Early kidney disease

As previously mentioned, the presentation of renal disease in ARPKD may be very variable. Renal failure is not a common cause of neonatal death and renal function may improve during the first months of life, as seen in other congenital kidney diseases on the CAKUT spectrum. In patients with a significant overt phenotype, urine output should be monitored from birth, and serum creatinine and electrolyte levels as well as acid-base status should be monitored according to the clinical course. Overall, patients with perinatally symptomatic ARPKD appear to have a worse long-term prognosis for renal function than children without perinatal symptoms. In young children, standard recommendations should be followed in principle, with peritoneal dialysis as the dialysis modality of choice. Overall, in a large international cohort study, the survival rate for renal replacement therapy in neonates and infants was approximately 80% at two years. In a North American cohort study, the overall survival rate at three years was approximately 80% for children who started renal replacement therapy in the first month of life and 85% for children who started renal replacement therapy within one year of birth. In resource-limited countries, the situation may be even more difficult. Although early-onset renal replacement therapy can be considered an established treatment, the decision to start, stop or discontinue renal replacement therapy may depend on multiple aspects of the patient and the family. Such decisions should be made by the family and by a multidisciplinary approach and may be supported by a formal ethical decision-making framework.

Concerns exist regarding the feasibility of peritoneal dialysis for ARPKD with renal enlargement. Therefore, a recent study by the International Pediatric Peritoneal Dialysis Network (IPPN) systematically compared children on peritoneal dialysis with ARPKD (n = 79) with controls with congenital nephrotic syndrome (n = 79) and CAKUT phenotype (n = 158). Patients were matched according to age and duration of dialysis. As previously reported, CAKUT patients demonstrated better overall survival than the other two groups, but there were no differences between the ARPKD and CNS cohorts. In the Kaplan-Meier several-year analysis, the three groups did not differ in survival with respect to the peritoneal dialysis technique. Peritoneal dialysis required minor adjustments to the prescription for ARPKD. Interestingly, some ARPKD patients had higher per-glucose ultrafiltration, which may be related to portal hypertension. It is noteworthy that the cohort studied was a cohort of young children with a median baseline age of 2.4 years, but the study was not designed to compare peritoneal dialysis in the first weeks of life. However, a subanalysis of data from patients in the first year of life did not show differences between patients with ARPKD and those with congenital nephrotic syndrome.

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Early nephrectomies in ARPKD and neurological sequelae

An important detail that could not be addressed in the IPPN study was nephrectomy for peritoneal dialysis in patients with ARPKD. ARPKD can demonstrate massive renal enlargement and pulmonary hypoplasia (Figure 3), and unilateral or bilateral nephrectomy has been suggested as a pulmonary indication as well as to improve nutrition and blood pressure control. However, evidence supporting the potential benefits of nephrectomy is limited and needs to be weighed against the potential risks and sequelae of nephrectomy, for example, resulting in loss of renal unit mass and renal function and subsequent need for renal replacement therapy. In addition, arterial hypotension after bilateral nephrectomy has also been reported to cause neurological damage in young peritoneal dialysis patients.

A recent study of ARegPKD compared children with ARPKD after early bilateral nephrectomy (both performed within three months of birth, VEBNE) with children on early bilateral nephrectomy (bilateral nephrectomy within one year of birth), early dialysis (dialysis started within three months of birth), and controls with larger total kidney volumes. Compared with all controls, patients with VEBNE most frequently had severe neurological complications, and VEBNE and documented hypotensive episodes were independent risk factors for the observed severe neurological complications. Patients on early bilateral nephrectomy and very early dialysis had more complications than total renal volume controls. These data may support a very cautious approach to bilateral nephrectomy, especially in the first months of life, when, for example, the maturation process of autonomic cardiovascular control seems to be ongoing. In some cases, the rapid growth of the remaining kidney after unilateral nephrectomy has required a second nephrectomy after a short interval after the first nephrectomy. Therefore, careful consideration should be given to whether some time can be bought before the first or second unavoidable nephrectomy.

Hypertension and hyponatremia

A common and serious problem in ARPKD during the first months of life is arterial hypertension, which can be very severe and may require multiple drug treatments. Due to experimental observations and general considerations, renin-angiotensin system inhibitors are considered to be the treatment of choice. The underlying pathophysiologic mechanisms leading to partially severe hypertension in ARPKD are unknown, but dysregulation of renal sodium and volume handling as well as impaired urinary dilution and activation of the renin-angiotensin system have been proposed. It has been suggested that hypertension may improve as renal function decreases. Replacement of hyponatremia with sodium chloride may exacerbate hypertension, which is usually a transient manifestation of ARPKD and occurs mainly in the first year of life. For the treatment of hyponatremia in ARPKD, general principles apply. In normovolemic or hypervolemic patients, fluid intake and nutrition should be minimized, for example, by concentrated feeds. Normal low sodium levels may need to be tolerated.

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Early extrarenal aspects

Failure to thrive is a common concern for children with early-onset CKD but may pose specific challenges for children with ARPKD. Respiratory distress with enlarged kidneys and underdeveloped lungs and uremia may affect feeding and nutrition early in life. Peritoneal dialysis requires filling the abdominal cavity, which may increase renal enlargement, although the previously mentioned study of peritoneal dialysis in ARPKD did not find differences in growth or body mass index between the three groups compared. More recently, the Childhood Renal Nutrition Working Group noted the importance of gastrostomy for long-term supplementation or enteral tube feeding alone in children with CKD. However, there are concerns about gastrostomy in ARPKD, as splenomegaly in patients with liver disease and portal hypertension has been reported to increase the risk of splenic injury due to other underlying conditions. In addition, the presence of stoma varies due to portal hypertension may be an issue of concern. Based on these considerations, ARPKD is classified as a relative contraindication to gastrostomy placement.

Therefore, a recent survey asked for the opinions and experiences of pediatric nephrology and pediatric gastroenterology/hepatology centers regarding gastrostomy placement in patients with ARPKD. Nearly 200 participants from 39 countries, most of them from pediatric nephrology centers, were enrolled. The benefits and complications of real-life data were retrospectively evaluated in a group of 38 patients with ARPKD. Most participants supported in principle the insertion of gastrostomy tubes in patients with ARPKD when necessary, for example, due to insufficient oral caloric intake. The reported complications in patients with ARPKD are in principle comparable to those in non-ARPKD patients, but the limitations of the survey methodology need to be kept in mind. More in-depth clinical data are needed as a basis for clinical recommendations. Nevertheless, the vast majority of centers that provide retrospective data on the patient's course believe that the gastrostomy approach is the right decision for their patients. It is wise to engage and collaborate with colleagues and centers that place gastrostomy tubes (e.g., pediatric gastroenterologists, pediatric hepatologists, pediatric surgeons, or appropriately experienced referral centers) as early as possible in daily clinical life.

In addition to this investigation, the CKiD cohort analysis analyzed growth in a group of ARPKD patients with a mean age of 7.9 years and compared the results with two matched control groups with other congenital chronic kidney diseases. In this older group, there was no evidence of a disease-specific effect of ARPKD on growth. It is clear that the families of severely affected children would greatly benefit from specific nutritional counseling. Furthermore, the value of psychosocial support for families of children with this early-onset chronic kidney disease cannot be overestimated. This includes contact with patient counseling groups such as PKD International. A detailed description of the importance and benefits of psychosocial support and family relationships is beyond the scope of this article.

Verbascoside

Outlook and summary

Autosomal recessive polycystic kidney disease remains a challenge in pediatric nephrology. Much has been learned in the last two decades, but many unanswered questions remain. There remains an urgent need to improve our understanding of the disease course and to identify additional specific, early, and accurate markers of prognostic risk for renal and liver disease, as well as prenatal prediction of postnatal respiratory status. These markers will help identify patients who may benefit from high-intensity therapeutic approaches, or who may not even need such interventions. In addition, our understanding of the molecular mechanisms leading to this serious disease is still very limited and more work needs to be done as a basis for the development of new and disease-specific therapies. the impressive developments in the field of ADPKD can serve as a template for some of the upcoming steps, but in addition, the specific problems of ARPKD, again including prenatal and perinatal aspects, need to be taken into account.

How do we use Cistanche?

Cistanches can be used to make water or wine to drink, which has the effect of nourishing the kidneys. Cistanches can be used to treat weakness of the waist and knees caused by kidney yang deficiency, which is a warm tonic. It is likely that kidney deficiency is a disease caused by frequent sex or overexertion, which may cause increased urination during the onset of the disease, accompanied by symptoms of weakness in the waist and knees, and must drink less water in life to avoid aggravating the burden on the kidneys.

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Max Christoph Liebau

Department of Pediatrics and Center for Molecular Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany