Clinically, the musculature and kidneys are connected primarily through creatinine. Creatinine is a muscle breakdown product that has been used clinically to evaluate kidney function for decades. In damaged muscles (e.g., rhabdomyolysis), myoglobin can enter the bloodstream and exert nephrotoxic effects. On the other hand, healthy muscles are believed to protect against inflammation-mediated kidney deterioration through several mechanisms. Macroscopically, the kidneys are anterior to the psoas muscles within Gerota’s fascia.[14][15][16][1]

Liddle syndrome: Liddle syndrome is a rare autosomal dominant disorder caused by gain-of-function mutations in genes encoding ENaC subunits. Symptoms include a triad of early-onset hypertension, hypokalemia, and metabolic alkalosis. Normal to low aldosterone activity and lack of response to spironolactone distinguish this syndrome from hyperaldosteronism. The clinician can achieve a definitive diagnosis through genetic testing. Treatment primarily involves maintaining a low sodium diet and the use of potassium-sparing diuretics called ENaC blockers (elaborated on in the Clinical Significance section).[17]

Carbonic anhydrase II deficiency: In the collecting ducts, carbonic anhydrase II (CAII) mediates the formation of carbonic acid from water and carbon dioxide. Carbonic acid then dissociates into a hydrogen ion and bicarbonate, which are handled differently by type A and type B intercalated cells (as described in the Structure and Function section). CAII deficiency is an autosomal recessive disorder that manifests clinically as osteopetrosis, cerebral calcification, and renal tubular acidosis (RTA). The renal tubular acidosis that manifests may be proximal (type II), distal (type I), or combined (type III). No specific treatment (aside from symptomatic) for CAII deficiency currently exists.[18][19]

Collecting duct carcinoma (CDC) is an aggressive form of renal cell carcinoma. CDC represents fewer than 2% of renal masses and usually carries a poor prognosis. Alterations in various genes, including NF2, SETD2, SMARCB1, and CDKN2A, have been identified in CDC cases. Patients with CDC generally undergo cytoreductive nephrectomies, which have been shown to improve survival outcomes (particularly when combined with chemotherapy/radiation).[20][21][22]

In addition to the conditions already mentioned, many clinical considerations involve the collecting ducts:

Nephrogenic diabetes insipidus (NDI): NDI is the inability of collecting ducts to concentrate tubular fluid due to an intrinsic renal complication. Such a complication can be acquired or genetic. Acquired causes include drug toxicities, electrolyte imbalances, and systemic disorders (e.g., autoimmune, amyloidosis, sarcoidosis, etc.). The most common cause of drug-associated NDI is due to lithium use. Lithium is believed to downregulate aquaporin 2 expression in principal cells. Genetic causes involve loss-of-function mutations in genes encoding either vasopressin receptor 2 (the receptor for ADH in the collecting ducts) or aquaporin 2. Clinically, NDI manifests as polyuria due to the excretion of excess water. This loss of fluid leads to secondary polydipsia. Diagnosis can be confirmed with a water deprivation test and a lack of response to desmopressin. Improvement with desmopressin would indicate central diabetes insipidus, which is due to impaired ADH release from the posterior pituitary gland. Treatment options for NDI include addressing reversible secondary causes, thiazide diuretics (with the optional addition of potassium-sparing diuretics), and low solute diets.[23]

Syndrome of inappropriate antidiuretic hormone secretion (SIADH): SIADH is characterized by excessive fluid retention due to aberrantly high ADH activity. SIADH can have many etiologies, including neoplasia, certain drugs, intracranial disorders, and pulmonary disorders. Clinically, SIADH appears as euvolemic hyponatremia with initially increased sodium excretion in the urine. Increased retention of solute-free water from the collecting duct increases circulating volume, diluting the serum sodium. However, this increase in circulating volume prompts a decrease in the renin-angiotensin-aldosterone system (RAAS) activity, which restricts sodium and water reabsorption by principal cells. Thus, the overall effect is the maintenance of normal circulating volume. Sodium excretion will eventually match sodium intake again with the establishment of a new steady state. Therapeutic strategies mainly involve addressing underlying etiologies and preventing severe hyponatremia. Care should be taken not to correct hyponatremia too rapidly, as this can lead to osmotic demyelination syndrome.[24][25][26]

Potassium-sparing diuretics: Potassium-sparing diuretics interfere with sodium reabsorption at principal cells. If less sodium reabsorption occurs, the lumen-negative transepithelial potential difference driving subsequent potassium secretion gets reduced. The result is increased excretion of sodium and water and decreased excretion of potassium. There are two groups of potassium-sparing diuretics: mineralocorticoid receptor (MR) antagonists and ENaC blockers.[27]

• MR antagonists: The intracellular MR is where aldosterone binds to enhance sodium reabsorption and potassium secretion in principal cells. Examples of MR antagonists are spironolactone and eplerenone. Spironolactone's primarily use is for hypertension, but it can be a adjunct to conventional heart failure regimens. To lessen the risk of hyperkalemia, a thiazide diuretic can be included to lower the spironolactone dosage. Despite the clinical efficacy of spironolactone, it can exert potentially distressing antiandrogenic effects in men like gynecomastia and erectile dysfunction. Eplerenone is understood to have fewer of these antiandrogenic side effects while maintaining clinical efficacy. [28]
• ENaC blockers: ENaC blockers are generally less efficacious for treating hypertension than MR antagonists. As such, the administration of ENaC blockers like amiloride and triamterene is usually with thiazide diuretics. As with MR antagonists, hyperkalemia is a potential side effect. Amiloride can also cause mild gastrointestinal discomfort. Triamterene use can potentially predispose hyperuricemia and kidney stone formation.[28]

Renal tubular acidosis: Types I, III, and IV RTA involve the collecting ducts. Type I RTA is classically an inability of type A intercalated cells to secrete hydrogen ions and reabsorb potassium ions, resulting in hyperchloremic (or normal anion gap) metabolic acidosis and hypokalemia with urine pH greater than 5.5. Type I RTA can be caused by genetic mutations, systemic (e.g., autoimmune, amyloidosis, sarcoidosis, etc.) diseases, and nephrotoxic drugs. Compounds like sodium bicarbonate and potassium citrate can correct the acid and potassium imbalances, respectively, but underlying causes should be addressed if present. Alternatively, type IV RTA is a consequence of aldosterone deficiency or resistance; this manifests primarily as hyperchloremic metabolic acidosis with hyperkalemia. Treatment strategies for type IV RTA include restricting potassium intake and administering bicarbonate if the acidosis necessitates it. Type III RTA is a very rare condition that manifests with characteristics of both type I and type II (not discussed in this review) RTA. Type III RTA can occur as a consequence of acetazolamide misuse or CAII deficiency.[29][30][31]

Hyperaldosteronism: Aberrantly increased aldosterone activity can result from primary or secondary causes. Primary causes include bilateral adrenal hyperplasia and aldosterone-producing adrenal tumors, which produce aldosterone regardless of RAAS activity. Classically, primary hyperaldosteronism manifests as hypervolemia, hypertension, hypokalemia, and metabolic alkalosis. Hypervolemia and hypertension are due to excessive sodium and water retention by principal cells. The alkalosis is due to excessive acid secretion by type A intercalated cells. While hypokalemia is considered a classic symptom, it is estimated to appear in fewer than 40% of cases. Secondary hyperaldosteronism is due to overactivation of RAAS. Many etiologies can stimulate RAAS activity, making a definitive symptom profile for secondary hyperaldosteronism difficult to establish. Treatment options include adrenalectomy, MR antagonists, and addressing any secondary causes.[32][33][34]

Cushing’s syndrome: Cortisol can exert mineralocorticoid effects at sufficiently high levels. In cells containing MR, an enzyme called 11-beta-HSD2 (11B-HSD2) metabolizes cortisol before it can bind to MR. Excess cortisol can overcome cellular 11B-HSD2 capacity, allowing cortisol to bind to MR. Binding to MR can lead to excessive sodium and water retention in the collecting ducts. This effect contributes to the hypertension seen in Cushing syndrome. Treatment involves addressing the cause of the excess cortisol (i.e., tapering corticosteroid use, resection of an adrenal tumor, etc.).[35]

In the last few years, many investigative avenues involving the collecting ducts have been subject to research. One study from 2017 characterized the role of TFCP2L1, a transcription factor, in mediating collecting duct development. Another study from 2018 demonstrated the development of tubulointerstitial fibrosis with the suppression of microRNAs within collecting duct cells. Most recently, a 2019 study found that tamoxifen downregulated collecting duct aquaporin 2 in an ADH-independent manner. These recent scholarly endeavors demonstrate the scientific and clinical necessities of understanding the renal collecting ducts.[36][37][38]