Aliskiren and losartan in patients with type 2 diabetes and nephropathy

Among patients with type 2 diabetes mellitus, angiotensin receptor blockers have improved renal outcomes. In an attempt to further suppress proteinuria and improve outcomes, angiotensin-converting enzyme inhibitors (ACEIs) have been used in combination with angiotensin receptor blockers (ARBs). Combination ACEI/ARB therapy has inconsistently resulted in better outcomes but has more consistently resulted in higher rates of adverse events.

In a new study by Parving et al., patients were randomized to receive the ARB losartan or losartan plus the ACEI aliskiren for 24 weeks. The primary outcome was a reduction in the ratio of urinary albumin to creatinine measured at 6 months. Treatment with aliskiren reduced the urinary albumin-to-creatinine ratio by 20% as compared with placebo (P<0.001). At week 24, the overnight urinary albumin excretion rate showed a similar reduction of 18% in the aliskiren group (P=0.009). Patients receiving placebo did not demonstrate a change in albumin-to-creatinine ratio, urinary albumin excretion rate, or blood pressure over 6 months. The albumin-to-creatinine ratio and urinary albumin excretion rates lowered significantly in patients receiving aliskiren, while blood pressure was similar to that in the placebo group and remained the same. All subgroups had similar reduction in albuminuria, based on gender or race, age, the presence of albuminuria, glomerular filtration rate, systolic and diastolic blood pressure, and glycated hemoglobin. Most notably, the group receiving aliskiren did not have an increased risk of either adverse events or serious adverse events.

Given that the benefits of aliskiren were independent of the urinary albumin excretion rate, the combination therapy could be used in all patients in whom suppression of microalbuminuria is the goal. A second option is to add aliskiren to an ARB after the failure of the ARB to achieve the targeted albumin excretion rate. The cost of drugs as well as the benefit of lowering albumin excretion rates among patients in whom microalbuminuria is already well suppressed will need to be defined when choosing between these two treatment strategies. (N Engl J Med 2008; 358: 2433–2446)

Lynda Szczech

The proteasome inhibitor bortezomib protects mice with lupus-like disease from nephritis

Antibody-mediated diseases such as systemic lupus erythematosus (SLE) are frequently difficult to treat and often do not achieve remission despite aggressive therapies such as high-dose glucosteroids and cyclophosphamide. Autoantibodies against multiple targets are critically involved in the pathogenesis of antibody-mediated diseases, and treatments are designed to decrease autoantibody generation. Current therapies can efficiently attack B lymphocytes, plasmablasts, and short-lived plasma cells but not long-lived plasma cells, which are resistant even to autologous and allogeneic stem-cell transplantations. The ubiquitin–proteasome pathway regulates intracellular protein turnover, and its function is crucial to cellular homeostasis. Proteasome inhibitors were initially synthesized as probes of proteolytic processes but were soon used as anticancer drugs when they were found to induce apoptosis preferentially in transformed cells.

The sensitivity of myeloma cells toward proteasome inhibitors was recently found to directly correlate with their immunoglobulin synthesis rates. Hence, Neubert et al. hypothesized that normal plasma cells may also be hypersensitive to proteasome inhibition owing to their extremely high amount of protein biosynthesis. NZB/W F1 mice spontaneously develop a disease closely resembling human SLE, and cyclophosphamide-resistant long-lived plasma cells represent a large fraction of autoreactive antibody-producing cells in the spleen. Using these mice, the authors found that the proteasome inhibitor bortezomib, which is approved for the treatment of multiple myeloma, eliminated both short- and long-lived plasma cells. Treatment with bortezomib depleted plasma cells producing antibodies against double-stranded DNA eliminated autoantibody production, and ameliorated glomerulonephritis (Figure). The drug prolonged survival of NZB/W F1 mice and another mouse strain with lupus-like disease, MRL/lpr mice. The elimination of plasma cells producing pathogenic autoantibodies represents a key therapeutic goal for efficient treatment of antibody-mediated diseases. Hence, the elimination of autoreactive plasma cells by proteasome inhibitors might represent a new treatment strategy for antibody-mediated diseases. (Nat Med 2008; 14: 748–755; doi:10.1038/nm1763)

Representative kidney sections, stained with periodic acid-Schiff stain (top) or anti-mouse IgG (bottom), from 60-week-old mice that had been treated with bortezomib (Bz) beginning at 18 weeks (middle) and 24 weeks (right) of age and from a 40-week-old control mouse (left).

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Juan Oliver

Using whole-organ genomic mapping to understand the development of bladder cancer

The search for the genomic sequences involved in human cancers can be greatly facilitated by maps of genomic imbalances identifying the involved chromosomal regions, particularly those that participate in the development of occult preneoplastic conditions that progress to clinically aggressive invasive cancer. The integration of such regions with human genome sequence variation may provide valuable clues about their overall structure and gene content. By extension, such knowledge may help us understand the underlying genetic components involved in the initiation and progression of these cancers. Majewski et al. describe the development of a genome-wide map of human bladder cancer that tracks its progression from in situ precursor conditions to invasive disease. They performed testing for allelic losses using a genome-wide panel of 787 microsatellite markers on multiple DNA samples extracted from the entire mucosal surface of the bladder and corresponding to normal urothelium, in situ preneoplastic lesions, and invasive carcinoma. The authors matched the clonal allelic losses in distinct chromosomal regions to specific phases of bladder neoplasia and produced a detailed genetic map of bladder cancer development. These analyses revealed three major waves of genetic changes associated with growth advantages of successive clones and reflecting a stepwise conversion of normal urothelial cells into cancer cells. The genetic changes map to six regions at 3q22–q24, 5q22–q31, 9q21–q22, 10q26, 13q14, and 17p13 (Figure), which may represent critical hits driving the development of bladder cancer. Finally, the authors defined a minimal deleted region associated with clonal expansion of in situ neoplasia. These findings provide new insights into the involvement of several non-coding sequences mapping to the region and identify novel target genes, termed 'forerunner genes', involved in early phases of cancer development. (Lab Invest 2008; 88: 694–721; doi:10.1038/labinvest.2008.27)

Identification of six critical chromosomal regions involved in the development of bladder cancer.

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Marc De Broe

Vasopressin regulates the renin–angiotensin–aldosterone system

In addition to water metabolism, arginine vasopressin (AVP) is involved in multiple other functions, which are mediated by three AVP receptors: V1a, V1b, and V2. The V1a receptor (V1aR) is widely expressed (particularly in the vasculature), whereas V1bR and V2R are mainly expressed in the anterior pituitary gland and the kidney, respectively. V1aR mediates vascular contraction, cellular proliferation, platelet aggregation, glycogenolysis, lipid metabolism, and glucose tolerance. In the kidney, V2R is expressed in the thick ascending limbs of Henle's loop and the collecting ducts. Because in the kidney V1aR is also detected in the juxtaglomerular apparatus, thick ascending limbs, and collecting ducts, both V1aR and V2R are likely involved in renal excretory function. When Aoyagi et al. recently generated V1aR-deficient (V1aR^-/-) mice, they found that these animals had lower circulating blood volume and blood pressure. Interestingly, these mice had decreased levels of plasma atrial natriuretic peptide and aldosterone. In a new follow-up study, the same authors used the V1aR^-/- mice to investigate the role of V1aR in urine concentration, renal function, and the renin–angiotensin system. They found that, when compared with wild-type controls, V1aR^-/- mice had lower glomerular filtration rate and urinary NaCl excretion as well as renal AVP-dependent cAMP generation and expression of V2R and aquaporin 2. In addition, urine volumes of V1aR^-/- mice were greater than those of wild-type mice, particularly during water loading, indicating impaired urinary-concentration ability. It is of great interest that plasma renin activity, angiotensin II level, and renin expression in the kidney were all decreased in these animals (Figure). Strikingly, the expression of renin stimulators such as neuronal nitric oxide synthase and cyclooxygenase-2 in macula densa cells, where V1aR was specifically expressed, was decreased in V1aR^-/- mice. These results indicate that, in addition to its well-known effects, AVP regulates body fluid homeostasis and renal function via its V1a receptor, particularly in the macula densa cells where it activates the renin–angiotensin system. (Am J Physiol Renal Physiol 2008; 295: F100–F107; doi:10.1152/ajprenal.00088.2008)

Immunostaining for renin in the granular cells and renal tubule of wild-type (WT) and V1aR^-/- mouse kidneys.

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Juan Oliver