Autosomal Dominant Polycystic Kidney Disease (ADPKD) presents a significant burden globally, including in Tunisia. This retrospective study aimed to characterize ADPKD cases in Tunisia, focusing on clinical manifestations, therapeutic interventions, and prognostic markers influencing progression to End-Stage Renal Disease (ESRD). Data from 107 patients over 21 years revealed a mean age of 53.43 years and a predominance of renal failure as the primary clinical presentation (47%). Notably, a substantial proportion (42/59) of patients without advanced renal failure at diagnosis progressed to ESRD during follow-up, with identified prognostic factors including anemia, urinary tract infections, kidney size, and cyst volume. These findings underscore the importance of early detection and personalized management strategies in ADPKD.

• Autosomal dominant polycystic kidney disease

• Chronic renal failure

• Prognostic factors

Driss N, Gorsane I, Barbouche S, Hajji M, Abderrahim E (2024) Autosomal Dominant Polycystic Kidney Disease in Tunisia: Clinical Characteristics, Therapeutic Management, and Prognostic Factors. J Clin Nephrol Res 11(1): 1120.

Autosomal dominant polycystic kidney disease (ADPKD) stands as the predominant genetic etiology leading to chronic end-stage renal disease (CKD) on a global scale [1]. Its prevalence is estimated to range between 1/1000 and 1/4000 births, contributing to approximately 8-10% of incident cases initiating renal replacement therapy in developed nations, thus emerging as the fourth leading cause of CKD worldwide [2,3]. However, despite its significant impact, ADPKD remains relatively understudied in Tunisia, with scarce research focusing on renal prognosis. Consequently, there is a pressing need to investigate the clinico-biological, radiological, therapeutic, and evolutionary particularities of ADPKD within the Tunisian population and evaluate prognostic factors influencing disease progression.

ADPKD typically manifests in adulthood, characterized by the development of multiple renal cysts culminating in the enlargement of kidneys. Beyond renal involvement, cystic or noncystic manifestations affecting various tissues or organs, such as liver cysts and intracranial artery aneurysms, pose significant clinical challenges [2].

The primary genetic etiology of ADPKD involves mutations in two genes: PKD1 and PKD2. PKD1, located on chromosome 16 (16p33.3), encodes for polycystin-1, while PKD2, situated on chromosome 11 (4q21), codes for polycystin-2. These proteins play crucial roles in calcium channel function and intracellular calcium flux regulation. Experimental evidence has shown that mutations in PKD1 or PKD2 lead to a reduction or loss of polycystin-1 or polycystin-2, resulting in aberrant intracellular signaling pathways and the development of renal cysts [3].

Understanding the molecular mechanisms underlying cystogenesis has paved the way for novel therapeutic interventions [4], although managing ADPKD patients remains challenging.

Despite notable progress in cardiovascular risk mitigation, dialysis, and renal transplantation over recent decades, managing patients with ADPKD remains a formidable task for nephrologists.The development of targeted therapies represents a promising frontier, yet barriers such as high treatment costs and limited accessibility hinder their widespread implementation, particularly in resource-constrained settings.

Study Area

This retrospective descriptive and analytical study was conducted in the Department of Internal Medicine A at Charles Nicolle Hospital, Tunis. It encompassed cases of ADPKD collected over a 21-year period from January 1, 2000, to December 31, 2020.

Inclusion Criteria

The study included patients diagnosed with autosomal dominant polycystic kidney disease who were hospitalized in the Internal Medicine A department of Charles Nicolle Hospital.

Exclusion Criteria

Patients seen only in consultation were not included. Additionally, patients whose records were destroyed or unavailable, or lacked essential clinical or biological parameters, were excluded.

Data Collection

An information sheet was developed to extract data from patient files.

Data Analysis

- Descriptive Study: Descriptive statistics, including univariate analysis, were used to describe demographic and clinical data.

- Analytical Study: An analytical study investigated predictive factors for CKD progression, excluding patients already at stage 5 at the time of ADPKD diagnosis. Fifty-nine patients were analyzed, with 42 progressing to CKD during the follow-up period [Group 1] and 17 not yet reaching CKD stage [Group 2].

- CKD Incidence Calculation: CKD incidence rates were calculated by dividing the number of patients starting renal replacement therapy by the duration of follow-up. Confidence intervals were calculated at 95% using standard formulas.

- Univariate Analysis: Survival curves, developed using the Kaplan-Meier method, were compared based on the Log Rank test, and logistic regression was employed. The test was considered significant when the p-value was less than 0.05.

- Multivariate Analysis: Multivariate analysis, aimed at estimating the risk of an event occurrence related to a risk factor, was performed using a stepwise logistic regression method. Initially, all factors with p-values between 0.05 and 0.15 were introduced into the regression model, and step by step, the least significant factor with a p-value was removed.

Ethical Consideration

Permission for the study was obtained from the head of the Department of Internal Medicine A at Charles Nicolle Hospital - Tunis. The local ethics committee approved the study, ensuring that the research procedures adhere to the required ethical standards.

Patient names were not used, and confidentiality was maintained.

The study revealed that ADPKD accounted for 0.56% of hospitalizations in our department over the study period, with an annual incidence of 8.9 cases. The average age of patients was 53.43 ± 10.8 years, with 57% falling between 40 and 59 years, and a notable male predominance (M/F sex ratio of 2.3). Parental consanguinity was present in 60% of cases, with first-degree kinship observed in 49 patients (45.8%). Renal failure was the most common presentation (47% of cases), with family screening leading to diagnosis in 8.5% of patients. Clinical manifestations at diagnosis included lumbar tenderness (80%), hematuria (60%), and hypertension (55%). Approximately 47% of patients were in stage 5 chronic kidney disease at diagnosis. Hematuria was prevalent in 56% of patients, with urinary tract infections identified in 20 patients. The mean kidney size was 16.25 ± 4.55 cm (right) and 17 ± 4.39 cm (left), with the largest renal cyst measuring 6 ± 3.11 cm. Treatment included symptomatic management (89.7%), dual or triple antihypertensive therapy (50%), and nephrectomy (6.5%). Most patients (84%) progressed to end-stage renal disease, primarily undergoing conventional hemodialysis (98.8%). Renal transplantation was performed in 3.73% of cases. Of the patients not at CKD stage, 71.1% progressed to CKD during follow-up. The mean follow-up duration was 10.2 ± 5.46 years. The annual incidence of CKD in ADPKD patients was 18.35%, with higher incidences observed in women, those with proteinuria, hematuria, hypertension, and urinary tract infections. Prognostic factors for CKD progression, including anemia, urinary tract infections, kidney size, and cyst volume, were identified through logistic regression analysis. However, evaluation of total renal volume as a prognostic factor was hindered by insufficient radiological data, as total renal volume was not measured in any patient.

Strength and weakness of the study

Strengths of the study:

1. Relevance: The study addresses a critical global health concern, focusing on ADPKD, a leading cause of end-stage renal disease worldwide.

2. Tunisian Focus: By specifically investigating ADPKD within the Tunisian population, the study provides valuable insights tailored to this demographic, potentially contributing to more targeted healthcare interventions.

3. Long Study Duration: The extensive 20-year study period allows for a comprehensive analysis of trends and outcomes over time, offering valuable longitudinal data for researchers and healthcare practitioners.

Weaknesses of the study:

1. Retrospective Design: As a retrospective analysis, the study is reliant on existing medical records, which may be incomplete or contain missing data, potentially impacting the accuracy and reliability of the findings .

2. Loss to Follow-up: Patients lost to follow-up can skew the data and compromise the accuracy of survival analysis, leading to potential biases in the results.

3. Absence of Total Renal Volume (TRV) Measurement: Without measuring TRV, a crucial prognostic factor in ADPKD, the study may lack a comprehensive understanding of disease severity and progression.

4. Lack of Genetic Analysis: The absence of genetic studies limits insights into the genetic factors influencing ADPKD prognosis in the Tunisian population, hindering the development of personalized treatment approaches.

5. Single-Hospital, Lack of Multi-center Research: Conducting the study at a single hospital limits the diversity and generalizability of the findings, highlighting the need for multi-center research to validate the results across different settings and populations.

6. Small Sample Size: A limited sample size may restrict the statistical power of the study, potentially leading to inconclusive findings or limited ability to detect significant associations or trends within the data.

In summary, while the study offers valuable insights into ADPKD within the Tunisian population, its limitations, including its retrospective design, loss to follow-up, lack of genetic analyses, single-hospital focus, absence of multi-center research, and limited sample size, should be considered when interpreting the results and drawing conclusions.

Epidemiological Aspects of ADPKD

ADPKD stands as the most prevalent genetic cause leading to end-stage renal failure and dialysis globally [1]. In our study, we aimed to estimate the prevalence of ADPKD in our department, yielding a rate of 0.56% and an annual incidence of 8.9 cases. These findings, however, may be subject to criticism due to challenges in accurately determining hospitalizations without complications. National epidemiological data on ADPKD and dialysis initiation in Tunisia are predominantly derived from retrospective or single-center studies, highlighting the need for more comprehensive research efforts. It’s important to note that in Tunisia, we lack a national registry for polycystic kidney disease, which further underscores the necessity for more extensive and systematic data collection methods. For instance, a multicenter study published in 2019 reported an incidence of 15.3 cases per year [5], shedding light on the disease burden within the Tunisian population.

Clinical Characteristics

Age: In our study, patients were diagnosed with ADPKD at a mean age of 53.43 ± 10.8 years, with most falling between 40 and 59 years old. This is consistent with international literature, where ADPKD diagnosis typically occurs between ages 27 and 89 [6,7]. The wide age range reflects genetic and allelic heterogeneity, with PKD1 and PKD2 mutations contributing to variations in diagnosis age [8]. Systematic family screening may influence the average age at diagnosis.

Gender: In our study, the majority of the population was male (70.1%) with a gender ratio of 2.3. This contrasts with large-scale studies such as the German Else-Kroener-Fresenius Registry [9], which did not show a significant gender difference. Our results may be influenced by patient selection bias, as only hospitalized patients were included.

Geographic Origin: According to our study, most patients reside in the Greater Tunis area, potentially due to migration between rural and urban areas. Previous cohorts by Barbouch et al. [10], and Saadaoui et al. [11], also noted a concentration of patients in the Northeast and Northwest, likely due to accessibility to hospital-university centers in Tunis. In a multicenter study by Hajji et al. [12], 64% of patients lived in the Northeast, 35.3% in the central region, and 22.7% in Greater Tunis, indicating that patients seek care closest to their residence. The European ERA-EDTA Registry reports higher prevalence of ADPKD among patients reaching end-stage renal failure in Belgium, France, Spain, and Sweden [1].

Renal and Extra-renal Manifestations of ADPKD: ADPKD is a progressive disease where renal cysts can start developing in utero, with a continuous growth throughout adulthood [13]. This cystic expansion leads to an exponential increase in total renal volume, hastening the progression to end-stage renal failure [14]. Clinical symptoms such as hypertension, abdominal pain, heaviness sensation, hematuria, and urinary tract infections are often observed decades before the onset of renal failure [15].

Prognosis Factors

Renal failure and its progression in autosomal dominant polycystic kidney disease (ADPKD) present significant challenges for prognosis and management. In our study, we sought to explore predictive factors influencing the progression of renal failure in ADPKD patients. However, our analysis was hindered by the lack of sufficient radiological data, particularly regarding total renal volume [16]. Without this crucial information, we were unable to comprehensively assess prognostic indicators [16,17]. Nevertheless, our study did reveal some insights into potential predictive factors for the advancement of chronic kidney disease (CKD) in ADPKD patients. We observed a higher incidence of CKD in women and individuals exhibiting proteinuria, hematuria, hypertension, and urinary tract infections. Additionally, logistic regression analysis identified several variables associated with a more rapid progression of CKD, including the presence of anemia, urinary tract infection, kidney size on ultrasound, and the volume of the largest cysts. However, it’s important to acknowledge the limitations of our findings, particularly the small size of our study cohort, which may impact the generalizability of our results. Moreover, the predominance of hospitalized patients in our study population suggests a potential selection bias towards individuals with more severe disease manifestations, further emphasizing the need for larger, more diverse studies to validate these findings and inform clinical decision-making in ADPKD management

Treatment

Treatment options for autosomal dominant polycystic kidney disease (ADPKD) have evolved significantly in recent years, contributing to improved patient outcomes. Despite these advancements, challenges remain in managing the disease effectively. Control of cardiovascular risk factors is paramount in ADPKD management, with interventions targeting the reninangiotensin system playing a central role due to its involvement in hypertension and renal disease progression [17,18]. However, our study found no significant renal survival benefit associated with the use of renin-angiotensin system blockers in our patient cohort. Emerging therapies, such as vasopressin receptor inhibitors (e.g., tolvaptan), somatostatin analogues, and mTOR inhibitors [19-21], hold promise but require further investigation to establish their efficacy. Unfortunately, access to these treatments is limited by their high cost and unavailability in our country. Regarding renal replacement therapy, hemodialysis (HD) remains the predominant modality for CKD treatment in ADPKD patients in Tunisia [22]. However, there is a growing trend towards preemptive renal transplantation, reflecting advancements in transplant medicine and the desire to improve patient outcomes and quality of life. This shift aligns with global trends observed in the European ERA-EDTA Registry [1], where the incidence of renal transplantation has increased steadily over the past two decades, highlighting the importance of considering transplantation as a viable option for eligible ADPKD patients.

Based on our findings and a comprehensive review of the literature, the management of patients with ADPKD is marked by its significant economic burden, given the frequent progression to end-stage renal failure and dialysis. In the absence of specific treatments, managing complications and addressing modifiable risk factors implicated in disease progression becomes crucial.

Recommendations

1. Implement systematic screening of families at risk for ADPKD.

2. Utilize renin-angiotensin system blockers for hypertension management.

3. Promote renal protection strategies.

4. Establish a national registry to comprehensively record all ADPKD cases, facilitating larger and more homogeneous population studies.

5. Advocate for the introduction of specific treatments for ADPKD in Tunisia by raising awareness among decision-makers.

6. Encourage social security funds to cover expenses for affiliated patients to ensure access to necessary treatments and interventions.

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