We studied the records of 300 patients with ADPKD over a period of 30 years. The average age of our patients at the time of diagnosis of the disease is 51.53 +/− 17 years with age extremes between 16 and 93 years. We noted a slight male predominance (168 men (56%) versus 132 women (44%)) with a M/F sex ratio of 1.27. The most common circumstances of discovery are RF (40%) and low back pain (30.3%). The disease is more rarely discovered during macroscopic hematuria, renal lithiasis, urinary infection, during family screening or incidentally by renal ultrasound. A family history of ADPKD was present in 99 patients (33%). HBP is present in 140 cases (46.7%) and anemia in 48 cases (16%) with an average hemoglobin level of 8 g/dl. 38 patients or 12.7% of cases are smokers. The urinary manifestations found were urolithiasis in 42 cases (14%), macroscopic hematuria in 44 cases (14.7%) and urinary infection in 31 cases (10.3%). 24-hour proteinuria was positive in 63 cases (21%) with an average rate of 800 mg/day and extremes of 100 and 1500 mg/day. A cystic complication was observed in 47 patients. This involves intracystic hemorrhage in 37 cases (12.3%), cyst infection in 9 cases (3%) and cyst rupture in one patient (0.3%). 64 patients or 21.3% of cases have hepatorenal polycystic disease. The other extra-renal manifestations observed were valvular heart disease in 3 cases (1%), left ventricular hypertrophy in 9 cases (3%), ischemic stroke in 6 cases (2%) and hemorrhagic in 3. cases (1%), inguinal and umbilical hernia in 7 cases each (2.3%). The median serum creatinine at the time of diagnosis is 15.5 mg/l [10; 34] (see Table 1 ).

Among our 140 hypertensive patients, 97 were on monotherapy with ACE inhibitors alone and 43 were on combination therapy with both ACE inhibitors and calcium channel blockers (CCB). ACE inhibitors alone reduced the mean systolic blood pressure from 150 mm Hg to 126 mm Hg and the mean diastolic blood pressure from 90 mm Hg to 72 mm Hg. For patients on combination therapy, their mean systolic blood pressure decreased from 170 mm Hg to 135 mm Hg, and the mean diastolic blood pressure from 94 mm Hg to an average of 75 mm Hg.

N = Number of patients.

Upon admission, 63 patients (21%), 39 men (62%) and 24 women (38%) already had ESRD with a GFR < 15 ml/min, 129 patients (43%) had a GFR between 15 and 60 ml/min, and 108 patients (36%) had a GFR > 60 ml/min.

After a median follow-up of 16 months, 89 out of 108 patients with a GFR > 60 ml/min upon admission maintained stable renal function, and 19 patients experienced renal function decline: 13 had a GFR between 15 and 60 ml/min, and 6 progressed to ESRD. For the 129 patients with a GFR between 15 and 60 ml/min: 6 improved their renal function (GFR > 60 ml/min), 85 maintained stable renal function (GFR between 15 and 60 ml/min), and 38 progressed to end-stage disease (see Table 2 ).

Figure 1 illustrates the evolution of creatinine clearance in our 300 patients included in the study between the time of diagnosis and the end of follow-up.

At admission:

Thus, at the end of the follow-up period:

This evolution demonstrates the deterioration of renal function in our patients throughout the follow-up period.

It is imperative to identify biomarkers and predictive factors for worsening renal function to prevent or at least slow down the progression of autosomal dominant polycystic kidney disease to end-stage disease.

When comparing groups A and B, patients with ESKD (GFR < 15) at the time of diagnosis have a family history of ADPKD (p = 0.025), hepatic cystic disease (p = 0.009), and more HBP (P = 0.002). For a history of macroscopic hematuria, cystic infection, urinary stones, and smoking, there is no significant difference between the 2 groups. There is also no sex predominance between the 2 groups ( Table 3 ).

N = number of patients.

After a median follow-up of 16 months, the comparison between groups C and D reveals that patients who progressed to ESRD are significantly younger (46.2 +/− 16 vs 52.24 +/− 17.5 (p = 0.029)) and more anemic (p =< 0.001). They also experienced macroscopic hematuria during follow-up (p = 0.001) and had an umbilical hernia (p = 0.034). Smoking, 24-hour proteinuria, HBP during follow-up, cystic infection, urinary tract infection, and intracystic hemorrhage are not significantly associated with renal function deterioration during follow-up ( Table 4 ).

N = Number of patients.

In univariate analysis, the factors associated with worsening renal function are young age (p = 0.039), anemia (p < 0.001), macroscopic hematuria (p < 0.001), and the presence of hepatic cystic disease ( Table 5 ).

In adjusted analysis, the predictive risk factors for the occurrence of ESKD are smoking (p = 0.019), anemia (p < 0.001), hepatic cystic disease (p < 0.001), and proteinuria (p = 0.022) ( Table 6 ).

PKRAD is a hereditary and progressive kidney disease with clinical manifestations appearing in the 3rd and 4th decades of life [5] [7] . The age of onset of renal dysfunction in this pathology varies. The decline in renal function begins after the fourth decade of life [12] , and by age 65, 45% - 70% of patients reach the stage of end-stage renal disease (ESRD) [13] .

In our study, 21% of our patients were already in ESRD at the time of diagnosis, compared to 23% in a Tunisian study [14] and 31.5% in a study conducted in Senegal [15] .

After a median duration of 16 months, 35.66% of our patients progressed to ESRD, compared to 54.6% and 45.8% after median durations of 25 [14] and 110 months [13] respectively.

Given the highly variable progression of PKRAD among individuals, it is essential to predict which patients will rapidly progress to renal insufficiency, in order to assess the benefit-risk ratio of any intervention and consider the early implementation of long-term renal protection measures. Thus, prognostic biomarkers need to be identified to predict future renal function decline. Clinical, biological, genetic, epigenetic, radiological, and environmental factors have been studied in various studies, including ours.

As previously mentioned, PKRAD is caused by mutations in the PKD1 and PKD2 genes. The presence of one or more family members who reached ESRD before the age of 55 suggests a PKD1 genotype, while satisfactory renal function until age 70 suggests a PKD2 genotype [16] . The PKD1 mutation is considered a risk factor for worsening renal function in PKRAD [12] . Unfortunately, our patients did not undergo genetic studies, which is a significant limitation of this study.

However, a family history of PKRAD can also be used as a diagnostic tool for the disease [17] . It is present in 33% of our patients and in 43.7% in a Tunisian study [14] . This family history is significantly reported among our patients who were immediately admitted to ESRD (p = 0.025). According to a 2016 Italian study, renal impairment is more severe in subjects with a family history of ESRD occurring before age 55 [18] .

The average age of our patients at the time of diagnosis is 51.53 +/− 17 years. It is 37 years in an Iranian study [19] and 43.1 ± 14.1 in a South Korean study [13] . We examined the effect of age on the deterioration of renal function. The average age of our patients in ESRD at admission is 53.06 +/− 15.6 years, and that of patients who progressed to ESRD during follow-up is 46.2 +/− 16 years. In our study, younger age is significantly associated with renal function deterioration in univariate analysis (p = 0.039) only. According to Panizo et al., younger age is an independent predictive factor influencing the progression of renal insufficiency in multivariate analysis [20] . According to Hajji et al., age > 40 years is a risk factor for progression to ESRD in multivariate analysis [21] . According to Park et al., age at diagnosis after 30 years (P = 0.007) is a predictive factor for ESRD in multivariate analysis [13] .

The influence of sex on PKRAD is reported by several authors. Male sex is associated with the early onset of hypertension (HTN) and a faster and more severe progression of renal function to end-stage renal [22] - [25] . In the Cox multivariate regression analysis of the Orskov et al. study, male sex is associated with a significant reduction in survival and an increased risk of death that can reach 34% after the onset of ESRD [26] . Gretz et al. reported that women progress to ESRD on average six years later than men [27] . In our series, we note a slight male predominance (168 men (56%) vs. 132 women (44%)), aligning with literature data [13] [14] with a male-to-female sex ratio of 1.27, but without a significant sex difference in terms of diagnosis (p = 0.288) or progression to ESRD (p = 0.508). This result is nonetheless supported by other studies that do not consider male sex a risk factor for worsening renal function in PKRAD [28] [29] .

We focused on the impact of cardiovascular risk factors in PKRAD, especially since about half of the patients in our series are hypertensive (46.7%). HTN is a serious complication of PKRAD that can lead to both an increased incidence of cardiovascular complications and a faster progression of renal insufficiency [30] , especially if it occurs early [12] [21] . It is a significant independent risk factor for progression to ESRD in multivariate analysis [20] [25] [31] , its control has a limited beneficial influence on the rate of progression in patients with advanced renal disease with significant renal insufficiency [31] [32] and reduces mortality [33] . In our study, patients in ESRD at admission are significantly more hypertensive (p = 0.002), but this HTN is not considered a predictive factor for ESRD in either univariate or multivariate analysis. The second well-known cardiovascular risk factor is smoking. 12.7% of our patients are smokers. Smoking is a predictive factor for ESRD occurrence (p = 0.019) in our study in multivariate analysis. It has been associated with rapid progression of renal function in a prospective observational study [34] . Smoking increases the risk of ESRD in men with chronic kidney disease in a dose-dependent manner [27] .

Anemia is rare in PKRAD [35] compared to other nephropathies, with higher hemoglobin levels in ESRD [36] . The production of erythropoietin by the cyst wall and parenchymal cells explains this fact [35] [37] . In our study, anemia is present in 48 out of 300 patients, with an average hemoglobin level of 8 g/dl (6 - 10 g/dl). It is significantly associated with poor renal prognosis in multivariate analysis (p < 0.001). Few studies have focused on anemia in PKRAD. A study conducted in Japan in 2019 found that anemia is a poor renal prognostic factor in PKRAD [38] .

In our study, 24-hour proteinuria is a factor in progression to ESRD in adjusted analysis (p = 0.022). It is positive in 63 patients (21%) with an average level of 800 mg/day, ranging from 400 to 1500 mg/day. Some studies have confirmed the role of proteinuria in the progression of chronic renal failure in PKRAD [20] . According to the MDRD (Modification of Diet in Renal Disease) study, higher levels of proteinuria are associated with a more marked decline in glomerular filtration rate (GFR) [39] . In another study of 270 adults with PKRAD, the 48 patients (18%) with proteinuria (300 mg/day) had more impaired renal function, higher blood pressure, larger kidney volume, and more aggressive renal disease progression (P < 0.05) [40] .

After an average follow-up of 16 months, the patients in our cohort who progressed to ESRD (group C) experienced at least one episode of macroscopic hematuria (p = 0.001). We do not know the exact age of onset of hematuria in our patients, but studies show that early (before age 30) [41] [42] and recurrent [22] macroscopic hematuria is a predictive factor for PKRAD progression [21] , affecting renal survival.

We also analyzed the relationship between urinary tract infections (UTIs) and renal insufficiency progression. UTI occurred in 31 of our patients, or 10.3%. It was not associated with worsening renal function and was not considered a predictive factor for ESRD. Contrary to our results, several small studies have linked UTIs in PKRAD patients to faster renal function decline. This is also confirmed by a Saudi study published in 2006 [32] . According to an uncontrolled study, antibiotic prophylaxis in recurrent UTIs significantly reduces UTI incidence and limits renal function loss [41] .

A relationship between kidney size and renal function is established [43] . Total kidney volume is associated with rapid disease progression [21] . According to Dalgaard et al., the median interval between palpable kidneys and ESRD is less than five years [44] . Unfortunately, total kidney volume was not calculated in our patients, which is a limitation of our study.

Cyst infection is found in 3% of cases in our study and is not associated with poor renal prognosis. However, it is in the Park et al. study in multivariate analysis (P = 0.005), which found it in 9.7% of their patients [13] .

We also examined the extra-renal manifestations of PKRAD. Liver cysts are the most common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD) and are often discovered incidentally, being clinically insignificant in most cases. They are present in over 90% of ADPKD patients over 35 years old [45] [46] . In our study, hepatic polycystic disease emerged as a predictive factor for renal function deterioration in both univariate and multivariate analyses (p = 0.001). A 2008 study comparing clinical characteristics of patients with isolated hepatic polycystic disease and those with both hepatic and renal polycystic disease concluded that the clinical course of isolated hepatic polycystic disease, despite a higher number of cysts, is relatively benign compared to the hepatorenal form [47] . Factors significantly associated with the development and severity of hepatic cysts in ADPKD patients, according to a Korean study, include advanced age, female sex, and larger kidney volume [48] .

The presence of an umbilical hernia was significantly associated with renal function deterioration in our study, though this was not confirmed in multivariate analysis and has not been reported in the literature.

Renal stones, cyst rupture, intracystic hemorrhage, and intracranial aneurysm rupture were not identified as predictive factors for end-stage renal disease (ESRD) in our study or the literature.

In conclusion, ADPKD can insidiously progress to ESRD, which marks the severity of the disease. In our study, smoking, anemia and hepatic polycystic disease were predictive risk factors for the onset of ESRD in multivariate analysis. However, the interpretation of 24-hour proteinuria remains limited regarding its role as a predictive factor for progression to ESRD.

Identifying these risk factors and predicting the individual progression of ADPKD could aid in implementing approved treatments, such as vasopressin V2 receptor antagonists (Tolvaptan), which are not currently used in our patients, thus slowing the progression of the disease.

Autosomal Dominant Polycystic Kidney Disease = ADPKD

End-stage chronic renal disease = ESRD

Chronic Kidney Disease = CKD

Chronic Renal Failure= CRF

Renal failure = RF

High blood pressure = HBP

Glomerular Filtration Rate = GFR

Estimated Glomerular Filtration Rate = eGFR

Angiotensin-Converting Enzyme Inhibitor = ACE inhibitor

Inhibitor Calcium Channel Blocker = CCB

Polycystin-1 = PC-1

Polycystin-2 = PC-2

Intracranial Aneurysm = ICA

The estimated glomerular filtration rate (eGFR) is calculated using a Modification of diet in renal disease (MDRD) equation.

Chronic kidney failure (CKD) is defined by an eGFR less than 60 ml/min/ 1.73m² (KDIGO 2012 classification).

GFR: glomerular filtration rate. *Renal damage manifested by histological and/or biological and/or morphological abnormalities.

Epidemiological profile

Name

Phone number:

Age:

Sex:M □F □

Family History:

Family history of ADPKD:yes □no □

Personal history:

Circumstances of discovery:

HBPyes □no □

Renal failureyes □no □

Lower back or abdominal painyes □no □

Gross hematuriayes □no □

Urinary Infectionyes □no □

Urolithiasisyes □no □

Family screening yes □no □

Chance discovery by imaging yes □no □

Median age at diagnosis

Serum creatinine at diagnosis:

Mean eGFR at diagnosis:

eGFR group at diagnosis: >60 ml/min □15 - 60 ml/min □<15 ml/min □

Kidney damage and complications:

Intracystic hemorrhageyes □no □

Cyst ruptureyes □no □

Cyst infectionyes □no □

Urolithiasisyes □no □

Gross hematuriayes □no □

Lower back or abdominal painyes □no □

Feveryes □no □

Extra –rénal damage

Liver damage: liver cysts + hepatomegaly (polycystic liver disease), liver fibrosis, pulmonary arterial hypertension.

Other cystic lesions: spleen, pancreas, arachnoid, seminal vesicle, ovaries.

Cardiac involvement: valvular heart disease, pericarditis, aortic aneurysm, mitral valve prolapse, left ventricular hypertrophy.

Brain damage: Ischemic vascular accident, transient ischemic attack, subarachnoid hemorrhage, rupture of intracranial aneurysms.

Digestive damage: constipation, abdominal or lower back pain, abdominal bloating, polyps, diverticulosis, esophagitis, gastroesophageal reflux, inguinal or umbilical hernia.

Others (carpal tunnel syndrome, sensory-motor neuropathy of all 4 limbs, male infertility, etc.).

Radiological data:

□ Renal and extrarenal ultrasound manifestations: Size of the kidneys, location, number of cysts:

□ Abdominal, brain or other scan:

Evolutionary profile of hypertension:

Blood pressure at the start of follow-up:

Blood pressure at the end of follow-up:

Therapeutic class:

Evolution:

Lost

Duration of follow-up:

Evolution: ESRD/Worsening renal function during follow-up/Stable renal insufficiency/Normal renal function

>60 ml/min □15 - 60 ml/min □<15 ml/min □

Factors for progression towards ESRD:

Age

Sex (male)

HBP

Macroscopic hematuria

Urinary Infection

Cyst Infection

Intracystic hemorrhage

24-hour proteinuria (>300 mg/day) Rate if positive:

Anemiahemoglobin level

Smoking