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Background: Guidelines for general hypertension treatment do not recommend the combined use of renin-angiotensin-aldosterone system (RAAS) inhibitors due to the risk of hyperkalemia. However, a recent clinical trial showed that polycystic kidney disease (PKD) patients had infrequent episodes of hyperkalemia despite receiving combined RAAS inhibitors. Because intrarenal RAAS is a main component for renal potassium handling, we further investigated the association between intrarenal RAAS activity and serum potassium level in patients with chronic kidney disease, particularly in PKD patients, and examined whether intrarenal RAAS activity has a prognostic role in patients with PKD., Methods: A total of 1788 subjects from the KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD) were enrolled in this study. Intrarenal RAAS activity was assessed by the measurement of urinary angiotensinogen (AGT). The primary outcome was the composite of all-cause mortality and renal function decline., Results: Patients with PKD had a significantly lower serum potassium level in chronic kidney disease stages 1 to 3b than non-PKD patients. In logistic regression analysis, after adjusting for multiple confounders, PKD patients had a significantly lower risk of hyperkalemia than non-PKD patients. In multivariable linear regression analysis, the urinary AGT/creatinine (Cr) ratio was negatively correlated with the serum potassium level (β = - 0.058, P = 0.017) and positively correlated with the transtubular potassium gradient (TTKG, β = 0.087, P = 0.001). In propensity score matching analysis, after matching factors associated with serum potassium and TTKG, PKD patients had a significantly higher TTKG (P = 0.021) despite a lower serum potassium level (P = 0.004). Additionally, the urinary AGT/Cr ratio was significantly higher in PKD patients than in non-PKD patients (P = 0.011). In 293 patients with PKD, high urinary AGT/Cr ratio was associated with increased risk of the composite outcome (hazard ratio 1.29; 95% confidence interval, 1.07-1.55; P = 0.007)., Conclusions: High activity of intrarenal RAAS is associated with increased urinary potassium excretion and low serum potassium level in patients with PKD. In addition, intrarenal RAAS activity can be a prognostic marker for mortality and renal function decline in these patients.

The anti-diuretic hormone arginine vasopressin is thought to be a detrimental factor in polycystic kidney disease (PKD). We previously reported that high water intake (HWI) reduced urine osmolality and urinary arginine vasopressin, improved renal function, and reduced the kidney/body weight ratio in PCK rats, an orthologous model of human PKD. In PKD patients, however, it is reported that HWI increases total kidney volume, urine volume, and urine sodium excretion, which could be a consequence of high salt intake. In the current study, we loaded PCK rats with high salt concurrently with HWI to determine whether this human-imitated condition exacerbates disease progression. PCK rats were assigned into 4 groups: control group (CONT: distilled water), HWI group (HWI: 5% glucose in water), HWI with 0.2% NaCl group (HWI+0.2%NaCl), and HWI with 0.45% NaCl group (HWI+0.45%NaCl). Total water intake during the experimental period was increased by 1.86-, 2.02-, and 2.42-fold in HWI, HWI+0.2%NaCl, and HWI+0.45%NaCl, and sodium intake was increased by 2.55- and 5.83-fold in HWI+0.2%NaCl and HWI+0.45%NaCl, respectively, compared with CONT. Systolic blood pressure was higher in HWI+0.2%NaCl and HWI+0.45%NaCl than in both CONT and HWI. Serum urea nitrogen, kidney/body weight ratio, cAMP, cystic area, and fibrosis index were significantly lower in HWI compared with CONT, and these ameliorative effects were not abrogated in either HWI+0.2%NaCl or HWI+0.45%NaCl. The amount of sodium excreted into the urine was increased by 2.50- and 8.38-fold in HWI+0.2%NaCl and HWI+0.45%NaCl, respectively, compared with HWI. Serum sodium levels were not different between the groups. These findings indicate that the beneficial effect of HWI against the progression of cystic kidney disease was not affected even by high salt-overload in this rodent model of PKD., Competing Interests: The authors have declared that no competing interests exist.

Objective: PKD is a genetic disease that is characterized by abnormally proliferative epithelial cells in the kidney and liver. Urinary exosomes have been previously examined as a source of unique proteins that may be used to diagnose and monitor the progression of PKD. Previous studies by our group have shown that AGS3, which is a receptor-independent regulator G-proteins, was markedly upregulated in RTECs during kidney injury including PKD. In this study, our goal was to determine whether AGS3 could be measured in exosomes using animals and humans with PKD., Results: In our study, urinary exosomes were isolated from PCK rats and the control Sprague-Dawley (SD) rats. AGS3 expression was significantly increased (P < 0.05) in PKD versus SD rats at 16 weeks of age. This increase was detectable in a time-dependent manner from 8 weeks of age and peaked at ~ 16-20 weeks (length of study). Similarly, in exosomes from human urine samples with PKD, AGS3 expression was significantly increased (P < 0.05) compared to healthy human controls where AGS3 was largely undetectable. In conclusion, the detection of AGS3 in urinary exosomes may be a novel biomarker for PKD, and provide new insight into the biology of tubular epithelial cell function during cystic disease progression.

Purpose of Review: Urine is the most useful of body fluids for biomarker research. Therefore, we have focused on urinary proteomics, using capillary electrophoresis coupled to mass spectrometry, to investigate kidney diseases in recent years., Recent Findings: Several urinary proteomics studies for the detection of various kidney diseases have indicated the potential of this approach aimed at diagnostic and prognostic assessment. Urinary protein biomarkers such as collagen fragments, serum albumin, α-1-antitrypsin, and uromodulin can help to explain the processes involved during disease progression., Summary: Urinary proteomics has been used in several studies in order to identify and validate biomarkers associated with different kidney diseases. These biomarkers, with improved sensitivity and specificity when compared with the current gold standards, provide a significant alternative for diagnosis and prognosis, as well as improving clinical decision-making.

Purpose: Since human urine is the most readily available biofluid whose proteome changes in response to disease, it is a logical sample for identifying protein biomarkers for kidney diseases., Experimental Design: Potential biomarkers were identified by using a multiproteomics workflow to compare urine proteomes of kidney transplant patients with immediate and delayed graft function. Differentially expressed proteins were identified, and corresponding stable isotope labeled internal peptide standards were synthesized for scheduled MRM., Results: The Targeted Urine Proteome Assay (TUPA) was then developed by identifying those peptides for which there were at least two transitions for which interference in a urine matrix across 156 MRM runs was <30%. This resulted in an assay that monitors 224 peptides from 167 quantifiable proteins., Conclusions and Clinical Relevance: TUPA opens the way for using a robust mass spectrometric technology, MRM, for quantifying and validating biomarkers from among 167 urinary proteins. This approach, while developed using differentially expressed urinary proteins from patients with delayed versus immediate graft function after kidney transplant, can be expanded to include differentially expressed urinary proteins in multiple kidney diseases. Thus, TUPA could provide a single assay to help diagnose, prognose, and manage many kidney diseases., Competing Interests: Statement The authors declare there are no conflicts of interest., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Extracellular vesicles (EVs) are bilayered lipid vesicles, 50-1000 nm in diameter and secreted by most types of cells. They contain many proteins, mRNAs, miRNAs, and lipids that reflect the pathophysiological state of the cells they originate from, and are therefore considered to be a rich source of potential biomarkers. In this issue (Pocsfalvi, G. et al., Proteomics Clin. Appl. 2015, 9, 552-567), Pocsfalvi et al. conducted pioneering investigations to determine whether changes in the protein content of EVs occur during progression of autosomal dominant polycystic kidney disease (ADPKD), a common genetic disorder that predominantly affects the kidneys. Most significantly, iTRAQ-based quantitative proteomics showed that cytoskeleton-regulating and Ca(2+) -binding proteins are differentially expressed in urinary EVs of ADPKD patients. Impressively, these proteins are involved in biological processes that are closely related to the pathogenic state of tubular epithelial cells in ADPKD, demonstrating the possibility to monitor the status of patients using urinary EVs., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: Recent findings indicate that urinary extracellular vesicles (EVs) might reflect the pathophysiological state of urinary system; and that EVs-induced ciliary signaling is a possible mechanism of intercellular communication within the tract. Here, we aimed to analyze the protein expression of urinary EVs during autosomal dominant polycystic kidney disease (ADPKD)., Experimental Design: EVs were isolated from pooled urine samples of healthy control and ADPKD patients at two different stages of the disease and under tolvaptan treatment using the double-cushion ultracentrifugation method. Proteins were identified and quantified by iTRAQ and multidimensional protein identification technology (MudPIT)-based quantitative proteomics., Results: Quantitative analyses identified 83 differentially expressed EV proteins. Many of these have apical membrane origin and are involved in signal transduction pathways of primary cilia, Ca(2+) -activated signaling, cell-cycle regulation, and cell differentiation., Conclusions and Clinical Relevance: The reduced AQP-2 and the increased APO-A1 levels observed in all ADPKD-affected groups may reflects the impaired renal concentrating capability of these patients and correlated with estimated glomerular filtration rate decline. The levels of some upregulated proteins involved in Ca(2+) -activated signaling declined upon tolvaptan treatment. The results obtained suggest that the quantitative proteomics of urinary EVs might be useful to monitor proteins difficult to access noninvasively, and thus advance our understanding of urinary tract physiology and pathology., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Patients with chronic kidney disease (CKD) are at risk of exhibiting expanded extracellular volume, and low-sodium diets are often prescribed to limit clinical complications from this condition. Fan et al. performed a post hoc study from the database of the Modification of Diet in Renal Disease Study. Their article, as well as other recent observations, suggests that a low-sodium diet may not be as beneficial as previously thought in all CKD patients.

Current guidelines recommend under 2 g/day sodium intake in chronic kidney disease, but there are a few studies relating sodium intake to long-term outcomes. Here we evaluated the association of mean baseline 24-h urinary sodium excretion with kidney failure and a composite outcome of kidney failure or all-cause mortality using Cox regression in 840 participants enrolled in the Modification of Diet in Renal Disease Study. Mean 24-h urinary sodium excretion was 3.46 g/day. Kidney failure developed in 617 participants, and the composite outcome was reached in 723. In the primary analyses, there was no association between 24-h urine sodium and kidney failure (HR 0.99 (95% CI 0.91-1.08)) nor on the composite outcome (HR 1.01 (95% CI 0.93-1.09)), each per 1 g/day higher urine sodium. In exploratory analyses, there was a significant interaction of baseline proteinuria and sodium excretion with kidney failure. Using a two-slope model, when urine sodium was under 3 g/day, higher urine sodium was associated with increased risk of kidney failure in those with baseline proteinuria under 1 g/day and with lower risk of kidney failure in those with baseline proteinuria of ⩾ 1 g/day. There was no association between urine sodium and kidney failure when urine sodium was ⩾ 3 g/day. Results were consistent using first baseline and time-dependent urinary sodium excretion. Thus, we noted no association of urine sodium with kidney failure. Results of the exploratory analyses need to be verified in additional studies and the mechanism explored.

Aim: The purpose of this research was to use metabolomics to investigate the cystic phenotype in the Lewis polycystic kidney rat., Methods: Spot urine samples were collected from four male Lewis control and five male Lewis polycystic kidney rats aged 5 weeks, before kidney function was significantly impaired. Metabolites were extracted from urine and analysed using gas chromatography-mass spectrometry. Principal component analysis was used to determine key metabolites contributing to the variance observed between sample groups., Results: With the development of a metabolomics method to analyse Lewis and Lewis polycystic kidney rat urine, 2-ketoglutaric acid, allantoin, uric acid and hippuric acid were identified as potential biomarkers of cystic disease in the rat model., Conclusion: The findings of this study demonstrate the potential of metabolomics to further investigate kidney disease., (© 2011 The Authors. Nephrology © 2011 Asian Pacific Society of Nephrology.)

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and affects 1 in 1,000 individuals. Ultrasound is most often used to diagnose ADPKD; such a modality is only useful late in the disease after macroscopic cysts are present. There is accumulating evidence suggesting that there are common cellular and molecular mechanisms responsible for cystogenesis in human and murine PKD regardless of the genes mutated, and, in the case of complex metabolomic analysis, the use of a mouse model has distinct advantages for proof of principle over a human study. Therefore, in this study we utilized a urinary metabolomics-based investigation using gas chromatography-time of flight mass spectrometry to demonstrate that the cystic mouse can be discriminated from its wild-type counterpart by urine analysis alone. At day 26 of life, before there is serological evidence of kidney dysfunction, affected mice are distinguishable by urine metabolomic analysis; this finding persists through 45 days until 64 days, at which time body weight differences confound the results. Using functional score analysis and the KEGG pathway database, we identify several biologically relevant metabolic pathways which are altered very early in this disease, the most highly represented being the purine and galactose metabolism pathways. In addition, we identify several specific candidate biomarkers, including allantoic acid and adenosine, which are augmented in the urine of young cystic mice. These markers and pathway components, once extended to human disease, may prove useful as a noninvasive means of diagnosing cystic kidney diseases and to suggest novel therapeutic approaches. Thus, urine metabolomics has great diagnostic potential for cystic renal disorders and deserves further study.

Background: The use of biopsies to determine kidney health after kidney transplantation is an invasive procedure with some risk to the patient. Consequently, a noninvasive test for transplanted kidney health would provide a significant advantage over current clinical practice., Methods: Urines from kidney donors before nephrectomy, pretransplant patients with native kidney disease, and posttransplant kidney recipients were examined for protein biomarkers to diagnose or prognose kidney disease. Proteins were extracted by C4 reverse phase affinity and analyzed by matrix assisted laser desorption/ionization time-of-flight mass spectrometry., Results: Urine from individuals with healthy kidneys showed few components other than two ubiquitous saposin B glycoisoforms. Patients with kidney disease lacked saposin B and showed new components in two patterns: the most common contained beta-2 microglobulin (B2M, m/z=11,732) plus one or more peaks at m/z=10,350, 9480, 4337, and 4180. Pattern 2 lacked beta-2 microglobulin but contained several degradation products of alpha-1 antitrypsin. Other pathologic components included urinary protein 1 (m/z=15,835), transthyretin (m/z=13,880), and a component at m/z=13,350., Conclusions: Patients with acute rejection showed profiles that ranged from those of kidney donors to those of advanced kidney disease. The range of patterns may be useful for analysis of transplant patients without complications and persons with developing kidney disease before or after transplant.

Background: It is not known whether angiotensin-converting-enzyme (ACE) inhibitors slow the progression of polycystic kidney disease (PKD). We performed a patient-level meta-analysis to compare the effect of antihypertensive regimens, including ACE inhibitors, to those without ACE inhibitors (controls) on kidney disease progression in patients with PKD., Methods: We analyzed a database of 11 randomized controlled trials including 1860 patients with nondiabetic kidney disease. We compared randomized groups for the decline in urine protein excretion and kidney disease progression (combined outcome of doubling of baseline serum creatinine or onset of kidney failure). We also performed multivariable linear regression and Cox proportional hazards analyses. Based on previous findings, we searched for interactions between the treatment effect (effect of ACE inhibitors vs. controls) and baseline urine protein excretion in both models., Results: Eight studies included a total of 142 subjects with PKD: 68 (48%) were randomized to ACE inhibitors and 74 (52%) were randomized to the control. Baseline mean (SD) urine protein excretion was 0.92 (1.40) g/day: 1.08 (1.50) g/day in the ACE inhibitor and 0.76 (1.28) g/day in the control group. During a mean follow-up of 2.3 years, mean (SD) urine protein excretion declined by 0.33 (1.11) g/day in the ACE inhibitor group and increased by 0.19 (0.88) g/day in the control group (P < 0.001). Kidney disease progression occurred in 50 patients: 20 patients (29%) in the ACE inhibitor group and 30 patients (41%) in the control group (P= 0.17). ACE inhibitors had a greater effect on lowering urine protein excretion and slowing kidney disease progression in patients with higher levels of baseline urine protein excretion (interaction P < 0.001 and P= 0.03, respectively)., Conclusion: As in other causes of non-diabetic kidney disease, antihypertensive regimens with ACE inhibitors are more effective in lowering urine protein excretion in patients with advanced PKD compared to regimens without ACE inhibitors, and this benefit is greater in patients with higher levels of baseline urine protein excretion. The effect of ACE inhibitors to slow kidney disease progression in PKD is inconclusive.

A case of polycystic kidney disease (PKD) associated with Klippel-Trenaunay-Weber syndrome is described. A 58-year-old man with chronic renal failure experienced urinary retention following gross hematuria. Intermittent drainage was necessary for significant urination for five days. Thereafter his urinary retention was relieved, but renal failure progressively developed and hemodialysis was started. Right hydronephrisis and hydroureter disappeared one month later. In spite of relief of obstruction, of which the cause was likely blood clots, renal function was not restored. Obstructive nephropathy was most likely explicable for notable deterioration in renal function. Our case might have susceptibilities to PKD development in terms of angiogenesis.

Because proteinuria has been demonstrated in patients with autosomal-dominant polycystic kidney disease (ADPKD), we have investigated whether proteinuria also occurs in the (cy/+) rat, a widely used model for ADPKD. Increased urinary excretion of proteins, in particular of albumin, can be found in 16-wk-old (cy/+) rats, with a gel electrophoresis pattern compatible with a tubular origin of proteinuria. Using FITC-labeled dextran as an in vivo tracer for renal tubular endosomal function, we could show that portions of cyst-lining epithelia from proximal tubules have lost the ability to endocytose, which is necessary for the reabsorption of low-molecular-weight proteins. By immunohistochemistry, the expression of other proteins implicated in endocytosis, such as the chloride channel ClC-5 and the albumin receptor megalin, correlated well with the presence and absence of FITC-dextran in cysts. As an example of growth factor systems possibly being affected by this endocytosis defect, we could detect increased urinary levels of insulin-like growth factor-I protein in (cy/+) animals. These data indicate that proteinuria and albuminuria in the aforementioned rat model for ADPKD are due to a loss of the endocytic machinery in epithelia of proximal tubular cysts. This may also affect the concentration of different growth factors and hormones in cyst fluids and thus modulate cyst development.

Background: Microbes have been suspected as provocateurs of polycystic kidney disease (PKD), but attempts to isolate viable organisms have failed. Bacterial endotoxin is the most often reported microbial product found in PKD fluids. We assessed potential microbial origins of endotoxin in cyst fluids from 13 PKD patients and urines of PKD and control individuals., Methods: Fluids were probed for endotoxin and nanobacteria, a new bacterium, by the differential Limulus Amebocyte Lysate assay (dLAL), genus-specific antilipopolysaccharide (LPS) antibodies, monoclonal antibodies to nanobacteria, and hyperimmune serum to Bartonella henselae (HS-Bh). Selected specimens were also assessed by transmission electron microscopy (TEM) and nanobacterial culture methods., Results: LPS or its antigenic metabolites were found in more than 75% of cyst fluids tested. Nanobacteria were cultured from 11 of 13 PKD kidneys, visualized in 8 of 8 kidneys by TEM, and immunodetected in all 13 PKD kidneys. By immunodetection, nanobacterial antigens were found in urine from 7 of 7 PKD males, 1 of 7 PKD females, 3 of 10 normal males, and 1 of 10 normal females. "Nanobacterium sanguineum" was dLAL positive and cross-reactive with antichlamydial LPS and HS-Bh. Some cyst fluids were also positive for LPS antigens from Escherichia coli, Bacteroides fragilis and/or Chlamydia, and HS-Bh, as were liver cyst fluids from one patient. Tetracycline and citrate inhibited nanobacterial growth in vitro., Conclusion: Nanobacteria or its antigens were present in PKD kidney, liver, and urine. The identification of candidate microbial pathogens is the first step in ascertaining their contribution, if any, to human disease.

To determine whether the renal nitric oxide (NO) system has a role in the pathogenesis of polycystic kidney disease (PKD) in Han:Sprague-Dawley (SPRD) rats, the NO synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), 70 mg/L, or L-arginine, 0.5 g/L, was administered to heterozygous diseased (cy/+) and homozygous normal animals. Urine nitrate and nitrite excretion was reduced by L-NAME treatment and, in the male cy/+ rats, increased by L-arginine administration. The administration of L-NAME significantly increased blood pressure in all groups, whereas L-arginine had no effect. L-NAME and L-arginine had a modest but significant overall effect on the severity of cystic disease in male rats, reflected by relative kidney weights and cyst volume densities. This effect was gender dependent because it was not observed in female animals. The administration of L-NAME resulted in a significant increase in plasma creatinine concentration of the cy/+ rats, which was more marked in male than female animals. These observations support the recently reported gender differences in the renal NO system and a small role for NO synthesis that can be inhibited by L-NAME in the pathogenesis of PKD in Han:SPRD rats. These observations do not exclude a more important role for the endogenous renal NO production in the pathogenesis of PKD in view of a recent report of a major NOS resistant to conventional inhibitors in the rat kidney.

Background/purpose: The type of renal dysplasia resulting from obstructive uropathy depends on the completeness of the obstruction and its timing with respect to the stage of glomerulogenesis at the time of the obstruction. The authors created a successful obstructive uropathy model in the female fetal lamb to demonstrate the differing pathogenesis of renal dysplasia., Methods: Female fetal lambs at 60 and 90 days' gestation had their urethra and urachus ligated transabdominally and were delivered by cesarean section at 145 days (full term). Kidney length and cortical thickness were measured, and samples were examined histologically. In the lambs operated on at 90 days, the urine was collected at delivery and Na and CI were measured and compared with the results obtained from normal full-term lambs., Results: Seven of 10 female lambs had hydronephrosis or dysplastic kidneys. The cortext to kidney length ratio was 10+/-3% in the 90-days hydronephrotic group versus 29+/-6% in the controls (P<.001). Morphologically, the 90-day model had dilatation of the collecting tubules with normal glomerular numbers. The 60-day model had tubular cysts with fibromuscular cuffing and reduced glomerular numbers. The fetal urine Na was 47+/-3.3 mmol/L in controls versus 78+/-24 mmol/L in the hydropnephrotic lambs (P<.05). The urine CI in these lambs was 38+/-8.6 mmol/L in controls versus 55+/-14.5 mmol/L in the hydronephrotic lambs (P<.05)., Conclusions: An obstructive uropathy model was created in female fetal lambs. There were no dysplastic changes in the kidneys in lambs operated on at 90 days' gestation, but there were definite dysplastic changes in those operated on at 60 days. Concentrations of Na and CI in the fetal urine are higher than normal in the 90-day model.

It was previously found that elevated levels of matrix metalloproteinase (MMP)-2 (gelatinase A) and -9 (gelatinase B) were synthesized and secreted into the medium by cultured kidney tubules derived from cystic C57BL/6J-cpk mice. To determine whether increased synthesis and secretion occur in vivo in this mouse model of polycystic kidney disease, kidney protein extracts, mRNA, and tissue sections were compared for expression and activity of MMP-2 and -9. Although both MMP were detected in tissue extracts, the differences in expression levels and activity in normal and cystic kidneys were far greater for MMP-2. High levels of MMP-2 seemed to result from increased expression by the cystic kidneys predominantly in the second and third postnatal weeks (a time when the kidneys are undergoing rapid cystic enlargement). Much of the increased MMP was present in the inactive zymogen form, although active enzyme was readily detected by sodium dodecyl sulfate-polyacrylamide gel zymography and in situ zymography. MMP-2 was abnormally localized to the interstitium and to foci between cysts, suggesting that MMP-2 may regulate collagen accumulation at those sites, thus allowing cyst enlargement and limiting the severity of interstitial fibrosis.

Tamm-Horsfall protein (THP) and epidermal growth factor (EGF) are both synthesized by tubular cells in the distal part of the nephron and excreted with the urine. The present study examines the urinary excretion rates of the two peptides in relation to functional tubular markers in patients with chronic nephropathy. Four groups of patients with moderate to severely reduced renal function were studied: glomerulonephritis (n = 10), diabetic nephropathy (n = 11), tubulointerstitial nephropathy (n = 13), and polycystic kidney disease (n = 8). The renal function was evaluated by glomerular filtration rate (GFR) as an indicator for the general renal function, lithium clearance (C(Li)) as an indicator for proximal tubular function, and absolute distal reabsorption of sodium (ADR(Na)) as an indicator for distal tubular function. The excretion rate of EGF was rather closely correlated with GFR, C(Li) and ADR(Na) (Spearman coefficients of variation 0.88, 0.69, and 0.74, respectively). The correlations between the excretion rate of THP and GFR, C(Li) and ADR(Na) were weaker (Spearman coefficients of variation 0.68, 0.42, and 0.44). When the effect of GFR had been accounted for by multiple variance analyses, the excretion rates of the two peptides were still associated with ADR(Na) but not with C(Li). In conclusion, the urinary excretion rates of especially EGF but also those of THP were correlated with renal function and distal tubular reabsorption of sodium in patients with chronic nephropathy.

Polycystic kidney disease (PKD) a is common disease in the human population that can lead to renal failure and death. Taxol has recently been reported to be of therapeutic benefit in the cpk mouse model of PKD. To determine whether these results also apply to other models of PKD, we studied the effects of taxol treatment on the development of renal cysts and biliary hyperplasia/dysplasia/fibrosis in the orpk mouse mutant, a unique murine model for human autosomal recessive PKD. We report no significant differences between the treatment and control groups with respect to weight gain, survival, urine to serum osmolality ratio, and serum concentration of liver enzymes. Moreover, renal cystic development was not affected by taxol treatment in the orpk mutant animals. This was confirmed by lectin staining and morphometric analysis of the renal cysts, which indicated no significant differences between treatment groups. Therefore, while taxol has a positive effect on the cystic kidney disease in cpk mutant mice, this effect is not applicable to all forms of PKD.

Studies in animals suggest that hepatocyte growth factor (HGF) is an important mediator of kidney development, compensatory growth and tubule repair following acute injury, however, evidence for HGF action in human renal disease is scant. To determine whether increased renal production of HGF occurs in man, urine HGF excretion rate was measured in normals and in patients with a variety of acute and chronic renal diseases. Urine samples were collected from 9 healthy individuals, 25 individuals with acute tubular necrosis (ATN), 20 individuals with chronic glomerular disease, 9 patients with polycystic kidney disease and 10 individuals with severe chronic renal failure not yet receiving renal replacement therapy. Samples were initially frozen and then HGF content measured by ELISA and factored for creatinine concentration measured by autoanalyzer. Detectable but low levels of HGF were found in the urine of normals and in patients with chronic glomerular or polycystic disease. Levels were also not increased in patients with advanced, chronic renal insufficiency. In contrast, a marked increase in urine HGF was observed in patients with acute renal failure. In addition, HGF excretion tended to correlate with disease severity as higher levels were observed in patients with oliguric ATN. Urine HGF levels declined to control values in patients recovering from ATN, generally within one week. These findings are consistent with a role for HGF in promoting tubule cell proliferation, differentiation and recovery from acute tubular injury in man.

In chronic renal failure, epidermal growth factor (EGF) excretion is decreased. In this study, asymptomatic adult polycystic kidney disease (APKD) patients with a relatively preserved glomerular filtration rate were examined. Excretion of EGF was studied in 6 patients with APKD (median age 42 years; serum creatinine [median] 95 [range-80-133] mumol/l) and compared with that of 28 healthy controls. EGF was determined in a spot morning urine by using a specific radioimmunoassay, and expressed in relation to creatinine excretion. Excretion of EGF in APKD was (median) 157 (range-13-359) and in the controls (median) 546 (range-238-1199) pmol/mmol creatinine (p < 0.001). Low excretion of EGF in APKD patients with preserved kidney function suggests a distal abnormality at an early stage of the disease, prior to the development of renal failure.

A wide range of renal prostaglandins in cysts has been studied as compared with their content in the daily urine, activity of plasma renin, level of adrenocorticotropic hormone (ACTH) in the tissues, methionine enkephalin and aldosterone. High activity of renin, met-enkephalin and ACTH was observed in the patients with one cyst. Under renal polycystosis the activity of plasma renin is higher and the amount of ACTH positively decreases. The comparison of prostanoids content in the cystic fluid of a single cyst and polycystic one demonstrates that the polycystic level of all prostanoids in the punctate increase 2-3 times.

It is generally recognized that the sonographic findings of infantile polycystic kidney disease (IPKD) are bilaterally enlarged kidneys, oligohydramnios, an absent fetal bladder, and the typical kidney texture. Since there is a broad spectrum of renal compromise with IPKD, in utero diagnosis is thought to be limited to the severe forms. This paper reports a mild case of IPKD, where the in utero diagnosis was established by measuring fetal urine production and amniotic fluid volume serially during pregnancy, and by ultrasonographic examination of fetal kidneys.

Normal Sprague Dawley (SPRD) rats of both sexes secrete an 165 kDa EGF prohormone in urine. Sexually mature Hannover-Sprague Dawley rats (Han:SPRD) heterozygous males and females with autosomal dominant polycystic kidney disease (ADPKD) secrete a prohormone of similar molecular mass in urine. The male, but not the female, also secretes two variant prohormone isoforms with molecular masses close to 200 kDa. Both the 165 and 200 kDa EGF prohormone isoforms are totally absent, in urine, at 11 months of age in male but not in female heterozygous Han:SPRD rats. At this age, the male kidneys exhibit numerous cysts filled with colorless fluids and these fluids contain abundant quantities of a 66 kDa EGF prohormone metabolite. Homozygous Han:SPRD rats which are born with cystic disease secrete only trace amounts of 165 kDa EGF prohormone in their urine while their normal looking littermates secrete the 165 kDa EGF prohormone in abundant quantities. The cyst fluids of homozygous rats contain trace amounts of 165 and 154 kDa EGF prohormone isoforms while the 66 kDa EGF prohormone metabolites present in abundant quantities. The massive amounts of 66 kDa EGF prohormone metabolite in cyst fluids of PKD rats suggests that EGF prohormone and its isoforms undergo aberrant proteolysis in association with cyst pathogenesis both in heterozygous and homozygous kidneys. The specific retention of the 66 kDa EGF prohormone metabolite within the cyst suggests that this molecule may function as a cystogen.

The C57BL/6J CPK heterozygous breeders secrete in urine a variant EGF-prohormone with a molecular mass of 154 kDa in addition to the normal 165 kDa EGF-prohormone. The 154 kDa prohormone is secreted as a heterodimer with the normal 165 kDa prohormone. The phenotypically normal littermates, like their parents, secrete the 154 and 165 kDa EGF-prohormones in urine while their cystic siblings secrete neither protein. Examination of renal extracts of normal littermates revealed the presence of the 165 kDa but not the 154 kDa EGF-prohormone; renal extracts of cystic siblings contained neither protein. Cyst fluid, however, contained 56 and 49 kDa EGF-immunoreactive proteins in high concentrations. The data suggest that in the absence of normal 165 kDa prohormone, the 154 kDa EGF-prohormone undergoes proteolysis and that the resultant fragments function as cystogens. Since normal siblings do not acquire renal cystic disease despite expressing the variant 154 kDa EGF-prohormone while the affected littermates, which lack the normal 165 kDa EGF-prohormone, manifest renal cystic disease, we suggest that congenital polycystic kidney disease is due to an inborn defect in the synthesis and secretion of the normal 165 kDa renal EGF-prohormone.

The prevalence and severity of polycystic kidney disease (PKD) induced by glucocorticoids in mice can be predicted by a mathematical "threshold" model. We studied the relationship between Na-K ATPase activity and cyst formation in C3H (low threshold for PKD) and DBA mice (high threshold). There was no difference in Na-K ATPase induction by 200 mg/kg methyl prednisolone acetate (MPA) (C3H; 97.4 nmol NADH/min/mg protein: DBA; 94.2 nmol NADH/min/mg protein). C3H mice demonstrated greater cyst formation than DBA animals as measured by area (20.1% relative area vs 13.9%, p < 0.05) or by calculated volume (7.4% relative volume vs 2.3%, p < 0.001). Significant relationships were seen between Na-K ATPase activity and logarithmically transformed area data in C3H animals and with cyst volume in both strains. Na-K ATPase activity is related to cyst formation in glucocorticoid induced PKD, but the level of Na-K ATPase activity is not a determinant of the threshold for glucocorticoid induced PKD.

We report a 35-year-old man with adult polycystic kidney disease (APKD) that developed nephroptic syndrome accompanied by a rapid worsening of renal function. Histologic examination showed marked tubulointerstitial chronic abnormalities and focal glomerulosclerosis (FGS) lesions in 24% of the glomeruli. With captopril, an renal function continued to deteriorate. No other cases of nephrotic-range proteinuria were detected among 65 APKD patients with renal insufficiency. Histologic examination of an other 12 kidneys removed from patients with APKD showed striking interstitial lesions, most of the glomeruli being normal. However, those patients with higher amounts of proteinuria had more glomeruli (14-32%) with FGS lesions.

To see whether there was any difference in the urine urokinase concentration between acquired cystic kidney disease (ACKD) group and control (non cyst) group in end stage renal disease patients (ESRD), we evaluated fifty ESRD patients who had been maintained on chronic hemodialysis for various period. The urine urokinase concentration was higher in the ACKD group (17.5 +/- 14.7 unit/ml, range 13.5-47.0 unit/ml, n = 9) than the control group (4.1 +/- 3.4 unit/ml, range 0.5-12.0 unit/ml, n = 36) (p less than 0.001), and polycyst group (2.6 +/- 1.8 unit/ml, range 1.0-5.1 unit/ml, n = 5) (p less than 0.01). But there was no difference between the control group and polycyst group. In the control group and the ACKD group, there was a direct relation between the dialysis duration and the urokinase concentration and the longer the dialysis duration, the higher the urine urokinase concentration (r squared = 0.424, p = 0.0001). The hemodialysis duration was longer in the ACKD group (42 +/- 17.0 months) than the control group (20.0 +/- 12.5 months) (p less than 0.005). These findings suggest that urokinase may be responsible for cystogenic degeneration in ESRD.

In a study to determine the proportion of unrecognised cases and the prevalence of treatable complications of autosomal dominant polycystic kidney disease (ADPKD), 46 probands were identified through genetics and renal clinics in Melbourne, Australia. 321 offspring of the probands who were older than 15 years and had not been previously diagnosed as having ADPKD were identified. 68 (21%) had ultrasound evidence of polycystic kidney disease. Of this previously undiagnosed group, 25 (37%) had one or more treatable complications at the time of diagnosis. The complications included 20 cases of hypertension (diastolic blood pressure 95 mm Hg or above), 7 cases of impaired renal function (serum creatinine 0.12 mmol/l or above), and 4 cases of bacterial urinary tract infection. 8 people had several complications. ADPKD has an important treatable component which is not being treated in a substantial proportion of affected individuals, because the disease is not being diagnosed despite the presence of a positive family history.

In 33 patients with autosomal dominant renal polycystosis the urine excretion of the electrolytes sodium and potassium was examined and analyzed in relation to the renal function and the arterial pressure. The clearances, the urine ratio and the excreted fractions of both electrolytes were calculated. It was established that by normal renal function and without arterial hypertension there were no significant differences in the parameters studied between the patients and the healthy controls. In the patients with arterial hypertension and preserved renal function the sodium clearance and urine excretion were lower, but the differences with the normotensive patients were not statistically significant. In the patients with chronic renal failure (when diuretic was applied) higher mean values of the excreted fractions of sodium and potassium were established. The results support the thesis that hypertension in renal polycystosis is of volumetric character.

Urinary tract infections (UTI) due to gram-negative bacteria are a serious complication in patients with polycystic kidney disease (PKD). Endotoxin, a component of the cell wall of gram-negative bacteria, has been reported to be pro-cystogenic in experimental animals. Because endotoxin levels in urines (endotoxiuria) from PKD patients have not been reported, the Limulus amebocyte lysate (LAL) assay, which detects picogram quantities of endotoxin, was used to probe for this cyst-promoting chemical. Fifteen PKD patients (seven females, eight males), asymptomatic for UTI, were tested and compared with 10 female and 10 male controls. All urines were assessed for (1) evidence of aerobic bacteria by routine quantitative cultures, (2) bacteria and pyuria by microscopic examination of gram-stained urine, and (3) bacterial endotoxin by the LAL assay. LAL tests were positive in 73% (11/15) of PKD patients, but only 25% (5/20) of controls (P = 0.0058). There was no significant difference in test positivity between PKD females (71%) and males (75%). There was no correlation of age, degree of renal dysfunction, or urine osmolality with endotoxiuria. Routine quantitative cultures were negative for gram-negative bacteria in PKD patients and all controls (except one female), as were microscopic findings for intact bacteria and pyuria. Thus endotoxiuria, in the absence of classical signs, symptoms, and microbiological findings of UTI, raises the possibility that endotoxin is available intrarenally to promote cystogenesis even before a potential susceptibility of PKD patients to classical UTI is manifested. Sources of urinary endotoxin observed in PKD patients, such as cryptic intrarenal sites or leakage from the gastrointestinal (GI) tract, remain to be defined.

A 44-year-old man, with autosomal dominant polycystic kidney disease and hypertension under satisfactory control, developed nephrotic syndrome with negative serology. Open renal biopsy revealed focal glomerular sclerosis. Prior to the appearance of heavy proteinuria, serum creatinine was 1.7 mg/dl. After the nephrotic syndrome had been established, renal function deteriorated rapidly and hemodialysis was started within 2.6 years. In patients with autosomal dominant polycystic kidney disease, the appearance of nephrotic range proteinuria along with a rapid decline in renal function indicates the presence of a glomerular lesion, which needs to be investigated by renal biopsy.

Substances having the chromatographic behaviour and the bioassay properties of prostaglandins (PGE and PGF) were detected in the urine of 30 patients with kidney disease and 15 healthy subjects. The mean urinary PGE and PGF values in 15 patients with chronic glomerular disease or nephrosclerosis were significantly lower than those of 15 patients with chronic pyelonephritis and other forms of chronic interstitial nephritis, polycystic kidney disease, obstructive nephropathy or diuretic phase of acute renal failure, and of the mean PGE and PGF values found in the healthy subjects. It was suggested that in contrast to disease affecting primarily the renal medulla, chronic glomerular disease and nephrosclerosis are accompanied by a decrease of renal prostaglandin synthesis and/or release.

The urinary excretion of beta-hexosaminidase in relation to creatinine was studied during one year in 30 consecutive patients with polycystic kidney disease (S-creatinine 75-1 000 micro mol/l) and 30 healthy controls. The excretion of beta-hexosaminidase was significantly increased in the patients and was positively correlated to S-creatinine and to the relative increase in S-creatinine during the year of the study. No correlation was found between the enzyme excretion and age, mean blood pressure, number of antihypertensive drugs, proteinuria or pyuria. A significant rise in beta-hexosaminidase excretion was observed in two patients with acute cyst bleeding and/or kidney infarction.

The renal excretion of 3 hydroxyproline (3 HYP) and 4 hydroxyproline (4 HYP) was investigated in control subjects and in patients with various renal diseases. In normal adult subjects urinary 3 HYP was 12.5 +/- 3.5 (SD) mumoles/24 hr, 4 HYP was 226 +/- 62 mumoles/24 hr and the percentage ratio 3 HYP/4 HYP 5.4 +/- 0.5. This ratio was reduced during growth because of a relative excess of 4 HYP. In patients with acute glomerular disease (n = 12) 3 HYP was increased to 17.1 +/- 5.8 mumoles/24 hr (P less than 0.01), and the ratio 3 HYP/4 HYP was 7.3 +/- 0.7% (P less than 0.01). Such an increase in 3 HYP was not observed in patients with chronic glomerulonephritis (n = 24) where 3 HYP was 9.6 +/- 5.0 mumoles/24 hr and 3 HYP/4 HYP 5.7 +/- 1.6% or with diabetic glomerulopathy (n = 6). In patients with chronic interstitial nephritis (n = 8) the 3 HYP/4 HYP ratio was decreased except in patients with polycystic renal disease (PKD) where it was increased (P less than 0.001). The daily urinary content of 3 HYP and 4 HYP was slightly altered by renal insufficiency. Urinary 3 HYP did not change significantly in patients with GN with the nephrotic syndrome whatever the histological lesion. These results indicate that urinary 3 HYP: 1) is increased when glomerulonephritis is clinically acute or subacute; 2) is increased in PKD whatever the level of renal insufficiency.

To determine what urinalysis findings are normal in patients maintained on chronic hemodialysis, we have studied the urine in 25 such patients. In end stage renal disease correlation with the original disease is lost, and urine characteristically contains many white blood cells and frequent white blood cell casts; microscopic hematuria is unusual even in patients whose original disease was a proliferative nephritis.

Infections involving cysts of patients with autosomal-dominant polycystic kidney disease (PCKD) are often refractory to therapy possibly because of poor penetration of antibiotics into cyst fluid. Ten patients with PCKD had blood urine and cyst fluid sampled at surgery or autopsy for antibiotic concentrations. Cysts were categorized as to their nephron site of origin by cyst fluid sodium concentrations. Drugs active against anaerobes such as metronidazole and clindamycin were present in therapeutic concentrations in both proximal and distal cysts. Ampicillin and trimethoprim-sulfamethoxazole had the best profiles considering likely infecting organisms and the antibiotic concentrations achieved in both type of cysts. It is likely that prolonged therapy with both of these drugs is necessary to insure therapeutic success. Other drugs that can be detected in cysts are lipid soluble, undergo tubular secretion, or have high pKa values. These include erythromycin, vancomycin, and cefotaxime. Aminoglycosides because of their predominant glomerular filtration and thus low filtration rate per single cystic nephron are undetectable in both proximal and distal cysts. Clinically, alternatives to aminoglycosides should be chosen for infected cysts in PCKD.

Hypertension occurring in patients with adult polycystic kidney disease (PKD) without substantially decreased glomerular filtration rate (GFRs) has not been sufficiently evaluated. Seven patients with bilateral PKD and serum creatinine clearances greater than 70 ml/min were studied to examine the roles of sodium retention and the renin-angiotensin system in their hypertension. These individuals demonstrated evidence of volume expansion and sodium-dependent hypertension. However, the renin-angiotensin system was not consistently depressed as a consequence, and two of the seven had significantly increased plasma renin activity values. It seems that patients with PKD who had normal GFRs retain rather than waste sodium and may become hypertensive. The contribution of the renin-angiotensin system is variable and seems to be a function of such factors as symmetry of the cystic involvement and the degree of intravascular volume expansion.

1. Lithium clearance measurements were made in 72 patients with chronic nephropathy of different aetiology and moderate to severely reduced renal function. 2. Lithium clearance was strictly correlated with glomerular filtration rate, and there was no suggestion of distal tubular reabsorption of lithium or influence of osmotic diuresis. 3. Fractional reabsorption of lithium was reduced in most patients with glomerular filtration rates below 25 ml/min. 4. Calculated fractional distal reabsorption of sodium was reduced in most patients with glomerular filtration rates below 50 ml/min. 5. Lithium clearance data were independent of whether renal disease was of primarily glomerular or tubular origin and, further, were not influenced by long-term conventional antihypertensive treatment. 6. It is concluded that, even with a reduced kidney function, the data are compatible with the suggestion that lithium clearance may be a measure of the delivery of sodium and water from the renal proximal tubule. With this assumption it was found that adjustment of the sodium excretion in chronic nephropathy initially takes place in the distal parts of the nephron (loop of Henle, distal tubule and collecting duct). With more severe impairment the proximal tubule also becomes involved in the adjustment.

Thirty patients with chronic renal diease -10 with polycystic kidney disease (PKD) and normal GFR; 10 with PKD and GFR is less than 30 ml+min; 10 with chronic glomerulonephritis (CGN) and GFR is less than 30 ml+min -and 10 normal subjects were investigated. The ability to concentrate urine maximally (T-CH2O) after water deprivation and the renal handling of water and electrolytes following hypertonic volume expansion were studied. A defect in T-CH2O was common in PKD patients even with normal GFR. In PKD patients with normal GFR, volume expansion was not followed by a natriuretic effect of the same magnitude as in controls. This ""inadequate natriuresis after volume expansion"" may be explained partly by chronic hyponatremia and partly by a functional defect, i.e. the incomplete arterial vasodilation in the kidney. At comparable degrees of renal insufficiency, T-CH2O was lower in PKD than in CGN patients. It seems likely that in PKD patients the increased endogenous osmotic load has exaggerated the tubular defect in urine concentration already present at normal GFR. Furthermore, volume expansion was followed by a significant increase in fractional sodium excretion only in PKD patients with renal insufficiency.