Medications

1. What classic syndromes involving the kidneys are associated with NSAIDs?

NSAIDs are well described to cause a number of clinical syndromes involving the kidneys many which are related to decrease in prostaglandin production by the kidneys. Whereas others are idiosyncratic, those associated with NSAIDs include:

• Acute kidney injury (AKI)

• Hyponatremia

• Hyperkalemia

• Hypertension

• Edema/congestive heart failure (CHF)

• Acute interstitial nephritis (AIN)

• Minimal change/membranous nephropathy

• Acute papillary necrosis

• Uroepithelial malignancies

The following factors increase the risk for APN:

• Preexisting CKD

• Concomittant diuretic or ACE-I use

• Older age

• Female sex

• Volume depletion

2. What are the clinical scenarios where ACE inhibitors and ARBS are likely to cause AKI?

Any clinical circumstance where perfusion to the kidney is impaired will cause a decline in glomerular filtration rate (GFR) and AKI by inducing efferent arteriolar vasodilatation through blockade of angiotensin II production or receptor binding. Clinical scenarios include:

• Disease states associated with hypotension

• Decreased blood volume (i.e., diuretics, diarrhea, vomiting, etc.)

• Decreased effective circulating blood volume (i.e., CHF, cirrhosis, nephrotic syndrome, etc.)

• Critical renal artery stenosis

• Treatment with medications such as NSAIDs, calcineurin inhibitors (CNIs), and vasoconstrictors

The typical scenario is that the GFR continues to decline with ACE inhibitor/ARB therapy and does not stabilize until drug withdrawal or correction of the underlying disease process. Stabilization of kidney function, without hyperkalemia or hypotension, with continued ACEi/ARB therapy is likely associated with beneficial effects on both the heart and the kidneys.

3. What are the major adverse effects on the kidney of ACE inhibitors and ARBs?

ACE inhibitors and ARBs are associated with AKI and hyperkalemia. These effects are due to inhibition of angiotensin II production by ACE inhibitors or competitive antagonism of the angiotensin II receptor by ARBs. This results in loss of angiotensin II–induced efferent arteriolar tone, leading to a drop in glomerular filtration fraction and GFR. The efferent arteriolal vasodilation reduces intraglomerular hypertension (and pressure-related injury) and maintains perfusion (and oxygenation) of the peritubular capillaries. Hyperkalemia occurs due to reduced adrenal aldosterone synthesis from decreased angiotensin II production/receptor binding. AIN is a rare complication of ACE inhibitors.

4. What are risk factors for the development of acute phosphate nephropathy (APN)?

Oral sodium phosphate-containing purgatives used for colonoscopy preparation can cause both acute and chronic kidney disease (CKD). The acute form is called APN. The following factors increase risk for development of APN. It is notable that two-thirds of patients that developed APN had three or more of these risk factors. APN may resolve or progress to CKD.

5. What are the histopathologic lesions associated with APN?

The hallmark of APN is abundant tubular and less prominent interstitial calcium phosphate deposits. Greater than 30 calcifications and sometimes greater than 100 calcifications per tubular profile may be seen. The calcifications form basophilic rounded concretions, are mainly confined to the distal tubules and collecting ducts, and are prominent in the kidney cortex. The calcifications do not polarize and have a strong histochemical reaction with the von Kossa stain, indicating that they are composed of calcium phosphate. Acute tubular degenerative changes and interstitial edema are seen with early lesions. Biopsies performed more than 3 weeks after exposure to sodium phosphate exhibit chronicity (tubular atrophy/interstitial fibrosis). Acute and/or chronic tubulointerstitial nephropathy, reminiscent of changes seen in nonresolving acute tubular necrosis (ATN), may be present. There may also be an association between PPI’s and hyponatremia via SIADH. But due to the paucity of data and the many confounding variables, causation has not been demonstrated.

6. What lesions in the kidneys can be caused by pamidronate and zoledronate?

The bisphosphonates have been described to cause a couple of lesions involving the kidneys. High-dose pamidronate causes collapsing focal and segmental glomerulosclerosis (FSGS) and minimal change lesion, along with some tubular injury. In contrast, high-dose zoledronate causes a pure tubular injury pattern with severe ATN. These agents target epithelial cells, visceral epithelial cells with pamidronate, and tubular epithelial cells with zoledronate.