures Can Reduce Serum Age Levels, But Can They Prevent Age-Mediated Tissue Damage?

Increased dialysis dose in peritoneal dialysis (ADEMEX) and hemodialysis (HEMO) has not improved all-cause mortality and should lead to studies of alternative treatment strategies. It has been suggested that the high concentration of advanced glycation end products (AGE) found in patients with end-stage renal disease may be a cardiovascular risk factor. In a small, randomized clinical trial of nondiabetic peritoneal dialysis patients, Uribarri et al. have tested the hypothesis that AGE concentrations can be decreased by a decrease in dietary AGE. The intervention consisted of different methods of home preparation of a self-selected menu. The low-AGE diet group had a 34 to 35% decrease in serum AGE (N-carboxymethyl-lysine and methylglyoxal derivatives), and the high-AGE group had a 26 to 29% increase. The intervention appears feasible, with only 5 of 26 patients being demonstrably noncompliant, and is worthy of further study.FIGURE

Epidemiology and Outcomes

Primary Vesicoureteric Reflux as a Predictor of Renal Damage in Children Hospitalized with Urinary Tract Infection: A Systematic Review and Meta-Analysis
Kids, UTI, and Reflux — Who Needs to Be Screened for What?

Primary vesicoureteric reflux in children has been associated with an increased risk of hypertension and chronic kidney disease, and it is recommended that children hospitalized with urinary tract infections should be screened for reflux. In the meta-analysis reported in this issue of JASN, Gordon et al. examined the value of a micturating cystography test for predicting renal scarring subsequently detected by Technetium scan. They report that a positive scan was observed in nearly 60% of children and that a positive cystogram had a positive likelihood ratio of 1.95 (95% CI, 1.51 to 2.54) and a negative likelihood ratio of 0.71 (95% CI, 0.58 to 0.85). As noted by the authors, the information provided by neither a positive nor a negative cystogram changed the pretest odds of detecting renal damage sufficiently to justify routine cystography. How should clinicians use this information? One should expect that the next revision of clinical practice guidelines for the evaluation and care of urinary tract infections in children will address this issue. Until revised guidelines are published, the summary evidence provided by Gordon et al. should be carefully weighed by clinicians in their diagnostic decision-making. Do these results mean that every child who is hospitalized with a UTI should be screened for renal scarring with a Technetium scan instead? This issue was not addressed by the meta-analysis, and the answer depends on future studies that will provide evidence about the prognostic and therapeutic value of Technetium scanning in this patient population. Until that evidence is available, clinicians must decide on a case-by-case basis how the results of a Technetium scan will modify their therapy of an individual patient.FIGURE

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