For decades, ill-defined autosomal dominant renal diseases have been reported, which originate from tubular cells and lead to tubular atrophy and interstitial fibrosis. These diseases are clinically indistinguishable, but caused by mutations in at least four different genes: UMOD, HNF1B, REN, and, as recently described, MUC1. Affected family members show renal fibrosis in the biopsy and gradually declining renal function, with renal failure usually occurring between the third and sixth decade of life. Here we describe 10 families and define eligibility criteria to consider this type of inherited disease, as well as propose a practicable approach for diagnosis. In contrast to what the frequently used term 'Medullary Cystic Kidney Disease' implies, development of (medullary) cysts is neither an early nor a typical feature, as determined by MRI. In addition to Sanger and gene panel sequencing of the four genes, we established SNaPshot minisequencing for the predescribed cytosine duplication within a distinct repeat region of MUC1 causing a frameshift. A mutation was found in 7 of 9 families (3 in UMOD and 4 in MUC1), with one indeterminate (UMOD p.T62P). On the basis of clinical and pathological characteristics we propose the term 'Autosomal Dominant Tubulointerstitial Kidney Disease' as an improved terminology. This should enhance recognition and correct diagnosis of affected individuals, facilitate genetic counseling, and stimulate research into the underlying pathophysiology.

Background and objectives The genetic cause of medullary cystic kidney disease type 1 was recently identified as a cytosine insertion in the variable number of tandem repeat region of MUC1 encoding mucoprotein-1 (MUC1), a protein that is present in skin, breast, and lung tissue, the gastrointestinal tract, and the distal tubules of the kidney. The purpose of this investigation was to analyze the clinical characteristics of families and individuals with this mutation.Design, setting, participants, & measurements Families with autosomal dominant interstitial kidney disease were referred for genetic analysis over a 14-year period. Families without UMOD or REN mutations prospectively underwent genotyping for the presence of the MUC1 mutation. Clinical characteristics were retrospectively evaluated in individuals with the MUC1 mutation and historically affected individuals (persons who were both related to genetically affected individuals in such a way that ensured that they could be genetically affected and had a history of CKD stage IV or kidney failure resulting in death, dialysis, or transplantation).Results Twenty-four families were identified with the MUC1 mutation. Of 186 family members undergoing MUC1 mutational analysis, the mutation was identified in 95 individuals, 91 individuals did not have the mutation, and111 individuals were identified as historically affected. Individuals with the MUC1 mutation suffered from chronic kidney failure with a widely variable age of onset of end stage kidney disease ranging from 16 to .80 years. Urinalyses revealed minimal protein and no blood. Ultrasounds of 35 individuals showed no medullary cysts. There were no clinical manifestations of the MUC1 mutation detected in the breasts, skin, respiratory system, or gastrointestinal tract.Conclusion MUC1 mutation results in progressive chronic kidney failure with a bland urinary sediment. The age of onset of end stage kidney disease is highly variable, suggesting that gene-gene or gene-environment interactions contribute to phenotypic variability.

The mitogen-activated protein (MAP) kinases contribute to altered cell growth and function in a variety of disease states. However, their role in the endothelial complications of diabetes mellitus remains unclear. Human endothelial cells were exposed for 72 h to 5 mM (control) or 25 mM (high) glucose or 5 mM glucose plus 20 mM mannitol (osmotic control). The roles of p38 and p42/44 MAP kinases in the high glucose-induced growth effects were determined by assessment of phosphorylated MAP kinases and their downstream activators by Western blot and by pharmacological inhibition of these MAP kinases. Results were expressed as a percentage (means Ϯ SE) of control. High glucose increased the activity of total and phosphorylated p38 MAP kinase (P Ͻ 0.001) and p42/44 MAP kinase (P Ͻ 0.001). Coexposure of p38 MAP kinase blocker with high glucose reversed the antiproliferative but not the hypertrophic effects associated with high-glucose conditions. Transforming growth factor (TGF)-␤1 increased the levels of phosphorylated p38 MAP kinase, and p38 MAP kinase blockade reversed the antiproliferative effects of this cytokine. The high glucose-induced increase in phosphorylated p38 MAP kinase was reversed in the presence of TGF-␤1 neutralizing antibody. Although hyperosmolarity also induced antiproliferation (P Ͻ 0.0001) and cell hypertrophy (P Ͻ 0.05), there was no change in p38 activity, and therefore inhibition of p38 MAP kinase had no influence on these growth responses. Blockade of p42/44 MAP kinase had no effect on the changes in endothelial cell growth induced by either high glucose or hyperosmolarity. High glucose increased p42/44 and p38 MAP kinase activity in human endothelial cells, but only p38 MAP kinase mediated the antiproliferative growth response through the effects of autocrine TGF-␤1. High glucose-induced endothelial cell hypertrophy was independent of activation of the MAP kinases studied. In addition, these effects were independent of any increase in osmolarity associated with high-glucose exposure. high glucose; endothelial cell; growth; p38 mitogen-activated protein kinase; p42/44 mitogen-activated protein kinase; transforming growth factor-␤1

Human endothelial cells were exposed to 5 mM glucose (control), 25 mM (high) glucose, or osmotic control for 72 h. TGF-beta1 production, cell growth, death, and cell cycle progression, and the effects of TGF-beta1 and TGF-beta neutralization on these parameters were studied. High glucose and hyperosmolarity increased endothelial TGF-beta1 secretion (P < 0.0001) and bioactivity (P < 0.0001). However, high glucose had a greater effect on reducing endothelial cell number (P < 0.001) and increasing cellular protein content (P < 0.001) than the osmotic control. TGF-beta antibody only reversed the antiproliferative and hypertrophic effects of high glucose. High glucose altered cell cycle progression and cyclin-dependent kinase inhibitor expression independently of hyperosmolarity. High glucose increased endothelial cell apoptosis (P < 0.01), whereas hyperosmolarity induced endothelial cell necrosis (P < 0.001). TGF-beta antibody did not reverse the apoptotic effects observed with high glucose. Exogenous TGF-beta1 mimicked the increased S phase delay but not endoreduplication observed with high glucose. High glucose altered endothelial cell growth, apoptosis, and cell cycle progression. These growth effects occurred principally via a TGF-beta1 autocrine pathway. In contrast, apoptosis and endoreduplication occurred independently of this cytokine and hyperosmolarity.

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Abstract-Chronic kidney disease is a major worldwide public health problem that causes substantial morbidity and mortality. Studies from the Asia-Pacific region have reported some of the highest chronic kidney disease prevalence rates in the world, but access to dialysis is limited in many countries, making it imperative to identify high-risk individuals. We performed a participant-level data overview of prospective studies conducted in the Asia-Pacific region to quantify the magnitude and direction of the associations between putative risk factors and renal death. Age-and sex-adjusted Cox proportional hazards models were applied to pooled data from 35 studies to calculate hazard ratios (95% CIs) for renal death associated with a standardized change in risk factors. Among 560 352 participants followed for a median of 6.8 years, a total of 420 renal deaths were observed. Continuous and positive associations among systolic blood pressure, diastolic blood pressure, fasting blood glucose, and total cholesterol levels with renal death were observed, as well as a continuous but inverse association with high-density lipoprotein cholesterol. Systolic blood pressure was the strongest risk factor for renal death with each SD increase in systolic blood pressure (19 mm Hg) associated with Ͼ80% higher risk (hazard ratio: 1.84; 95% CI: 1.60 to 2.12). Neither cigarette smoking nor excess weight was related to the risk of renal death (PϾ0.10). The results were similar for cohorts in Asia and Australia. These results suggest that primary prevention strategies for renal disease should focus on individuals with elevated blood pressure, diabetes mellitus, and dyslipidemia. (Hypertension. 2009;54:509-515.)

In conclusion, a unique and novel method for the differential isolation of both glomerular and tubulointerstitial endothelial cells has been developed. Significantly, characterization of these populations suggests a role for HUVECS in the study of renal tubulointerstitial disease.

Endothelial cell exposure to high glucose was associated with a MMP/TIMP profile that increased extracellular matrix production which was attenuated by concurrent exposure to atorvastatin. Consequently, a mechanism by which the atherosclerotic plaque regression that is observed in patients taking these drugs has been demonstrated.