Changes in tubular biomarkers with dietary intervention and metformin in patients with autosomal dominant polycystic kidney disease: a post-hoc analysis of two clinical trials.

BACKGROUND: Tubular biomarkers, which reflect tubular dysfunction or injury, are associated with incident chronic kidney disease and kidney function decline. Several tubular biomarkers have also been implicated in the progression of autosomal dominant polycystic kidney disease (ADPKD). We evaluated changes in multiple tubular biomarkers in four groups of patients with ADPKD who participated in one of two clinical trials (metformin therapy and diet-induced weight loss), based on evidence suggesting that such interventions could reduce tubule injury. METHODS: 66 participants (26 M/40 F) with ADPKD and an estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73m2 who participated in either a metformin clinical trial (n = 22 metformin; n = 23 placebo) or dietary weight loss study (n = 10 daily caloric restriction [DCR]; n = 11 intermittent fasting [IMF]) were included in assessments of urinary tubular biomarkers (kidney injury molecule-1 [KIM-1], fatty-acid binding protein [FABP], interleukin-18 [IL-18], monocyte chemoattractant protein-1 [MCP-1], neutrophil gelatinase-associated lipocalin [NGAL], clusterin, and human cartilage glycoprotein-40 [YKL-40]; normalized to urine creatinine), at baseline and 12 months. The association of baseline tubular biomarkers with both baseline and change in height-adjusted total kidney volume (HtTKV; percent change from baseline to 12 months) and estimated glomerular filtration rate (eGFR; absolute change at 12 months vs. baseline), with covariate adjustment, was also assessed using multiple linear regression. RESULTS: Mean ± s.d. age was 48 ± 8 years, eGFR was 71 ± 16 ml/min/1.73m2, and baseline BMI was 30.5 ± 5.9 kg/m2. None of the tubular biomarkers changed with any intervention as compared to placebo. Additionally, baseline tubular biomarkers were not associated with either baseline or change in eGFR or HtTKV over 12 months, after adjustments for demographics, group assignment, and clinical characteristics. CONCLUSIONS: Tubular biomarkers did not change with dietary-induced weight loss or metformin, nor did they associate with kidney disease progression, in this cohort of patients with ADPKD.

Identifying the main predictors of urine output in autosomal-dominant polycystic kidney disease (ADPKD) patients taking tolvaptan.

BACKGROUND: Few works have analyzed factors associated with urine output in ADPKD patients taking tolvaptan (TVP). METHODS: We selected 24-h urine samples from ADPKD patients treated with TVP. Urine osmolality/creatinine ratio was used as estimator of urinary osmolar load. RESULTS: We included 127 urine samples from 61 patients. After TVP, urine output doubled with a parallel reduction in urine solute concentration. However, when expressed as urine solute/creatinine ratios, no significant changes were observed. Daily osmolar load and osmolality/creatinine ratio did not change significantly. Before TVP, urine output was positively correlated with body weight and urine osmolality/creatinine ratio and negatively with eGFR, urine morning osmolality, and 24-h urine-calculated osmolality. After TVP, urine output was positively correlated with body weight, eGFR and negatively with age. There was a poor correlation with urine-calculated osmolality. We constructed a predictor model using mixed-effects modeling and we found that urine output was related to lower age, higher body weight, higher eGFR, and greater doses of TVP. When body weight was removed, urine output was also related to male sex and a higher daily osmolar excretion. Equation of prediction was: Urine output (mL/day) = 2771-52.9 × Age (years) + 58.4 × Weight (kg) + 18.7 × eGFR (mL/min) + 870 (if TVP = 90/30 mg) + 517 (if TVP = 60/30 mg). CONCLUSION: Patients taking TVP will undergo an increase about twice in urine production from baseline. Greater doses of TVP cause a progressive increase in urine production. GFR, age, and body weight are the main predictors of future urine output in patients taking TVP.

Evaluation of sirtuin 1 (SIRT1) levels in autosomal dominant polycystic kidney disease.

PURPOSE: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease and the majority of patients have a PKD-1 or PKD-2 mutation. Sirtuin 1 (SIRT1) has roles in cellular aging, antioxidant activity, cellular proliferation. In an experimental study, inhibition of SIRT1 was found to delay renal cyst development in ADPKD. The purpose of this study is to determine the SIRT1 levels in ADPKD patients. To our knowledge, this is the first study that investigating blood and urine SIRT1 levels in ADPKD patients. METHODS: Sixty-seven patients with ADPKD and 34 control cases with normal renal functions and without renal cysts were included in this study. Serum and urine SIRT1 concentrations were determined by human enzyme-linked immunosorbent assay (ELISA) kit. 24-h urine samples were used for urine SIRT1 measurements. RESULTS: The urine SIRT1 levels were statistically significantly lower in ADPKD patients group (p < 0.001). Although blood SIRT1 levels of ADPKD patients were higher than control cases but there were no statistically significant difference between the groups in terms of blood SIRT1 levels. Urine SIRT1 levels (ß = 2.452, CI 95% 1.419-4.239, p = 0.001) were found an independent factor in multivariate regression analysis for ADPKD. CONCLUSIONS: Urine SIRT1 levels were lower in ADPKD patients than control group. The low urinary SIRT1 levels despite the similar blood SIRT1 levels might be due to the impaired metabolism of SIRT1 in ADPKD patients; this state might has a role in cyst development.

Coregulation Analysis of Mechanistic Biomarkers in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder leading to deterioration of kidney function and end stage kidney disease (ESKD). A number of molecular processes are dysregulated in ADPKD but the exact mechanism of disease progression is not fully understood. We measured protein biomarkers being linked to ADPKD-associated molecular processes via ELISA in urine and serum in a cohort of ADPKD patients as well as age, gender and eGFR matched CKD patients and healthy controls. ANOVA and t-tests were used to determine differences between cohorts. Spearman correlation coefficient analysis was performed to assess coregulation patterns of individual biomarkers and renal function. Urinary epidermal growth factor (EGF) and serum apelin (APLN) levels were significantly downregulated in ADPKD patients. Serum vascular endothelial growth factor alpha (VEGFA) and urinary angiotensinogen (AGT) were significantly upregulated in ADPKD patients as compared with healthy controls. Arginine vasopressin (AVP) was significantly upregulated in ADPKD patients as compared with CKD patients. Serum VEGFA and VIM concentrations were positively correlated and urinary EGF levels were negatively correlated with urinary AGT levels. Urinary EGF and AGT levels were furthermore significantly associated with estimated glomerular filtration rate (eGFR) in ADPKD patients. In summary, altered protein concentrations in body fluids of ADPKD patients were found for the mechanistic markers EGF, APLN, VEGFA, AGT, AVP, and VIM. In particular, the connection between EGF and AGT during progression of ADPKD warrants further investigation.

Extracellular vesicles and exosomes generated from cystic renal epithelial cells promote cyst growth in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is caused by germline mutations of PKD1 or PKD2 on one allele and a somatic mutation inactivating the remaining normal allele. However, if and how null ADPKD gene renal epithelial cells affect the biology and function of neighboring cells, including heterozygous renal epithelial cells, fibroblasts and macrophages during cyst initiation and expansion remains unknown. Here we address this question with a "cystic extracellular vesicles/exosomes theory". We show that cystic cell derived extracellular vesicles and urinary exosomes derived from ADPKD patients promote cyst growth in Pkd1 mutant kidneys and in 3D cultures. This is achieved by: 1) downregulation of Pkd1 gene expression and upregulation of specific miRNAs, resulting in the activation of PKD associated signaling pathways in recipient renal epithelial cells and tissues; 2) the activation of fibroblasts; and 3) the induction of cytokine expression and the recruitment of macrophages to increase renal inflammation in cystic kidneys. Inhibition of exosome biogenesis/release with GW4869 significantly delays cyst growth in aggressive and milder ADPKD mouse models, suggesting that targeting exosome secretion has therapeutic potential for ADPKD.

Effect of Vasopressin on the Hypothalamic-Pituitary-Adrenal Axis in ADPKD Patients during V2 Receptor Antagonism.

BACKGROUND: Patients with autosomal dominant polycystic kidney disease (ADPKD) are treated with a vasopressin V2 receptor antagonist (V2RA) to slow disease progression. This drug increases vasopressin considerably in these patients with already elevated baseline levels. Vasopressin is known to stimulate the hypothalamic-pituitary-adrenal (HPA) axis through V1 and V3 receptor activation. It is unknown whether this increase in vasopressin during V2RA treatment affects glucocorticoid production. METHODS: Twenty-seven ADPKD patients were studied on and off treatment with a V2RA and compared to age- and sex-matched healthy controls and IgA nephropathy patients, the latter also matched for kidney function. Vasopressin was measured by its surrogate copeptin. Twenty-four-hour urinary excretions of cortisol, cortisone, tetrahydrocortisone, tetrahydrocortisol, allotetrahydrocortisol, and the total glucocorticoid pool were measured. RESULTS: At baseline, ADPKD patients demonstrated a higher copeptin concentration in comparison with healthy controls, while urinary excretion of cortisol and cortisone was lower (medians of 0.23 vs. 0.34 µmol/24 h, p = 0.007, and 0.29 vs. 0.53 µmol/24 h, p < 0.001, respectively). There were no differences in cortisol and cortisone excretion compared to IgA nephropathy patients. Cortisol, cortisone, and total glucocorticoid excretions correlated with kidney function (R = 0.37, 0.58, and 0.19, respectively; all p < 0.05). Despite that V2RA treatment resulted in a 3-fold increase in copeptin, only cortisone excretion increased (median of 0.44 vs. baseline 0.29 µmol/24 h, p < 0.001), whereas no changes in cortisol or total glucocorticoid excretion were observed. CONCLUSIONS: Increased concentration of vasopressin in ADPKD patients at baseline and during V2RA treatment does not result in activation of the HPA axis. The impaired glucocorticoid production in these patients is related to their degree of kidney function impairment.

Urinary Lithogenic Risk Profile in ADPKD Patients Treated with Tolvaptan.

BACKGROUND AND OBJECTIVES: Nephrolithiasis is a common health problem in autosomal dominant polycystic kidney disease (ADPKD) and significantly contributes to patient morbidity. Recently, Tolvaptan has been introduced for the treatment of ADPKD, but whether it is associated with alterations of the urinary lithogenic risk profile remains unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted an analysis of participants enrolled in the Bern ADPKD registry, a prospective observational cohort study. Twenty-four-hour urine analyses were performed at baseline and then at yearly follow-ups. Relative supersaturation ratios for calcium oxalate, brushite, and uric acid were calculated with the program EQUIL2. Unadjusted and multivariable mixed-effects linear regression models, adjusted for age, sex, body mass index, eGFR, net acid excretion, and height-adjusted total kidney volume, were used to assess the association of Tolvaptan with urinary parameters relevant for kidney stone formation. The maximum individual follow-up time was 3 years, median follow-up time 1.9 years, and cumulative follow-up time 169 years. RESULTS: In total, 125 participants (38 with and 87 without Tolvaptan treatment) were included in the analysis. In multivariable analysis, Tolvaptan treatment was associated [adjusted estimate of the difference between Tolvaptan and no Tolvaptan; 95% confidence interval (CI)] with lower urine relative supersaturation ratios for calcium oxalate (-0.56; 95% CI, -0.82 to -0.3; P<0.001), brushite (-0.33; 95% CI, -0.54 to -0.11; P=0.004), and uric acid (-0.62; 95% CI, -0.88 to -0.37; P<0.001), and with higher urine citrate in mmol/mmol creatinine per day (0.25; 95% CI, 0.05 to 0.46; P=0.02) and calcium in mmol/mmol creatinine per day (0.31; 95% CI, 0.09 to 0.53; P=0.006) excretion. In addition, Tolvaptan treatment was associated with lower net acid excretion in mEq/mmol creatinine per day (-0.54; 95% CI, -0.90 to -0.17; P=0.004) and higher net gastrointestinal alkali absorption in mEq/mmol creatinine per day (0.57; 95% CI, 0.26 to 0.88; P<0.001). CONCLUSIONS: Tolvaptan treatment is associated with a significantly improved urinary lithogenic risk profile in patients with ADPKD.

Urinary Angiotensinogen in addition to Imaging Classification in the Prediction of Renal Outcome in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Intrarenal renin-angiotensin system (RAS) is known to play the major role in the development of hypertension and renal progression in autosomal dominant polycystic kidney disease (ADPKD). Urinary angiotensinogen to creatinine ratio (AGT/Cr) was suggested as a novel biomarker to reflect intrarenal RAS activity. This study was performed to evaluate urinary AGT/Cr as a predictive biomarker for renal function decline in addition to imaging classification in a prospective ADPKD cohort. METHODS: From 2011 to 2016, a total of 364 ADPKD patients were enrolled in the prospective cohort called the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD). Among them, a total of 207 subjects in chronic kidney disease stage 1-4 with baseline urinary AGT and total kidney volume and subsequent renal function follow-up data over more than 1 year were included in the analysis. Patients were defined as slow progressors (SP) if they are classified as 1A or 1B by imaging classification whereas rapid progressors (RP) if they are classified as 1C-1E. Patients were divided according to AGT/Cr quartiles and annual estimated glomerular filtration rate (eGFR) slope was compared among highest quartile (hAGT group) and the rest of quartiles (lAGT group). Patients were divided into 4 groups to evaluate the predictive value of urinary AGT/Cr in addition to imaging classification: SP/lAGT, SP/hAGT, RP/lAGT, and RP/hAGT. The Cox regression model was used to evaluate the hazard ratio (HR) between groups. RESULTS: The mean age was 45.9 years and 88.9% had hypertension. Baseline eGFR was 79.0 ± 28.4 mL/min/1.73 m² and median height-adjusted total kidney volume was 788.2 (471.2; 1,205.2) mL/m. The patients in the hAGT group showed lower eGFR (72.4 ± 24.8 vs. 81.1 ± 29.2 mL/min/1.73 m², P = 0.039), lower plasma hemoglobin (13.0 ± 1.4 vs. 13.7 ± 1.6 g/dL, P = 0.007), higher urinary protein to creatinine ratio (0.14 [0.09, 0.38] vs. 0.07 [0.04, 0.12] g/g, P = 0.007) compared to the lAGT group. The hAGT group was an independent risk factor for faster eGFR decline after adjusting for gender, RP, baseline eGFR, and other known risk factors. During median follow-up duration of 4.6 years, a total of 29 renal events (14.0%) occurred. The SP/hAGT group showed significantly higher risk of developing renal outcome compared to SP/lAGT group (HR, 13.4; 95% confidence interval, 1.282-139.324; P = 0.03). CONCLUSION: Urinary AGT/Cr can be a useful predictive marker in the patients with relatively small ADPKD. Various biomarkers should be considered to define RP when implementing novel treatment in the patients with ADPKD.

KIM-1 and Kidney Disease Progression in Autosomal Dominant Polycystic Kidney Disease: HALT-PKD Results.

BACKGROUND: Cyst compression of renal tubules plays a role in the progression of autosomal dominant polycystic kidney disease (ADPKD) and may induce expression of kidney injury molecule-1 (KIM-1). Whether urinary KIM-1 indexed for creatinine (uKIM-1/Cr) is a prognostic marker of disease progression in ADPKD is unknown.In this secondary analysis of a prospective cohort study, we sought to determine whether patients with high as opposed to low uKIM-1/CR at baseline had greater rates of eGFR loss and height-adjusted total kidney volume (HtTKV) increase. METHODS: Baseline uKIM-1/Cr values were obtained from 754 participants in Halt Progression of Polycystic Kidney Disease (HALT-PKD) studies A (early ADPKD) and B (late ADPKD). The predictor was uKIM-1/Cr, which was dichotomized by a median value of 0.2417 pg/g, and the primary outcomes were measured longitudinally over time. Mixed-effects linear models were used in the analysis to calculate the annual slope of change in eGFR and HtTKV. RESULTS: Patients with high uKIM-1/Cr (above the median) had an annual decline in eGFR that was 0.47 mL/min greater than that in those with low uKIM-1/Cr (p = 0.0015) after adjustment for all considered covariates. This association was seen in study B patients alone (0.45 mL/min; p = 0.009), but not in study A patients alone (0.42 mL/min; p = 0.06). High baseline uKIM-1/Cr was associated with higher HtTKV in the baseline cross-sectional analysis compared to low uKIM-1/Cr (p = 0.02), but there was no difference between the groups in the mixed-effects model annual slopes. CONCLUSION: Elevated baseline uKIM-1/Cr is associated with a greater decline in eGFR over time. Further research is needed to determine whether uKIM-1/Cr improves risk stratification in patients with ADPKD.

Urinary metabolites associate with the rate of kidney function decline in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: The variable course of autosomal dominant polycystic kidney disease (ADPKD), and the advent of renoprotective treatment require early risk stratification. We applied urinary metabolomics to explore differences associated with estimated glomerular filtration rate (eGFR; CKD-EPI equation) and future eGFR decline. METHODS: Targeted, quantitative metabolic profiling (1H NMR-spectroscopy) was performed on baseline spot urine samples obtained from 501 patients with ADPKD. The discovery cohort consisted of 338 patients (56% female, median values for age 46 [IQR 38 to 52] years, eGFR 62 [IQR 45 to 85] ml/min/1.73m2, follow-up time 2.5 [range 1 to 3] years, and annual eGFR slope -3.3 [IQR -5.3 to -1.3] ml/min/1.73m2/year). An independent cohort (n = 163) was used for validation. Multivariate modelling and linear regression were used to analyze the associations between urinary metabolites and eGFR, and eGFR decline over time. RESULTS: Twenty-nine known urinary metabolites were quantified from the spectra using a semi-automatic quantification routine. The model optimization routine resulted in four metabolites that most strongly associated with actual eGFR in the discovery cohort (F = 128.9, P = 7×10-54, R2 = 0.724). A model using the ratio of two other metabolites, urinary alanine/citrate, showed the best association with future annual change in eGFR (F = 51.07, P = 7.26×10-12, R2 = 0.150). This association remained significant after adjustment for clinical risk markers including height-adjusted total kidney volume (htTKV). Results were confirmed in the validation cohort. CONCLUSIONS: Quantitative NMR profiling identified urinary metabolic markers that associated with actual eGFR and future rate of eGFR decline. The urinary alanine/citrate ratio showed additional value beyond conventional risk markers.

Osmolalidad urinaria en pacientes con poliquistosis renal: ¿medida o calculada? / Urinary osmolality in patients with polycystic kidney disease: Measured or calculated?

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Analysis of the polycystin complex (PCC) in human urinary exosome-like vesicles (ELVs).

The polycystin-1 (PC1), polycystin-2 (PC2) and fibrocystin proteins, the respective products of the PKD1, PKD2 and PKHD1 genes, are abundant in urinary exosome-like vesicles (ELVs) where they form the polycystin complex (PCC). ELVs are 100 nm diameter membrane vesicles shed into the urine by the cells lining the nephron. Using MS/MS analysis of ELVs from individuals with PKD1 mutations and controls, we show that in addition to the well-described GPS/GAIN cleavage event in PC1 at 3048 aa and the proprotein convertase cleavage (PPC) event in fibrocystin at 3616 aa, there are multiple other cleavage events in these proteins. The C-terminal 11 transmembrane portion of PC1 undergoes three cleavage events in vivo. The absence of peptides from the C-terminal cytoplasmic tail of fibrocystin implies a cleavage event close to its single TM domain prior to loading onto the ELVs. There is also evidence that the C-terminal tail of PC2 is also cleaved in ELVs. Native gel analysis of the PCC shows that the entire complex is  > 2 MDa in size and that N-terminal GPS/GAIN cleaved PC1 and PPC cleaved fibrocystin ectodomains can be released under non-reducing conditions and resolve at 300 kDa. This paper shows that the three major human cystogene proteins are detectable in human urinary ELVs and that all three undergo post-translational proteolytic processing. Human urinary ELVs may be a useful source of material in the search for proteins that interact with the PCC.

Sodium and urea excretion as determinants of urine output in autosomal dominant polycystic kidney disease patients on V2 receptor antagonists: impact of dietary intervention.

PURPOSE: Tolvaptan, a vasopressin V2 receptor antagonist, slows the decline in renal function in autosomal dominant polycystic kidney disease (ADPKD). However, it increases urine output such that patient adherence could be compromised. In a cohort of patients with ADPKD on tolvaptan, we aimed to identify the contribution of sodium and urea excretion rate to daily urine output, and to evaluate the effectiveness of dietary counseling on sodium and urea excretion rates. METHODS: Retrospective analysis of 30 ADPKD patients who underwent a single session of personalized dietary counseling to reduce sodium and protein intake before initiation of tolvaptan. Creatinine and 24-h urine were obtained regularly on treatment. Generalized estimation equations were used. RESULTS: Mean age and median eGFR were 44 ± 11 years and 52 (43-74) ml/min/1.73 m2. Tolvaptan increased diuresis from 2.5 to 5.2 l/day. After adjusting for the dose of tolvaptan, an increase in sodium and urea excretion rate by 50 mmol/day was associated with an estimated additional urine volume of 0.6 l/day (95% CI 0.4-0.8 l/day; P < 0.001) and 0.25 l/day (95% CI 0.11-0.39 l/day; P < 0.001), respectively. Dietary counseling resulted in a transient reduction of sodium excretion by 19 mmol/day during the first 4 months (P = 0.016) but resulted in a more sustained reduction in urea excretion by 69 mmol/day (P = 0.008). CONCLUSION: Both sodium and urea excretion rates contribute significantly to daily urine volume in patients treated with tolvaptan, and a single session of dietary counseling was transiently effective in reducing sodium intake but achieved a more sustained reduction in protein intake. Dietary counseling should be considered in the management of ADPKD patients treated by tolvaptan.

Rapid Progression of Autosomal Dominant Polycystic Kidney Disease: Urinary Biomarkers as Predictors.

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 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, ß2 microglobulin (ß2MG), 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 m2, 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 ß2MG and MCP-1 showed the strongest association with rapidly progressive disease. A urinary biomarker score was created by summing the ranking of tertiles of ß2MG 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 ß2MG 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.

Tiny Non-coding RNAs in Body Fluids, Possible Biomarkers for Autosomal Dominant Polycystic Kidney Disease.

The functional and structural disease with autosomal dominant inheritance (ADPKD) shows a poly cystic nature is described by the presence of epithelial cysts in the human renal parenchyma. There are no standard and reliable biomarkers for the detection of ADPKD in early stages which delays the therapeutic approaches. Ideal biomarkers of ADPKD, should have high sensitivity, specificity, and excellent association with disease pathogenesis and development. Both in vitro cellular and in vivo studies on animal models proved the significant roles of miRNAs in the course of ADPKD. In addition, different studies have explored miRNAs up or down regulation both in renal tissue and extracellular fluids in ADPKD which represent novel indicators applicable for diagnosis or targeted therapy. Since urine is a non-invasive, easily accessible sample for ADPKD, it could be the best sample for diagnosis. Additionally, due to early action of miRNAs for regulation the gene expression or because of their unique chemical properties, detectable urine miRNAs can be employed as appropriate biomarkers for timely diagnosis or intensive care of the progression of renal destruction or response to treatment. In this review, the specific microRNAs involved in the pathogenesis of PKD will be discussed with a particular focus on extracellular miRNAs with possibility for application as biomarkers.

Pretransplant Nephrectomy for Large Polycystic Kidneys in ADPKD (Autosomal Dominant Polycystic Kidney Disease) Patients: Is Peritoneal Dialysis Recovery Possible after Surgery?

The choice of modality for renal replacement therapy in patients with ADPKD varies, often based on patient choice, physician-related factors, and resource availability. For a long time peritoneal dialysis (PD) was considered as relative contraindication due to the possible limited intraperitoneal space. In recent years, some studies suggested it is a valid option also in patients with ADPKD to be considered as a first line treatment in potentially fit patients. Diuresis volume lowering and potential permanent damage of peritoneal integrity, both leading to a necessary switch to haemodialysis, are the two most important dangers after nephrectomy, especially if bilateral, in PD patients. We performed a retrospective analysis of patient underwent native polycystic kidney nephrectomy in order to state the possibility to recover peritoneal dialysis after surgery.

Proteomic Analysis of Urinary Microvesicles and Exosomes in Medullary Sponge Kidney Disease and Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND AND OBJECTIVES: Microvesicles and exosomes are involved in the pathogenesis of autosomal dominant polycystic kidney disease. However, it is unclear whether they also contribute to medullary sponge kidney, a sporadic kidney malformation featuring cysts, nephrocalcinosis, and recurrent kidney stones. We addressed this knowledge gap by comparative proteomic analysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The protein content of microvesicles and exosomes isolated from the urine of 15 patients with medullary sponge kidney and 15 patients with autosomal dominant polycystic kidney disease was determined by mass spectrometry followed by weighted gene coexpression network analysis, support vector machine learning, and partial least squares discriminant analysis to compare the profiles and select the most discriminative proteins. The proteomic data were verified by ELISA. RESULTS: A total of 2950 proteins were isolated from microvesicles and exosomes, including 1579 (54%) identified in all samples but only 178 (6%) and 88 (3%) specific for medullary sponge kidney microvesicles and exosomes, and 183 (6%) and 98 (3%) specific for autosomal dominant polycystic kidney disease microvesicles and exosomes, respectively. The weighted gene coexpression network analysis revealed ten modules comprising proteins with similar expression profiles. Support vector machine learning and partial least squares discriminant analysis identified 34 proteins that were highly discriminative between the diseases. Among these, CD133 was upregulated in exosomes from autosomal dominant polycystic kidney disease and validated by ELISA. CONCLUSIONS: Our data indicate a different proteomic profile of urinary microvesicles and exosomes in patients with medullary sponge kidney compared with patients with autosomal dominant polycystic kidney disease. The urine proteomic profile of patients with autosomal dominant polycystic kidney disease was enriched of proteins involved in cell proliferation and matrix remodeling. Instead, proteins identified in patients with medullary sponge kidney were associated with parenchymal calcium deposition/nephrolithiasis and systemic metabolic derangements associated with stones formation and bone mineralization defects. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_04_24_CJASNPodcast_19_06_.mp3.

Urinary T cells correlate with rate of renal function loss in autosomal dominant polycystic kidney disease.

Several innate immune response components were recognized as outcome predictors in autosomal dominant polycystic kidney disease (ADPKD) and their causative role in disease pathogenesis was confirmed in animal models. In contrast, the role of adaptive immunity in ADPKD remains relatively unexplored. Therefore, we evaluated T cell populations in kidney and urine of ADPKD patients using flow cytometry and confocal immunofluorescence microscopy approaches. These analyses revealed ADPKD-associated overall increases in the number of intrarenal CD4 and CD8 T cells that were associated with a loss of polarity in distribution between the cortex and medulla (higher in medulla vs. cortex in controls). Also, the urinary T cell-based index correlated moderately with renal function decline in a small cohort of ADPKD patients. Together, these data suggest that similar to innate immune responses, T cells participate in ADPKD pathogenesis. They also point to urinary T cells as a novel candidate marker of the disease activity in ADPKD.

Kidney Function Reserve Capacity in Early and Later Stage Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND AND OBJECTIVES: It is assumed that in autosomal dominant polycystic kidney disease (ADPKD), kidney function remains in the normal range for several decades because of hyperfiltration of remnant nephrons. In this study, we investigate the extent to which patients with ADPKD hyperfilter. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this cross-sectional study, we measured GFR as urinary clearance using continuous infusion of 125I-iothalamate. Kidney function reserve capacity was determined as increase in measured GFR after adding a dopamine infusion of 4.4-6 mg/h. Potential kidney donors were used as healthy controls and matched by age and sex to patients with ADPKD for comparisons across age groups and CKD stages. Hyperfiltration was defined by a loss of kidney function reserve capacity compared with healthy controls. RESULTS: A total of 300 participants were studied. In the youngest age group (18-29 years), measured GFR was not different between patients with ADPKD and healthy controls (103±21 versus 111±9 ml/min per 1.73 m2; P=0.14). In this age group kidney function reserve capacity was higher compared with healthy controls (11.1%±8.3% versus 5.3%±6.5%; P=0.04). Moreover, kidney function reserve capacity was similar to healthy controls in patients with ADPKD with early-stage disease (eGFR≥60 ml/min per 1.73 m2), either overall or when divided into fast or slow progressors according to their Mayo height-adjusted total kidney volume class. However, in patients with ADPKD, lower measured GFR was associated with lower kidney function reserve capacity (ß=1.0 [95% confidence interval, 0.5 to 1.5] % per 10 ml/min per 1.73 m2; P<0.001). Kidney function reserve capacity was therefore lower compared with healthy controls at older age and later CKD stages. CONCLUSIONS: Patients with early-stage ADPKD, either classified as having rapidly or slowly progressive disease, are able to increase their GFR in response to dopamine. Hyperfiltration, defined by a loss of kidney function reserve capacity, may therefore not be an early phenomenon in ADPKD.