Chapter 49. Sickle Cell Nephropathy

The major clinical consequences of sickle cell disease (SCD) are crises from vascular obstruction by sickled cells and anemia because of red blood cell (RBC) destruction. The obstruction can cause hematuria and renal papillary necrosis (RPN) with a defect in tubular function, especially in urinary concentration. The chronic consequences include sickle cell glomerulopathy, more indirectly related to sickling, and a specific form of renal malignancy.

Essentials of Diagnosis

• Acute gross hematuria or persistent microscopic hematuria.
• Without RBC casts or dysmorphic (other than sickle) RBCs.
• Ultrasound or helical computed tomography (CT) shows distinctive medullary abnormalities.

General Considerations

Hematuria in SCD is a specialized form of the sickle crisis, the consequence of renal medullary sickling, vascular obstruction, and RBC extravasation. The low PaO2, high osmolality, and acidic environment of the renal medulla lead to sickling.

Pathogenesis

The renal pathology associated with isolated hematuria, shows relatively insignificant changes, primarily medullary congestion. The later RPN in SCD is a focal process, with some collecting ducts surviving within a diffuse area of fibrosis. The relevant medullary pathology in SCD is found in the region of the collecting ducts, the inner medulla, and the papilla. Within the medullary fibrosis the vasa rectae are destroyed, following initial dilation and engorgement. The RPN of SCD contrasts with the RPN observed in analgesic abuse, in which the vasa rectae typically are spared, and most lesions occur in peritubular capillaries. Because calyces are affected separately and sequentially in SCD, acute obstruction and renal failure are uncommon.

Clinical Findings

Symptoms and Signs

Gross and often painless hematuria is dramatic and is usually unilateral (L>R) due to increased left renal vein pressure. Hematuria occurs at any age and is more often seen with a (higher gene frequency) sickle trait (HbAS).

RPN is usually discovered by radiologic investigation of patients with painless gross hematuria. However, hematuria is not invariably present in RPN, with no difference in the incidence between symptomatic (65%) and asymptomatic (62%) patients. RPN can be found even in young children.

Acute renal failure is not uncommon in SCD; it is seen most often with infections and evidence of rhabdomyolysis, and in patients with lower hemoglobin (Hb) (˜6.4 versus 8.7 g/dL). Volume depletion is a common precipitating cause. It is likely that nonsteroidal anti-inflammatory agents are partly responsible for some episodes of acute renal failure, in view of the maintenance of the glomerular filtration rate (GFR) in SCD by prostaglandin mechanisms.

Rhabdomyolysis with acute renal failure and disseminated intravascular coagulation has been seen, albeit rarely, in those with sickle trait who undergo rigorous military training, and there is an apparently increased risk of sudden unexplained death in patients with sickle trait.

Priapism is a specialized vasoocclusion of the penis, which was found as often as 42% in one series. A painful, hot, tender erection, most often on waking, lasts up to 3 hours. This can be preceded by days or weeks of “stuttering.”

Laboratory Findings

A drop in Hb is unusual in acute hematuria.

Imaging Studies

Increased echodensity of medullary pyramids on ultrasound is typical of SCD, and in the absence of hypercalciuria, medullary echodensity in a patient with hematuria should suggest a sickle hemoglobinopathy (Figure 49–1).

In one series, 39% of 189 patients had at least calyceal clubbing and 23% had definite RPN. Cortical scarring, as found in pyelonephritis, should not accompany the calyceal clubbing of SCD, but a history of infection appears more common in RPN in SCD. A “medullary” form of RPN is common, with an irregular medullary cavity, often with sinus tracts. Sonography can sometimes identify the early medullary form of papillary necrosis. Later, a distinctive “garland” shadowing pattern of calcification of the medullary pyramids can be present.

Unusually, pyelography has been done when SCD was not recognized. Helical CT can detect RPN earlier than sonography. Ultrasound reflectivity in young SCD patients (aged 10–20 years) has found diffuse or medullary echogenicity in a minority of patient, a finding that is not RPN.

Differential Diagnosis

Sickle cell crises are painful episodes of vasoocclusion, often accompanied in the second or third day by fever without documented infection. The abdominal crisis is similar to a “surgical” abdomen but usually without rebound tenderness. In the presence of gross hematuria, the origin of the pain is often assumed to be the kidney, but careful palpation of the kidneys should be distinctive.

Continued or persistent gross hematuria likely represents a form of renal “sickle crisis” in a known HbSS or HbAS patient. Other treatable causes of hematuria, including the recently described distinctive renal medullary carcinoma in patients with sickle hemoglobin, must be excluded. Severe pain makes the diagnosis of renal sickle crisis less likely, whereas moderate discomfort often lateralizes the bleeding. Renal and bladder ultrasound can rule out bleeding from a stone or tumor and may aid in the diagnosis of RPN (see below).

Treatment

1. In view of the benign pathology in SCD hematuria, conservative management is appropriate. Bed rest is often recommended to avoid dislodging hemostatic clots.

2. It is advisable to maintain high rates of urine flow by encouraging increased intake or infusion of hypotonic fluids (4 L/1.73 m2 surface area per day) combined with administration of diuretics (a thiazide or a loop diuretic such as furosemide), which should help clear clots from the bladder. The resulting diuresis would reduce medullary osmolarity, which would help to alleviate sickling in the vasa rectae. Sodium-containing fluids may tend to increase sodium retention (see below).

3. Alkalinization of the urine by 8–12 g NaHCO3 (per 1.73 m2) per day may reduce sickling in a urine environment, but this may not be relevant to medullary sickling. The O2 affinity of Hb is theoretically increased in a more alkaline environment.

4. After failure of treatment with fluid administration and alkalinization, ϵ-aminocaproic acid (EACA) can be tried to inhibit fibrinolysis, allowing clots to mediate hemostasis. The effective dosage in an adult is 8 g/day.

5. Arteriographic localization and local embolization of the involved renal segment may avoid nephrectomy, only rarely required for uncontrolled bleeding.

6. Newer surface-active polymers may abort sickle crises, and could possibly abort the acute hematuria of SCD.

7. General treatment strategies for SCD, by decreasing the proportion of rheologically abnormal cells, can reduce the risk of recurrence of cerebral vasculopathy and probably other complications. These include frequent transfusions and measures to increase fetal Hb including 5-azacitidine and hydroxyurea.

Essentials of Diagnosis

• Concentrating defect—maximum 414 mOsm/kg after 8–10 hours of thirst, compared with 911 mOsm/kg in controls. This is reversible by transfusion in children. Urinary diluting capacity is normal.
• Incomplete distal renal tubular acidosis (RTA) (minimum urine pH 5.8 versus 5.1 in controls).
• Impaired K+ secretion–an aldosterone resistance.
• Less creatinine (Cr) secretion.

General Considerations

The tubular dysfunction of SCD manifests a defect in urine concentration, while dilution is maintained. Hydrogen ion and potassium secretion functions are only mildly affected, and proximal tubular mechanisms are exaggerated.

Pathogenesis

Sickling and vascular congestion of the medulla, accompanying gross hematuria, with sluggish blood flow that fails to remove reabsorbed sodium, are probably responsible for reversible concentrating defects in younger children. Medullary fibrosis and permanent destruction of collecting ducts result in irreversible concentrating defects.

Generation of vasopressin is normal in SCD, and the concentrating defect is not responsive to vasopressin.

Since urinary dilution depends upon solute reabsorption in the cortical ascending loop of Henle, which is not involved in SCD patients, the urine diluting capacity is normal.

Since acid excretion depends upon a proton gradient most associated with the (nonaffected) cortical “intercalated” collecting duct cells, a severe acidification defect is unlikely. However, since juxtamedullary nephrons, which reabsorb HCO3−, are also severely involved in SCD, some defect in acid and K+ excretion may occur.

Tubular Secretory Processes

Tubular secretory processes are spared in SCD, so there is a significant disparity between creatinine clearance (CCr) and inulin clearance (CIn), an expression of increased tubular secretion of Cr in SCD. The increased CCr normally produced by a Cr load is lost in SCD, showing loss of Cr secretory reserve. Uric acid secretion is increased and may be a functional adaptation to high uric acid generation.

Role of Prostaglandins in Sickle Cell Disease Tubular Dysfunction

Increased vasodilatory prostaglandins (PG) may help to explain SCD tubular dysfunction. PG inhibition by indomethacin usually decreases the fractional excretion of Na (FeNa) minimally (by 16%). However, in SCD this decline in FeNa is even more exaggerated (42%). PGs also appear to have a greater than normal effect on the delivery of sodium to the distal diluting segment. Whereas in normal conditions urinary dilution is not affected by PG inhibition, in SCD it decreases such urinary diluting capacity.

SCD patients fail to increase net acid excretion in response to indomethacin inhibition of PG synthesis because of decreased NH4+ excretion. It is likely that NH4+ excretion is normally maintained at maximum in SCD by endogenous PGs.

Clinical Findings

Symptoms and Signs

The most common tubular abnormality in SCD is a urinary concentrating defect, which can even be measured in sickle trait. In children, the concentrating defect may be accompanied by enuresis and an increased risk of dehydration during water deprivation. The concentrating defect is unique to sickling hemoglobinopathies, as no concentrating defect have been described in other anemias. Urinary dilution remains normal.

Laboratory Findings

An incomplete distal RTA may complicate SCD, but is usually not a clinical problem. The minimum urine pH achieved in response to NH4Cl loading is not as low as in controls (5.8 versus 5.1), but total NH4 excretion is normal. Consequently, titratable acidity is reduced. With the tendency to decreased K+ secretion, this resembles a type IV renal tubular acidosis, resulting from an aldosterone-independent end-organ failure secondary to medullary fibrosis.

While there is a shift of K+ into cells that is protective against the large load of K+ released from sickled cells, this shift is under β2 stimulation, so that β-blockers or ACE inhibition may result in hyperkalemia.

Diuretic response is poor in SCD, because it depends on this increased distal sodium delivery. Proximal tubular phosphate reabsorption, which usually parallels sodium reabsorption, is also increased. This may also cause hyperphosphatemia, especially in the presence of an increased phosphate load generated by hemolysis.

Treatment

Treatment of tubular disorders in SCD is usually unnecessary if renal function is normal. The risk of dehydration caused by decreased urinary concentrating ability requires earlier treatment of diarrhea or vomiting.

1. Avoid volume expansion as a treatment for sickle crises. Administration of large volumes of standard sodium-containing fluids to significantly anemic patients with increased sodium reabsorption may result in congestive heart failure.

2. The edema accompanying severe anemia may be difficult to treat because the response to diuretics is diminished.

3. K+ may be elevated by hemolysis, especially if there is renal insufficiency. β-Blockers or angiotensin-converting enzyme (ACE) inhibition should be avoided as they may aggravate hyperkalemia.

Essentials of Diagnosis

• Proteinuria is the hallmark of chronic steroid-sensitive nephropathy (SSN). Of adults with SCD 15–40% are found to have abnormal proteinuria or nephrotic syndrome.
• Progression to kidney failure for nephrotic syndrome in SCD may be more rapid than in other causes of nephrotic syndrome.
• Hypertension is unusual in SCD (2–6%) compared to the published incidence for the black population in the United States of 28%, at all age ranges.

General Considerations

Chronic renal failure (CRF) is a major organ failure in SCD, probably the consequence of the progression of focal segmental glomerulosclerosis (FSGS). Overall, 5–18% of SCD patients will develop CRF.

Pathogenesis

Hyperfiltration is recognized in SCD by increased GFR, especially in children. An even greater increase in effective renal plasma flow (ERPF) (all plasma that goes through the filtering units) results in a lower than normal filtration fraction, the proportion of a substance flowing through the kidney that is filtered. Increased cortical blood flow itself could cause decreased tubular secretion by limiting diffusion from rapidly flowing plasma. Alternatively, a distinctive increased glomerular permeability (tested by dextrans) may exist in SCD nephropathy, not explained by purely hemodynamic changes. Proximal tubular “hyperfunction” in SCD may be a compensation for the distal tubular injury, mediated by the PG systems (see above). The net effect of PG inhibition is to reverse hyperfiltration. The dramatically increased ERPF and decreased filtration fraction of SCD are returned toward normal. If hyperfiltration is a necessary predecessor of glomerulopathy in SCD, then prostaglandins may explain the early development of FSGS.

Glomerulopathy in SCD has been attributed to immunopathogenic mechanisms, because of a reported membranoproliferative glomerulonephritis (MPGN). However, most now agree that evidence of immune complex deposition is usually lacking in SCD patients with heavy proteinuria.

Possible mechanisms of the SCD nephropathy associated with FSGS include hyperfiltration and glomerular hypertrophy. Hyperfiltration, combined with direct endothelial damage by occlusion with sickled cells, might lead to endothelial hyperplasia and ultimately fibrosis. Any hypothesis should take into account that glomerular hypertrophy is always present in SCD, probably related to the anemia itself, but proteinuria is not invariable in SCD and appears to be unrelated to the number and severity of SCD crises or the presence of hematuria or demonstrated RPN.

Systemic hypertension is notably absent in these patients. The presence of hyperfiltration, glomerular hypertrophy, and FSGS does not imply that these findings are sequential or causative. A common stimulus may be operative, such as the growth-promoting hormones and inflammatory cytokines, to which the glomerulus may be sensitive. It is possible that FSGS is the consequence rather than the cause of interstitial fibrosis, which might obstruct the efferent glomerular capillaries, raising intraglomerular pressure and resulting in progressive (reactive) sclerosis.

The iron deposited as hemosiderin in tubular cells has been suspected of playing a role in the chronic nephropathy of SCD, but the mechanism is not clear. Experimentally, saturated iron complexes can induce a nephrotic syndrome in rabbits.

Prevention

The prevention of sickle cell nephropathy (SCN), or preventing its progression, may involve measures to prevent both sickle crises and hyperfiltration (see below).

Clinical Findings

Symptoms and Signs

The association of significant proteinuria with SCD was often recognized sporadically and usually described as a nephritic process.

The definition of SCN that is most accepted now is associated with nephrotic-range proteinuria. While long-term studies have not been done, it appears to have a more rapid course than other causes of nephrotic syndrome. Two-thirds of patients developed renal failure within 2 years. The onset of renal failure was heralded by increasingly inadequate erythropoiesis, and carried a survival time of 4 years.

Laboratory Findings

Hyperfiltration complicates the estimation of GFR, whose upper limits of the normal range are not certain even with the “gold standard” of inulin clearance. The reliability of the clearance methods that can substitute for inulin clearance have certainly not been validated in the elevated range. For most clinical purposes, an accurate measure of GFR is unnecessary. A decrease in GFR, particularly when accompanied by proteinuria, is ominous.

Imaging Studies

For clinical purposes, renal ultrasound should be adequate to estimate kidney size and to exclude the likelihood of renal medullary carcinoma (see Figure 49–1).

Special Tests

The usual glomerular finding in sickle cell nephropathy is FSGS, which is intimately associated with glomerular hypertrophy. Immunofluorescence is positive only for IgM, C3, and C1q irregularly in sclerotic segments. Electron microscopy confirms the absence of immune complex-type dense deposits. There was focal electron-lucent expansion of the subendothelial zone with occasional mesangial cell interposition. No new mesangial matrix material is observed to suggest MPGN.

Differential Diagnosis

Proteinuria detected by dipstick in a patient with SCD should be quantified and renal function assessed. Diseases other than sickle cell glomerulopathy should be considered. If hematuria is present, RBC casts may point to pathology other than sickle cell glomerulopathy. Hypertension, hypocomplementemia, and antinuclear antibodies also suggest other diagnoses. Judging from the relatively uniform findings in our series, few other additional studies are indicated. Microalbuminuria has been found in SCD patients >9 years of age, and may predict those with future glomerulopathy.

Treatment

• Slowing the progression of SCN to chronic renal insufficiency (CRI) in SCD involves modifications in physiology, which also affect growth factors.
• Efforts to reduce sickling crises are of unknown value.
• Renal transplantation for end-stage kidney failure can dramatically improve patient survival compared to dialysis.

The patients with proteinuria in our series were not those with either the most frequent sickle crises or the severest anemia. Nevertheless, some factors in the sickle cell condition must predispose to the nephropathy. Therefore, it is reasonable to attempt to minimize sickling and those factors known to promote FSGS in other primary diseases or in animal models, but it is unknown whether hemodynamic alterations can alter the progression of FSGS to CRI.

Protein Restriction

Because high protein intake accelerates the development of FSGS in uninephrectomized rats, without necessarily causing glomerular hyperperfusion, it is attractive to consider protein restriction in the management of SCD nephropathy, as is being tried in several forms of renal disease. In children, restriction of protein intake may carry unreasonable risks. Delayed growth and development are already particular risks in the patient with SCD. Therefore, we advise only the avoidance of an unusually high protein intake that is greater than the recommended dietary allowance.

Angiotensin-Converting Enzyme Inhibition

Glomerular hyperperfusion and proteinuria could be mediated through increased glomerular capillary pressure, reduction of which by ACE inhibition might protect the glomerulus from FSGS.

In our 2-week trial of enalapril therapy in 10 patients with mild SCD nephropathy, blood pressure, GFR (CIn), and ERPF (p-aminohippuric acid clearance) did not change significantly, whereas proteinuria diminished by 57%, rebounding after treatment withdrawal. A more recent 6-month controlled trial of enalapril in 22 SCD patients with microalbuminuria showed a significant decrease in the treatment group, while the control group increased. Whether long-term ACE inhibitor therapy has a salutary effect in preventing renal insufficiency is untested.

Other Treatments

Specific treatment of the patient with SCD and renal failure has been poorly explored, and the problems of CRI are only magnified by SCD. Patients with renal failure, even mild, can have symptomatic anemia requiring transfusion. In some patients, treatment with erythropoietin can variably restore hemoglobin concentrations to higher levels. A few patients have been treated with hydroxyurea plus erythropoietin with apparent benefit.

Dialysis and Transplantation

Renal transplantation is a better option than long-term dialysis for the SCD patient with CRI.

In our review of the U.S. Renal Data System files for 2000, we found 1656 SCD patients, 237 transplanted and 1419 not transplanted, who did not have causes of CRI other than likely SCN. While in the transplanted SCD patient survival was worse than that of all African-American patients without SCD, the lifetable projected survival times were still quite close, with approximately 50% survival at 15 years. Using an age-adjusted cohort of African-American patients as controls, the difference statistically disappeared. Comparing the nontransplanted SCD patients with the cohort of African-American patients, survival was quite different, but both were extremely poor: 14% for SCD patients and 25% for African-American patients at 10 years. A comparison of the 153 transplanted SCD patients with those who received no transplant showed a far better survival curve, 56% versus 14% at 10 years.

These results indicate that transplantation is a better option for the SCD patient with renal failure. However, results may be less satisfactory than for other African-American patients, and grafts have been lost due to demonstrable massive sickling events.

Bone marrow transplantation can cure SCD, and the possibility of its coupling with other transplants will undoubtedly be explored. Caution will be needed, in view of the possible increase in parvovirus, a common agent of aplastic crisis that might be especially dangerous in the transplant patient.

Animal experiments have shown the promise of genetic transduction of an antisickling hemoglobin to cure sickling in mice.

Essentials of Diagnosis

• Presents with gross hematuria and abdominal flank pain, less commonly with weight loss and a palpable mass.
• Its possibility requires that hematuria be investigated with some imaging modality, at least ultrasound.
• With survival of only 15 weeks from the time of surgery, and little evidence of response to different immunotherapies and chemotherapies, early diagnosis is the best therapeutic option.

General Considerations

A distinctive renal medullary cell carcinoma in some patients with SCD is exceptionally aggressive. Its development is probably related to the other renal medullary pathology of SCD, RPN, and medullary fibrosis.