Evaluation of rapid progression of renal disease

ADPKD exhibits highly variable clinical features, especially during progression to ESKD. With the recent approval of a drug that slows the progression of kidney disease, it has become more important to diagnose patients with rapidly progressing kidney disease. Risk assessment for renal progression includes three categories of factors: genetic testing, total kidney volume (TKV), and other clinical features.

Genetic testing

The different clinical features of ADPKD are closely related to loci effects. patients with PKD1 mutations are more aggressive than those with PKD2 mutations. the median age of ESKD onset is 58 years in PKD1 patients and 79 years in PKD2 patients. the HOPE-PKD study also showed that ESKD onset was earlier in PKD1 patients compared to PKD2 patients (64.9 years vs. 72.9 years). The age of onset of ESKD in Korean ADPKD patients was earlier in PKD1 patients and earlier in PKD2 patients. Further studies are needed to determine whether the etiology is genetic or acquired.

In addition, PKD1 patients were classified into three groups: nonsense, shift, and typical splice site mutations were classified as mutations truncating the protein (PKD1 PT), small in-frame insertions/deletions affecting less than 5 amino acids were classified as PKD1 in-frame insertions/deletions (PKD1 IF indel), and nonsynonymous missense or atypical splice site mutations were classified as PKD1 non-truncated (PKD1 NT). Table 2 shows the mutation frequency of HOPE-PKD compared with other large cohorts. The proportions of PKD1 PT and PKD1 NT were similar in the Korean ADPKD cohort.

In addition, patients with PKD IF indel, PKD1 NT, and PKD2 had a reduced risk of ESKD (risk ratio [HR] 0.35, 0.10, and 0.03, respectively) and death (HR 0.31, 0.20, and 0.18, respectively) compared with patients with PKD1 PT. The HOPE-PKD study also showed that when PKD1 PT was used as the reference PKD2 had a 0.22-fold lower HR in ESKD. However, the risk of ESKD in PKD1 IF indel and PKD1 NT patients did not differ from PKD1 PT patients, and the risk of death did not differ between the four groups. The reason for the different prognosis of PKD1 NT from previous studies in the present study has not been clarified and is expected to be verified by ongoing studies.

Other clinical characteristics

Researchers in the GENCYST study identified four variables that were significantly associated with age at ESKD onset: male, hypertension by age 35, first urinary event by age 35, and PKD mutation type. They developed a new prognostic scoring system (ADPKD [PROPKD] score in predicting renal outcome) that accurately predicted renal outcome. at age 60 years, Kaplan-Meier analysis yielded a probability of ESKD of 19.3% for the low-risk group, 60.8% for the intermediate-risk group, and 91.9% for the high-risk group.

The ERA-EDTA Working Group on Inherited Kidney Diseases and the European Renal Best Practice provide algorithms to assess indications for the initiation of treatment for ADPKD. They defined rapid progression using historical eGFR decline (confirmed eGFR decline ≥5 mL/min/1.73 m² within 1 year and/or confirmed eGFR decline ≥2.5 mL/min/1.73 m² within 5 years or more) and historical renal growth (htTKV increased more than 5% per year using three repeated measurements). They also defined possible rapid progression using baseline htTKV predicted progression based on age and/or genotype indexing:htTKV with Mayo class 1C, 1D, 1E or ultrasound length and gt compatible; 16.5 cm and/or truncated PKD1 mutation + early symptoms (i.e. PROPKD score>6). Finally, they defined possible rapid progression by a family history of ADPKD with ESKD ≤58 years. The working group has applied these criteria to patients with eGFR ≥30 mL/min/1.73 m² and recommended treatment with tolvaptan.

A multinational, multicenter retrospective cohort study is currently underway to determine the clinical characteristics of rapidly progressing ADPKD patients from six countries in the Asia-Pacific region (Australia, China, Hong Kong, Korea, Taiwan, and Turkey); using the currently recommended rapid progression.

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Treatment

Before tolvaptan was approved as a disease remission drug, patients with ADPKD were mostly treated symptomatically. Here, we will discuss the treatment associated with renal symptoms and renal disease progression in ADPKD. Screening and treatment of extrarenal manifestations will be discussed in other opportunities.

Blood pressure control

Hypertension is the most common renal symptom of ADPKD and a major risk factor for the progression of renal failure and cardiovascular complications. Blood pressure increases from a relatively young age and is known to be associated with the activation of the renin-angiotensin-aldosterone system early in the disease. The HALT Progression in Polycystic Kidney Disease (HALT- PKD) study showed that in patients with early hypertensive ADPKD (15 ~ 49 years), eGFR > strict blood pressure control (95/60 to 110/75 mmHg) compared to standard blood pressure control (120/70 to 130/80 mmHg) was associated with a slow increase in TKV, no overall change in eGFR, a greater decrease in the left ventricular mass index, and greater reduction in urinary albumin excretion. Therefore, blood pressure regulation to ≤130/80 mmHg is recommended, but if the patient is 18 ~ 50 years of age, eGFR > blood pressure control to 60 mL/min/1.73 m2 ≤110/80 mmHg is recommended. angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are the first-line treatment for ADPKD.

Water intake

In ADPKD, antidiuretic hormone antidiuretic hormone is increased. The binding of pressing to pressing V2 receptors located in the distal tubules and collecting ducts leads to increased intracellular cAMP concentrations and activation of protein kinase A, which is associated with cyst growth. Therefore, it is theoretically speculated that heavy water consumption may inhibit antidiuretic hormone production and cyst growth. An expert review suggested that urination by ingesting 2.5 - 4 liters of water per day and lowering urinary osmolality to ≤250 mOsm/kg may slow cyst growth by consistently inhibiting antidiuretic hormone secretion. Chebib and Torres recommended moderate hydration enhancement over a 24-hour period (daytime, bedtime, and nighttime if awake) to maintain a mean urinary osmolality of ≤ 280 mOsm/kg.

However, there is no clear evidence that heavy water consumption has a significant effect on changes in TKV and renal function in patients with ADPKD.

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Cyst infection

Cyst infection and urinary tract infection are common complications in patients with ADPKD; therefore, it is difficult to identify renal cysts and/or hepatic cyst infection. Confirmation of the diagnosis includes extracting cyst fluid from suspected cysts to identify the pathogen or observing the clinical presentation: Fever of 38.5˚C or higher for 3 days with abdominal pain (usually in a specific area) and elevated C-reactive protein of 50 mg/L or higher can exclude cyst bleeding. In recent years, [18F]fluorodeoxyglucose-labeled leukocyte (WBC)-positron emission tomography (PET)/CT has become an effective imaging test for the diagnosis of cystic infection. In a study of 19 Korean patients with suspected cystic infection in ADPKD, WBC-PET/CT detected 64% of cystic infection cases compared with 50% detected by conventional imaging. 2 false-positive cases of WBC-PET/CT were seen in 5 cases without cystic infection.

The fluoroquinolone series has good cyst penetration and is used as the main empirical antibiotic for treatment, with changes based on culture results and treatment outcomes. Antibiotic maintenance for 4 ~ 6 weeks is usually recommended, but the appropriate duration of antibiotic administration, timing of treatment response assessment, and timing of surgical drainage still need further study.

Nutrition

In ADPKD patients, many complications may occur due to the mass effect caused by enlarged kidneys or liver. Since Korean patients are smaller than Western patients, there is a possibility of more severe mass effects. In Korea, ADPKD patients with PLD develop stress-related organ enlargements such as leg edema (20.4%), ascites (16.6%), and hernia (3.6%). Moderate to severe stress-related symptoms were most commonly associated with abdominal distention (13.6%), followed by early satiety (10.6%), resulting in poorer oral intake. A cross-sectional study of Korean patients with ADPKD showed that 7.3% of patients were mild to moderately malnourished (modified subjective global assessment [SGA] scores of 4 and 5) and 21.7% were at risk for malnutrition (SGA score of 6). After adjusting for other risk factors including renal function, HtTKV, and htTKLV were the only significant predictors of malnutrition.

Malnutrition was one of the strongest predictors of mortality and morbidity in patients with CKD. In patients with ADPKD, a decrease in renal function combined with an increase in kidney and/or liver volume is likely to result in malnutrition. Therefore, regular assessment of nutritional status and appropriate treatment are needed. Bioelectrical impedance analysis and SGA have been reported to be useful methods in assessing the nutritional status and abdominal cystic organ impact in patients with ADPKD.

As with other CKD patients, individualized strategies based on each patient's nutritional status, clinical comorbidities, and disease severity are recommended to prevent malnutrition, slow the progression of CKD, and reduce mortality.

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Antidiuretic hormone V₂ receptor antagonists

The Phase III study of the efficacy and safety of Tolvaptan for autosomal dominant polycystic kidney disease and its outcomes (TEMPO 3:4) was a randomized controlled trial enrolling 1445 patients under 50 years of age with ADPKD with TKV and gt;750 mL and GFR >60 mL/min (estimated using the Cockcroft-Gault formula). At 3 years of tolvaptan treatment, kidney volume increased by 2.8% in the treatment group compared to 5.5% in the placebo group, showing approximately 50% suppression. It also reduced pain and the rate of decline in renal function.

Replication Evidence for Preservation of Renal Function: The Tolvaptan in ADPKD Investigation of Safety and Efficacy (REPRISE) trial included patients with more advanced ADPKD than the TEMPO 3:4 study. The REPRISE study showed that for patients with advanced ADPKD (18 - 55 years of age with an eGFR of 25 - 65 mL/min/1.73 m2 or 56 - 65 years of age with an eGFR of 25 - 44 mL/min/1.73 m2), tolvaptan caused a slower decline in renal function than placebo over a 1-year period.

Clinically important liver enzyme concentrations were increased (4.4% in the tolvaptan group and 1% in the placebo group) [58]. However, a long-term safety study showed that monthly liver monitoring during the first 18 months of tolvaptan exposure and every 3 months thereafter enabled early detection of transaminase elevations and effective intervention.

Tolvaptan was approved by the Food and Drug Safety Agency in 2015. A study to evaluate the safety and efficacy of Tolvaptan for the treatment of autosomal dominant polycystic kidney disease (ESSENTIAL) in Korean adult patients is currently underway to evaluate the safety and efficacy of Tolvaptan for the treatment of Korean patients with ADPKD (NCT03949894).

Hyperuricemia

It is well known that uric acid levels rise as renal function declines; however, whether hyperuricemia directly worsens renal function remains controversial. Although there are no consistent recommendations for the treatment of asymptomatic hyperuricemia in patients with CKD, most Korean physicians treat asymptomatic hyperuricemia in patients with CKD to prevent CKD progression and cerebrovascular complications.

A retrospective study reported the association of high serum uric acid levels with increased risk of premature hypertension, large renal volume, and ESKD in patients with ADPKD, but the study failed to show an independent effect of hyperuricemia on renal progression in Korean patients with ADPKD. However, they also demonstrated that correction of hyperuricemia with uric acid-lowering drugs may attenuate renal progression in the early stages of CKD. Further prospective studies are needed to verify the effect of controlling hyperuricemia on disease progression in ADPKD.

Other potential therapies

Several therapeutic targets have been identified that may slow the progression of renal cysts in ADPKD, and many trials are investigating various therapeutic approaches, including rapamycin inhibitors, growth inhibitor analogs, sphingolipid reduction therapy targeting sphingolipids, and mechanistic targets for tyrosine kinase inhibitors. These studies are expected to provide new and better therapeutic approaches for patients with ADPKD.

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Conclusions

ADPKD is the most common inherited kidney disease associated with decreased renal function and ESKD. ADPKD not only causes structural and functional defects in both kidneys, but is also accompanied by various extrarenal complications, and therefore needs to be managed from the early stages of the disease. ADPKD is known to be caused by defects in PKD1 and PKD2, which encode the proteins PC1 and PC2, respectively. in addition to establishing genetic tests and image analysis methods to predict the clinical course of the disease, pharmacological treatments have been attempted to prevent disease progression. It is important for physicians to select patients at high risk for various factors and treat them at the appropriate time to slow disease progression and prevent complications.

It is expected that the KNOW-CKD study, the HOPE-PKD study, and the ADPKD subcohort study of the Korean iCKD cohort study will provide data on the genetic and clinical characteristics of Korean ADPKD patients. the ESSENTIAL study will also evaluate the safety and efficacy of tolvaptan in Korean ADPKD patients. It is hoped that through these studies, physicians will be able to better understand the characteristics of Korean ADPKD patients and provide appropriate treatment for these patients

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