Metformin Therapy in Autosomal Dominant Polycystic Kidney Disease: A Feasibility Study.

RATIONALE & OBJECTIVE: Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that leads to kidney failure and has few treatment options. Metformin is well tolerated and safe in other patient populations. The primary objective of this clinical trial was to determine the safety and tolerability of metformin in patients with ADPKD and without diabetes mellitus. STUDY DESIGN: Prospective randomized controlled double-blind clinical trial. SETTING & PARTICIPANTS: 51 adults aged 30-60 years with ADPKD, without diabetes, and an estimated glomerular filtration rate (eGFR) 50-80 mL/min/1.73 m2. EXPOSURE: Metformin (maximum dose 2,000 mg/d) or placebo for 12 months. OUTCOME: Coprimary end points were the percentage of participants in each group prescribed at the end of the 12-month period: (1) the full randomized dose or (2) at least 50% of the randomized dose. Secondary and exploratory outcomes were the effect of metformin compared with placebo on (1) the percentage change in total kidney volume (TKV) referenced to height (htTKV in mL/m) and (2) the change in eGFR over a 12-month period. RESULTS: The participants' mean age was 48 ± 8 (SD) years, and eGFR was 70 ± 14 mL/min/1.73 m2. The metformin group had no cases of lactic acidosis, and there was 1 episode of mild hypoglycemia in each group. Participants in the metformin group reported more adverse symptoms, mostly related to the gastrointestinal tract. Eleven of 22 metformin-treated participants (50%) completed the treatment phase on the full dose compared with 23 of 23 in the placebo group (100%). In the metformin group, 82% of participants tolerated at least 50% of the dose, compared with 100% in the placebo group. In exploratory analyses, changes in htTKV or eGFR were not significantly different between the groups. LIMITATIONS: Short study duration. CONCLUSIONS: We found that 50% or more of the maximal metformin dose was safe and well tolerated over 12 months in patients with ADPKD. Safety of other preparations of metformin as well as its efficacy should be tested in future clinical trials. FUNDING: Government and philanthropic grants (NIDDK and the Zell Foundation). TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT02903511.

Patterns of Kidney Function Decline in Autosomal Dominant Polycystic Kidney Disease: A Post Hoc Analysis From the HALT-PKD Trials.

BACKGROUND: Previous clinical studies of autosomal dominant polycystic kidney disease (ADPKD) reported that loss of kidney function usually follows a steep and relentless course. A detailed examination of individual patterns of decline in estimated glomerular filtration rate (eGFR) has not been performed. STUDY DESIGN: Longitudinal post hoc analysis of data collected during the Halt Progression of Polycystic Kidney Disease (HALT-PKD) trials. SETTING & PARTICIPANTS: 494 HALT-PKD Study A participants (younger; preserved eGFR) and 435 Study B participants (older; reduced eGFR) who had more than 3 years of follow-up and 7 or more eGFR assessments. MEASUREMENTS: Longitudinal eGFR assessments using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation. PREDICTORS: Demographic, clinical, laboratory, and imaging features of participants. OUTCOMES: Probability of linear and nonlinear decline patterns or of stable eGFR calculated for each participant from a Bayesian model of individual eGFR trajectories. RESULTS: Most (62.5% in Study A and 81% in Study B) participants had a linear decline in eGFR during up to 8 years of follow-up. A proportion (22% in Study A and 13% in Study B) of progressors had a nonlinear pattern. 15.5% of participants in Study A and 6% in Study B had a prolonged (≥4.5 years) period of stable eGFRs. These individuals (Study A) had significantly smaller total kidney volumes, higher renal blood flows, lower urinary albumin excretion, and lower body mass index at baseline and study end. In Study B, participants with reduced but stable eGFRs were older than the progressors. Two-thirds of nonprogressors in both studies had PKD1 mutations, with enrichment for weak nontruncating mutations. LIMITATIONS: Relatively short follow-up of a clinical trial population. CONCLUSIONS: Although many individuals with ADPKD have a linear decline in eGFR, prolonged intervals of stable GFRs occur in a substantial fraction. Lower body mass index was associated with more stable kidney function in early ADPKD.

Serum uric acid, kidney volume and progression in autosomal-dominant polycystic kidney disease.

BACKGROUND: Hyperuricemia has been implicated in the development and progression of chronic kidney disease, both in animal experiments and in clinical studies. As a potentially modifiable risk factor, we examined whether serum uric acid levels correlate with early hypertension, kidney volume and progression to end-stage renal disease (ESRD) in autosomal-dominant polycystic kidney disease (ADPKD). METHODS: Retrospective analysis of a prospective observational study of the natural history of ADPKD, conducted at the University of Colorado between 1985 and 2005. Included are 680 ADPKD adults who provided data on blood pressure, renal volume, renal function, uric acid, age at the onset of ESRD or last known age without ESRD. Serum uric acid levels were examined as a continuous variable and as gender-specific quartiles. The main outcome of interest was age at the onset of ESRD; secondary outcomes were hypertension onset before age 30 years and total kidney volume (TKV) at the study visit. RESULTS: Subjects with early-onset hypertension had higher age-adjusted serum uric acid levels than those with no or late-onset hypertension despite similar creatinine clearance. After adjusting for age, gender and creatinine clearance, there was a 5.8% increase in TKV and 4.1% increase in TKV/body surface area for every 1 mg/dL increase in uric acid (P = 0.007). The multivariate-adjusted Cox regression demonstrated a greater hazard ratio for ESRD for subjects in the 4th and 3rd quartiles of uric acid compared with the 1st [4.8 (2.6-8.9; P < 0.001) and 2.9 (1.6-5.3; P < 0.001)]. CONCLUSIONS: Higher serum uric acid levels are associated with earlier onset of hypertension, larger kidney volume and increased hazard for ESRD in ADPKD independent of gender, body mass index and renal function at the study visit. Randomized interventional studies will be necessary to examine whether treating hyperuricemia has a protective role in ADPKD.

Serum Uric Acid and Progression of Autosomal Dominant Polycystic Kidney Disease: Results from the HALT PKD Trials.

BACKGROUND: Epidemiological studies have suggested that elevated serum uric acid may contribute to the progression of chronic kidney disease. However, no large prospective study has examined whether hyperuricemia is an independent risk factor for the progression of autosomal dominant polycystic kidney disease (ADPKD). METHODS: We measured uric acid in stored serum samples from the 2-year study visit of 671 participants from the HALT PKD multicenter trials. Participants were categorized according to uric acid tertiles. For Study A (participants aged 15-49 years with preserved kidney function, n=350), we used linear mixed effects models to examine the association between uric acid and repeated measures of height-adjusted total kidney volume (htTKV), the primary outcome for Study A. For Study B (participants aged 18-64 with decreased kidney function, n=321), we used Cox proportional hazards models to assess the hazard for the combined endpoint of 50% loss in estimated glomerular filtration rate (eGFR), end-stage kidney disease (ESKD), or death, the primary outcome for Study B. To assess the association of uric acid with the slope of eGFR decline (secondary outcome of HALT A and B), we used linear mixed effects models for the combined population of Study A and B. RESULTS: In the unadjusted model, the annual change in htTKV was 2.7% higher in the highest uric acid tertile compared to the lowest (p<0.001), but this difference became insignificant after adjustment for gender. Men had faster TKV growth than women (p<0.001). There was no difference in eGFR decline between the 3 uric acid tertiles. Hazard ratios for the clinical endpoint were 2.9 (95% confidence interval, 1.9-4.4) and 1.8 (1.1-2.8) respectively in the high and medium uric acid groups in unadjusted and partially adjusted models (p<0.001), but the significance was lost after adjustment for baseline eGFR. Results were similar when uric acid was examined as a continuous variable. CONCLUSION: Elevated serum uric acid is not an independent risk factor for disease progression in ADPKD.

The value of genotypic and imaging information to predict functional and structural outcomes in ADPKD.

BACKGROUNDA treatment option for autosomal dominant polycystic kidney disease (ADPKD) has highlighted the need to identify rapidly progressive patients. Kidney size/age and genotype have predictive power for renal outcomes, but their relative and additive value, plus associated trajectories of disease progression, are not well defined.METHODSThe value of genotypic and/or kidney imaging data (Mayo Imaging Class; MIC) to predict the time to functional (end-stage kidney disease [ESKD] or decline in estimated glomerular filtration rate [eGFR]) or structural (increase in height-adjusted total kidney volume [htTKV]) outcomes were evaluated in a Mayo Clinic PKD1/PKD2 population, and eGFR and htTKV trajectories from 20-65 years of age were modeled and independently validated in similarly defined CRISP and HALT PKD patients.RESULTSBoth genotypic and imaging groups strongly predicted ESKD and eGFR endpoints, with genotype improving the imaging predictions and vice versa; a multivariate model had strong discriminatory power (C-index = 0.845). However, imaging but not genotypic groups predicted htTKV growth, although more severe genotypic and imaging groups had larger kidneys at a young age. The trajectory of eGFR decline was linear from baseline in the most severe genotypic and imaging groups, but it was curvilinear in milder groups. Imaging class trajectories differentiated htTKV growth rates; severe classes had rapid early growth and large kidneys, but growth later slowed.CONCLUSIONThe value of imaging, genotypic, and combined data to identify rapidly progressive patients was demonstrated, and reference values for clinical trials were provided. Our data indicate that differences in kidney growth rates before adulthood significantly define patients with severe disease.FUNDINGNIDDK grants: Mayo DK058816 and DK090728; CRISP DK056943, DK056956, DK056957, and DK056961; and HALT PKD DK062410, DK062408, DK062402, DK082230, DK062411, and DK062401.

Determinants of Progression in Early Autosomal Dominant Polycystic Kidney Disease: Is it Blood Pressure or Renin-Angiotensin-Aldosterone-System Blockade?

BACKGROUND: The HALT PKD trial in early autosomal dominant polycystic kidney disease (ADPKD) showed that intensive control of systolic blood pressure to 95-110 mmHg was associated with a 14% slower rate of kidney volume growth compared to standard control. It is unclear whether this result was due to greater blockade of the renin-angiotensin-aldosterone system (RAAS) by allowing the use of higher drug doses in the low blood pressure arm, or due to the lower blood pressure per se. METHODS: In this secondary analysis of HALT PKD Study A, we categorized participants into high and low dose groups based on the median daily equivalent dose of RAAS blocking drugs used after the initial dose titration period. Using linear mixed models, we compared the percent change in total kidney volume and the slope of estimated glomerular filtration rate (eGFR) between the 2 groups. We also assessed the effects of time-varying dose and time-varying blood pressure parameters on these outcomes. RESULTS: Subjects in the high dose group (n=252) did not experience a slower increase in total kidney volume than those in the low-dose (n=225) group, after adjustment for age, sex, genotype, and BP arm. The chronic slope of eGFR decline was similar in the 2 groups. Higher time-varying systolic blood pressure was associated with a steeper decline in eGFR. CONCLUSION: ADPKD progression (as detected by eGFR decline and TKV increase) was ameliorated by intense blood pressure control as opposed to pharmacologic intensity of RAAS blockade.

Effect of Statin Therapy on the Progression of Autosomal Dominant Polycystic Kidney Disease. A Secondary Analysis of the HALT PKD Trials.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) commonly results in end-stage renal disease (ESRD), yet a long-term treatment that is well tolerated is still lacking. In a small randomized trial in children and adolescents pravastatin administration for 3 years was associated with reduced renal cyst growth, but no large trial has tested the effect of statins in adults. METHODS: We performed a post-hoc analysis of the HALT PKD trials to compare outcomes of participants who never used statins with those who used statin for at least 3 years. Because statins were not randomly allocated, we used propensity score models with inverse probability of treatment weighting to account for imbalances between the groups. For subjects in Study A (preserved renal function, n=438) relevant outcomes were percent change in total kidney and liver volume and the rate of decline in estimated glomerular filtration rate (eGFR); for those in Study B (reduced renal function, n=352) we compared time to the composite endpoint of death, ESRD or 50% decline in eGFR. Follow-up was 5-8 years. RESULTS: There was no difference in any outcome between the 2 groups. However, limitations of this analysis are the small number of statin users in Study A, different statin drugs and doses used, non-randomized allocation and advanced disease stage in Study B. CONCLUSION: Although this post-hoc analysis of the HALT PKD trials does not demonstrate a benefit of statin therapy, conclusions remain preliminary. A larger randomized trial in young people with ADPKD is necessary to answer the question whether statins can slow renal cyst growth and preserve kidney function.

Design and baseline characteristics of participants in the study of antihypertensive therapy in children and adolescents with autosomal dominant polycystic kidney disease (ADPKD).

In this manuscript, we describe our ongoing randomized clinical trial to assess the efficacy of blood pressure control with angiotensin converting enzyme (ACE) inhibition on renal cyst growth over a 5-year study period in children and young adults aged 4-21 years with autosomal dominant polycystic kidney disease (ADPKD). Baseline demographic and laboratory data for the study groups are reported. Results of this study could significantly impact the standard of care for management of ADPKD in this population.

Relationship between renal volume growth and renal function in autosomal dominant polycystic kidney disease: a longitudinal study.

In autosomal dominant polycystic kidney disease (ADPKD), renal function remains normal for many years into adult life while cysts form and expand progressively, starting in childhood. The longitudinal relationships between renal volume growth, hypertension, and renal function loss have not been examined in detail. At the University of Colorado (Denver, CO), 229 adult subjects with ADPKD participated in a longitudinal study from 1985 to 2001. Sequential ultrasound examinations were performed at a mean interval of 7.8 +/- 3.1 years (range, 2.6 to 15.1 years). Renal volume was calculated using a standard formula for a modified ellipsoid. The Modified Diet in Renal Disease equation was used to calculate glomerular filtration rate (GFR). The mean annual increase in renal volume was 46 +/- 55 cm3, and mean annual decline in GFR was 2.4 +/- 2.8 mL/min/1.73 m2. Men had faster renal growth, more severe hypertension, and a faster decline in GFR than women of similar ages. Multiple linear regression showed a significant relationship between rate of change in GFR and renal volume growth rate, initial renal volume, proteinuria, and age at entry. Correlational analysis showed a significant correlation between GFR and renal volume over time (R = -0.53) and between follow-up renal volume and follow-up GFR (R = -0.50) for both men and women. We conclude that renal volume and rate of renal volume growth may be useful markers for disease progression in early stages of ADPKD when GFR is preserved.

Endothelial dysfunction and angiogenesis in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially lethal hereditary disease. The hall mark of the disease is the development of innumerable cysts in kidneys and liver. However, a vascular phenotype including the early occurrence of hypertension, abnormalities in renal blood flow, intracranial and aortic aneurysms, spontaneous coronary and cervicocephalic artery dissections, and dolichoectasias of intracranial arteries is also part of the spectrum of ADPKD. While endothelial dysfunction occurs early in ADPKD and precedes the onset of hypertension, the pathogenesis of endothelial dysfunction has not been extensively studied. Development of endothelial dysfunction in ADPKD (as in other conditions characterized by endothelial dysfunction) has been linked to oxidative stress and vascular inflammation. Vascular dysfunction with increased contraction and decreased relaxation causes downstream tissue ischemia, a potent stimulus for angiogenesis. Evidence of angiogenesis on the surface of renal cysts has been documented in human ADPKD. In addition, high levels of angiogenic growth factors including vascular endothelial growth factor have been reported in cyst fluid and in the circulation of patients with ADPKD. In the following chapter we summarize recent studies examining the role and pathogenesis of endothelial dysfunction and neoangiogenesis in ADPKD.

Glomerular hyperfiltration: definitions, mechanisms and clinical implications.

Glomerular hyperfiltration is a phenomenon that can occur in various clinical conditions including kidney disease. No single definition of glomerular hyperfiltration has been agreed upon, and the pathophysiological mechanisms, which are likely to vary with the underlying disease, are not well explored. Glomerular hyperfiltration can be caused by afferent arteriolar vasodilation as seen in patients with diabetes or after a high-protein meal, and/or by efferent arteriolar vasoconstriction owing to activation of the renin-angiotensin-aldosterone system, thus leading to glomerular hypertension. Glomerular hypertrophy and increased glomerular pressure might be both a cause and a consequence of renal injury; understanding the renal adaptations to injury is therefore important to prevent further damage. In this Review, we discuss the current concepts of glomerular hyperfiltration and the renal hemodynamic changes associated with this condition. A physiological state of glomerular hyperfiltration occurs during pregnancy and after consumption of high-protein meals. The various diseases that have been associated with glomerular hyperfiltration, either per nephron or per total kidney, include diabetes mellitus, polycystic kidney disease, secondary focal segmental glomerulosclerosis caused by a reduction in renal mass, sickle cell anemia, high altitude renal syndrome and obesity. A better understanding of the mechanisms involved in glomerular hyperfiltration could enable the development of new strategies to prevent progression of kidney disease.

Glomerular hyperfiltration and renal progression in children with autosomal dominant polycystic kidney disease.

BACKGROUND AND OBJECTIVES: The purpose of this study was to determine whether glomerular hyperfiltration (GH) occurring early in autosomal dominant polycystic kidney disease (ADPKD) is indicative of more rapid disease progression in children. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: One hundred eighty children with ADPKD (ages 4 to 18 years) with normal renal function were examined by renal ultrasound. Renal volume was calculated using a standard formula for a modified ellipsoid. Creatinine clearance was calculated from serum creatinine and 24-hour urine creatinine. GH was defined as creatinine clearance ≥140 ml/min per 1.73 m(2). RESULTS: Thirty-two children had GH (mean age 11.4 ± 3.6 years) and 148 had normal renal function (mean age 10.8 ± 3.9 years). Patients with GH at baseline demonstrated an increased rate of total renal volume growth (ß: rate of change = +19.3 ± 10.8 cm(3)/year) over 5 years compared with those without GH at baseline (ß = -4.3 ± 7.7 cm(3)/year), P = 0.008. Those with GH at baseline experienced a faster decline in creatinine clearance in subsequent years (ß = -5.0 ± 0.8 ml/min per 1.73 m(2) per year) compared with those without GH at baseline (ß = +1.0 ± 0.4 ml/min per 1.73 m(2) per year), P < 0.0001. CONCLUSIONS: This study revealed that occurrence of GH in ADPKD children is associated with a significantly faster decline in renal function and higher rate of kidney enlargement over time. GH combined with the increased renal volume may therefore be used as an early marker for a more severe progression of ADPKD in children.

Hemodialysis access success: beyond the operating room.

BACKGROUND: Publication of the Kidney Disease Outcomes Quality Initiative (KDOQI) Guidelines has reinforced an already increased focus within the Veterans Health Administration (VHA) on arteriovenous (AV) hemodialysis (HD) vascular access. Meeting these KDOQI goals has been the responsibility of individual VHA centers. We responded by organizing a dedicated HD AV clinic to provide preoperative evaluation and postoperative follow-up. METHODS: The records of 130 patients referred from January 2004 through June 2006 to our AV HD clinic were retrospectively reviewed. A minimum of 6 months of postoperative follow-up was required. RESULTS: AV fistulae were performed in 71% of the patients, with approximately 45% being Brescia-Cimino fistulae. Importantly, only 38% of AV fistulae matured and were used without secondary intervention. The remaining 62% of AV fistulae each required 2.2 +/- .3 interventions. The final AV fistula use rate was approximately 85%. CONCLUSIONS: To meet these KDOQI guidelines, the VHA should continue to support the concept of dedicated AV HD teams and clinics. This is essential because the majority of our new AV fistulae required secondary intervention for AV fistulae maturation and use. A dedicated HD access team should better be able to assess AV fistula maturation and organize subsequent intervention to promote AV fistulae use.

Recurrence of intracranial aneurysms in autosomal-dominant polycystic kidney disease.

BACKGROUND: The natural history of intracranial aneurysms (ICAs) in individuals with autosomal-dominant polycystic kidney disease (ADPKD) is poorly defined. METHODS: We followed twenty ADPKD subjects, eleven with ruptured and nine with intact ICA, for 15.2 +/- 8.1 years (range, 6.0 to 33.2 years). Initial diagnosis was by four-vessel cerebral angiography in eighteen subjects. Follow-up examinations were four-vessel cerebral angiography in fourteen and magnetic resonance angiography (MRA) in six subjects. We examined the occurrence of new ICAs, an increase in size of existing ICAs, recurrent rupture or surgical intervention, and death. RESULTS: Age at initial diagnosis of ICA was 37.7 +/- 10.4 years (range, 20.2 to 53.1 years). Seventeen subjects (85%) had an anterior and three (15%) had a posterior ICA at initial diagnosis. On restudy, five subjects (25%) had a significant change, consisting of new ICAs in a different location in all five and an increase in size of an existing ICA in two of the five. All subjects with ruptured ICA and one subject with intact ICA had undergone surgery at the time of initial diagnosis. Ten subjects (50%) underwent further surgery 8.1 +/- 6.1 years later (1.3 to 17 years). No subject died during follow-up and one subject experienced a recurrent RICA (RICA). We were unable to identify risk factors associated with development of a new ICA or increase in size of an existing ICA. CONCLUSION: Individuals with ADPKD and ICA appear to be at moderate risk for new ICAs and increase in size of existing ICAs; mortality and risk of recurrent rupture, however, appear to be low.