Deletion of Cdh-16 Ksp-cadherin leads to a developmental delay in the ability to maximally concentrate urine in mouse

Ksp-cadherin (Cadherin-16) is an atypical member of the cadherin superfamily of cell adhesion molecules that is ubiquitously expressed on the basolateral membrane of epithelial cells lining the nephron and the collecting system of the mammalian kidney. The principal aim of the present study was to determine if Ksp-cadherin played a critical role in the development and maintenance of the adult mammalian kidney by generating and evaluating a mouse line deficient in Ksp-cadherin. Ksp-null mutant animals were viable and fertile, and kidneys from both neonates and adults showed no evidence of structural abnormalities. Immunolocalization and Western analyses of Na/K-ATPase and E-cadherin indicated that Ksp-cadherin is not essential for either the genesis or maintenance of the polarized tubular epithelial phenotype. Moreover, E-cadherin expression was not altered to compensate for Ksp-cadherin loss. Plasma electrolytes, total CO2, BUN, and creatinine levels were also unaffected by Ksp-cadherin deficiency. However, a subtle but significant developmental delay in the ability to maximally concentrate urine was detected in Ksp-null mice. Expression analysis of the principal proteins involved in the generation of the cortico-medullary osmotic gradient and the resultant movement of water identified misexpression of Aquaporin-2 in the inner medullary collecting duct as the possible cause for the inability of young adult Ksp-cadherin deficient animals to maximally concentrate their urine. In conclusion, Ksp-cadherin is not required for normal kidney development but its absence leads to a developmental delay in maximal urinary concentrating ability.

The Urinary Excretion of Uromodulin is Regulated by the Potassium Channel ROMK

Uromodulin, the most abundant protein in normal urine, is produced by cells lining the thick ascending limb (TAL) of the loop of Henle. Uromodulin regulates the activity of the potassium channel ROMK in TAL cells. Common variants in KCNJ1, the gene encoding ROMK, are associated with urinary levels of uromodulin in population studies. Here, we investigated the functional link between ROMK and uromodulin in Kcnj1 knock-out mouse models, in primary cultures of mouse TAL (mTAL) cells, and in patients with Bartter syndrome due to KCNJ1 mutations. Both global and kidney-specific Kcnj1 knock-out mice showed reduced urinary levels of uromodulin paralleled by increased levels in the kidney, compared to wild-type controls. Pharmacological inhibition and genetic deletion of ROMK in mTAL cells caused a reduction in apical uromodulin excretion, reflected by cellular accumulation. In contrast, NKCC2 inhibition showed no effect on uromodulin processing. Patients with Bartter syndrome type 2 showed reduced urinary uromodulin levels compared to age and gender matched controls. These results demonstrate that ROMK directly regulates processing and release of uromodulin by TAL cells, independently from NKCC2. They support the functional link between transport activity and uromodulin in the TAL, relevant for blood pressure control and urinary concentrating ability.

New Insights in the Pathogenesis of Cisplatin-Induced Nephrotoxicity

Cisplatin (cis-diamminedichloroplatinum II) is a widely used chemotherapeutic agent. However, efficacy and clinical utility of this drug is significantly limited by severe side effects such as nephrotoxicity which develops due to renal accumulation and bio-transformation in proximal tubular epithelial cells. Cisplatin-induced nephrotoxicity can be manifested as acute kidney injury (AKI), or as different types of tubulopathies, salt wasting, loss of urinary concentrating ability, and magnesium wasting. The attenuation of cisplatin-caused AKI is currently accomplished by hydration, magnesium supplementation or mannitol-induced forced diuresis. However, mannitol treatment causes over-diuresis and consequent dehydration, indicating an urgent need for the clinical use of newly designed, safe and efficacious renoprotective drug, as an additive therapy for high dose cisplatin-treated patients. Accordingly, we emphasized current knowledge regarding molecular mechanisms responsible for cisplatin-caused nephrotoxicity and we described in detail the main clinical manifestations of cisplatin-induced renal dysfunction in order to pave the way for the design of new therapeutic approaches that can minimize detrimental effects of cisplatin in the kidneys. Having in mind that most of cisplatin-induced cytotoxic effects against renal cells are, at the same time, involved in anti-tumor activity of cisplatin, new nephroprotective therapeutic strategies have to prevent renal injury and inflammation without affecting cisplatin-induced toxicity against malignant cells.

Partial nephrogenic diabetes insipidus associated with lithium therapy

A 40-year-old Caucasian man developed excessive thirst and polyuria particularly at night over the preceding 6 months. He had been taking lithium for 16 years for the treatment of bipolar affective disorder. Investigations revealed subnormal maximum urinary concentrating ability after 8 hours of water deprivation and only a borderline response of urine osmolality to exogenous desmopressin given by intramuscular injection. A plasma copeptin concentration was elevated at 23 pmol/L. These results were consistent with partial nephrogenic diabetes insipidus. He was encouraged to increase his water intake as dictated by his thirst. In addition, he received amiloride with some improvement in his symptoms. Clinicians should be aware of the risk of nephrogenic diabetes insipidus with long-term lithium use and seek confirmation by a supervised water deprivation test augmented with a baseline plasma copeptin. If increased water intake is insufficient to control symptoms, amiloride may be considered.

Senior Loken syndrome with Atypical Retinitis Pigmentosa: a rare manifestation of rare disease

Senior Loken syndrome is an autosomal recessive condition characterized by combination of nephronophthisis and retinal degeneration. The earliest presenting features include polyuria and polydipsia secondary to impaired urinary concentrating ability. Nephronophthisis progresses to end stage kidney disease (ESKD) during second decade. The treatment of choice for ESKD due to nephronophthisis is renal transplantation. Retinal lesions are variable ranging from severe infantile onset retinal dystrophy to more typical retinitis pigmentosa. There is a spectrum of other features associated with this condition including skeletal, dermatological and cerebellar anomalies. Till date very few cases have been reported due to lack of awareness of this rare condition. Here, we report a case of Senior loken syndrome with atypical retinitis pigmentosa in a 14-year-old boy.