Larry Hanover

A study conducted in Ireland in patients with polycystic kidney disease (PKD) found that a combination of cutting-edge molecular genetic tools diagnosed 83% of Irish patients known to have the disease, discovered 36 novel variants, and found that seemingly unrelated individuals carrying the same variant probably inherited it from a common ancestor.

PKD is an inherited disorder that causes of clusters of cysts to develop, resulting in enlarged kidneys and loss of function. PKDs are not only the leading cause of inherited renal disease overall in the world, affecting an estimated 12.5 million individuals, but 

a leading cause of end-stage kidney disease

, researchers recruited a cohort of 169 Irish PKD patients to explore the genetic variations of the population, one that is conducive to study due to its relative homogeneity. Focus largely was on autosomal dominant disease (ADPKD), with previous research showing that 85% of patients reach ESKD by age 65, although those with the rarer autosomal recessive disease (ARPKD) also were studied.

Researchers used a combination of molecular genetic tools to achieve an 83% diagnostic rate (141 patients). They succeeded in diagnosing 91% of the 141 patients using next generation sequencing (NGS) alone but needed to use long-range polymerase chain reaction (LR-PCR) and Sanger sequencing approaches for the others. LR-PCR and Sanger sequencing remain the gold standard, the authors wrote, but NGS is establishing its utility as an automated method that can perform a high volume of tests in a short time. 

Two-thirds of the patients (113) were identified an AD pathogenic variant in 

which has a high GC-content and is in a segmentally duplicated part of the genome with 6 pseudogenes, making it challenging to identify. The study confirmed earlier research showing that patients with AD pathogenic genetic variants tend to reach ESKD at an earlier age than those with 

 in the study were estimated to reach ESKD at age 50, and those with 

The researchers also identified 14 AD pathogenic variants in 

 in multiple unrelated patients. The most likely reason would be that the patients are distant relatives and the variants come from a common ancestor, the researchers wrote.

The study also compared the standard Mayo Clinic variant classification guidelines against those published the American College of Medical Genetics and Genomics (ACMG), which have been embraced by the scientific community but not gained traction among researchers for regular use. The ACMG guidelines were less effective in diagnosis, with only a 71% diagnostic rate compared to 83% for Mayo, according to the study.

Among the weaknesses, the authors said, is that ACMG is better for pediatric-onset rare diseases, not adult. They noted that ACMG guidelines were developed for clinical use, while those for Mayo were designed for research only.

However, using those guidelines did result in identifying 36 novel, likely disease-causing variants.

Benson KA, Murray SL, Senum SR, et al. The genetic landscape of polycystic kidney disease in Ireland. 

 (2021). Published online January 16, 2021. doi: 10.1038/s41431-020-00806-5

Articles

Cutting-edge genetic tools diagnosed 83% of Irish patients with polycystic kidney disease (PKD), identified 36 novel variants, and discovered that seemingly unrelated individuals with the same variant likely inherited it from a common ancestor.




Genetic Picture Emerges of Polycystic Kidney Disease in Ireland 

Systemic-immune inflammation index (SII), a novel measure based on neutrophil, platelet, and lymphocyte counts utilized in predicting disease progression in cancer, can be used for predicting the onset of psoriasis, according to a new study.

Researchers at a university hospital in Turkey performed a study comparing patients with psoriasis with an age- and gender-matched control group of those with other noninflammatory dermatologic diseases to determine if SII could play a role in the management of the skin disease.

In the study, published this month in the

International Journal of Clinical Practice

, researchers found that patients with psoriasis had significantly higher SII values (

 <.05), indicating the index can be used to predict psoriasis activation.

The study further evaluated patients in association with another measure called psoriasis area severity index (PASI) to measure disease severity. Four body parts—head, arms, trunk, and legs—were evaluated for PASI score based on the percentage of affected skin area. Severity was rated through 3 clinical signs: skin redness, localized hardening of the skin, and peeling.

Patients at or over the 50th percentile in the index, as well as patients whose nails and genital areas were affected, also had significantly higher SII values (

<.05) than those in the control group. Those with scalp and joint psoriasis did not have higher SII values.

Psoriasis is a chronic inflammatory skin disease affecting 0.5% to 11.4% of the world’s adult population. The authors wanted to evaluate the index in relation to psoriasis because they suspected its inclusion of 3 main parameters of complete blood cell count might provide a level of precision in predicting the disease’s progression. Currently used laboratory tests are insufficient for that purpose, they said.

“SII has not been used for the evaluation of psoriasis activation before and in our opinion it may be beneficial for physicians who work in the field,” the authors wrote.

Given the challenge of accurate psoriasis prognosis, however, they recommended that SII be used in conjunction with physical examination and conservative laboratory tests.

The study evaluated 71 patients with psoriasis who were admitted to a dermatology outpatient clinic from 2017-2019 against a control group of 70 patients.

Other indices have been assessed in the literature—red cell distribution width, mean platelet volume, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio were the most commonly used. However, the authors said, factors such as anemia, infection, and other inflammatory markers may affect those indices. Furthermore, their utility has not been validated through high-quality studies.

The authors contended that the strength of SII over NLR is the inclusion of platelet counts. Platelets play a crucial role in immune-mediated processes such as releasing antimicrobial proteins and producing inflammatory cytokines. They also play a role in clotting, the process of preventing clots from growing, and the physiological process through which new blood vessels form from pre-existing vessels.

Dincer Rota D, Tanacan E. The utility of systemic-immune inflammation index for predicting the disease activation in patients with psoriasis. 

. 2021;e14101. Published online February 22, 2021. doi:10.1111/ijcp.14101.

The novel systemic-immune inflammation index (SII) can be used to predict the onset of psoriasis.

Using a Novel Inflammation Index to Predict Psoriasis Onset

A new study has found that the cause of a child’s 

 (PAH) might be important in determining risk of mortality.

, looked at various factors used in an internationally developed risk stratification strategy to assess which ones had evidence of being significant in determining a child’s prognosis from the deadly disease.

It found those with idiopathic PAH had a higher risk than those whose PAH was associated with congenital heart disease (CHD) and other etiologies. It also determined that higher resistance to blood flow from the pulmonary artery to the left atrium was connected to risk. However, the authors were unable to determine whether other factors, taken alone or in combination, affected risk.

Children with PAH have stiff pulmonary arteries, forcing the heart to work harder to pump blood to the lung, leaving the child out of breath and at risk of failure of the right ventricle. New target therapies have decreased mortality and morbidity in recent decades, but given low pediatric patient numbers in studies, devising treatment strategy has been challenging, the authors wrote.

Researchers from Hungary used records from 58 patients with PAH treated between 1995 and 2019. They found that patients with idiopathic PAH had increased mortality risk compared to those whose disease was congenital. There were 12 patients with idiopathic disease in the study group; 32 had PAH associated with CHD.

They also found that patients with higher pulmonary vascular resistance index had significantly increased risk.

The researchers additionally looked at other factors, including demographics, World Health Organization functional class (WHO FC) as well as various signs of right ventricular failure from echocardiography and cardiac catheterization.

The authors found that clinical parameters such as WHO functional state (

.0866), clinical evidence of right ventricular failure (

 = .630) had no significant prognostic value. Nor did the presence of pathology in echocardiograms such as right atrium (RA)/right ventricle (RV) enlargement, reduced left ventricle (LV) size, increased RV/LV ratio, reduced tricuspid annular plane systolic excursion, and pericardial effusion (

= .0576). Due to low sample size, however, the authors cautioned against considering these finds as major evidence against their effect and favored further study.

The authors also examined several risk factors in combination, but again found no significant impact on survival.

Records used in the study showed a 29% mortality rate over a 5.4-year span. Median age of diagnosis was 4.2 years.

The risk stratification strategy examined in the study was assembled by the Pediatric Task Force of the 5th World Symposium on Pulmonary Hypertension in 2019 using available evidence to determine at initial diagnosis which child patients were at higher or lower risk levels. Since the physical and financial burden is high for the aggressive combination therapy used for high-risk patients—which includes intravenous or subcutaneous prostacyclin treatment—making such evaluations of risk is critical.

The adult risk stratification is inappropriate for children due to differences in cause, the authors said. For example, 4%-12% of adults had PAH associated with congenital heart disease, compared with 36% for children.

Ablonczy L, Ferenci T, Somoskövi O, et al. Prognostic value of early risk stratification in pediatric pulmonary arterial hypertension. 

. 2021;S0041-1345(21)00081-6. Published online February 20, 2021. doi:10.1016/j.transproceed.2021.01.047.

The study examined various factors used in an internationally developed risk stratification strategy to assess which ones had evidence of being significant in determining a child’s prognosis from the deadly disease.

Understanding Mortality Risk in Pediatric Pulmonary Arterial Hypertension

Despite the introduction of guidelines 9 years ago for slowing the progression of 

 (CKD), a review of real-world data shows that adherence is low and the recommendations are inconsistently applied among the United States and other countries.

The Kidney Disease: Improving Global Outcomes guidelines for treating CKD were adopted in 2012. Key recommendations include targets for blood pressure (BP), using renin-angiotensin-aldosterone system inhibitors (RAASi), and advising patients not undergoing dialysis to cut back on salt and protein.

However, a review of real-world data, published in 

, found that adherence to the guidelines was low in the United States, Brazil, France, and Germany and that there was considerable variation among the countries.

CKD affects 11% to 13% of the population worldwide. Although awareness of the disease and the corresponding risks of kidney failure, cardiovascular disease, and death has risen, the authors said, advances in preventing kidney failure have been slow and the need for kidney replacements is rising in some high-income nations, prompting the need for better understanding of adherence to guidelines.

The investigators reviewed data from the Chronic Kidney Disease Outcomes and Practice Patterns Study database, a prospective cohort study of patients with moderate and advanced CKD in the 4 countries. The data represented 7204 patents from 118 clinics, including 1511 patients from 29 clinics in the United States.

The study showed adherence in the United States was consistently low in the key categories. Only 27% of patients were receiving any kind of dietary advice to slow CKD progression, and only 38% were at or below the systolic BP target of 130/80 mm Hg. In addition, even though RAASi are considered a first-line treatment for CKD, the United States ranked lowest among the 4 countries, with only 52% of patients receiving the drugs.

As far as treating patients with CKD and comorbid diabetes, whose blood sugar levels (hemoglobin A1c of about 7%) represent a fourth target, the United States fared better than in the other categories. There was 56% adherence on keeping track of hemoglobin A1C levels.

Overall, BP control (≤140/90 mm Hg) ranged from 49% in France to 76% in Brazil, and Brazil (52%) was the only country with more than 40% of patients with blood pressure ≤130/80 mm Hg. Prescription of RAASi ranged from 52% in the United States to 81% in Germany.

Patients with CKD who did not have diabetes had a poor record of hitting all 3 targets, ranging from 10% in the United States to 32% in Brazil. Diabetes, as expected, was found to be a leading cause of CKD and a major comorbidity. For patients with diabetes who were measured on meeting the 3 key targets, along with glycemic control, the range for meeting all 4 targets ranged from 6% in the United States to 11% in Brazil.

The study also noted low adherence in measurement of albuminuria or proteinuria. The conditions were routinely measured in fewer than half of patients in the United States, Brazil, and Germany, with proteinuria measured more often than albuminuria in all countries. Results also showed that dipstick proteinuria was often used alone despite potential inaccuracy.

The authors further noted surprise to see that measuring the albumin-to-creatinine ratio did not seem to be standard practice.

One positive result was that 12% or less of the populations in the 4 countries were current smokers, making this just about the only recommended lifestyle change with demonstrated adherence. Patients reported getting advice on low sodium intake, but not for protein, potassium, or phosphorus intake. A majority had no access to expert dietary advice at all.

“Adherence to recommendations to slow CKD progression is low in typical practice settings,” the authors concluded, “and substantial variation among countries for some indicates opportunities for improvement.”

Stengel B, Muenz D, Tu C, et al. Adherence to the kidney disease: improving global outcomes CKD guideline in nephrology practice across countries. 

.2021;6(2):437-448. doi:10.1016/j.ekir.2020.11.039

Adherence to guidelines for slowing chronic kidney disease is low, with substantial variation among the United States and other countries.


Larry Hanover

Articles

Genetic Picture Emerges of Polycystic Kidney Disease in Ireland

Using a Novel Inflammation Index to Predict Psoriasis Onset

Understanding Mortality Risk in Pediatric Pulmonary Arterial Hypertension

Slowing CKD, Adherence to Care Guidelines Need to Improve, Study Says