Stages Of Polycystic Kidney Disease Research Articles

Sheathless CE-MS based metabolic profiling of kidney tissue section samples from a mouse model of Polycystic Kidney Disease

Capillary electrophoresis-mass spectrometry (CE-MS) using a sheathless porous tip interface emerged as an attractive tool in metabolomics thanks to its numerous advantages. One of the main advantages compared to the classical co-axial sheath liquid interface is the increased sensitivity, while maintaining the inherent properties of CE, such as a high separation efficiency and low sample consumption. Specially, the ability to perform nanoliter-based injections from only a few microliters of material in the sample vial makes sheathless CE-MS a well-suited and unique approach for highly sensitive metabolic profiling of limited sample amounts. Therefore, in this work, we demonstrate the utility of sheathless CE-MS for metabolic profiling of biomass-restricted samples, namely for 20 µm-thick tissue sections of kidney from a mouse model of polycystic kidney disease (PKD). The extraction method was designed in such a way to keep a minimum sample-volume in the injection vial, thereby still allowing multiple nanoliter injections for repeatability studies. The developed strategy enabled to differentiate between different stages of PKD and as well changes in a variety of different metabolites could be annotated over experimental groups. These metabolites include carnitine, glutamine, creatine, betaine and creatinine. Overall, this study shows the utility of sheathless CE-MS for biomass-limited metabolomics studies.

Effects of TORC1 Inhibition during the Early and Established Phases of Polycystic Kidney Disease

The disease-modifying effects of target of rapamycin complex 1 (TORC1) inhibitors during different stages of polycystic kidney disease (PKD) are not well defined. In this study, male Lewis Polycystic Kidney Disease (LPK) rats (a genetic ortholog of human NPHP9, phenotypically characterised by diffuse distal nephron cystic growth) and Lewis controls received either vehicle (V) or sirolimus (S, 0.2 mg/kg by intraperitoneal injection 5 days per week) during the early (postnatal weeks 3 to 10) or late stages of disease (weeks 10 to 20). In early-stage disease, sirolimus reduced kidney enlargement (by 63%), slowed the rate of increase in total kidney volume (TKV) in serial MRI by 78.2% (LPK+V: 132.3±59.7 vs. LPK+S: 28.8±12.0% per week) but only partly reduced the percentage renal cyst area (by 19%) and did not affect the decline in endogenous creatinine clearance (CrCl) in LPK rats. In late-stage disease, sirolimus reduced kidney enlargement (by 22%) and the rate of increase in TKV by 71.8% (LPK+V: 13.1±6.6 vs. LPK+S: 3.7±3.7% per week) but the percentage renal cyst area was unaltered, and the CrCl only marginally better. Sirolimus reduced renal TORC1 activation but not TORC2, NF-κB DNA binding activity, CCL2 or TNFα expression, and abnormalities in cilia ultrastructure, hypertension and cardiac disease were also not improved. Thus, the relative treatment efficacy of TORC1 inhibition on kidney enlargement was consistent at all disease stages, but the absolute effect was determined by the timing of drug initiation. Furthermore, cystic microarchitecture, renal function and cardiac disease remain abnormal with TORC1 inhibition, indicating that additional approaches to normalise cellular dedifferentiation, inflammation and hypertension are required to completely arrest the progression of PKDs.

Inhibition of Sodium-GlucoseCotransporter 2 with Dapagliflozin in Han: SPRD Rats with Polycystic Kidney Disease

Background/Aims: Dapagliflozin (DAPA) is a selective inhibitor of the sodium-glucose cotransporter 2 (SGLT2) which induces glucosuria and osmotic diuresis. The therapeutic effect of DAPA in progressing stages of polycystic kidney disease (PKD) has not been studied. Methods: We examined the effect of DAPA in the Han: SPRD rat model of PKD. DAPA (10 mg/kg/day) or vehicle (VEH) was administered orally via gavage to 5 week old male Han: SPRD (Cy/+) or control (+/+) rats (n = 8-9 per group) for 5 weeks. Blood and urine were collected at baseline and after 2.5 and 5 weeks of treatment to assess renal function and albuminuria. At the end of the treatment, rats were sacrificed and kidneys were excised for histological analysis. Results: After 5 weeks of treatment, DAPA-treated Cy/+ and +/+ rats exhibited significantly higher glucosuria, water intake and urine output than VEH-treated rats. DAPA-treated Cy/+ rats also exhibited significantly higher clearances for creatinine and BUN and less albuminuria than VEH-treated Cy/+ rats. DAPA treatment for 5 weeks resulted in a significant increase of the kidney weight in Cy/+ rats but no change in cyst growth. The degree of tubular epithelial cell proliferation, macrophage infiltration and interstitial fibrosis was also similar in DAPA-and VEH-treated Cy/+ rats. Conclusion: The induction of glucosuria with the SGLT2-specific inhibitor DAPA was associated with improved renal function and decreased albuminuria, but had no effect on cyst growth in Cy/+ rats. Overall the beneficial effects of DAPA in this PKD model were weaker than the previously described effects of the combined SGLT1/2 inhibitor phlorizin.

New Options for Old Diseases:Aquaretics (Vasopressin Receptor Antagonists)

There are multiple receptors for vasopressin (ADH) named the V1a, V1b, and V2 receptors. The V2 receptors primarily mediate the antidiuretic response, while V1a and V1b receptors principally cause vasoconstriction and mediate adrenocorticotropin release, respectively. Some oral formulations of vasopressin receptor antogonists tolvaptan, satavaptan, and lixivaptan — are selective for the V2 receptor, while an intravenous agent, conivaptan, blocks both the V2 and V1a receptors and is approved for the management of patients with euvolemic hyponatremia (mostly due to SIADH) and hypervolemic hyponatremia. The vasopressin receptor antagonists produce a selective water diuresis without affecting sodium and potassium excretion. The ensuing loss of free water will tend to correct the hyponatremia in patients with SIADH. Elevated levels of vasopressin may contribute to the increase in systemic vascular resistance in heart failure via stimulation of the V1a receptor, which is found on vascular smooth muscle cells, and also promote renal water retention via the V2 receptor, leading to the development of hyponatremia. At present, conivaptan is the only vasopressin receptor antagonist approved for use. In patients with heart failure, conivaptan both raises the serum sodium concentration and, via blockade of the V1a receptors, diminishes afterload, possibly improving systemic hemodynamics. V2 receptor antagonists (aquaretics) have a critical role in the management of the hyponatremia of SIADH, heart failure, ascites of hepatic failure and they may also diminish the cystogenesis in the early stages of polycystic kidney disease.

Behaviour of Arterial Pressure in Different Stages of Polycystic Kidney Disease

Arterial pressure was measured in 94 adult patients with polycystic kidney disease (PKD) and the data obtained were compared with those of two groups of patients with other chronic renal diseases. Pat

Autosomal dominant polycystic kidney disease. Early diagnosis and consideration of pathogenesis.

Renal function studies and excretory urograms were performed for 16 asymptomatic subjects at risk for polycystic kidney disease (PKD). The subjects represented five unrelated families, and ranged in age from 11 to 26 years. Fourteen subjects with normal excretory urograms underwent percutaneous renal biopsy. An additional renal biopsy specimen was obtained at the time of nephrectomy from a subject who had PKD. In four of the 14 subjects who had biopsies, PKD was documented about three years later by excretory urograms with nephrotomograms, renal radionuclide imaging, and gray-scale ultrasonography. Light-microscopic findings of dilated distal and collecting tubules suggested early manifestations of PKD in the renal biopsy specimens from five of the 14 subjects. In three of these five subjects, but also in one of nine subjects without light-microscopic changes of tubular dilatation, PKD was documented three years later. By electron microscopy, no differences in fine structural details were seen between specimens with and without tubular dilation observed by light microscopy, except for splitting of the lamina densa of the glomerular capillary basement membrane, which was present in only two specimens with light-microscopic changes of tubular dilation from subjects with PKD documented three years later, and in the nephrectomy specimen. Renal function studies were normal for 14 subjects, including four who had documented PKD. These data suggest that lightmicroscopic changes of tubular dilatation (seen in five of the 14 specimens, including three from the four restudied subjects in whom PKD was documented three years later) and electronmicroscopic changes of lamina densa splitting (seen only in two specimens with light-microscopic changes of tubular dilatation from subjects with PKD documented three years later and in the nephrectomy specimen), may be the earliest recognizable histologic changes in the carriers of the abnormal gene for PKD. However, because in the early stages of PKD these histologic changes may not be diffusely distributed, we do not advocate renal biopsy, but would suggest excretory urograms (with nephrotomography), radionuclide imaging, or gray-scale ultrasonography as the initial diagnostic procedures.