Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation, leading to growth in kidney volume and renal function decline. Although therapies have emerged,... Show moreAutosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation, leading to growth in kidney volume and renal function decline. Although therapies have emerged, there is still an important unmet need for slowing the rate of disease progression in ADPKD. High intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP) are involved in cell proliferation and fluid secretion, resulting in cyst formation. Somatostatin (SST), a hormone that is involved in many cell processes, has the ability to inhibit intracellular cAMP production. However, SST itself has limited therapeutic potential since it is rapidly eliminated in vivo. Therefore analogues have been synthesized, which have a longer half-life and may be promising agents in the treatment of ADPKD. This review provides an overview of the complex physiological effects of SST, in particular renal, and the potential therapeutic role of SST analogues in ADPKD. Show less
Messchendorp, A.L.; Meijer, E.; Visser, F.W.; Engels, G.E.; Kappert, P.; Losekoot, M.; ... ; DIPAK-1 Study Investigators 2019
Background: Markers currently used to predict the likelihood of rapid disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) are expensive and time consuming to... Show moreBackground: Markers currently used to predict the likelihood of rapid disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) are expensive and time consuming to assess and often have limited sensitivity. New, easy-to-measure markers are therefore needed that alone or in combination with conventional risk markers can predict the rate of disease progression. In the present study, we investigated the ability of tubular damage and inflammation markers to predict kidney function decline. Methods: At baseline, albumin, immunoglobulin G, kidney injury molecule 1, beta 2 microglobulin (beta 2MG), heart-type fatty acid-binding protein, neutrophil gelatinase-associated lipocalin, and monocyte chemotactic protein-1 -(MCP-1) were measured in 24-h urine samples of patients participating in a study investigating the therapeutic efficacy of lanreotide in ADPKD. Individual change in estimated glomerular filtration rate (eGFR) during follow-up was calculated using mixed-model analysis taking into account 13 -eGFRs (chronic kidney disease EPIdemiology) per patient. Logistic regression analysis was used to select urinary biomarkers that had the best association with rapidly progressive disease. The predictive value of these selected urinary biomarkers was compared to other risk scores using C-statistics. Results: Included were 302 patients of whom 53.3% were female, with an average age of 48 +/- 7 years, eGFR of 52 +/- 12 mL/min/1.73 m(2), and a height-adjusted total kidney volume (htTKV) of 1,082 (736-1,669) mL/m. At baseline, all urinary damage and inflammation markers were associated with baseline eGFR, also after adjustment for age, sex and baseline htTKV. For longitudinal analyses only patients randomized to standard care were considered (n = 152). A stepwise backward analysis revealed that beta 2MG and MCP-1 showed the strongest association with rapidly progressive disease. A urinary biomarker score was created by summing the ranking of tertiles of beta 2MG and MCP-1 excretion. The predictive value of this urinary biomarker score was higher compared to that of the Mayo htTKV classification (area under the curve [AUC] 0.73 [0.64-0.82] vs. 0.61 [0.51-0.71], p = 0.04) and comparable to that of the predicting renal outcomes in -ADPKD score (AUC 0.73 [0.64-0.82] vs. 0.65 [0.55-0.75], p = 0.18). In a second independent cohort with better kidney function, similar results were found for the urinary biomarker score. Conclusion: Measurement of urinary beta 2MG and MCP-1 excretion allows selection of ADPKD patients with rapidly progressive disease, with a predictive value comparable to or even higher than that of TKV or PKD mutation. Easy and inexpensive to measure urinary markers therefore hold promise to help predict prognosis in ADPKD. Show less
BACKGROUND & AIMS: Polycystic liver disease is the most common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). There is need for robust long-term evidence for... Show moreBACKGROUND & AIMS: Polycystic liver disease is the most common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). There is need for robust long-term evidence for the volume-reducing effect of somatostatin analogues. We made use of data from an open-label, randomized trial to determine the effects of lanreotide on height-adjusted liver volume (hTLV) and combined height-adjusted liver and kidney volume (hTLKV) in patients with ADPKD. METHODS: We performed a 120-week study comparing the reno-protective effects of lanreotide vs standard care in 305 patients with ADPKD (the DIPAK-1 study). For this analysis, we studied the 175 patients with polycystic liver disease with hepatic cysts identified by magnetic resonance imaging and liver volume >2000 mL. Of these, 93 patients were assigned to a group that received lanreotide (120 mg subcutaneously every 4 weeks) and 82 to a group that received standard care (blood pressure control, a sodium-restricted diet, and antihypertensive agents). The primary endpoint was percent change in hTLV between baseline and end of treatment (week 120). A secondary endpoint was change in hTLKV. RESULTS: At 120 weeks, hTLV decreased by 1.99% in the lanreotide group (95% confidence interval [CI], -4.21 to 0.24) and increased by 3.92% in the control group (95% CI, 1.56-6.28). Compared with the control group, lanreotide reduced the growth of hTLV by 5.91% (95% CI, -9.18 to -2.63; P < .001). Growth of hTLV was still reduced by 3.87% at 4 months after the last injection of lanreotide compared with baseline (95% CI, -7.55 to -0.18; P = .04). Lanreotide reduced growth of hTLKV by 7.18% compared with the control group (95% CI, -10.25 to -4.12; P < .001). CONCLUSIONS: In this subanalysis of a randomized trial of patients with polycystic liver disease due to ADPKD, lanreotide for 120 weeks reduced the growth of liver and combined liver and kidney volume. This effect was still present 4 months after the last injection of lanreotide. Show less
