Genetic panel for early-onset CKD of unknown cause

Genetic GNmedium

A 23-year-old man is referred for evaluation of CKD. During a life insurance evaluation 4 months ago, a serum creatinine of 1.7 mg/dL was found. The patient has no significant medical history, and he was born at term. He takes no prescribed or over-the-counter medications, including NSAIDs, herbal products, or illicit drugs. The patient's mother is well. His father died in a motor vehicle accident at age 26. Both the patient and his 20-year-old sister have had nocturia since childhood. Review of systems is otherwise negative. On examination, BP is 110/70 mm Hg, heart rate is 64/min, and body mass index is 24 kg/m². Pupils, fundi, and visual acuity are grossly normal. Hearing is grossly intact to whispered speech. Heart, lung, and abdominal examinations are normal, and there is no edema or rash. Laboratory data: sodium 142 mEq/L (reference 136–145); potassium 4.0 mEq/L (3.5–5.0); total CO₂ 23 mEq/L (23–28); creatinine 1.8 mg/dL (0.7–1.3); calcium 9.5 mg/dL (8.6–10.2); phosphorus 3.4 mg/dL (3.0–4.5); albumin 4.2 g/dL (3.5–5.5); urine albumin-to-creatinine ratio 42 mg/g (<30). Urinalysis reveals specific gravity 1.010, trace albumin, and no blood. Microscopy is unremarkable. Kidney ultrasound shows normal-sized kidneys with mildly increased echogenicity. Which of the following tests would be MOST LIKELY to yield a diagnosis?

  1. A.24-hour urine protein electrophoresis
  2. B.Kidney disease genetic panelCorrect
  3. C.Kidney biopsy
  4. D.Vision and hearing testing

Explanation

In this patient with CKD of unknown etiology, low-grade albuminuria, and a family history of nocturia, a kidney disease genetic panel may be revealing. CKD that occurs before the age of 25 years has a high likelihood of genetic origin. Nocturia, as experienced by this patient and his sibling, suggests a concentrating defect that can be an early symptom of CKD. Testing for monogenic forms of kidney disease has traditionally been cumbersome and expensive, but several commercially available genetic testing panels are now available in the United States. Autosomal dominant tubulointerstitial kidney disease (ADTKD) is most likely given the possibility of an affected sibling, along with the clinical features of low-grade albuminuria and possible concentrating defect. Although management options are limited, identification of a genetic cause of CKD may help with future family planning. Twenty-four-hour urine protein measurement, especially for low molecular weight proteins, could be considered for patients with suspected Dent disease, an X-linked disorder caused by a mutation in a voltage-gated chloride transporter in renal tubular lysosomes. This disease is also accompanied by calciuria and phosphaturia, causing nephrocalcinosis, which is not present in this patient. Kidney biopsy would not be expected to be diagnostic in this patient with minimal albuminuria, no hematuria, and a bland urine sediment. Histologic findings in ADTKD are nonspecific. Formal vision and hearing testing may assist with early diagnosis of Alport syndrome, another genetic disorder involving one of several genes encoding components of type IV collagen, a constituent of the GBM. The absence of hematuria and significant proteinuria make Alport syndrome less likely.

Why each option

A.
Urine protein electrophoresis for low molecular weight proteinuria targets Dent disease, which causes hypercalciuria and nephrocalcinosis, absent here.
B.
Correct. CKD before age 25 with bland sediment, low-grade albuminuria, and familial nocturia suggests ADTKD, best diagnosed with a kidney genetic panel.
C.
Biopsy in ADTKD shows only nonspecific tubulointerstitial fibrosis and would not establish the diagnosis with this bland sediment.
D.
Vision and hearing testing support Alport syndrome, but the absence of hematuria and significant proteinuria makes type IV collagen disease unlikely.

Reference: Köttgen A, Kidney Int 2022 (genetics in CKD: conclusions from a KDIGO Controversies Conference); Groopman EE, N Engl J Med 2019 (diagnostic utility of exome sequencing for kidney disease)

This is one of 1,100 questions in the MedBoardSA nephrology bank, with timed test mode, tutor mode, and progress tracking by topic.

Practise the full bank

More Genetic GN questions

Browse other topics